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May Longevity Research Newsletter
June 17, 2024
Awareness
Longevity
May Longevity Research Newsletter

Introduction

Welcome back, Vitalians! Please join us in congratulating the ARTAN team for raising $300k in VitaDAO’s 2nd IPT launch! We look forward to bringing you more updates on this exciting project as the team works towards developing therapeutic candidates aimed at suppressing mutations that drive aging.

 

If you recall, last year there was quite a stir in the longevity community when funding for the Dog Aging Project was discontinued. Now, you have the opportunity to support this great initiative by contributing to help continue the study.

In other news, Alpha Fold has achieved another milestone with the release of AlphaFold 3, which now predicts the structure and interactions of all of life’s molecules!

This month, we're excited to bring you an interview with Dr. Adam Freund, CEO of Arda Therapeutics - a biotechnology company taking aim at chronic diseases and aging by eliminating the pathogenic cells that drive these conditions. Dr. Freund shares his insights from his extensive experience in longevity research, which spans academia, industry, and founding his own company. Enjoy!

Longevity Literature Hot Picks

Preprint Corner in collaboration with

The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.

Check out these latest preprints, which have all been entered into the 2Q24 longlist to be in the running to receive a coveted place in The Longevist. As always, you can refer preprints for consideration in The Longevist and the person who recommends the highest-voted preprint of the quarter will receive a prize of 200 VITA!

IF1 Protein Controls Aging Rate

This paper reveals that inhibiting F1F0 ATP hydrolysis, while allowing ATP synthesis, correlates with increased maximal lifespan and reduced aging biomarkers in mice, suggests metabolic heat generation via F1F0 ATP hydrolysis is vital for homeothermy, and proposes a novel class of anticancer drugs that selectively inhibit F1F0 ATP hydrolysis, potentially slowing aging and sparing normal cells from harmful side effects.

In vitro heterochronic parabiosis identifies pigment epithelium-derived factor as a systemic mediator of rejuvenation by young blood

This study establishes an in vitro heterochronic parabiosis system to identify factors like pigment epithelium-derived factor (PEDF), which extends replicative lifespan of human fibroblasts, reverses age-related decline in aged mice, and supports PEDF as a key mediator of the rejuvenating effects of young blood, offering a valuable platform for discovering circulating factors involved in aging and rejuvenation.

In vivo reprogramming of Caenorhabditis elegans leads to heterogeneous effects on lifespan

This study demonstrates for the first time that inducing in vivo reprogramming in C. elegans using a heat-inducible system can lead to premature death with varying toxicity across developmental stages, paralleling the effects observed in mice, and suggests this model could enhance our understanding of development and in vivo reprogramming.

The CALERIE™ Genomic Data Resource

The CALERIE-2™ trial, the first randomized controlled study of long-term caloric restriction (CR) in healthy, non-obese humans, supports CR's benefits on biological aging, and its resultant publicly accessible genomic datasets from multiple tissues provide a valuable resource for advancing translational geroscience.

The Latent Aging of Cells

The authors hypothesize that DNA methylation, beyond being an informative biomarker, could be crucial to understanding the interplay between aging, (de)differentiation, and epigenetic reprogramming, as our unsupervised analysis reveals shared methylation patterns across these processes and a distinct aging signal in tissues that resists reprogramming, suggesting that aging and reprogramming are not fully mirrored processes.

Pleiotropy and Disease Interactors: The Dual Nature of Genes Linking Ageing and Ageing-related Diseases

Ageing-related diseases (ARDs), despite their diverse phenotypes, share common biological processes rooted in ageing mechanisms, which can be explored for unified therapeutic strategies; using a network approach, we found that ageing-related genes are indirectly associated with multiple ARDs via protein-protein interactions and KEGG pathways, with genes affecting multiple ARDs either being broadly modulatory or specialized, and machine learning identified potential novel ageing-related genes involved in protein metabolism, stabilization, development, and cellular response to stimuli.

Published Research Papers

Aging clocks based on accumulating stochastic variation

Featured in the inaugural edition of The Longevist - this innovative research shows that aging clocks can be built on accumulating stochastic variation.

Temporal dynamics of the multi-omic response to endurance exercise training

The Molecular Transducers of Physical Activity Consortium detailed extensive molecular changes in rats undergoing endurance training, identifying key pathways affecting health-related conditions. Their comprehensive data is publicly available for further exploration of exercise's effects on multiple tissues.

Brain-muscle communication prevents muscle aging by maintaining daily physiology

Studies on arrhythmic mice demonstrate that linking central and muscle-specific clocks preserves daily functions and prevents premature muscle aging. The research highlights that muscle clocks play a critical role in filtering harmful signals and integrating vital functions, influenced significantly by eating patterns.

Nature of epigenetic aging from a single-cell perspective

Dynamics of DNA methylation (DNAm) at both tissue and single-cell levels in mice is studied, comparing changes from early development to adult aging and incorporating single-cell RNA sequencing to better understand epigenetic aging. Epigenetic aging includes both co-regulated changes and significant stochastic elements.

The killifish germline regulates longevity and somatic repair in a sex-specific manner

Germline depletion in killifish enhances damage repair in females and extends lifespan and metabolic health in males. This suggests that germline manipulation can lead to sex-specific aging responses, challenging traditional views on evolutionary tradeoffs between reproduction and longevity.

APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease

APOE4 homozygotes consistently show early and pronounced Alzheimer's pathology and biomarker levels, suggesting that APOE4 homozygosity constitutes a distinct genetic form of the disease.

3D genomic mapping reveals multifocality of human pancreatic precancers

Study showing widespread pre-cancerous mutations in the pancreas, with adults harbouring hundreds of precursors of pancreatic cancer. 

Converting cell death into senescence by PARP1 inhibition improves recovery from acute oxidative injury

Inhibiting PARP1 in response to high oxidative stress shifts cells from death to a senescent state, aiding in tissue regeneration. This process, called CODIS, reduces mitochondrial Ca2+ overload and improves recovery in a mouse model of kidney damage.

Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy

The effectiveness of immune cells in controlling tumor growth and response to immunotherapy in cancers follows circadian rhythms, suggesting that incorporating time-of-day considerations could enhance clinical outcomes.

Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators

SenCID, a machine learning tool, effectively identifies senescent cells in both bulk and single-cell transcriptomes, using a comprehensive dataset to categorize cells into six distinct senescence identities. 

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging

SGLT2 inhibitor canagliflozin reduces senescent cell accumulation and improves metabolic health in obese mice, distinctively outperforming insulin treatment. Canagliflozin not only lessens senescence in adipose tissue but also extends lifespan in mice with premature aging.

Published Literature Reviews, Hypothesis, Perspectives and more

The beginning of becoming a human

The 14-day post-fertilization stage marks the differentiation of soma from the germline and signifies key transitions in early embryogenesis, which recent scientific insights suggest may redefine organismal life's beginning, linking to broader biological processes such as aging.

Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight

Epigenetic factors play a key role in skin aging by activating senescence programs that lead to structural and functional declines. Geroprotective medications aim to restore this epigenetic balance.  

Psychogenic Aging: A Novel Prospect to Integrate Psychobiological Hallmarks of Aging

Psychological factors, crucial for healthspan and longevity, are often overlooked in aging frameworks. Psychogenic Aging research, a new biogerontology branch, explores how these factors affect longevity.

Job Board

Joao Pereira has two post-doc positions (two years) open at UAB (starting July/August) to study reproducibility in iPSC models, mostly organoids and assembloids! The other to study aging and Alzheimer’s! Starting salary 70k!

News and Media

Turn Biotechnologies Signs Global Licensing Agreement with HanAll Biopharma to Develop Eye and Ear Therapies

VitaDAO portfolio company Turn Bio signs a deal valued at $300 million USD to revolutionize age-related therapies worldwide.

Increased longevity will bring profound social change

An interesting piece from the Financial Times, discussing how with increased lifespans, people will have to work longer and pension systems will need to be transformed.

'Rejuvenating' mitochondria may help fight toxic proteins in Alzheimer's

Why is exercise good for you? Scientists are finding answers in our cells

Could delaying menopause boost women's health? 1 woman shares her story

Rapamycin: Could a simple pill add years to your life? 

‘A lot of nonsense being spouted’: Nobel laureate Venki Ramakrishnan on the anti-ageing industry

Resources

Conferences

Conference season is upon us, which ones will you attend?

Longevity Summit Dublin

13-16th June, Dublin, Ireland

Aging and Rejuvenation Conference 

8-10th July, Paris, France

ARDD

26-30th August, Copenhagen, Denmark

BSRA 2024

4th - 6th September

9th International Cell Senescence Association (ICSA) Conference

7th - 9th November, Puerto Varas, Chile

Tweets of the Month

Dan Go: 5 simple ways to test how long you'll live

British Society for Research on Ageing

Ageing vs Aging

What's your default spelling?

And the Brits have it with “ageing” - absolutely no selection bias from the poll being answered by followers of the British Society for Research on Ageing…

Podcasts and Webinars

Check out the latest episode of The Sheekey Science Show, where Eleanor features the top 3 preprints from the current Longevist edition.

NewLimit Progress Update 2024

Some exciting updates on partial reprogramming from New Limit.

Longevity & Aging Series

NUS Medicine’s Healthy Longevity Webinar Series

Debates: How to Defeat Aging – $10K Prize! Aubrey de Grey VS Peter Fedichev

Longevity by Design: The Impact of DNA Damage & Lifestyle on Aging & Longevity Medicine with Dr. Morten Scheibye-Knudsen

The Biohacker Podcast Presents: The Longevity Revolution with Professor Nir Barzilai

Existential Threads, where curiosity meets deep thinking! Unravel the complex science of longevity and debunk popular health myths

The Optispan Podcast with Matt Kaeberlein:
Reversing Biological Age: Have we finally found the answer?

DON'T Take Resveratrol Until You Watch This Video

Interview with Adam Freund

Life sciences entrepreneur and executive with a Ph.D. in molecular and cell biology and 18 years of experience in research and drug development.

Founder and CEO, Arda Therapeutics - a biotechnology company taking aim at chronic diseases and aging by eliminating the pathogenic cells that drive these conditions.

What inspired you to enter longevity research?

For as long as I have been a scientist, I have been driven to study aging. It is one of, if not the, largest sources of suffering and loss. There is no reason to assume that our current lifespan is optimal: we live longer than our ancestors, yet no one suggests that shorter lifespans would be beneficial, and our descendants will hold the same perspective, whether they live two, three, or ten times longer than we do now. The biology of aging might appear intractable at first, but once you recognize that longevity is indeed modifiable - supported by ample experimental evidence across various species - why would you study anything else?

How has the field changed since you started?

The longevity field has matured significantly from focusing on individual pathways like telomere biology and sirtuins to embracing more complex, cell-centric approaches like cellular reprogramming and senolytics. Unfortunately, it hasn’t changed much in the way the matters most: intervention efficacy. We have characterized the changes that occur with aging more thoroughly, particularly at the levels of the transcriptome, epigenome, and increasingly, the cellular architecture of tissues, but the most effective interventions 20 years ago (calorie restriction, insulin/IGF inhibition, and mTOR inhibition) are still the most effective interventions today.

Other than your own, what do you think have been the biggest/important discoveries in the field?

I am most excited by interventions that have the potential to restore health, such as removing pathogenic cells or resetting epigenetic states, as compared to interventions that delay further decline. The former is superior to the latter in multiple ways - health impact, addressable market, ease of clinical development. It might be preferable to focus on delaying aging if it is substantially more feasible than reversing decline, but this is unlikely: preventing a system from degrading is often far more difficult than restoring it every so often. Restorative interventions are still relatively unproven, but I am excited by their potential.

What advice would you give to people currently working in longevity research?

Select projects based on their potential impact rather than mere curiosity; almost every topic becomes more interesting the more you learn about it. Evaluate interventions, don’t just compile another catalogue of age-related changes. Don’t assume that any species showing age-related decline has translational relevance; work with human data or closely related mammalian species, and hone in on conserved mechanisms by evaluating multiple species. Carefully nurture and protect your credibility.

Which aspect of longevity research do you think requires more attention?

The role of postnatal development programs in establishing the rate of aging. Time to sexual maturity is one of the best predictors of remaining lifespan across vertebrates, and the interventions that most reproducibly extend lifespan (e.g. insulin/IGF mutations) delay postnatal development. If developmental trajectories establish aging rate, it also explains why the heritability of lifespan is so low within species: purifying selection. The mutations that would most dramatically extend lifespan also dramatically delay postnatal development, leading to low viability and depleting those mutations from the population. Modulating developmental pathways in adulthood may provide longevity benefits without the detrimental effects.

Is ageing a disease?

Whether a condition is generally considered a disease vs “normal aging” is primarily based on the prevalence of that condition in the general population: an isolated group whose members all harbour presenilin-1 mutations would characterize Alzheimer’s as “normal aging” because it would be universal. This controversy, therefore, reduces to a question of reference point (shameless plug for a thought piece I wrote on this topic). Irrespective of how we label it, aging is a process that can and should be therapeutically altered. 

You made some interesting academic discoveries related to cellular senescence when working in the late Prof. Judith Campisi’s lab - including how p38MAPK can regulate the SASP and that Lamin B1 loss is a biomarker of senescence. Could you tell us a bit about your research during this period and what your thoughts on senolytics in general are as a longevity therapy?

I joined the Campisi lab as the group was recognizing that senescent cells secrete pro-inflammatory factors. I was able to make a few contributions to our understanding of SASP regulation and in vivo biomarkers of senescence, and our work reinforced the concept that senescent cell depletion or inhibition could be an effective therapeutic strategy. Senolytics started gaining traction near the end of my graduate work, and while there has been a lot of effort put into their development, it is increasingly clear that in vitro models of senescence don’t have simple correlates in vivo. This has led to challenges with clinical translation and is one of the reasons I started Arda Therapeutics: there is a lot of evidence that pathogenic cell depletion has therapeutic potential, but starting from the senescence hypothesis may not be the most effective way to identify targets. At Arda, we use single cell data from human patients to identify pathogenic cell states, which has higher odds of clinical translation.

You then went on to identify a mechanism involved in telomerase trafficking, which if perturbed can prevent telomere elongation and cause disease. Please could you tell us about this?

For my postdoc, I went to Stanford to study telomere biology. I was interested in novel regulators of telomerase, so I developed a high-throughput RNA in situ hybridization assay and used it to perform a whole-genome screen to identify factors that altered telomerase RNA localization. This screen identified several novel telomerase regulators and clarified the mechanism of action of pathogenic mutations that cause the human condition dyskeratosis congenita. This turned into a few impactful publications, but by the end of my postdoc, I was convinced that, although telomeres play an important role in multiple aspects of human biology (dyskeratosis congenita, aplastic anemia, idiopathic pulmonary fibrosis, and cancer), telomere shortening is not a primary driver of aging. So I went looking for ways to re-orient my work towards aging biology.

Next you worked at Calico, what was that experience like?

I had always been interested in industry, but in 2014 there were not many opportunities to work on aging outside of academia. However, as I was getting ready for my next career move, Calico was announced – a longevity-focused biotech with a $1B budget. I immediately applied and was lucky enough to be hired as a principal investigator. I built a group developing new ways to quantify physiological aging, and I also initiated and was the scientific lead for Calico’s first therapeutic program targeting a conserved longevity pathway. This latter project snowballed into a full-fledged drug development program that is now in clinical trials, which was an incredible journey.

Currently, you are the founder and CEO of Arda Therapeutics, a company that aims to identify and eliminate pathogenic cells to prevent several diseases. What do you have in the pipeline and what can we look forward to next?

At Arda, we are taking aim at chronic diseases and aging by eliminating the pathogenic cells that drive these conditions. I have been incubating the idea of therapeutic cell depletion since my graduate work studying cellular senescence, but the more I studied senolytics, the more convinced I became that there was a broader opportunity to target other types of pathogenic cells. The difficulty was in identifying those cell states and targeting them with enough precision to be clinically viable. With the ascendance of single cell sequencing technology, which allows us to count cell states the way bulk transcriptomics counts mRNAs, we can finally turn this idea into a reality. At Arda, we use single-cell data from human patients to identify pathogenic cells and specific markers to target them. We then design therapies to eliminate these - and only these - cells. We are building a broad pipeline across multiple indications, starting with inflammation and immunology.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. 

In case you missed it, we leave you with the DeSci Berlin talk recordings from Day 1 and Day 2

See you next month!

Further Reading

Young blood-mediated cerebromicrovascular rejuvenation through heterochronic parabiosis: enhancing blood-brain barrier integrity and capillarization in the aged mouse brain

Welcome back, Vitalians! Please join us in congratulating the ARTAN team for raising $300k in VitaDAO’s 2nd IPT launch! We look forward to bringing you more updates on this exciting project as the team works towards developing therapeutic candidates
Read more
IP for Goundbreaking Gene Therapy funded onchain
June 13, 2024
Awareness
Longevity
IP for Goundbreaking Gene Therapy funded onchain



For the first time, $300,000 has been raised by a community to fund and steer innovative research for a single treatment, addressing multiple aspects of aging. VitaDAO has successfully tokenized its second IP-NFT, Artan Bio, supporting a groundbreaking gene therapy project led by biotech experts Dr. Michael Torres and Dr. Anthony Schwartz. 💫

Meet the team

Dr. Torres, who holds a PhD in Cancer Biology from UT-Southwestern in Dallas, has previously co-founded ReCode Therapeutics, a clinical-stage genetic medicines company that has secured over $300M in funding. He now works as the CEO of CrossBridge Bio, an oncology-focused company focused on developing next-generation dual payload antibody-drug conjugates

Dr. Anthony Schwartz, a VitaDAO Entrepreneur in Residence, will act as the project manager for this project. He has founded at least 15 startups, primarily focused on autoimmune diseases and cancer, which have led to large financings and an FDA-approved product. He is also a lecturer at Johns Hopkins.

Artan Bio's Mission

Artan Bio is pioneering the promising field of gene therapies. The company aims to develop therapeutic candidates to suppress mutations driving aging through genetic factors. Led by experienced entrepreneurs who have advanced drug development platforms into human clinical trials, Artan Bio is at the forefront of innovative medical research.

Decentralized Science: A New Era of Research

The Decentralized Science narrative uses blockchain and decentralization to improve funding and collaboration in science. VitaDAO funds and develops real-world research using Molecule’s IP-NFT and IPT frameworks. IP-NFTs tokenize intellectual property on the blockchain, while IPTs (Intellectual Property Tokens) are fungible tokens representing ownership of the associated scientific research IP-NFT, placing control in the hands of the community.

Real-World Assets and Overcoming the Valley of Death

One of the biggest challenges in scientific research and drug development is the "valley of death," where early-stage discoveries often fail to reach patients. By tokenizing real-world assets like intellectual property, VitaDAO empowers the community to directly support and benefit from scientific advancements.

This decentralized model allows members to vote on IP governance, input on research priorities, and influence fund allocation, paving the way for transparent, inclusive, and equitable medical innovation.

Introducing VITARNA

VitaDAO’s 2nd launch of IPTs is VITARNA, enabling token holders to interact directly with the work of Artan Bio. This team is committed to identifying compounds that could potentially suppress gene mutations driving aging. VITARNA is one of the earliest applications of IPTs. A total of 5,000,000 (one million) VITARNA IP Tokens were minted using the Artan Bio IP-NFT.

  • 20% of the supply will be sold to VITA token holders; these tokens will be vested for 12 months.
  • Project researchers will receive 16% of the total supply over a 4-year vesting period.
  • 4% will be distributed to service and technology partners.
  • VitaDAO retains 60% of the total VITARNA supply of which 4 % is reserved for distribution to the VitaDAO community who contribute to building the project.

Research and Development Goals

Artan Bio's initial support from VitaDAO, via a Sponsored Research Agreement (SRA), funds the design and validation of their engineered suppressor system (VDP-103) in cells with targetable mutations. The goal is to confirm the validity of this approach. Artan Bio seeks to continue development beyond the initial project to further IP development and validate the system in animal models, supporting preclinical translation and establishing a candidate for clinical trials.

VitaRNA by Artan Bio - DeSci Berlin 2024

A Groundbreaking Path

While the research is in its early stages, extensive testing in pre-clinical and clinical studies is necessary to evaluate safety and efficacy before any treatments become available. By pooling resources and brainpower, VitaDAO and Artan Bio aim to achieve breakthrough solutions that could lead to longevity for all.`

VitaRNA Website: https://vitarna.xyz/

VitaRNA contract address: 0x7b66e84be78772a3afaf5ba8c1993a1b5d05f9c2

VitaRNA on Uni V3

VitaRNA on Coingecko: https://www.coingecko.com/en/coins/vitarna 

Read more
Rapamycin, Caloric Restriction, and Inflammaging with Dr. Arlan Richardson - The VitaDAO Aging Science Podcast
May 27, 2024
Awareness
Podcast
Rapamycin, Caloric Restriction, and Inflammaging with Dr. Arlan Richardson - The VitaDAO Aging Science Podcast



In the current episode of The VitaDAO Aging Science Podcast, we dive into the intricate world of rapamycin, caloric restriction, and inflammaging with the distinguished Dr. Arlan Richardson. Dr. Richardson, a pioneer in aging research with a career spanning over five decades, shares his extensive knowledge and groundbreaking insights. We discuss his pioneering work on rapamycin, the complexities of caloric restriction, and the role of chronic inflammation in aging. This episode also touches on the significance of necroptosis, the intriguing connections between senescence and inflammation, and the future of aging interventions. Join us as we explore these vital topics and their implications for human longevity, shedding light on the critical role of preclinical studies in advancing our understanding of aging.

Brief Bio – Dr. Arlan Richardson

Arlan Richardson, earned his Ph.D. in biochemistry from Oklahoma State University in 1968, and for the past 50 years has devoted his career to aging research at Illinois State University, the University of Texas Health Science Center at San Antonio (where he directed the Barshop Institute on Longevity and Aging Studies), and the University of Oklahoma Health Sciences Center.

Dr. Richardson's research has focused on various aspects of aging: (i) the effects of aging and dietary restriction on gene expression in rats and mice, (ii) testing the oxidative stress theory of aging by measuring the effect of alterations in the antioxidant defense system on the lifespan and pathology of transgenic and knockout mice, and (iii) studying the effect of rapamycin on aging and age-related diseases. He is currently studying the mechanism responsible for genotype differences in response to dietary restriction and the role of chronic inflammation in aging.

Aging, rapamycin and the clinic

Arlan expressed disappointment in the hesitancy to test rapamycin in healthy individuals. In the 70s when he started it seemed it would difficult to change the lifespan of any organism at all, but then in 2008 with rapamycin came a big breakthrough; and a time of confusion and disappointment for us basic scientists:

"I am sitting here thinking, oh now, those of us in the basic sciences got you something that will potentially slow aging in humans and now I thought everybody, all the clinical people, will be running to us and saying  we want to test it and we are sitting back about fifteen years and there is hardly [any progress]..." (Arlan Richardson)

We both agreed that hope for faster clinical translation of rapamycin.

On being a generalist and working in science

"My whole career has been in aging...I am basically led by where the experiments go.. I go where I think the models will allow me to.” (Arlan Richardson)

Arlan has never stuck with one subject area. He studied caloric restriction and small molecules like rapamycin or necrostatin with the only unifying theme being his focus on preclinical work in rodents. As long as he can get something to work in mice or rats, he is interested and, during the podcast, we discuss how “getting things to work” is not always trivial.

In fact, earlier during his career studied rats but then everyone else moved to mice because they are easier to keep and more amenable to genetic manipulation. Nevertheless he wants to study rats once again over mice due to their closer resemblance to humans in terms of disease pathology and their higher genetic diversity. Given this, Arlan decided to develop a hybrid cross, akin to the HET3 mouse, just in rats. He emphasizes that these rats also have higher mitochondrial genetic diversity than HET mice, making them a great model to study future longevity interventions. Unsurprisingly Arlan was one of the co-authors of a recent review with the memorable name “Bring back the rat!”.

Finally, Arlan highlighted that many breakthroughs in biogerontology were made by junior people, e.g. Clive McCay (mice) or Tom Johnson (worms). Perhaps younger people are less biased, he adds.

Necroptosis, senescence, inflammation and aging

If you have never heard the word “necroptosis” before you are not alone. Arlan joked that he too did not know about this pathway when an immunologist first suggested he should look into this pathway in one of his mouse models.

Necroptosis, a form of programmed cell death distinct from apoptosis, is highly inflammatory and may contribute to the aging pathology in the brain, liver and adipose tissue. It is characterized by the release of damage-associated molecular patterns (DAMPs), which exacerbate inflammation—a key feature of aging known as inflammaging. Interestingly necroptosis can lead to the release of inflammatory TNFa which itself can promote necroptosis, in a vicious cycle.

Key proteins involved in this process include RIPK1, 3 and MLKL. Arlan found that necroptosis increases with aging and is counteracted by caloric restriction. Presently he studies animals transgenic for MLKL to gain a better understanding of necroptosis and he also studies the ncroptosis inhibitor necrostatin. He found necrostatin reduces age-related inflammation and, surprisingly also, senescence suggesting these two are connected.

Arlan believes that senolytics show some promise. In this regard he is more optimistic than Rich Miller, although he also highlights a lack of gold standard lifespan studies with senolysis. When I asked him about his top three interventions he mentions caloric restriction, dwarfism and rapamycin. These are the interventions supported by the strongest evidence so far, he argues.

The great ILSXISS caloric restriction controversy (somewhat technical)

During the podcast Arlan and I talked about the controversial ILSXISS publication and his effort to replicate and qualify the findings of the original papers (now published as Unnikrishnan et al. 2021). Let me give you my account of the story.

Briefly, the original study by Liao and Rikke et al. showed that when CR was tried in dozens of heterogenous – although still inbred – so called ILSXISS strains the intervention produced no benefit on average. This shocked some of us since it was counter to the consensus saying that CR is highly robust. Others dismissed this publication because of some methodological flaws. To his credit, Arlan took the findings seriously and sought to address some of the issues raised that weakened the conclusions from the original paper.

His decisions were partly driven by science and partly by funding constraints. As we mentioned multiple times during the podcast, there is so much to study and too little grant money. Given limited funding Arlan decided to re-test a well-defined subset of ILSXISS strains in a study with larger sample sizes, using graded CR and measuring potential explanatory variables. The choice of strains is crucial as I will explain in a moment.

When we started working on our manuscript to highlight the need for long-lived controls in mouse lifespan studies (Pabis et al. 2023) one of the areas I focused on was a re-analysis of the ILSXISS dataset. I was one of the people who wanted to find a flaw in the ILSXISS study because I truly wanted to believe in CR. Trust me, if anything, I was biased in favor of the CR hypothesis. After months of analysis, I came away none the wiser and more confused. Perhaps with a more nuanced opinion.

Unnikrishnan is considered to weaken the conclusions of the original paper because the authors “focused … on those..[originally] lines reported to show a decrease in lifespan” and found that, on average, neither of them showed lifespan shortening in their new study. That is amazing, perhaps it means the whole dataset should be shifted upwards, so to say. This would imply that the other lines should show a much more pronounced benefit and CR would be beneficial on average. Unfortunately, these other lines could not be tested.

There is an alternative more pessimistic hypothesis. In our analysis we confirmed that while control lifespans in the diverse ILSXISS papers are somewhat consistent, the CR response is not. Whatever the reason for this, it means you cannot select non-responders because you are most likely just selecting based on noise. So if the strains reanalysed by Unnikrishnan are perfectly average in their CR response this would mean their result is entirely consistent with the whole body of ILSXISS data showing that the average mouse does not benefit from CR. The only way to distinguish the optimistic and pessimistic interpretation is by also retesting the top responders from the original paper. If the top responders show no benefit of CR in a re-test the pessimistic hypothesis is right, if the top responders show at least some benefit it suggests that the optimistic hypothesis might be right (1). 

On a positive note, recent data shows that CR does work in highly heterogenous diversity outbred (DO) mice (Di Francesco et al. 2023). There is a lot left to learn and the CR hypothesis remains alive!

References and further reading

Mohammed, Sabira, et al. "Necroptosis contributes to chronic inflammation and fibrosis in aging liver." Aging cell 20.12 (2021): e13512.
https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13512

25 Years after age-1: Genes, Interventions and the Revolution in Aging Research
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686982/

Unnikrishnan, Archana, et al. "Reevaluation of the effect of dietary restriction on different recombinant inbred lines of male and female mice." Aging Cell 20.11 (2021): e13500.

Pabis, Kamil Konrad, et al. "The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience." bioRxiv (2023): 2023-10.
https://www.biorxiv.org/content/10.1101/2023.10.08.561459v1.abstract

Di Francesco, Andrea, et al. "Regulators of health and lifespan extension in genetically diverse mice on dietary restriction." bioRxiv (2023): 2023-11.

Carter, Christy S., et al. "Bring back the rat!." The Journals of Gerontology: Series A 75.3 (2020): 405-415.

(1) And even that study design might be problematic since the best and worst responders from the original study with small group sizes are likely to regress towards the mean in a much larger study. Science is complicated!

Read more
INTRODUCING VitaRNA by Artan Bio
May 23, 2024
Awareness
Longevity
INTRODUCING VitaRNA by Artan Bio

VitaDAO is tokenizing the ArtanBIO IP-NFT, a gene therapy project, with a goal of raising $300,000 for research advancement.

Crowdsale link: https://vitarna.xyz

In exchange, the community will be granted voting power to govern the IP, and participate in R&D decision-making and capital allocation.

For the first time, a community is coming together to fund and steer innovative research for a single treatment addressing multiple aspects of ageing.

ArtanBIO is exploring the promising field of gene therapies that could help address aging-related genetic factors. The Company’s approach aims to develop therapeutic candidates that could potentially suppress mutations that may drive aging. ARTAN is led by two entrepreneurs who have led advanced drug development platforms into human trials. 

Meet the team

Dr. Torres, who holds a PhD in Cancer Biology from UT-Southwestern in Dallas, has previously co-founded ReCode Therapeutics, a clinical-stage genetic medicines company that has secured over $300M in funding. He now works as the CEO of CrossBridge Bio, an oncology-focused company focused on developing next-generation dual payload antibody-drug conjugates

Dr. Anthony Schwartz, a VitaDAO Entrepreneur in Residence, will act as the project manager for this project. He has founded at least 15 startups, primarily focused on autoimmune diseases and cancer, which have led to large financings and an FDA-approved product. He is also a lecturer at Johns Hopkins. 




By decentralizing funding and intellectual property ownership, this initiative gives the VitaDAO community a voice in the research direction. Members will be able to vote on the governance of the IP, provide input on research priorities, and have a say in how funds are allocated.

It's very early-stage research, but this community-driven model opens up an exciting path for democratizing access to cutting-edge therapies. All research must undergo extensive testing in pre-clinical and clinical studies to evaluate safety and efficacy before any treatments could become available.

The goal is to pave the way for more transparent, inclusive, and equitable medical innovation. By pooling resources and brainpower, we can work towards breakthrough solutions that could one day improve human healthspans and longevity for all.

The VitaRNA Story

VitaDAO’s initial support for Artan Bio, via a Sponsored Research Agreement (SRA), has been to fund the design and validation of their engineered suppressor system (VDP-103) in cells with targetable mutations to confirm validity of the approach.

Artan Bio seeks to continue development of the engineered suppressor system beyond the initial project with VitaDAO to further the IP development, and further validate the system in animal models to support preclinical translation and establish a development candidate for use in clinical trials.

VITARNA Tokemics

IP Tokens represent membership in an IP pool containing the IP and R&D data attached to their parent IP-NFT.  

The IP Tokens of the ArtanBio IP-NFT are denoted by the token symbol “VITARNA.”  

The rights of VITARNA token holders are governed by the IPT Membership Agreement.

About the IPT crowdsale

The VitaDAO community is being offered an opportunity to further support the work of Artan Bio through participation in the crowdsale of IP Tokens raising $300,000 USD in support of the project.

The genesis VITARNA token sale will be a fixed-price sale with pro rata distribution, overflow refunds, and 12 month vesting.

20% of VITARNA tokens will be sold to VITA holders at a fixed price determined by an estimated budget of the future funding needs of the project for its next phase


Want to directly influence outcomes in longevity science research?

Support VitaRNA: https://vitarna.xyz


Tokenizing the Artan Bio IP-NFT
Read more
April Longevity Research Newsletter
May 14, 2024
Maria Marinova & Rhys Anderson
Longevity
Awareness
April Longevity Research Newsletter

Introduction

Welcome back Vitalians and please join us in congratulating The Fission Pharma team for passing the Snapshot vote to receive VitaDAO funding!

 

Fission Pharma is developing a protein-protein interaction inhibitor that cuts the link between chronic inflammation and mitochondrial dysfunction to treat multiple age-related diseases and extend human lifespan.

In this issue we will be exploring the Boundaries of Aging and what goes beyond the Established Hallmarks.

Aging is a universal process that affects all living organisms. In 2013, a seminal paper was published which sought to categorize the aging process by establishing a number of common hallmarks of aging. These hallmarks, which include genomic instability, telomere attrition, mitochondrial dysfunction, and cellular senescence, among others, provide a robust framework for studying the biological underpinnings of aging. A follow-up paper was published in 2023 which introduced more hallmarks of aging, however, as our understanding deepens, it becomes increasingly clear that these hallmarks may not fully capture the entirety of the aging process. This realization has spurred scientists to both refine existing theories and explore new frontiers in aging research.

As the field of geroscience progresses, researchers are beginning to identify additional factors that might influence aging but are not encompassed by the current hallmarks.

The ongoing updates to the aging hallmarks reflect the dynamic nature of scientific understanding. As researchers uncover more about the complex interactions between different biological systems, it becomes essential to revise and expand the aging framework. This includes integrating systems biology approaches to understand the interactions between various hallmarks, rather than viewing them in isolation.

This topic was inspired by some discourse in Longevity Twitter/X so don’t miss our Tweet of the month section for some spicy takes. And as always make sure you get to the end to find this month’s interview with Prof. David Vilchez where we discuss a number of innovative approaches he employs in his lab to understand the aging process.

Longevity Literature Hot Picks

Preprint Corner in collaboration with

The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.

The VitaDAO community recently voted (almost) unanimously to continue funding The Longevist through 2024. So let’s kick off these latest preprints, which have all been entered into the 2Q24 longlist to be in the running to receive a coveted place in The Longevist. As always, you can refer preprints for consideration in The Longevist and the person who recommends the highest-voted preprint of the quarter will receive a prize of 200 VITA!

Long-term fasting remodels gut microbial metabolism and host metabolism

Analog epigenetic cell memory by graded DNA methylation

Comprehensive Whole Genome Sequencing Reveals Origins of Mutational Signatures Associated with Aging and Temozolomide Chemotherapy

A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer’s disease and aging research

Age-Invariant Genes: Multi-Tissue Identification and Characterization of Murine Reference Genes

Published Research Papers

Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism

Young blood's small extracellular vesicles (sEVs) rejuvenate old tissues, improving molecular, mitochondrial, cellular, and physiological aspects in mice. They extend lifespan, reduce senescence, and enhance tissue function by altering proteomes and boosting mitochondrial metabolism via PGC-1α.

Epigenetic age oscillates during the day

Epigenetic age predictions show a 24-hour cycle, with the youngest and oldest estimates around midnight and noon. Testing 17 clocks revealed that 13 exhibit daily oscillations, suggesting the importance of time-of-day in obtaining accurate epigenetic age estimates.

Spatiotemporal transcriptomic changes of human ovarian aging and the regulatory role of FOXP1

The study uses single-cell RNA sequencing to analyze human ovarian aging, identifying molecular changes in eight ovarian cell types. It highlights the DNA damage response in oocyte aging and the regulatory role of FOXP1, which declines with age and impacts ovarian function, suggesting new targets for therapy.

A lipidome landscape of aging in mice

Explores aging's impact on lipid metabolism using lipidomics across mouse life stages, the findings suggest age-related changes in fatty acids and a link between sulfonolipids and the microbiome. In male kidneys, certain glycolipids were enriched in aged mice, with enzymes identified that could be targets for reducing sex-specific kidney disease risks.

Doxycycline decelerates aging in progeria mice

Doxycycline (DOX) extends lifespan and alleviates aging symptoms in a mouse model of progeria by improving nuclear structure, reducing cellular aging, and decreasing IL6 inflammation. DOX also counteracts harmful protein acetylation, showcasing its potential as a therapy.

Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system

Rapamycin suppresses aging by inhibiting TORC1-S6K signaling, which, when activated, disrupts cellular health and increases inflammaging. This pathway's effects, mediated by Syntaxin 13 and impacting the IMD pathway, are observed from flies to mammals.

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis

The study reveals a novel role for brown adipose tissue (BAT) in metabolic health, beyond its known function in thermogenesis. Impairing BAT's mitochondrial catabolism of BCAAs leads to systemic insulin resistance without affecting body weight or energy expenditure. BAT uses these amino acids to synthesize non-essential amino acids and glutathione, mitigating oxidative stress and supporting insulin signaling. 

A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence

Increased transposon and intron expression in aging is linked to transcriptional readthrough and intron retention. Analysis of RNA-seq datasets shows these transcriptional defects escalate with age, particularly in humans, driving transposon activity.

U-shaped association between sleep duration and biological aging: Evidence from the UK Biobank study

A UK Biobank study of 241,713 participants shows a U-shaped link between sleep duration and aging. Both short (≤5 hours) and long (≥9 hours) sleep durations correlate with accelerated aging compared to 7 hours, mediated by biomarkers like cystatin C and GGT.

Dietary restriction extends lifespan across different temperatures in the fly

The effect of dietary restriction (DR) on lifespan in Drosophila melanogaster across temperatures (18°C and 21°C) is examined, using a strain known to benefit at 25°C. Findings show DR consistently extends lifespan, regardless of temperature.

 

NMR metabolomic modeling of age and lifespan: A multicohort analysis

Nuclear magnetic resonance (NMR) metabolomic age models were assessed using blood samples from approximately 31,000 UK and Finnish individuals. While the correlation with chronological age was moderate, these models effectively predicted mortality and diseases like cardiovascular disease.

Identification of senescent, TREM2-expressing microglia in aging and Alzheimer’s disease model mouse brain

High-throughput mass cytometry identified distinct microglial populations in Alzheimer's disease using the 5×FAD mouse model. Senescent microglia expressing TREM2 differ from disease-associated microglia (DAM) and are linked with cognitive decline. TREM2-null mice had fewer senescent microglia, and treatment with senolytic ABT-737 improved cognition and reduced brain inflammation.

N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer’s disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk

DMT, a natural psychedelic and Sig-1r agonist, improves cognitive function, reduces Aβ accumulation, and restores Sig-1r levels in 3×TG-AD mice. It enhances ER-mitochondria interactions, calcium dynamics, and mitochondrial function.

Methylation entropy landscape of Chinese long-lived individuals reveals lower epigenetic noise related to human healthy aging

Long-lived individuals (LLIs) show suppressed epigenetic noise compared to controls. LLIs have specific genomic regions with lower methylation entropy, mainly in promoters, impacting aging-related disorder heritability. Neutrophils maintain this unique epigenetic stability.

Published Literature Reviews, Hypothesis, Perspectives and more

The senescence-associated secretory phenotype and its physiological and pathological implications

This review explores how the senescence-associated secretory phenotype (SASP) can both positively and negatively affect our body in various health and disease conditions, as well as its influence on our overall health over time. Additionally, it discusses how the SASP can be used as a health indicator and how substances that block SASP might be used to treat cancer and other conditions related to aging.

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

This review examines the latest research on methods that enhance the regenerative abilities of aged stem cells in mammals. The authors emphasize that rejuvenating these cells is a key strategy for maintaining overall body health as we age and discuss new techniques that could potentially extend both health and longevity.

Job Board

Payel Sen is looking to recruit a postdoc to study muscle stem cell aging at the NIA. Interested candidates with expertise in chromatin biology, genomics and stem cell biology are encouraged to apply directly to payel.sen@nih.gov. 

Xu Chen is hiring an NIH-funded postdoctoral fellow position at http://xuchenlab-ucsd.org to study tau pathophysiology in Alzheimer's disease and related dementia - more details here.

Dena Dubal is hiring postdoctoral fellows to study the longevity factor klotho and brain resilience in aging and Alzheimer's – using cellular, molecular, behavioral, and bioinformatic approaches. DM on Twitter/X if interested!

The Gurkar lab at the University of Pittsburgh, focusing on aging and DNA repair,  is hiring for 3 positions: Lab Manager/Research Specialist, Mouse-house Technician, Post-doctoral Fellows. If interested please send your CV with name, email, and phone numbers of references to agurkar1@pitt.edu.

A number of open positions at the Buck Institute are available. Check out their website to see if you can find a match: from postdoc and masters positions to admin and even a CFO.

Shift Bio are currently hiring for a Machine Learning Research Scientist to build and improve our cell simulation models, and work on algorithms that help us to prioritise potential rejuvenation interventions. 

News and Media

VitaDAO-backed Rubedo lands $40m to advance senescence-targeting therapeutics into clinical trials

Science is closing in on the frailties of old age

SENS Research Foundation and Lifespan(dot)io Announce Intent to Merge, Forming a Novel Longevity Entity

Beiersdorf and Rubedo announce multi-year partnership to develop breakthrough anti-aging solution

Vitalia: Living the Longevity Dream

A Honduran tourist island has attracted a lot of people interested in longevity.

Life Biosciences Presents Groundbreaking Data at ARVO Demonstrating Restoration of Visual Function in Nonhuman Primates

Your Dog Will Have an Anti-Aging Drug Before You Do

Geroscience luminary, Dr. Nir Barzilai, appointed President of the Academy for Health and Lifespan Research

NASA discovered bacteria that wouldn't die. Now it's boosting sunscreen

New Research Suggests That Cutting Exposure to Common Chemicals Could Slow Aging

Donate to the British Society for Research on Ageing (BSRA) - A medical research charity focused on slowing ageing, not disease

 

Resources

Problem choice and decision trees in science and engineering with accompanying Tweet.

Conferences

Who’s excited for conference season? It’s that time of the year again. Have you booked your flights?

Gordon Research Conference (GRC)

2-7th June, Barcelona, Spain

American Aging Association Annual Meeting (AGE)

2-5th June  Madison, Wisconsin USA

Longevity Summit Dublin

13-16th June, Dublin, Ireland

Aging and Rejuvenation Conference 

8-10th July, Paris, France

ARDD

26-30th August, Copenhagen, Denmark

BSRA 2024

4th - 6th September

9th International Cell Senescence Association (ICSA) Conference

7th - 9th November, Puerto Varas, Chile

Tweets of the Month

Here are some spicy tweets relating to the hallmarks of aging:

https://twitter.com/MartinBJensen/status/1784244762842992906

https://twitter.com/dweinkove/status/1784246336574894112

And some other interesting picks of the month:

Food for thought on mitochondrial transplantation

Why Karl Pfleger is cautiously optimistic on rejuvenation progress

Peter Fedichev discusses whether a comprehensive theory of aging is necessary to fundamentally solve aging

And more from Peter: Let’s run an experiment: if you suggest a reference to an interesting paper concerning aging in the comment to this post, i will try to write up how aging phenomenology explains its results.

Podcasts and Webinars

Longevity & Aging Series

NUS Medicine’s Healthy Longevity Webinar Series

Episode 2 of the Longevity Acceleration Podcast is out - they speak to Reason of Repair Biotechnologies about the gene delivery problem, the prospects for repairing aging damage, and more. Check it out!

Dr. Brad Stanfield discusses what is the ‘best’ diet to prevent disease and live a long, healthy life?

The Sheekey Science Show has a Theme Tune!

Longevity by Design, Produced by InsideTracker: The Impact of DNA Damage & Lifestyle on Aging & Longevity Medicine with Dr. Morten Scheibye-Knudsen

Biohackher: The Longevity Revolution with Professor Nir Barzilai (libsyn.com)

Interview with Prof. David Vilchez

Prof. David Vilchez is a distinguished researcher at Cologne Excellence Cluster on Aging and Aging-Associated Diseases, focusing on the intersection of proteostasis, aging, and stem cell functionality. His innovative research employs a combination of iPSC-based disease modelling, genetic studies in C. elegans, advanced proteomics, and plant research to explore cellular and organismal responses in age-related diseases. 

What inspired you to enter longevity research?

Since my undergraduate studies, I have been passionate about the complexity of the nervous system and neurodegenerative diseases. During my PhD, I focused on a rare disease linked to the accumulation of aggregates in neurons and deficits in proteolytic systems. When I was searching for labs to conduct my postdoc, I came across a recent paper from Andy Dillin’s lab in C. elegans. They discovered that longevity mechanisms, such as the reduced insulin pathway, can prevent the accumulation of pathological aggregates associated with Alzheimer’s disease. I was fascinated by the potential of C. elegans as an organismal model for neurodegenerative diseases involving protein aggregation. Joining Andy’s lab opened a new horizon for me, and I became very interested in how we can slow down aging for multi-disease prevention. This led us to the idea of studying the immortality of pluripotent stem cells and applying these mechanisms in post-somatic cells, such as neurons, to prevent diseases.

Which of the current theories of ageing do you think are the most convincing?

I believe that all current theories of aging are plausible. It is crucial to recognize the interconnectedness between these theories and remain open-minded to new findings that can either update or introduce completely unexpected theories. For instance, the disposable soma theory of aging postulates that organisms invest resources to protect their germline, leading to somatic tissue deterioration and aging. This has been supported by many studies, including work from our laboratory. However, we have recently demonstrated that this not always the case. For instance, advantageous conditions such as moderate cold temperature can delay germline aging, leading to extended fertility. In turn, the rejuvenated germline release longevity signals that maintains somatic fitness at cold temperature, a process that coordinates extended fertility and long lifespan without sacrificing any of these features.

How has the field changed since you started?

Since I began working in the aging field during my postdoc, I have witnessed significant evolution. One notable positive change is the increasing number of labs joining the field, bringing new perspectives crucial for advancing longevity research.

What mistakes do you think the longevity field has made?

There are certainly areas where approaches could have been adjusted, but I would not classify them as mistakes. Like any other field, aging research has progressed based on the prevailing theories, available knowledge, and methodologies at the time. As a field that is continuously evolving, it's important to remain open to exciting and unexpected discoveries that will shape our understanding in the future.

Other than your own, what do you think have been the biggest/important discoveries in the field?

The initial discoveries that modulating pathways such as insulin signaling can extend longevity were paradigm-shifting, demonstrating that aging is a regulated process. In my opinion, a recent key finding is the possibility of delaying aging through partial reprogramming strategies.

What advice would you give to people currently working in longevity research?

My advice is to remain open-minded and expect the unexpected, which holds true for any research field.

Is ageing a disease?

Aging is a natural and progressive stage in the life cycle of any animal. However, aging is a primary risk factor for multiple diseases. The key focus lies in the potential to delay aging to enhance our quality of life and prevent multiple diseases simultaneously.

Many researchers focus on the established hallmarks of aging as central mechanisms driving the aging process. In your view, do these hallmarks comprehensively account for the complexity of aging, or should the scientific community also explore beyond this framework? Would you focus on other overlooked processes that might be equally or more significant?

The hallmarks of aging provide a valuable framework for understanding the aging process. However, aging is a multifaceted phenomenon, and it's essential for the scientific community to explore beyond these established hallmarks to fully comprehend its complexity. We must remain open to the possibility of updating these hallmarks and discovering new, unexpected factors that contribute to aging. For instance, the recent updates to the hallmarks of aging demonstrate this evolving understanding. In our laboratory, we are committed to exploring overlooked processes that may be equally or more significant, guided by the insights gained from our results and the findings from other laboratories.  

Your lab has studied how certain plant proteins might have potential applications in neurodegenerative diseases. Do you think we can learn more from the plant kingdom that could be impactful for human aging?

The research in our lab on certain plant proteins and their potential applications in neurodegenerative diseases has opened up intriguing possibilities. The longevity of stem cell reservoirs in plants like the Sequoia tree, which can remain active for over 2,000 years, highlights the remarkable biological processes in the plant kingdom. We are certainly open to the idea that insights from plant biology could lead to novel approaches in preventing human aging. Currently, we are actively exploring this hypothesis as part of our ongoing research efforts.

What role does temperature play in the aging process? We know about heat shock and proteostasis but your recent paper has highlighted a protective mechanism activated by cold temperatures. Can we use acute temperature shifts or mild but constant variation of body temperature to modulate the aging process?

Temperature plays a crucial role in the aging process for both poikilotherms and homeotherms. While we are familiar with the effects of heat shock and proteostasis on aging, our recent research has shed light on a protective mechanism activated by moderate cold temperatures. We have found that mild cold temperature not only extends lifespan but also delays reproductive aging in C. elegans. Additionally, it can delay the accumulation of pathological protein aggregates in both C. elegans and human cell models.

These findings are particularly significant given the increasing incidence of age-related diseases in our population. They offer a new perspective on how to delay or prevent these disorders. In our laboratory, we primarily focus on maintaining mild and constant low temperatures throughout the entire adult life of C. elegans. However, we have also explored shorter periods (24 hours) of cold temperature in human cells. So it will be fascinating to assess whether short periods of mild cold temperature can also have beneficial effects at the organismal level. 

While acute temperature shifts are not our current research focus, further studies in this area are needed to explore their potential impact on the aging process and therapeutic applications.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!

Further Reading

LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion

Effect of Isocaloric, Time-Restricted Eating on Body Weight in Adults With Obesity: A Randomized Controlled Trial

Welcome back Vitalians and please join us in congratulating The Fission Pharma team for passing the Snapshot vote to receive VitaDAO funding!
Read more
VitaDAO Letter: From Dubai to London
May 14, 2024
Sarah Friday
Awareness
VitaDAO Letter: From Dubai to London

VitaDAO Letter: From Dubai to London




Hey there, Vitalians! Welcome to the monthly VitaDAO Newsletter, a recap of all that's happened and is happening within the VitaDAO community. Spoiler alert: as always, a lot was going on last month! VitaDAO members have been busy coordinating a DeSci Summit in Dubai, sponsoring DeSci London, passing two new governance proposals, and launching $VITA on Base. In this newsletter, you'll find recaps of past important events, updates on votes happening in the DAO, and exciting opportunities to contribute.

👋New here?

Welcome! VitaDAO is a decentralized organization of individuals from across the globe working to fund early-stage longevity research. You might be wondering, “So, what is the point of having a $VITA token?” $VITA is a governance token that allows members to contribute to the DAO’s decision-making. By allowing the community to vote on which research projects to fund, VitaDAO leverages the collective knowledge of its community to support projects that might not otherwise be funded. If you’re interested in learning more about how VitaDAO funds longevity research through IP-NFTs, check out VitaDAO’s whitepaper. 

🌎DeSci in Dubai

DeSci hit Dubai with a storm. Amid the biggest rainstorm in decades, researchers, innovators, and enthusiasts gathered in Dubai for two Crypto x Longevity events in Dubai: the DeSci Summit and the Akshay Summit. At the Museum of the Future, VitaDAO hosted the DeSci Summit Dubai. Held during #TOKEN2049 week, this summit featured notable speakers such as @balajis and @bryan_johnson, along with 16 other in-person speakers such as ​Maxim Kholin, ​Akshay BD, ​Paul Kohlhaas, and ​Dr. Sameer Al Ansari. Todd White, VitaDAO’s Coordination Steward, gave a talk titled “Pharma On-Chain: Making Drug Development Liquid (Again)”. Max Unfried from VitaDAO discussed the world of DeSci and VitaDAO contributor Anthony Schwartz talked about launching a Biotech Company with crypto. You can watch a live stream of DeSci Summit Dubai on Twitter! 

"DAOs help build coalitions of customers and patients that actually want the treatment and will help get it through the regulatory process." -Balaji

The second DeSci event in Dubai was the Akshay Summit, a health and longevity gathering. In a fun twist, Nuseir Yassin lost a friendly bet to Akshay BD, resulting in the hosting of the Akshay Summit at the Nas House. This event featured speakers @bryan_johnson and @balajis alongside founding members from Mito Health, Ultrahuman, Let's Live, Fittr, VitaDAO, and CryoDAO. Attendees had the opportunity to work out, take ice baths, measure their BMI, check their HRV, test their grip strength, and more before listening to Bryan Johnson and Balaji Srinivasan followed by 10 short talks. The Summit was a wild success with over 3500+ applications for just 200 spots.

🇬🇧Sponsoring DeSci London

As if visiting Dubai wasn’t enough travel, VitaDAO members also attended and sponsored DeSci London. On Day 1 (a live stream of Day 1), Logan Bishop-Currey from Molecule and recipient of VitaDAO’s first IPT, Victor Korolchuk, talked about tokenized research projects and how they work in practice. On Day 2 (a live stream of Day 2), Maria Marinova discussed DeSci and Longevity on a panel with David Wood from the London Futurists, Michael Geer from the Humanity Health App, and 8-year-old Nina.

🏆The Longevity Challenge Goes On

The challenge continues! In February, VitaDAO launched its monthly Longevity Challenge, a competition to reward active community engagement on Discord. The first challenge focused on optimizing exercise for longevity. In Nina’s Quick & Easy Guide on Exercise for Longevity, Nina Patrick defines different types of exercises and outlines the creation of an exercise plan. In March, the second challenge launched, focusing on improving health through the optimization of nutrition. Nina authored another guide that outlined the importance of balancing glucose, increasing fiber, and avoiding added sugar and processed foods. 

This month, the third Longevity Challenge is underway: Thermal Therapy! In her third guide, Nina outlines what thermal therapy is and the science behind it. Participants in the challenge can collect points by posting images of activities on Discord that showcase thermal therapy practices, inviting friends, and initiating conversation on Discord. Prizes include 100 VITA to the first-place winner, 50 VITA to the second-place winner, and 25 VITA to the third-place winner. Ultimately, all participants win through the improvement of one’s lifestyle. Join the challenge on the VitaDAO Discord server channel #longevity-challenge today. 

🤑$VITA is LIVE on Base 

$VITA is now on Base! Base, a Layer 2 blockchain, was launched by Coinbase to improve Ethereum's scalability and speed. The good news for you? It operates off-chain, thus reducing transaction costs. This allows for cheaper ways to participate in VITA and its governance. $VITA can also be found on Gnosis and Optimism! Find the Base official contract and Aerodrome Pool

Image

🚨VitaDAO in the Wild 

📣Ch-ch-ch-ch-changes: What YOU voted for!  

Thanks to your votes, we’re making things happen! Since the last newsletter, two proposals successfully passed on Snapshot. These proposals include: 

  • VDP-143 (The Funding of Fission Pharma): Fission Pharma is developing a protein-protein interaction inhibitor that cuts the link between chronic inflammation and mitochondrial dysfunction to treat multiple age-related diseases and extend human lifespan. This project was originally proposed as funding an external company with VDP-123 and was rejected. It was then revised as a VitaDAO company building project worth $250k and proposed as VDP-143 on March 15th, 2024. This proposal approved a research plan expansion to be covered with $83,333 in co-funding from Cerebrum DAO in exchange for a share of the resulting IP-NFT. The total approved project budget is $333,333.

  • VDP-144 (The Longevist Annual Review Proposal): The Longevist is a quarterly issued preprint overlay journal where key opinion leaders in both academia and industry vote on chain on the top preprints. This proposal approved a budget of 25,000 $VITA for curator compensation and 15,000 $VITA + $35,000 USDC for operations for the Longevist in 2024. The VDP also outlined Longevist achievements thus far and five objectives for the future including:some text
    • Expanding and developing a curator network
    • Strengthening outreach and engagement
    • Growing an academic reader community
    • Developing and distributing educational material for the general public
    • Hosting an annual Longevist award ceremony

💪Exercise Your Right to Vote

Visit VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Together, we can shape the future of VitaDAO and accelerate decentralized science.

💸Refer a Project, Get Compensated

VitaDAO is always looking for unique projects to fund. The cool part is that VitaDAO wins when you refer projects through the opportunity to grow its portfolio. The project wins as it can receive funding. The general public has the chance to win through the development of novel therapeutics to increase healthy lifespan. And YOU can win through compensation for your referral. Referrals for projects that are relevant to VitaDAO can earn 400 $VITA, locked for 1 year if independent reviewers score it over 3.6/5. If a project is funded, the bounty increases by $2000. If a project successfully exits as a spinout or is outlicensed, the bounty increases to 1% of the proceeds or IPT equivalent. That's what I call a win, win, win, win! Refer a project today!  

🤝What’s Going DAOn

Want to stay up to date with all that's going on? Join us on Discord, subscribe to our Twitter, visit our website, and follow our Instagram! You can now connect your wallet to VitaDAO’s Members Portal to learn about exclusive member benefits and find VitaDAO’s treasury dashboard. Find updated information on VitaDAO's funded projects on our website

Want to join the team? Apply to be a Web3 Marketing Lead and DAO Governance Lead. If you enjoyed reading this newsletter, make sure to subscribe! 

Hey there, Vitalians! Welcome to the monthly VitaDAO Newsletter, a recap of all that's happened and is happening within the VitaDAO community.
Read more
March 2024 Longevity Research Newsletter
April 17, 2024
Maria Marinova, Rhys Anderson
Awareness
March 2024 Longevity Research Newsletter

March Longevity Research Newsletter

Introduction

Welcome back Vitalians!

An article on VitaDAO has been published in Nature Biotechnology! It is a case study on the potential of DAOs for funding and collaborative development in the life sciences. In this article, the authors explore VitaDAO’s role in revolutionizing life sciences funding through blockchain technology.

In this month's edition, we delve into the fascinating intersection of regeneration and aging biology, exploring how insights from the natural world's remarkable regenerative processes can illuminate the pathways to healthier aging. While some creatures in nature can astonishingly regenerate lost limbs or damaged organs, humans have much more limited regenerative capabilities, primarily resulting in scar formation rather than true regeneration. 

We are excited to bring you an interview with Prof. Nicole Ehrhart, the director of Columbine Health Systems Center for Healthy Aging at Colorado State University. She shares her fascinating journey into longevity research, initially inspired by the limitations in tissue regeneration in higher mammals. This led her to explore aging biology, where she recognized a significant intersection with her prior work in tissue regeneration. Dr. Ehrhart's research leverages her background in veterinary medicine and surgical oncology, focusing on naturally occurring disease models in animals to improve clinical outcomes in both humans and canines. She emphasizes the importance of multidisciplinary collaboration in advancing aging research and highlights the unique benefits of using companion dogs in clinical trials to accelerate the development of age-reversal therapies.

Longevity Literature Hot Picks

Preprint Corner in collaboration with

The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.

And just like that, Q1 is over! Check out these latest preprints, which have all been entered into the 1Q24 longlist to be in the running to receive a coveted place in The Longevist. As always, you can refer preprints for consideration in The Longevist

Rejuvenation of aged oocyte through exposure to young follicular microenvironment

Comparative analysis of mouse strains for in vivo reprogramming

Association between prescription drugs and all-cause mortality risk in the UK population

cGAS-STING is responsible for aging of telomerase deficient zebrafish

Unravelling the Transcriptomic Symphony of Sarcopenia: Key Pathways and Hub Genes Altered by Muscle Ageing and Caloric Restriction Revealed by RNA Sequencing

Senolytic CAR T cells reverse aging-associated defects in intestinal regeneration and fitness

Machine learning predicts lifespan and underlying causes of death in aging C. elegans

A torpor-like state (TLS) in mice slows blood epigenetic aging and prolongs healthspan

Published Research Papers

Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity

Aging of the immune system involves a shift from lymphoid-supporting to myeloid-biased hematopoietic stem cells, leading to reduced adaptive immunity and increased inflammation. This exiting new study shows that eliminating myeloid-biased cells in aged mice rejuvenates their immune system.

Formation of memory assemblies through the DNA-sensing TLR9 pathway

Interested in how memory works at the molecular level? Check out the News & Views from Ben Kelvington and I in Nature on this exciting paper from Jelena Radulovic that describes links between DNA damage, innate immunity and memory!

Epigenetic aging of human blood cells is influenced by the age of the host body

The study reveals that the age of a stem cell transplant recipient affects the epigenetic aging of donor cells, accelerating it in older recipients and decelerating it in younger ones, indicating the recipient's body age influences transplanted cell aging.

Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis

The CALERIE™ 2 trial on caloric restriction (CR) showed mixed effects on telomere length attrition over two years, with initial increased attrition in CR participants that lessened in the second year, suggesting a complex interaction between CR and telomere health that warrants further study.

Sildenafil as a Candidate Drug for Alzheimer’s Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons

Can Viagra treat Alzheimers? The study analyzed millions of insurance claims revealing 30-54% reduced prevalence of disease among those taking drug. In brain cells from AD patients, drug lowered levels of neurotoxic tau proteins and inflammation.

The common marmoset as a translational model of age-related osteoarthritis

The study validates common marmosets as a model for human age-related knee osteoarthritis (OA), showing that geriatric marmosets display OA characteristics similar to humans, including increased prevalence and severity with age, and notable sex differences.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models

Using AI, researchers discovered TNIK as a target for treating idiopathic pulmonary fibrosis (IPF), leading to the development of the anti-fibrotic drug INS018_055. This drug showed promising anti-inflammatory and anti-fibrotic effects in vivo, with its safety confirmed in phase I trials.

Ergothioneine promotes longevity and healthy aging in male mice

Ergothioneine (ERGO), when supplemented daily in male mice, extended their lifespans and reduced age-related frailty and cognitive decline, pointing to its beneficial role in promoting healthy aging through multiple biological pathways.

CheekAge: a next-generation buccal epigenetic aging clock associated with lifestyle and health

CheekAge, a new epigenetic aging clock developed from cheek swabs and lifestyle/health data of 8,000 adults, accurately predicts age and correlates with health factors like BMI and smoking. It is non-invasive, validated across different conditions and available through a free online tool.

Intermittent rapamycin feeding recapitulates some effects of continuous treatment while maintaining lifespan extension

Intermittent rapamycin treatment in mice extends lifespan with fewer side effects than chronic treatment, although chronic treatment more effectively improves overall healthspan. Both approaches similarly benefit lifespan in males and mitigate certain age-related conditions, but chronic treatment shows a slight survival advantage in females.

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner

EOD intermittent fasting reduced aging-related frailty in male mice by decreasing energy intake and enhancing renal hydrogen sulfide production, improving various health measures. However, it showed minimal benefits in females, indicating gender-specific effects.

A molecular index for biological age identified from the metabolome and senescence-associated secretome in humans
The Healthy Aging Metabolic (HAM) index, comprising 25 metabolites, effectively predicts healthy aging across genders and races. Key metabolites driving aging and elevated inflammation markers in rapid agers were identified, suggesting metabolic pathways significantly influence biological aging.

An  Updated  Prioritization  of  Geroscience-Guided  FDA-Approved  Drugs  Repurposed to Target Aging

Geroscience focuses on delaying aging-related diseases by targeting aging mechanisms, aiming to extend lifespan and healthspan. Recent updates add bisphosphonates, GLP-1 receptor agonists, and beta blockers as promising gerotherapeutics. 

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation

Chemical reprogramming rejuvenates aged mouse fibroblasts by altering their molecular profile and reducing biological age, particularly by enhancing mitochondrial function. This approach suggests a promising avenue for reversing aging effects in vivo, highlighting the need for further investigation.

Mitophagy defect mediates the aging-associated hallmarks in Hutchinson–Gilford progeria syndrome

Mitophagy defects contribute to the premature aging in Hutchinson-Gilford progeria syndrome (HGPS) by impairing mitochondrial function. Using UMI-77 to induce mitophagy improved aging markers in HGPS and aged mice.

Endothelial-specific telomerase inactivation causes telomere-independent cell senescence and multi-organ dysfunction characteristic of aging

Knocking out the Tert gene in endothelial cells (ECs) of mice induced signs of aging such as senescence and tissue hypoxia, leading to leaky blood vessels, cognitive impairments, and decreased muscle endurance. The study highlighted a shift towards glycolysis for energy, due to reduced mitochondrial function, even in the presence of normal telomere lengths in certain tissues. 

Published Literature Reviews, Hypothesis, Perspectives and more

Translation is an emerging constraint on protein homeostasis in ageing

This review explores how the aging process disrupts the correlation between transcript levels and protein products, influenced by diminished protein synthesis capacity and a decreased ability of aging cells to adapt their proteomes to stress, potentially due to factors like reduced ribosomal function and increased mistranslation.

Time is ticking faster for long genes in aging

Recent studies have shown that with age, longer genes tend to show reduced expression across various species and cell types, potentially due to polymerase stalling from DNA damage. Here the authors term this phenomenon gene-length-dependent transcription decline (GLTD) and also describe its role in age-related diseases.

Pharmacological interventions in human aging

A comprehensive database called AgingDB has been created to consolidate information on over 130 clinical trials focused on pharmacological interventions in aging, covering areas like glucose homeostasis, metabolic interventions, senolytics, and mTOR inhibition. This resource aims to make it easier for individuals to find and stay updated on trials targeting aging, marking a significant shift towards treating aging as a manageable medical condition.

Expanding our thought horizons in systems biology and medicine

Buck Institute “Jennifer Lovejoy expands our thought horizon regarding systems biology RE: the importance of measuring behavior and exposome, both new frontiers in research on aging”.

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging

The gonad is heavily implicated in C. elegans aging, as removing its proliferating stem cells or inducing stem cell quiescence through starvation significantly extends lifespan, a phenomenon also seen in other nematodes. This review explores the mechanisms behind gonad-mediated lifespan extension, including lipid signaling and transcriptional changes, and suggests that insights from these studies could enhance our understanding of aging's mechanisms and evolution across different species.

Hungry for biomarkers of aging

The geroscience hypothesis, which suggests that interventions targeting biological hallmarks of aging could delay or prevent age-related diseases and disabilities, has sparked significant interest due to early evidence that these mechanisms are modifiable. This approach highlights the necessity and potential challenges of developing and using biomarkers of aging to optimize human health in a transformative way.

Job Board

The Kapahi lab at The Buck Institute has 2 postdoc positions available - using bioinformatic approaches from flies and humans to study the role of circadian clocks and nutrient-responsive pathways influencing eye and neuronal degeneration using flies and conserved orthologs from humans

Professorship in Computational and Systems Biology of Aging and Aging-associated diseases at CECAD Cologne

Looking for a PhD position? Retro might have something in store for you!

Retro College is now accredited in both the EU and USA to grant PhDs.

They have welcomed the first 2 students, and have openings for 3 more.

Postdoc position in the Singh Lab at UCSF to study aging, age-related diseases, and diapause using multi-omics in the African killifish.

News and Media

Longevity: how science is pushing the boundaries for the first 150-year-old human

Using Ultrasound to Assist Gene Therapy

This approach opens up heart muscle cells for potential therapies.

Aeovian Pharmaceuticals doses first participants in Phase 1 clinical trial, strengthens leadership team and raises additional $50 million financing

Hevolution Foundation Announces $20 million Impact Investment to Advance Promising Aging Therapies, Leading a $50 million Series A Extension in Aeovian Pharmaceuticals

‘Ageing isn’t inevitable’: The 100-Year-Life co-author on how to live well for longer

Daniel Ek's new bet on longevity

“The upper echelons of Stockholm society will soon have a new place to spend their money: a luxurious longevity clinic half-owned by the founders of Spotify.”

How to ‘switch on’ your anti-ageing genes – and live longer

A call to arms to save the genome

Silicon Valley Startup Announces Planned Trials of “Fountain of Youth” Treatment Targeting 130-Year Lifespans for Astronauts

By Biotech Explorers powered by a Bioreactor-Grown Mitochondrial Transplantation - a technique that our parent firm Mitrix Bio

Resources

In the publication section above, we introduced AgingDB - a new database of pharmacological trials targeting aging - and here we’d like to share another list of aging clinical trials from AgingBiotech.info!

New Aging Books!

From Nobel Prize winning Biologist Venki Ramakrishnan: 

Why We Die: The New Science of Ageing and the Quest for Immortality (Hardback)

A review of the book from Prof. Charles Brenner.

And, Andrew J Scott’s new book “The Longevity Imperative: Building a Better Society for Healthier, Longer Lives” is out in the UK and soon available in the US.

David Sinclair et al., previously published a paper on The economic value of targeting aging - now check out a YouTube video explaining these ideas!

Prizes

The Million Molecule Challenge, supported by The Longevity Prize, is still open and accepting applications - submit a compound and we will finance the testing at the Ora Labs. There’s no jury for this one, the winners are awarded based on results alone. 

Want to know how it’s going so far? See Leaderboard here.

Conferences

Aging & Gerontology

8-9th April, Valencia, Spain

Midwest Aging Consortium Aging Research Symposium

28-30th April, Columbus, OH

Longevity Med Summit

8-9th May, Lisbon, Portugal

Rejuvenation Startup Summit

10-11th May, Berlin, Germany

BSRA 2024

4th - 6th September

Tweet of the Month

Steven Austad

For geroscientists out there, why do we call them "clocks?"  Clocks tell time of day.  Calendars tell days, months, and years.  Clocks tell us what time to eat and sleep. Calendars tell us our age. They should be epigenetic or proteomic calendars.

Podcasts and Webinars

Longevity & Aging Series

NUS Medicine’s Healthy Longevity Webinar Series

Dr. Jean Hebert: Progressive Brain Tissue Replacement and How we Beat Aging!

STARTALK: Is Aging a Disease? Epigenetics with David Sinclair

The Optispan Podcast with Matt Kaeberlein: Rapamycin's SURPRISING Effects on Aged IMMUNE SYSTEMS

Interview with Professor Nicole Ehrhart

Bio: Dr. Nicole Ehrhart, VMD, MS, directs the Columbine Health Systems Center for Healthy Aging at Colorado State University. Holding the Ross M. Wilkins M.D. Limb Preservation Foundation University Chair in Musculoskeletal Oncology and Biology, she is also a board-certified veterinary surgeon and a leader in both national and international surgical organizations.

What inspired you to enter longevity research? 

I am a clinician scientist who utilizes a wide spectrum of animal models in aging research but I focus on naturally-occuring disease models to aid in translation of discovery to clinical application The first phase of my research career was focused on tissue engineering and regenerative medicine, ie combining synthetic or biologic scaffolds, signals and progenitor cells to regenerate tissue following trauma, infection or tumor surgery. One of the questions that drove my curiosity was why humans and other higher mammals have such limited tissue regeneration capacity as compared to creatures such as salamanders, for example , who can regenerate entire limbs following an amputation. Higher mammals can achieve a small amount of tissue regeneration, but beyond this limited response they simply form scar tissue instead of replacing native tissue. Through my work and others, we learned that a fundamental reason why higher mammals such as humans, horses, dogs etc. do not regenerate large amounts of native tissue following acute injury was due to exhaustion of the tissue stem cell pool.   I spent a lot of time working on strategies to “rejuvenate” tissue stem cells. When the cellular hallmarks of aging were first described, I was fascinated to learn that stem cell exhaustion was one of the fundamental drivers of cellular aging. There was an intersection I hadn’t been aware of between my work and what was, at the time, the rather nascent field of aging biology. It dawned on me that the same strategies we were using to boost tissue regeneration following acute tissue loss could potentially be applied to the slow, insidious loss of tissue volume or function associated with aging. I could see that the impact potential was huge. Not everyone suffers from acute tissue loss but every one of us ages and loses tissue function and mass along the way, just very slowly. That was the inspiration to enter longevity research. 

Which of the current theories of ageing do you think are the most convincing?

This is a difficult question to answer because we continue to refine our knowledge about aging biology daily. The field is literally exploding with new data that are rapidly shaping and re-shaping our understanding. These advancements in our knowledge are not linear and iterative. Therefore, instead of concerning ourselves with which theory is most convincing, we need to understand that they each represent parts of larger story which is yet incomplete. We are still the blind men trying to make a theory about the entire elephant but we only have perspective on separate parts of the whole, to use a common analogy. I believe we should be focusing on the intersections of the different theories to see what bigger picture is beginning to crystalize.  

How has the field changed since you started?

Geroscience has gained more recognition as a distinct field of study, leading to increased funding opportunities from government agencies, private foundations, and the biotech industry. This has allowed researchers to pursue more ambitious projects and collaborations. Progress in identifying new and refined biomarkers of aging, will be crucial for assessing longevity interventions. This area has also progressed since I entered the field.

What mistakes do you think the longevity field has made?

In the past, there has been a tendency to search for single interventions or "magic bullets'' for extending lifespan, overlooking the complexity of aging processes. This approach does not take into account the interrelatedness of the drivers of aging. In addition, there has been too much emphasis on data collected from traditional laboratory animal models such as fruit flies, worms and mice. This approach has resulted in extremely important mechanistic and proof of concept data that has advanced our overall knowledge greatly. However, as exciting as these results are, the models do not at all mimic the complexity of human aging.  When we use these data alone to move forward with human clinical trials, it's common for such interventions to fail or, even worse, have unintended negative consequences. This has led to a lot of disillusion and loss of credibility in aging biology. Further investment to successfully translate these discoveries becomes too high risk and many exciting and potentially highly efficacious interventions are abandoned at that point. To solve this problem, we need to build a better bridge across the huge translation gap. Investing in this niche will better inform go/no-go decisions for new longevity therapeutics and is a powerful, cost-effective way to de-risk and accelerate gerotherapeutics.

Is ageing a disease?

Modern medicine is based upon detection and subsequent diagnosis of a specific condition which is then treated. However, changes in our cells and tissues are occuring with the passage of time. We call this “aging”. Older bodies are made up of older cells that are less and less able to repair from the wear and tear of everyday function or damage. Subsequently, when enough unrepaired damage accumulates within an organ or body system, the system fails to work properly. We recognize this end dysfunction as a “disease”. So maybe the question is: are accumulating changes that are upstream of the onset of a disease diagnosis also part of the “disease”. My answer to this is “yes”. Aging is a modifiable process that occurs over time and we should not wait until the dysfunction is so severe so as to put a specific name on it to treat it. 

Given your unique background in veterinary medicine and surgical oncology, how does this perspective enrich your approach to aging research, and are there specific insights or methodologies from these fields that can notably advanced the study of aging biology?

The  direction forward must also include a way to study aging on an accelerated timeline,which brings us to the topic of model organisms in research. Laboratory mice – the most common species involved in testing the safety and effectiveness of a drug prior to human clinical testing – are astoundingly poor models of human aging. They live in highly controlled environments, eat identical diets and are genetic twins of one another. This is a far cry from humans, who are genetically diverse and have a myriad of social, economic, environmental and lifestyle behaviors that influence their health outcomes. Consequently, a mouse-to-man approach for new drugs has historically been unsuccessful. Primates, our closest genetic relatives, are an alternative model in which to study age reversal drugs, but primates also have long lives, and when in a laboratory environment, they are not subject to the same variations in environment, exposures and habits as human populations. However, there is another promising approach: a species that lives among us, shares our environments, lifestyle habits and social structures. They develop the same diseases of aging as humans, are genetically diverse and have access to well-established heath care systems and interventions, yet they age much more rapidly than humans. Enter the companion dog. Pet dogs have coevolved with humans and represent a unique animal population that could be a powerful bridge to accelerating the development and approval of age reversal drugs in humans. There are millions of companion dogs in the United States, for example,  and the quality of veterinary care has paralleled human medical care, such that there is a large population of dogs living to old age and developing diseases of aging naturally, just as humans do. The development of well-designed clinical trials to show health span extension in family dogs would need to include all the ethical and safety considerations of human clinical trials. Studies such as these are conducted while the pet continues to live out their daily life in their home with their family – while the medical team conducting the trial carefully ensures that their health and well-being are maintained. Pet owners can choose if they wish to voluntarily enrol their companion dogs in a study and participate in citizen science, collaborating with researchers to share observations, thereby cocreating and contributing to scientific outcomes. Engaging companion dogs in health span clinical trials provides a chance to enhance their wellbeing and life span, not only for their benefit, but also as a more accurate predictor of the effectiveness of health span-extending drugs in human populations. Given the identical nature of most age-related diseases between dogs and humans, and the shorter canine life span, the overall effect would be the acceleration of meaningful health span extension therapies for humans that our animal companions will benefit from too. In my opinion, well designed, placebo controlled, multi-institutional clinical intervention studies in companion dogs;  which incorporate all the safety and ethical considerations that are employed in human clinical trials yet cost a fraction of the amount for a similar human clinical trial, are a vastly underutilized resource. 

As the director of Columbine Health Systems Center for Healthy Aging how do you foster collaboration across different fields to advance aging research and are there particular focus areas that are emphasised?

I truly believe that the answers to the most challenging human issues, such as aging, lie at the intersections between disciplines. Academia is very good at drilling down deeply within specific science disciplines, but we have sometimes failed to bring the lens of multiple scientific domains to bear on a single challenge.   Colorado State University’s Center for Healthy Aging unites and facilitates interdisciplinary research teams across multiple scientific fields to address the grand challenge of global aging. Our work creates research teams comprised of many disciplines- from the behavioral sciences to engineering to medicine. My personal passion and focus is to find novel ways to bridge the gap between discovery in geroscience and meaningful healthspan interventions that will impact how we, and the creatures we share our world with, can live our best lives.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!

Further Reading

Nanoplastics causes heart aging/myocardial cell senescence through the Ca2+/mtDNA/cGAS-STING signaling cascade

Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma

Neuroprotective treatment with the nitrone compound OKN-007 mitigates age-related muscle weakness in aging mice

How excess niacin may promote cardiovascular disease

An article on VitaDAO has been published in Nature Biotechnology! It is a case study on the potential of DAOs for funding and collaborative development in the life sciences. In this article, the authors explore VitaDAO...
Read more
Entropy and Epigenetics in Aging Science with Peter Fedichev and Jan Gruber - The VitaDAO Aging Science Podcast
April 7, 2024
Awareness
Podcast
Entropy and Epigenetics in Aging Science with Peter Fedichev and Jan Gruber - The VitaDAO Aging Science Podcast



In the current episode of The VitaDAO Aging Science Podcast, we explore the fascinating intersection of entropy, epigenetics, and aging with our esteemed guests, Peter Fedichev, founder of Gero and a trailblazer in longevity research, and Prof. Jan Gruber from Yale-NUS, known for his deep understanding of the physics behind aging. As we navigate through Peter Fedichev's recent paper that sparked heated discussions on the limits of age-reversal, we'll delve into the science of stochastic changes in methylation patterns, the controversial debate around the reversibility of aging, and the impact of entropy on human longevity. This episode will also shine a light on the vital role of VitaDAO in science funding, the challenges faced by PhD students in today's economic climate, and the exciting potential of naked mole rats in aging research.

A brainstorming session about science funding and the impact of entropy on human aging – a talk with Peter Fedichev and Jan Gruber

Peter Fedichev is considered by many of my colleagues as an extraordinarily creative and productive aging researcher. This is one of two reasons why I invited him on the VitaDAO aging podcast. The second is that Peter’s recent paper attracted a lot of controversial debate on the longevity subreddit (1) and I was hoping we could clarify some of the issues that people raised.

https://www.reddit.com/r/longevity/comments/y8ewm3/aging_clocks_entropy_and_the_limits_of_agereversal/

In his paper Peter claims that stochastic changes in methylation patterns impose a hard limit on our ability to reverse aging (2). In this podcast we discussed this thesis and whether reprogramming refutes his ideas.

We also talked about the hardships of PhD students, the role of VitaDAO in science funding, linear and non-linear features that change with age, the difference between hallmarks of aging and proximal causes of aging, the mean-field effect, stable and unstable animals, naked mole rats and more. Although ultimately we may have failed to really break down and simplify his work for the general audience, the journey was still a worthwhile one and I hope you will enjoy our podcast, even though the second part is quite technical.

Below I will provide a few comments that might be useful to better understand the podcast.

Brief bio – Peter Fedichev and Jan Gruber

“Peter Fedichev, Ph.D., is an entrepreneur and scientist with over 20 years of experience in academic research and biotech business. He is a founder of Gero, a longevity startup focused on developing therapies that will extend a healthy human lifespan. Peter’s scientific background lies in the field of condensed matter physics, biophysics and bioinformatics…His dream is to defeat aging and experience life in space.”

peter fedichev | GIANT Health London 9-10 December 2024


https://loop.frontiersin.org/people/203716/bio

Prof. Jan Gruber (Yale-NUS) is another physicist turned biologist with space travel ambitions. I invited him because he is very familiar with Peter’s work in the hope that he could explain the math better than I can. Not only is Jan quite familiar with the physical ideas behind Peter’s research but he is also one of the most knowledgeable aging researchers I have met.

Jan Gruber - Associate Professor - National University of Singapore |  LinkedIn

Science funding and PhD life

Peter thinks that VitaDAO should hire more experts and delegate decisions to them. Both Jan and Peter suggested to fund risky projections at an early stage. You can listen to the podcast to for the whole discussion covering more of the nuance here.

Another conversation we had was about the life of PhD students and we all probably agreed that the funding situation is rather dire, needing improvement.

"economically the life of a PhD student is pretty hard these days… the system is broken" (Peter Fedichev)

In that context it is interesting to note that VitaDAO realized the extent of this problem and now offers small amounts of money to young and/or low-income students and researchers. These are called the VitaDAO fellowships. The idea is that a small sum can make a big difference to someone who is in need, making it a very effective program. As far as I can tell, these fellowships are partly supported by external donations allowing VitaDAO to focus most of their internal funds on funding research while still doing community building together with other donors.

https://www.vitadao.com/fellowship

Epigenetics and epigenetic clocks

Genes encode the information to produce various proteins. Genetics deals with genes while epigenetics describes the regulation of gene expression through epigenetic marks. There are two major types of epigenetic marks which can affect gene expression. Histone marks and DNA methylation. The latter is usually attached to so called CpG islands (which are stretches of Cytosine and Guanine bases) and the object of study in most clock papers. In general, CpG methylation is thought to reduce the expression of nearby genes. However, more interestingly, it appears that these CpG methylation patterns change in certain ways with age, thus allowing us to predict a person’s age based on their DNA methylation.

What is entropy and how does it relate to aging?

Simply put, entropy describes the amount of disorder in a system. The amount of entropy in the universe increases over time, which is equivalent to the second law of thermodynamics. Similarly, the amount of entropy increases in a closed system and will thereby limit its functionality. Since biological systems are complex any increase in entropy ultimately poses an issue for their functioning.

However, the earth is considered an open system so the limitations imposed by the physical concept of entropy do not apply. On the other hand, there is a closely related concept of stochastic damage which is very similar and, indeed, such damage is considered a major driver of aging. So in way the idea that entropy drives aging was never really in doubt.

I would say the major differences in opinion are related to the number and heterogeneity of these lesions that comprise molecular damage. Optimists like Aubrey de Grey would argue that there are only few types of damage that limit human lifespan and the robust lifespan extension effects seen with compounds like rapamycin may also be taken as support for the malleability of aging.

What makes Peter Fedichev’s work interesting is that it entails a rather pessimistic interpretation instead. In the case of epigenetic aging, given the large number of CpG islands that all show stochastic or entropic changes over time it would very difficult to intervene and reverse this damage. It is not physically impossible to reverse that damage at so many different genetic loci, but technically exceedingly difficult – to put it mildly.

Perhaps inspired by the great Russian writer Peter explained that each aged cell will accumulate entropic changes, but each cell will have different changes. As they say: “All happy families are alike, but every unhappy family is unhappy in its own way” (Leo Tolstoy)

While perhaps unpopular among Biohackers and Longevity Advocates, there is strong support for the idea that epigenetic changes are stochastic. Indeed, Björn Schumacher and David Meyer from CECAD just published a manuscript showing that this stochastic variation is sufficient to construct aging clocks. While I have not read it, I do respect their work and presume that it is solid (3).

Nevertheless, Peter is optimistic that we could at least radically slow aging, as he explains in the podcast. I would speculate that perhaps compounds such as rapamycin can only slow aging and bona fide rejuvenation is indeed difficult.

Does reprogramming and evolution prove that entropy is irrelevant?

“But my biggest issue is that I can't square their claims against the fact that the cells in our body are millions of generations old. For women and men, they generally have been alive for 20+ years before their gametes are used/generated for the next generation. Now these cells maintain their DNA in a more highly regulated way, but doesn't this throw cold water on entropy after aging has occurred?” (Poster 1)

“Now, I have said I don't necessarily agree with the paper. And that is because we have empirical evidence, and Dr. Sinclair is on the record saying, that there is a "backup copy" of lost information somewhere in the cell.” (Poster 2)

“I don't really have theoretical objections to this like most of the respondents here do, but purely empirical ones: aging has already been reversed in several organisms. So there is obviously something wrong with the theory,” (Poster 3)

Indeed, evolution shows that entropy does not limit the existence of life per se, since complex cellular organisms have existed almost since the dawn of time.

Moreover, researchers have found that epigenetic reprogramming during early embryogenesis could contribute to rejuvenation of the species. Reprogramming here means the erasure and resetting of epigenetic marks which is reflected in a reduction of epigenetic age. Many commenters have argued that the success of such reprogramming, both partial in the lab and natural in the womb, implies that Peter’s thesis of irreversibility must be wrong. Hence epigenetic aging must be reversible.

Without going into much detail, I do think they have a point. However, most people seem to forget another major ingredient necessary for rejuvenation of the species’ bloodline, which is selection. Just to give a few examples, men produce hundreds of millions of sperm, which are in competition with each other for general and especially mitochondrial fitness because they have to race towards an egg cell to fertilize. This competition will help to filter out sperm cells with high entropy because these will, most likely, show reduced swimming ability, reduced ability to penetrate the egg’s zona pellucida, reduced ability to produce viable offspring, etc.

In fact, we have strong empirical evidence for selection as a complementary mechanism that together with reprogramming should reduce epigenetic age (and entropy). The almost exponential increase in fetal chromosomal abnormalities seen with the mother’s age proves that reprogramming is not enough (4). In nature, spontaneous abortions, failure to fertilize and implant – which can be caused by chromosomal abnormalities among other issues – would select against offspring with low functional status. It is tempting to speculate that a fetus or embryo that, by chance, inherited a higher epigenetic age would be selected against, at some stage.

This is my own thesis and Peter discusses some other arguments in the podcast.

What are stable and unstable organisms?

As far as I understand, in his framework Peter categorizes organisms in two groups based on their dynamic stability. When looking at physiologic traits like complete blood counts, humans show a low auto-correlation of these values whereas mice show high levels of auto-correlation. This means that a perturbation in mice would persist for longer, whereas humans are able to return to equilibrium quicker; i.e. they are more stable (5, 6).

“we observed that the fluctuations of physiological indices in humans are also dominated by a collective variable characterized by a relatively long but finite auto-correlation time (in the range of a few weeks) and associated with age and all-cause mortality. The number of individuals exhibiting signs of the loss of dynamic stability (measured by exceedingly long auto-correlation times) increased exponentially with age at a rate matching the mortality doubling rate from the Gompertz mortality law” (6)

One implication is that the effects of anti-aging treatments should persist for a long time in mice, whereas the effects in humans would be transient and small to begin with, at least during midlife which he characterizes as a period of stability.

This idea of mice being dynamically unstable is conceptually similar, although distinct, to the broader notion of mice being fragile and short-lived. You could perhaps say it is another line of evidence in favor of this idea. When we say mice are short-lived we do not just mean it in the trivial sense. Of course they are! What we generally like to do is to compare the lifespan of animals to the expected lifespan based on their body mass which is also known as the longevity quotient. Small species tend to live shorter lives. Mice, however, are even shorter-lived than expected based on their size, which is also the reason why all of us are so interested in naked mole rats that are the opposite – unusually long-lived for their size.

References

1. “Aging clocks, entropy, and the limits of age-reversal”
https://www.reddit.com/r/longevity/comments/y8ewm3/aging_clocks_entropy_and_the_limits_of_agereversal/

2. Tarkhov, Andrei E., Kirill A. Denisov, and Peter O. Fedichev. "Aging clocks, entropy, and the limits of age-reversal." bioRxiv (2022): 2022-02.
https://www.biorxiv.org/content/10.1101/2022.02.06.479300v2.abstract

3. Schumacher, Björn, and David Meyer. "Accurate aging clocks based on accumulating stochastic variation." (2023).
https://scholar.google.at/scholar?hl=en&as_sdt=0%2C5&as_ylo=2010&q=Accurate+aging+clocks+based+on+accumulating+stochastic+variation&btnG=

4. https://www.preimplantationgeneticdiagnosis.eu/pgd/risk-of-aneuploidy-and-maternal-age.aspx#:~:text=However%2C%20the%20frequency%20of%20aneuploidy,50%25%20of%20embryos%20are%20abnormal.

5. Avchaciov, Konstantin, et al. "Unsupervised learning of aging principles from longitudinal data." Nature Communications 13.1 (2022): 6529.

6. Pyrkov, Timothy V., et al. "Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit." Nature communications 12.1 (2021): 2765.

In the current episode of The VitaDAO Aging Science Podcast, we explore the fascinating intersection of entropy, epigenetics, and aging with our esteemed guests, Peter Fedichev, founder of Gero, and Prof. Jan Gruber
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February Longevity Research Newsletter
March 10, 2024
Maria Marinova & Rhys Anderson
Awareness
Longevity
February Longevity Research Newsletter

Introduction

Hi Vitalians, greetings from Vitalia. You might have heard about the city of life in Roatan, Honduras. 

VitaDAO hosted a Life Extension Conference, held from February 23 to February 25, 2024, in the pop-up city of Vitalia, Honduras, was a profound journey into the future of human longevity. Nestled within Próspera's special economic zone on the idyllic Roatán Island, Vitalia emerged as a beacon of innovation, drawing inspiration from the visionary minds of Vitalik Buterin and Balaji Srinivasan. This unique event attracted over 200 attendees from around the globe, uniting them in a shared vision for a future where extended healthspan and lifespan are not just possible but expected. With a collective eye towards decentralized cities of longevity, speakers and participants alike embraced the notion of these new frontiers in the eternal quest for a longer, healthier life.

Vitalia's existence represents more than a transient assembly. It serves as a foundational step towards the creation of permanent districts dedicated to longevity, poised to fundamentally transform the biotech landscape. The special economic zone of Prospera in Roatán has a legal environment that is conducive to medical freedom and pioneering work, setting an exhilarating stage for progressive dialogues. This year's gathering not only underscored the symbiotic relationship between urban planning and health but also brought to light emerging biological research and the future of medical practices. 

Projects such as Vitalia are at the forefront of accelerating longevity therapeutics development. Currently, aging is not officially recognized as a disease indication for clinical trials, raising the question of how aging should be classified. The debate is polarized; some firmly argue that aging is indeed a disease, while others strongly disagree, with many viewing the debate as a distraction from the primary goal of trying to understand and treat the age-related pathologies. This month, we're thrilled to bring you an interview with Dr. Barry Bentley, who received an Impetus Longevity Grant to explore this every topic. Enjoy!

Longevity Literature Hot Picks

Preprint Corner in collaboration with

The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.

Check out these latest preprints, which will be entered into the 1Q24 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity

Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP

Published Research Papers

Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results

Targeting senescent cells in the retina with UBX1325, a senolytic drug, reduces damage in diabetic macular edema (DME). This approach, shown to be safe in a phase 1 trial, offers a potential new treatment strategy for DME, necessitating further research for validation.

Defining the progeria phenome

The study introduces a novel approach for diagnosing progeroid disorders by developing a 'progeria phenome' and a machine-learning classifier available at https://www.mitodb.com. It also identifies new associations between certain diseases and progeroid syndromes, enhancing our understanding and diagnosis of premature aging conditions.

Wealth Redistribution to Extend Longevity in the US

A study linking wealth inequality to survival rates in the US suggests redistributing wealth could increase median longevity by up to 2.2 years, potentially aligning US mortality rates with OECD averages. Simulations indicate that policies promoting wealth equality, including those inspired by Japan's distribution, minimum inheritance, and baby bonds, could significantly reduce survival disparities.

Protein signatures of centenarians and their offspring suggest centenarians age slower than other humans

The New England Centenarian Study identified unique protein signatures in centenarians, suggesting that despite acquiring aging markers similar to those in younger, shorter-lived individuals, they do so later in life. The study highlights specific serum proteins associated with senescence and longevity.

Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts

This research reveals that plasma membrane damage (PMD) leads to cellular senescence, contributing to aging. In budding yeast, PMD was linked to shorter lifespans, but lifespan extension was possible by upregulating membrane repair mechanisms. In human fibroblasts, PMD induced senescence through the Ca2+–p53 pathway, with upregulation of repair factor ESCRT-III mitigating this effect. 

Genome-wide profiles of DNA damage represent highly accurate predictors of mammalian age

Recent advancements in genome-wide mapping techniques for single-strand breaks and abasic sites in DNA have enabled the discovery of precise age-related genomic patterns of DNA damage in mice. These patterns offer superior age prediction accuracy compared to traditional transcriptome analysis, focusing on a select group of genes. 

Inhibition of S6K lowers age-related inflammation and increases lifespan through the endolysosomal system

Inhibiting TORC1 with rapamycin extends lifespan across species, a process mediated by S6K. In Drosophila, S6K activation in the fat body negates rapamycin's benefits, affects lysosome structure, and reduces inflammaging, linked through Syntaxin 13. Gender differences in inflammaging response to rapamycin were observed, with significant effects in females but not in males.

Published Literature Reviews, Hypothesis, Perspectives and more

Cellular senescence: Neither irreversible nor reversible

Cellular senescence, traditionally viewed as irreversible, might under certain conditions be transient. They suggest that senescence is a variable journey, not a permanent state, and cells can potentially return to the cell cycle, entering a distinct post-senescent phase with unique functional and clinical outcomes.

Targeting ageing with rapamycin and its derivatives in humans: a systematic review

Rapamycin and derivatives benefit immune, cardiovascular, and skin aging with no significant impact on endocrine, muscle, or nerve systems, and unassessed effects on other bodily systems. While safe in healthy individuals, they increased infections and cholesterol in those with age-related diseases, indicating a need for further and long-term studies.

Validation of biomarkers of aging

Efforts to identify omic-based biomarkers for biological aging aim to predict health outcomes and assess anti-aging interventions. However, a unified approach for validating these biomarkers before clinical use is missing. This review discusses the validation challenges and proposes recommendations to improve the process.

Missing centenarians are an international concern

Job Board

Loyal is looking for a Chief of Staff! Loyal aims to help dogs live longer and maintain their quality of life as they age, hoping to do the same for humans one day.

The Kapahi lab is seeking postdocs for an eye aging and neurodegeneration project using flies and mammals. For questions regarding this position, please email Pkapahi@buckinstitute.org or visit the website.

Postdoctoral Positions available at Brown University Center on the Biology of Aging (BoA). A list of participating investigators and detailed descriptions of faculty research programs can be found on their website

Assistant or Associate Full Professor of Geroscience positions at UCSD:

Assistant Professor - (Tenure-track): Apply

Associate or Full Professor - (Tenured): Apply

News and Media

Hevolution Announces 49 Awards to Catalyze Discovery in Healthspan Science Through Innovative $115 Million Grants Program

BioAge Announces $170 Million Oversubscribed Series D Financing to Accelerate Development of Obesity and Metabolic Disease Therapeutics

Caloric Restriction Extends Reproductive Lifespan in Hens

Life Biosciences and Forge Biologics Announce cGMP Manufacturing Partnership to Advance Development of Novel Gene Therapies for Aging- Related Diseases

Solving Atherosclerosis: The Small but Mighty Molecule. Cyclarity’s Dr. Matthew O’Connor talks about ending atherosclerosis

Why age matters when it comes to cancer

Neurona Therapeutics Raises $120M to Advance Groundbreaking Pipeline of Regenerative Cell Therapy Candidates for Chronic Neurological Disorders

Resources

Reproductive aging resources - compiled by Carol Magalhaes.

Prizes

Longevity Prize Million Molecule challenge with Ora Biomedical

Propose interventions to extend C. elegans lifespan, with a chance to win a prize for the most effective approach. Ora Biomedical has developed the WormBot-AI platform, combining robotics and AI to study longevity in C. elegans, a model organism for aging research. This technology enables quantitative assessment of lifespan and healthspan on a large scale, advancing our understanding of longevity.

Biomarker Challenge, our open-science competition rewarding folks who can best predict chronological age, survival/mortality and multi-morbidity incidence using biomarker data. Challenge officially begins March 1st.

Developing and validating aging biomarkers for clinical trials is challenging due to data limitations and collaboration barriers between scientists. To address this, Biolearn, an open-source toolset, was created. It harmonizes omics datasets and calculates existing aging biomarkers. More about Biolearn:

Biolearn, an open-source biomarker validation library and platform enabling easy and versatile analyses of biomarkers of aging data. 

Biolearn is a tool that simplifies the analysis of biomarkers of aging data. It allows users to easily import data from publicly available sources like the Gene Expression Omnibus, National Health and Nutrition Examination Survey, and the Framingham Heart Study. Biolearn also includes reference implementations for common aging clocks such as the Horvath clock and DunedinPACE, which can be run with just a few lines of code. 

Join Biolearn Discord.

Conferences

Aging and Gerontology

April 08-09, 2024

Valencia, Spain

5th Annual MAC Aging Research Symposium

April 28 – 30, 2024

Columbus, OH, USA

The Longevity Med Summit

May 8 - 9, 2024

Lisbon, Portugal

The Rejuvenation Startup Summit 2024

May 10-11, 2024

Berlin, Germany

Tweet of the Month

Carol Magalhaes:

Why has menopause become a normal part of every woman's life, when it causes unnecessary suffering?

Why is reproductive aging research still significantly underfunded when half of the population experiences menopause?

I believe this *needs* to change, so I wrote a piece about how to delay menopause to extend longevity.

Podcasts and Webinars

Longevity & Aging Series

NUS Medicine’s Healthy Longevity Webinar Series

A great list of Aging Podcasts

80,000 Hours Podcast - Laura Deming on the science that could keep us healthy in our 80s and beyond

Matt Kaeberlein’s new podast covering a variety of topics related to longevity and healthspan - An introduction to the study of RAPAMYCIN

How this tiny mutant mouse lives so, so long

Interview with Barry Bentley

Dr Bentley is the Head of the Bioengineering Research Group and Bio-AI Laboratory at Cardiff Metropolitan University. His current research focuses on the development of laboratory systems for cryopreservation, and the development of classification and staging systems for age-related pathology within the context of the WHO ICD-11.

What inspired you to enter longevity research?

I have been fascinated and unsettled by ageing, probably for as long as I have been aware of ageing as a concept; however, I can pinpoint the exact moment I became interested in longevity as a topic of scientific research. In early 2006 I was travelling around China and teaching English on a gap year before starting university. One night, I found myself in a dimly lit internet café on the outskirts of Wenzhou city, where I was browsing through forums on science and technology to pass the time. I stumbled across a link to an article discussing the Methuselah Foundation, which led me down the rabbit hole into the world of ageing research. The prospect of slowing or even reversing biological ageing was and still is a radical idea, sounding, to some, like a concept straight out of science fiction. The realisation that there were people who were seriously working on such a seemingly intractable problem captured my imagination. I already knew at that point that I wanted to become a research scientist, but that was the nudge that shifted my focus to the biological sciences, and ultimately led to my current career.

Which of the current theories of ageing do you think are the most convincing?

Each theory has its proponents, and various degrees of evidence supporting them. With the incredible progress that has been made in developing robust epigenetic clocks, the field seems to have shifted in favour of programmed theories of ageing in recent years. With how complex biology is, and how much is still unknown, I personally think it would be a mistake to commit to any one view or theory of ageing at this point; in fact, I would not be surprised if we find that all of the main theories are true to varying extents, with ageing being a highly heterogeneous process. To inelegantly coin a phrase: I suspect there is more than one way to age a cat.

How has the field changed since you started?

The biggest change has undoubtedly been the amount of interest in the field, and consequently, the amount of investments now being made in longevity research. Whether that is because the problems of an ageing population are finally starting to become too profound to ignore, or the science has reached a level of maturity that is finally investible, society as a whole is starting to take note.

What mistakes do you think the longevity field has made?

Until recently, the longevity field – as distinct from the broader field of ageing research – had serious credibility issues, which it still has yet to completely rid itself of. Starting as a fringe area, it unfortunately became associated with some questionable groups: unscrupulous people selling snake oil, biohackers doing questionable self-experiments, and futurists who were making predictions with little consideration for the realities of research. The field did a poor job of distancing itself from the more unsavoury ideas and actors. The strength of the science now speaks for itself, but reputational damage remains.

What advice would you give to people currently working in longevity research?

Like all areas of research, the main advice I would give is to be open minded. We do not yet know which approaches will be required to effectively slow or reverse ageing – there is just too much that we don’t yet know. To make progress, we’ll need to continue asking questions, trying new approaches, and robustly challenging our assumptions.

You were awarded an Impetus grant to explore how ageing should be classified. Why is this important?

That’s a great question. Before I answer, let me give some context to how the project came about: In 2016 and 2017, my collaborator, Dr Stuart Calimport, and I were discussing our frustrations that even though the scientific understanding of ageing was rapidly improving, the science was not filtering down to the bedside to influence the way patients were treated. Part of the reason for this, we realised, was due to clinical classifications.

The World Health Organization (WHO) maintains a standard list of clinical codes, known as the International Classification of Diseases (ICD), which are used as the standard terminology by all WHO member states. These are used for recording diagnoses and treatments, for statistical and epidemiological purposes, for healthcare resourcing, approving clinical trials, medical billing, and so on – in short, they are at the core of virtually everything that happens within a health system.

Unfortunately, classifications for ageing-related changes are extremely limited in the ICD, which limits the ability to accurately describe and address ageing-related pathologies. As the idiom goes: you can’t manage what you don’t measure; and the ICD does not currently have the capacity to describe, and thus measure, ageing-related pathologies. Some groups have proposed to work around this by classifying ageing itself as a disease, but not only is this contentious, it also fails to address the heterogeneous nature of ageing – different organs and tissues age in different ways, and I believe we need the ability to capture this.

We had initial success in getting ageing recognised as a cause of disease by the WHO in 2019 [1], following which we published a large multi-author paper in Science proposing a consortium to develop a comprehensive and systematic classification system for ageing-related pathologies [2]. Norn Group thankfully saw the value in this, and awarded us an Impetus Grant to make it a reality. So far, we have recruited approximately 300 experts, who we are working with to develop these new classifications.

 [1] https://doi.org/10.1089/rej.2019.2242

[2] https://doi.org/10.1126/science.aay7319

You recently hosted a consensus meeting to define the criteria for an ageing-related pathology, could you give us the highlights of this meeting?

This was the first meeting of the consortium to develop the classifications for ageing-related pathologies. Of course, to develop those classifications, it is essential that the consortium members have agreement on what constitutes an ageing-related pathology – so this was the main goal of the first meeting: to define the criteria that will allow us to differentiate an ageing-related pathology from others. We had a wide range of input from clinicians and scientists, but there was pretty much unanimous support for three criteria that were proposed: Firstly, that the damage must develop or progress with increasing age; that it should be associated with, or contribute to, functional decline or increased susceptibility to functional decline; and that, for the purposes of clinical classification, it must be based on evidence from studies in humans.

Our consortium coordinator, Dr Emma Short, who is a consultant histopathologist and research associate, did a brilliant job of chairing the meeting, and is working on writing-up the outcome of the discussions, which we will be publishing in the near future.

Is ageing a disease?

There is little agreement amongst gerontologists on how to classify ageing, mainly because ageing is such a catch-all term that refers to many things: biological age, as a sociological status or marker, chronological advancement, appearance, etc. Personally, I think the debate is somewhat counterproductive. Regardless of how we use the term, and whether we call it a disease, the fact remains that people become sicker as they get older. My own approach is to focus on those aspects that make people sick: the underlying ageing-related pathology.

What are you currently working on in the lab?

In addition to my work classifying age-related pathology, I am fortunate to have received a Fulbright Award, which is enabling me to work at Harvard Medical School and Massachusetts General Hospital this year on the development of new technologies for the cryopreservation of cells, tissues, and organs. It has been an ambition of mine for a long time to make contributions in this area, so it’s exciting to finally be making that a reality.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!

This time we’ll leave you hanging, waiting for some exciting developments on our Members Portal. VitaDAO will soon enable $VITA holders to stake their tokens in exchange for health products and services. Keep an eye out!

Further Reading

Age-Associated Differences in Recovery from Exercise-Induced Muscle Damage

Association of testosterone and sex hormone-binding globulin with all-cause and cardiovascular disease mortality in older Chinese men

Mendelian randomization reveals apolipoprotein B shortens healthspan and possibly increases risk for Alzheimer’s disease

Intermittent fasting promotes rejuvenation of immunosenescent phenotypes in aged adipose tissue

Unraveling Histone Loss in Aging and Senescence

Hi Vitalians, greetings from Vitalia. You might have heard about the city of life in Roatan, Honduras. 
Read more
Stake $VITA in Exchange for Health Products and Services 🤩
March 4, 2024
Awareness
Longevity
Stake $VITA in Exchange for Health Products and Services 🤩

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We're introducing a revolutionary feature soon for $VITA token holders: the ability to stake $VITA your tokens in exchange for premier health products and services aimed at enhancing your longevity.
Read more
A Beginner’s Guide to Vitalia
February 22, 2024
Morgan J. Weaver
Awareness
Longevity
A Beginner’s Guide to Vitalia


Vitalia builds a decentralised city for longevity biotech development, initiated by a 3-month pop-up city experience (open to short and long-term visitors, you can apply here)

Written by Morgan J. Weaver, published in collaboration between VitaDAO and Stranded Technologies.

The curious technophile ventures forth across the small and wondrous meatspace of a pop-up city-within-a-charter-city in Roatan, Honduras, chronicling the emergence of an experimental biotech startup hub, crypto-augmented Special Economic Zone, and nuclear reactor of liberal governance, big brains, and disruptive ideas¹.

Gazing out at a horizon so vividly turquoise that I begin to question whether my coffee has been trendily microdosed, it is easy to mistake this globally-renowned SCUBA destination and idyllic Caribbean getaway as a mere tourist haven. Postcard-perfect palms sway in a breeze that feels gentle as bathwater, laden with small coconuts which occasionally drop to Earth. Grass roofs top shallow fishing and diving docks, just as in too-perfect vacation stock photos. Small waves break against the world’s second-largest barrier reef, just a kilometer from shore--a penumbra of fantastical corals surrounding something possibly much stranger to us land-dwellers.

Framed in this vivid environment is a buzzing hub of ambitious STEAM activity, alive with provocative and audacious ideas, and an unquantifiable mass of intellectual horsepower and optimistic creativity. The air is laden with, What if? Legal engineers, doctors, biohackers, web3 developers, research scientists, psychologists, community builders and entrepreneurs in myriad verticals have convened in tropical Roatan’s Pristine Bay for a 2-month pop-up network city called Vitalia: The City of Life, with a theme that sounds surreal to many: Make Death Optional.

Why here and why now? Vitalia was chosen as a physical manifestation of what some might classify as a Network Society--a decentralized group cooperating and coordinating their energies around a set of unifying philosophies, which occasionally physically manifests-- permanently, temporarily, centrally or in a decentralized manner. The concept was popularized by Balaji Srinivasan, whose interactive and streamlined book on the concept, The Network State, may be read in its entirety, free of charge, here. This touchdown on Caribbean shores is no accident--Roatan is home to Próspera ZEDE (Zona de Empleo y Desarrollo Económico), a Honduran Special Economic Zone and charter city. Founded around 2021, Próspera is considered one of the most autonomous of existing Special Economic Zones, including Singapore, Hong Kong and Dubai. Próspera’s financial backers include Pronomos Capital, a fund led by Patri Friedman, the founder of the Seasteading Institute and backed by Peter Thiel, Naval Ravikant, Tim Ferriss and Marc Andreessen--well-recognized names and veterans of startup societies and early investing. However, these names make up only a small fraction of investment into Próspera and their role has been overstated by the media. Most of Próspera investors are not as well-known, include only a few institutional VCs, and invest in the space out of conviction--a bet on a different future which they believe should exist. Próspera’s success seemed too early cypherpunk, not ready even for the most forward-looking VCs. Given its continual and steady development over the course of recent years, this may soon change.

The concept of Próspera is uncomplicated: streamlined legal code and liberal governance, paired with the goal of economic prosperity through entrepreneurship and rapid development encouraged by low business taxes, will empower residents, citizens and businesses, and allow Próspera’s government to cover its own operating costs, unlike many existing governments. In addition to fresh legal and policy approaches, financial technologies such as cryptocurrency are part of this plan to empower residents, citizens, and businesses. For example, Próspera hosts AmityAge - a Bitcoin Education Center that has onboarded roughly 60 businesses on the island to accept Bitcoin payments. Próspera also offers cryptocurrency as legal tender, and accepts payments from multiple blockchains including Ethereum and Solana. Businesses can be incorporated here (e.g. LLCs) quickly and efficiently. And since law may be copied, one can, for instance, set up a Delaware-style corporation, or copy and iterate on a variety of other legal structures that have proven successful in the past.  Businesses in the ZEDE are free to transact in crypto without securities laws, and they are allowed to tokenize their assets and require no capital gains tax. The ZEDE itself has investment protection under both national law and international treaties, granting investors, entrepreneurs and residents the stability to build and invest with a long time horizon.

Las Verandas resort, the main campus upon which Vitalia is held.

Próspera’s jurisdiction includes several parcels of land including Pristine Bay, consisting of loosely themed neighborhoods including the Beta District. The Beta District harbors Duna, a 14-story residential tower currently under construction, and Las Verandas, a luxury golf resort including larger villas and condominiums for year-round living, plus a small piece of land on which GARM Clinic, a medical tourism destination offering cutting-edge longevity treatments, sits. Próspera ZEDE’s jurisdiction also encompasses a mainland Honduran shipping port (Satuye, in Las Ceiba) where port workers and their families are expected to live, facilitating shipments back and forth and by extension speeding along the significant construction that is needed to build this charter city.

Before delving into Vitalia, we’d be remiss to ignore VitaDAO, a closely involved organization that sits at several intersections including longevity biotech, web3, culture, startup incubation, and funding mechanism innovation. For non-web3 readers, I direct you to a quick introduction to the Decentralized Autonomous Organization (DAO), a web3 concept consisting of a collective of participants, working under some common goal, that coordinates decision-making and resources through code in a permanent ledger--a blockchain. VitaDAO’s bottom line is to slow, stop, and even reverse aging, which includes the extension of healthspan as well as lifespan.  

You may be wondering at this point why aging is a target--not cancer or osteoporosis or metabolic syndrome, or even addiction. Aging is VitaDAO’s target because of the 150,000 human deaths per day on planet Earth, roughly 100,000 are caused by aging itself, which includes age-related disease that is a direct result of the aging process³.  Let us sit with this for a moment: aging is more deadly than any disease, group of diseases, or cause of death including accidents, addiction, war, starvation, or infection.  If aging itself were viewed as a primary disease, two-thirds of these deaths could be prevented if a cure were reached.  And if the aging process could be reversed, delayed, or otherwise mitigated, we could look forward to living a greater number of healthy, productive years--years spent with our families, partners and communities, years learning, pursuing growth and picking up meaningful longer-term projects.  The potential of the human species and civilization as a whole, unfettered by mortality, is incalculable.  At this point we can direct critical and inquiring readers to VitaDAO’s Longevity Briefing Primer for a more detailed overview of this goal, its supporting philosophy and mechanisms.

What’s more, in industrialized nations, up to 90% of deaths per year are related to aging and age-related disease³.  Perhaps most provocative of VitaDAO’s founding vision is the idea that aging is a disease, and that we should make death optional by understanding and eliminating this disease. This idea creates friction in the US regulatory system, as the FDA currently neither recognizes nor legitimizes the development of therapies aimed at the enhancement of currently healthy people, as opposed to the treatment of disease or disability. The FDA does not currently recognize aging as a disease.

So if aging is a target, what is the shape of the organization that aims to prevent it?  VitaDAO is composed of scientists, researchers, web3 and web2 professionals, academics, dealmakers, venture capital, and others collectively pushing decentralized science forward in the arena of longevity and enhancement biotech, complemented by web3 technologies, to solve some of the most persistent problems of traditional science.  Examples of problems VitaDAO is working to solve include the high cost of Big Pharma-style clinical trials, averaging $2.3 billion per therapy² according to Deloitte, and the regulatory bottlenecks of conducting clinical research.  Other persistent issues of traditional science in academia and institutions, or “tradsci”, include the gatekeeping and misaligned incentives of academic publishing, patient data privacy and sovereignty, and access to and compensation for dataset usage. This is all backed by a belief that the current biomedical research apparatus is failing to deliver treatments and progress in a timely manner, and the data-backed observation that Big Pharma has stagnated for years, failing to bring treatments to market for sick and dying people.  While approved pharmaceutical drugs occasionally do unknown harm, as opposed to known side effects, deaths from the lack of therapies that weren’t approved sooner, or were mired in regulatory complications kill far more people than those who die from approved drugs.  According to Zina Sarif of Yendou, a melanoma research foundation, 10,000 cancer deaths per year could be prevented by existing drugs stuck in long trials.  

Here in Pristine Bay we witness the tinder of an enabling legal platform combined with the spark of innovative biotech and other industries, agitating for faster, cheaper, more efficient regulatory processes. And Vitalia, a gust of oxygen funneling in a migration of scientists, researchers, technologists, and entrepreneurs for the pop-up city and its numerous mini-conferences, with aims to convert some of these to permanent residency.  Part of this thrust consists of four conferences: two on Longevity Biotech bookending the event, the second on Crypto Cities & Startup Societies, and the third conference on AI & Tech Progress.

Aubrey de Grey and Bryan Johnson in a fireside chat with Vitalia co-initiator and VitaDAO steward Laurence Ion.

The first of these 3-day weekend conferences, Longevity Biotech Part I, featured notable speakers and serious contributors to the fields of longevity, rejuvenation biotech, geriatrics and gerontology, such as Aubrey de Grey, José Cordeiro, and billionaire biohacker and elven-skinned longevity advocate Bryan Johnson. I sat in on two days of lectures. Surprisingly, there was not a huge emphasis on lifestyle interventions--considering that so far, even a rigorous regimen of sleep, healthy diet, social wellness, and stress management can only get us so far, with the most genetically blessed of us, lifestyle unknown, living to about 116 or so. An increased healthspan augmented by lifestyle, so the common thread went, will allow us to access the next available rejuvenation technologies as they arrive, until a final innovation to stop aging is found.  Cryonics, or whole body or brain preservation by special freezing techniques, are currently considered a great Plan B amongst many longevity experts and researchers.  

Talks during the first Longevity Biotech conference focused on dozens of potential biotechnologies for rejuvenation and making death optional.  Rather than wishful thinking about juice cleanses or sleep protocols prolonging life far past anything we’ve seen so far (which lifestyle advocates admit won’t take us to immortality), talks focused on bone marrow rejuvenation, cohesive theories of aging such as mitochondrial dysregulation and biological clocks located in individual bodily cells as well as specific clusters of cells in the brain, and even the occasional homebrew science project, such as an introduction to the art of running an electrical current through muscle tissue (monkeys and scientists) to express target molecules, such as ebola antibodies, based on injected mRNA.

The second conference, Crypto Cities & Startup Societies, spanned the weekend of February 2-4. In the spare weekend between conferences, Vitalians explored the island’s bays, reefs, eateries, and other local gems. A bonfire with ecstatic dancing was thrown on the beach in front of the Pool Club, a sprawling, multi-story building on Las Verandas and the de facto center of gravity of the event that houses coworking, an aerial silks space, a gym, meeting rooms, cold plunge and sauna, a salon, and a biohacking lab. Other weekend entertainments included locally grown cacao, freediving certification, local art, Lionfish spearfishing, Palmetto Bay and its brewery, and local Howler monkeys. An all-ages, Vitalian DJ’d party at Roatan Yacht Club with dancing, open laptops containing glucose data charts, and intense philosophical conversations about consciousness and the nature of work unfolded.

What separates Vitalia from a Web2-style conference, or even a Web3 conference (some of which exude a distinct festival energy), is both tangible and not. Many of the organizers involved also had a hand in attending or organizing Zuzalu and Zuconnect, two legendary Web3 events that concentrated the best and brightest--intelligent, creative, weird and open-minded dreamers with diverse backgrounds, mostly united by their agency and idealism. These events were founded by Vitalik Buterin, founder of Ethereum, and you can read more about his reason for creating these genre-defining events here. Part of Vitalia’s unique culture is its do-it-yourself approach to organizing--anyone can organize workshops, events, activities, and groups. Hackathons spur infrastructure development and experimentation to support the Vitalia and Zuzalu-adjacent community itself with open-source, tailor-made event tooling such as ZK-gated forums, ticketing, and scheduling software. Attention to the whole person is also something that separates this event from a typical Web3 conference--wellness activities abound--from holotropic breathwork to men’s and women’s groups, to circling and authentic relating, to meditation and pilates and yoga and improv. Artists and psychologists and podcasters and scientists rub shoulders with hackers and VC investors. The Zuzalu formula, the Zuclear reactor, is alive and well at Vitalia. It feels less like a tech conference and more like a summer camp for gifted adults, where conversations flow freely and cross-pollination of ideas is abundant.

Vitalia isn’t just high-caliber brains, but heart as well. International community-builders work with New Governance experts to engineer a culture and a city that will stick--something that will have staying power and encourage people to plant their flags, start families, and build in a technological, regulatory and ideological frontier nestled in the tropics, given a shot at changing the world by investors, innovators, and the Honduran government.

  1. Tribute to Neil Stephenson’s 1996 Wired gem, Mother Board, Mother Earth, on the intro.
  2. Cost of pharmaceutical asset development: https://www.genengnews.com/gen-edge/the-unbearable-cost-of-drug-development-deloitte-report-shows-15-jump-in-rd-to-2-3-billion/
  3. Age-related mortality statistics: https://en.wikipedia.org/wiki/Aging-associated_diseases#:~:text=Of%20the%20roughly%20150%2C000%20people,is%20higher%2C%20reaching%2090%25.
  4. Honduran criminal law applies in the ZEDE--things that were already illegal in Honduras, such as abortion and illegal drugs including psychedelics, are also illegal in the ZEDE.

The curious technophile ventures forth across the small and wondrous meatspace of a pop-up city-within-a-charter-city in Roatan, Honduras, chronicling the emergence of an experimental biotech startup hub, crypto-augmented Special Economic Zone
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Challenging Mouse Models in Aging Science with Dr. Dan Ehninger - The VitaDAO Aging Science Podcast
February 15, 2024
Podcast
Awareness
Challenging Mouse Models in Aging Science with Dr. Dan Ehninger - The VitaDAO Aging Science Podcast

In this episode of the VitaDAO Aging Science Podcast I spoke with Dr. Dan Ehninger about the shortcomings of modern mouse research as he sees them. I share many of the same concerns and think we do have to ensure that the foundations of biogerontology are sound. Although I do believe that the time for clinical translation is now, in parallel we must work on these foundational questions, some of which include:

  • Does rapamycin and caloric restriction really work and are these treatments robust? And what do we mean when we say “really” and “robust”?
  • The mouse is a fundamentally flawed model due to its shortlifespan and lab adaptations – but how flawed is it? Do the flaws preclude meaningful conclusions in aging research?
  • How to design mouse studies that mitigate these flaws?
  • How do we measure aging, functional decline, aging rate outside of lifespan? (e.g. using age-sensitive phenotypes; ASPs, to use a term from Dan’s research)

Although I am a longevity optimist and may not always agree with all the points that Dan makes, I think it is important for skeptics to be heard. It was a pure coincidence that I stumbled on his work, which some of my colleagues have never heard of. After reading several of his papers, I decided it is time to highlight his outstanding and controversial work as a service to the community.

Dr. Dan Ehninger – Brief Bio

Dan Ehninger is a Senior Research Group Leader at the German Center for Neurodegenerative Diseases (DZNE) in Bonn. His group is interested in the biology of aging and the pathogenesis of age-related brain disorders. He studied medicine at Charité University Medicine/Berlin, Harvard Medical School/Boston and University College London. From 2001 to 2004, he carried out his graduate work in the laboratory of Gerd Kempermann at the Max Delbrück Center for Molecular Medicine in Berlin, where he worked on the behavioral regulation of adult hippocampal neurogenesis and adult cell formation in the neocortex. His postdoctoral work (2004 to 2009) with Alcino J. Silva at University of California - Los Angeles focused on molecular and cellular mechanisms of cognitive impairments in mouse models of neuropsychiatric disorders. In 2010, Dan Ehninger joined the faculty of the German Center for Neurodegenerative Diseases (DZNE) and was later promoted to a tenured Senior Research Group Leader position.

A person in a suitDescription automatically generated


https://www.dzne.de/en/research/research-areas/fundamental-research/research-groups/ehninger/research-areasfocus/

Mice are very short-lived

There are three major issues with mice as a model:

1) They are shorter-lived than expected based on their weight – in the wild early death is compensated by fast reproduction. This means the “tricks” we use to extend mouse lifespan might not work on humans, because we already evolved to utilize these enhancements and more.  One solution is to learn from longer-lived animals, which is what comparative biogerontologists do. We discussed this topic in an earlier podcast with Vera Gorbunova.

2) Mice develop cancer more readily than humans (probably related to point 1), which is the key reason why Dan thinks they fail to faithfully capture aspects of human aging. At least if all you do is measure lifespan.

3) Strains we use in research labs are further adapted to fast growth and reproduction. Thus reproducing and growing even faster than in the wild. One solution to this problem is using more diverse strains, as discussed with Rich Miller in an earlier podcast.

Why do we still run mouse studies? Because using mice is better than the alternatives like cell culture, invertebrates, reading tea leaves, etc. Whereas the truly superior alternatives are not feasible or affordable. Did you know that a large phase III study in humans targeting mortality, as is often done for cardiovascular drugs and will be necessary for anti-aging treatments, can cost north of 100 million dollars?

Healthspan and lifespan uncoupling

There are two schools of thought on the matter of healthspan. Some people believe that it is difficult or impossible to extend lifespan substantially without improving health. Others believe that by now we have so many examples of healthspan-lifespan uncoupling that we must consider these almost independent.

To give an example of such healthspan-lifespan uncoupling in mice we do not need to look very far. A recent study found that reducing the levels of the famous Myc oncogene in mice extends lifespan by reducing cancer while leading to premature aging-like phenotypes (Wang et al. 2023). These include fatty liver, reduced strength, fur quality and spinal degeneration.

To give some more real-world examples of healthspan-lifespan uncoupling in humans, women live longer than men while having more age-related diseases. Testosterone replacement therapy could improve quality of life in older men even though it worsens CVD risk factors, but the effects on mortality are controversial (1).

No matter which school you belong to, there is emerging consensus that longevity treatments need to improve health and affect reasonable biomarkers of aging, especially functional ones.

The rate and trajectory of change in these markers can teach you a lot about the underlying mechanism of your intervention. That discussion is at the heart of our podcast episode.

Disease modifying drugs vs. Band-Aid solutions

I like to use these terms from pharmacology to think about potential longevity drugs and treatments. 

“Disease modifying drugs” are pharmacological agents that aim to modify the underlying pathophysiology of a disease, potentially slowing down or halting the progression of the disease. In contrast, non-disease modifying drugs typically focus on symptom management without significantly influencing the underlying disease progression. For example, in the case of Alzheimer’s disease a cholinesterase inhibitor such as donepezil would be symptomatic, whereas anti amyloid antibodies should be disease modifying. For osteoarthritis painkillers are typical examples of a symptomatic solution whereas senolytics – it is hoped – could be disease modifying.

Dan’s argument, as I understand it, is that several lifespan extending treatments have age-independent effects on aging-related phenotypes. He calls them age-sensitive phenotypes; ASPs. This was something his group saw for mTOR hypomorphism, dwarfism and intermittent fasting in mice (Xie et al. 2022). Based on this age-independent effect he speculates that these treatments do not slow aging and instead extend lifespan by delaying cancer. All perfectly reasonable, although I do have some questions even after the podcast. 

Why would these treatments improve ASPs in young animals? I would presume if they did nothing for aging the null hypothesis would be that some ASPs go down and others go up. Maybe we can discuss this the next time! Another issue that I find counterintuitive is that usually such “band-aid” solutions do NOT alter the course of a disease and the benefits do NOT persist over a long time and well into old-age. Normally, I would expect a convergence towards the expected path with a non-disease modifying drug or treatment. This is what I would call a “band-aid solution” but rapamycin and CR seem to be much more than that.

A graph of a solution and a rejuvenationDescription automatically generated

Many would argue that the actual mechanism of action does not matter. “If it works it works”. Caution is warranted here, however. We only know that these treatments work in mice and mouse cancer incidence is much higher than in humans (2). It also matters in the long term. When developing robust therapies we need to build on solid foundations. If CR only operated through cancer inhibition than all the effort to search for CR-mimetic drugs in order to slow aging would be wasted.

Wider context and reception

While the points made by Dan might seem controversial at first glance they are being echoed by many other researchers. Not everyone agrees on the specifics, but there is emerging consensus that we have problems with our model systems and need to improve. Steve Austad, for example, is a big proponent of studying the longevity mechanisms employed by ultra long-lived species rather than short-lived mice. We will interview him soon on this topic. Similarly, Peter Fedichev believes that the mouse is not an adequate model and he focuses on data mining human datasets instead to find new gerotherapeutics. Rich Miller believes that currently used mouse strains lack genetic diversity and we should focus on using heterogeneous strains while Arlan Richardson would like to validate treatments in rats, that are even more genetically distinct from regular lab mice.

Summary and conclusions

Ultimately, I do think that the high incidence of cancer in mice exaggerates the benefits of certain treatments, in agreement with Dan. There are, however, two interesting counter arguments to Dan’s theory which states that almost all the benefits of longevity interventions are due to cancer. 1/ If it was so easy than many more drugs should extend lifespan. Plenty of drugs tested for lifespan extension have strong chemoprevention data, either theoretical or preclinical, yet they fail to extend lifespan. The only drug that works robustly is coincidentally in a major growth sensing pathway, mTOR, which is also decreased by several other canonical interventions like dwarfism and calorie restriction. 2/ Taueber’s paradox dictates that the wholescale eradication of cancer in humans would only lead to a 5% increase in lifespan because other age-related diseases progress at the same time. In a similar vein, the attenuation of cancer in mice might not be enough for substantial lifespan extension, although this would require modelling studies to prove conclusively.

I also agree with Dan that our mouse studies would be much better if we included young treated controls too. Researchers with sufficient funding should run such controls much more often.

I think – and that is my personal speculation – that rapamycin is an odd drug that leads to partial rejuvenation and does not operate by slowing aging per se. This would explain some of the results seen in Dan’s data (see Xie et al. 2022 for mTOR hypomorphic mice, see Neff et al. 2013 for rapamycin). 

Indeed, it seems that there is a causal pathway between fast growth and fast aging. The pathways that enable fast growth, tissue regeneration and reproduction may be harmful in the long run.  There is a switch-like aspect to CR and CR-like states, which is consistent with the idea they may have evolved as a response to acute nutrient starvation and famines. Perhaps this can explain why they are beneficial without slowing all aspects of aging?

This and many other questions remain to be answered. Let’s get on with the work so we can slow aging as effectively as possible in humans.

Further reading

(1) It is possible that high dose testosterone therapy is beneficial while regular HRT is actually beneficial: “Fewer deaths occurred with testosterone treatment (six [0·4%] of 1621) than placebo (12 [0·8%] of 1537) without significant differences between groups (odds ratio [OR] 0·46 [95% CI 0·17–1·24]; p=0·13).”
https://www.thelancet.com/journals/lanhl/article/PIIS2666-7568(22)00096-4/fulltext

(2) Cancer could bias almost every single functional outcome and aging phenotype except perhaps histopathology. Imagine a mouse with underlying cancer. Will it have high or low frailty? Will it cooperate in a water maze or have high grip strength?

Our manuscript with Prof. Brian Kennedy and Matt Kaeberlein on the importance of long-lived mouse controls which would help to mitigate some of the “artefactual” or “idiosyncratic” non-age related deaths in mice:
Pabis, Kamil Konrad, et al. "The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience." bioRxiv (2023): 2023-10.
https://www.biorxiv.org/content/10.1101/2023.10.08.561459v1.abstract

CR Plus, CR adjacent, CR independent - what the heck?
A blog post in which I worry about the lack of new models in mouse aging since most of them seem to be anti-anabolic and CR-adjacent.
https://biogerontolgy.blogspot.com/2020/09/cr-plus-cr-adjacent-cr-independent-what.html?q=anabolism

Keshavarz, Maryam, et al. "Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?." Molecular Psychiatry 28.1 (2023): 242-255.
Note: a recent review where Dan goes into his arguments

Xie, Kan, et al. "Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice." Nature Communications 13.1 (2022): 6830.

Keshavarz, Maryam, et al. "Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?." Molecular Psychiatry 28.1 (2023): 242-255.

Keyfitz, Nathan. "What difference would it make if cancer were eradicated? An examination of the Taeuber paradox." Demography 14 (1977): 411-418.
https://link.springer.com/article/10.2307/2060587

Neff, Frauke, et al. "Rapamycin extends murine lifespan but has limited effects on aging." The Journal of clinical investigation 123.8 (2013): 3272-3291.

Ham, Daniel J., et al. "Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle." Nature communications 13.1 (2022): 2025.

Wang, Huabo, et al. "Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation." Cell reports 42.8 (2023).

In the upcoming episode of The Science of Aging Podcast, we dive deep into the critical questions surrounding mouse models in aging research with our special guest, Dr. Dan Ehninger...
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January Longevity Research Newsletter
February 6, 2024
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
January Longevity Research Newsletter

Introduction

Welcome back Vitalians. I’m sure that most of you would have by now heard the sad news that renowned Professor Judith Campisi has passed away. In place of our usual interview, this month we would like to dedicate an in memoriam to her followed by a few words from one of her protégés, Marco Demaria. 

It used to be believed that human cells could proliferate indefinitely, until Leonard Hayflick performed some pioneering experiments in the early 1960s which showed this was not the case, and after a reproducible number of divisions, later coined the “Hayflick Limit” cells would permanently stop dividing. On one hand this was viewed as a tumour suppressor mechanism, although it also had implications for aging, in that tissues would not be able to replenish themselves.

In 1995, Prof. Campisi discovered a senescence marker - named senescence-associated beta galactosidase or SAβ-gal - that enabled scientists to detect senescent cells both in cell culture and in vivo. Almost 30 years and 8000 citations later, SAβ-gal still remains the most commonly used marker to detect senescent cells. Some notable examples of its use include the seminal papers showing that removal of senescent cells can extend lifespan in mice and the discovery that senescent cells play a role in growth and patterning during mammalian embryonic development.

Then, in the early 2000s, Judith Campisi made a remarkable discovery showing that senescent cells are associated with a unique secretory phenotype, coined the senescence-associated secretory phenotype or SASP. She then began to elucidate the significance of this, leading to numerous discoveries that the SASP could cause inflammation and even drive cancer. This caused an explosion in the senescence field, with her and others discovering that the SASP was also involved in immune clearance of senescent cells, could elicit damage in neighbouring cells, was required for optimal wound healing and more.

With ~500 papers and over 100 thousand citations one can’t begin to comprehend the significance of her research. Her discoveries transcended the senescence/cancer fields and added much needed credibility to the ageing field in general, by describing a detrimental, yet tangible phenotype which can be therapeutically targeted. There are now a large number of biotech companies working on “senomorphics” specifically aiming to attenuate the SASP in hope of extending human healthspan and lifespan.

Now we would like to share a few words from Marco Demaria.

“Judy was a passionate scientist, always looking forward and always digging in the unknown. She hated to do incremental research; her goal was to always find the new. She was highly creative but also extremely rigorous – you could not convince her very easily without showing many repeats of the same experiment. She kept repeating: 'The data are the data'.

Her laboratory was a family, and she tried to help everybody within and outside the laboratory.  She was positive and collaborative also in the most difficult moments. All the people she met were impressed by her kindness and openness. She never said no to a glass of wine and a performance on the dance floor, reflecting her very social attitude and her italian blood.  

She supported me from the first day I joined her lab, and she kept doing so after I left. She told me the importance of doing science the right way, not to care about impact factors. She taught me how you can be a confident leader, how you can manage many things with a smile on your face. She always found the right words to advise and encourage me through different parts of my career. I will miss all the endless conversations on science and life we had, listening to her stories and memories, and seeing her spontaneous interest for everything I told her.”

Finally, here is a podcast she recorded for the Buck Institute 



Introducing: Monthly Longevity challenge

Focus on a topic every month starting with a quick and easy guide on exercise for longevity from Nina Patrick. We have also announced a competition for the community to share their attempt on the challenge and post proof or work(out) in our discord channel. The most active members will not only crush their goals but also be awarded a prize of 200 VITA

Longevity Literature Hot Picks

Preprint Corner in collaboration with

The Longevist is an overlay journal spotlighting the most promising longevity studies each quarter through a collaborative and transparent process, leveraging insights from a panel of global experts in the longevity space.

The Q4 2024 shortlist is now in the hands of the curators as they vote to determine they favourite preprints of the quarter! In the meantime, check out the 3rd issue of The Longevist and look out for our newly assigned ISSN!

Longevity-featured research (Q2 2023 shortlist) now published in Frontiers in Aging

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging

Check out these latest preprints, each of these will be entered into the Q1 2024 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

A universal molecular mechanism driving aging

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer’s disease in aging mice

Published Research Papers

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2

Chemotherapy triggers the upregulation of PD-L2 in cancer cells, aiding their evasion from the immune system and supporting tumor growth. Blocking PD-L2, in combination with chemotherapy, effectively clears senescent cancer cells, offering a potent anti-tumor strategy.

Titan mice as a model to test interventions that attenuate frailty and increase longevity

The Titan mouse, a short-lived species, presents a valuable model for aging research due to its brief lifespan and early signs of aging. Dietary changes and senolytic drug treatments, like Navitoclax, have shown promising results in extending lifespan and reducing signs of senescence in these mice. 

OXR1 maintains the retromer to delay brain aging under dietary restriction

The mtd/OXR1 gene affects lifespan extension through dietary restriction by maintaining cellular trafficking processes. Its decline contributes to aging and neurodegeneration, but enhancing its function offers potential for treating age-related disorders and extending lifespan.

NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis

The study finds that mitochondrial dysfunction leads to T-cell aging and senescence, mediated by the cGAS-STING pathway. Increasing NAD+ levels with nicotinamide mononucleotide (NMN) can prevent this senescence and improve immune function and survival in mice.

An accurate aging clock developed from large-scale gut microbiome and human gene expression data

Utilizing a large dataset of 90,303 stool samples, the study developed a refined microbiome-aging model, revealing correlations between biological age and lifestyle or health factors—such as higher predicted ages in individuals on a paleo diet or with IBS, and lower in vegetarians. 

Long term methionine restriction: Influence on gut microbiome and metabolic characteristics

The Methionine restriction (MR) diet improves metabolism in mice but has minimal long-term effects on the gut microbiome, with age being a more significant factor in microbial changes than diet. Early stages of MR diet showed specific microbial alterations, but aging predominantly influenced the microbiome composition over time.

Mathematical recapitulation of the end stages of human ovarian aging

Using mathematical models, this study accurately predicts individual variability and population-wide patterns in ovarian aging, specifically the timing of menopausal transition (MT) and age at natural menopause (ANM). 

The immunity and redox clocks in mice, markers of lifespan

The Immunity and Redox Clocks, developed from immune and redox markers in mice, accurately estimate biological age, correlating with lifespan and the effects of lifestyle interventions. These models, validated with strong accuracy, offer a tool for quantifying aging and assessing interventions' impacts on longevity.

Mucosal TLR5 activation controls healthspan and longevity

Stimulating TLR5 with a flagellin fusion protein improves lifespan and health in mice, showing benefits like reduced aging signs, enhanced cognitive and stem cell functions, and better bone and lung health. It also strengthens intestinal integrity, highlighting TLR5 stimulation as a promising strategy for healthy aging.

Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone

The study suggests Alzheimer's disease (AD) can be linked to early exposure to growth hormone treatments contaminated with amyloid-beta (Aβ), indicating AD may have iatrogenic forms transmitted through medical intervention, similar to Creutzfeldt-Jakob disease. 

Published Literature Reviews, Hypothesis, Perspectives and more

Hand grip strength as a proposed new vital sign of health: a narrative review of evidences

Hand grip strength (HGS) is a crucial measure of muscle function, particularly in the aging population. This review highlights its relevance to health, showing that HGS can reliably assess muscle strength. Low HGS is associated with various diseases and health issues, making it a valuable biomarker and potential vital sign throughout life.

Sleep disorders and Alzheimer’s disease pathophysiology: The role of the Glymphatic System. A scoping review

This review investigates the link between Alzheimer's disease (AD) and sleep disturbances, focusing on their impact on the glymphatic system. It includes 70 research articles and categorizes findings related to protein aggregation, glymphatic markers, circadian dysregulation, and potential interventions. 

Genome Instability and DNA Repair in Somatic and Reproductive Aging

DNA repair is essential for genetic maintenance, differing between somatic and germ cells. DNA damage contributes to aging and diseases like cancer. Germ cells' stringent DNA repair mechanisms can inform strategies for improving somatic DNA repair and maintaining health during aging.

Seven knowledge gaps in modern biogerontology

The editorial summarizes the responses from the Biogerontology editorial board regarding crucial unanswered questions in aging research. Seven knowledge gaps are categorized into evolutionary aspects, survival and death mechanisms, and aging heterogeneity. 

From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity

Intrinsic capacity, a combination of physical and mental abilities, is vital for functional ability. Its decline, often linked to aging, is affected by chronic inflammation. This review examines the connection between chronic inflammation, inflammation-related markers, and intrinsic capacity.

Aging research comes of age

A surge in funding has transformed aging research, making it a mature and dynamic field with promising results. Researchers now have the resources to delve deeper into the mechanisms of aging using tools like 'omics approaches and larger study sizes. While several hallmarks of aging have been identified, researchers acknowledge that aging is a complex process with multiple contributing mechanisms. 

Distinguishing between driver and passenger mechanisms of aging

Identifying which changes drive aging is difficult, and empirical approaches using animal models and human genetics have been employed. Overall, our understanding of the drivers of human aging is incomplete, but uncovering them has the potential to revolutionize biomedical research, especially in the context of a growing global aging population.

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

The past decade has advanced aging research, revealing new hallmarks of aging and potential longevity interventions. Plant-derived compounds are also under investigation. Recent developments, approaches targeting aging hallmarks, and the potential of plant-based compounds in promoting longevity are discussed.

Job Board

Dr Ferriera’s lab at The University of Edinburgh is seeking an independent and motivated Senior Research Technician to be part of an interdisciplinary team studying ageing and regeneration.

Head of a research group wanted for Genome Maintenance Mechanisms in the Department of Radiation Biology in Cologne, Germany.

Computational Life Science Research Professional at the Wyss-Corey Lab at Stanford University.

LongeVC is looking for a senior associate.

Buck Institute for Research on Aging is looking for a Postdoctoral Researcher to join the Gerencser lab.

Join the Kapahi Lab as a Research Associate.

The Kapahi Lab is looking for a dynamic and driven individual to join their team as a Research Associate at the Buck.

Bill Keyes is looking to recruit a PhD student studying senescence through their international call.

Marketing Manager at Loyal. Their mission is to bring the first FDA approved aging drugs to the market, and have already achieved ground-breaking milestones on our path to gaining FDA approval for the first lifespan extension drug for any species.

Postdoc position available in Björn Schumacher’s lab, Institute for Genome Stability in Ageing and Disease. CECAD-Cluster of Excellence in Aging Research, University of Cologne. investigating the fundamental role of DNA damage in aging and how inheritance of stable genomes is regulated.

The Chellappa lab is hiring a Postdoctoral Research Associate in Aging, Metabolism and Host-microbiome interactions at Brown University Department of Molecular Microbiology and Immunology.The project will focus on studying the host and microbial metabolism using systems biology approach. 


Ora Biomedical, Inc. is a longevity biotechnology company dedicated to revolutionizing healthy lifespan by targeting aging. They are recruiting a Research Scientist in  Seattle.

News and Media

The Future of Longevity: The Battle Against Human Aging (NFX Original)
Short Documentary

What is behind ageing’s causal wheel?

Cells Across the Body Talk to Each Other About Aging

The Meme King of Longevity Now Wants to Sell You Olive Oil

Congratulations to Thomas A. Rando, MD, PhD, who has been appointed as the newly elected President of the Board of Directors for AFAR

Scientists can tell how fast you're aging. Now, the trick is to slow it down

Life span increases in mice when specific brain cells are activated

Growing old while staying young: The unique mechanisms that defy aging in plants

It's not your life span you need to worry about. It's your health span

The Biomarkers of aging consortium has launched a newsletter - sign up here!

Dr. Brad Stanfield’s rapamycin and exercise study has now been fully funded, with help from various donors, including VItaDAO with a 50k USD contribution.

Obesity drugs have another superpower: taming inflammation

CAR T Therapy Lowers Senescence, Improves Health in Mice

Life Biosciences Presents Groundbreaking Data at ARVO Demonstrating Restoration of Visual Function in Nonhuman Primates

Resources

Biolearn, an open-source biomarker validation library and platform enabling easy and versatile analyses of biomarkers of aging data. 

Biolearn is a tool that simplifies the analysis of biomarkers of aging data. It allows users to easily import data from publicly available sources like the Gene Expression Omnibus, National Health and Nutrition Examination Survey, and the Framingham Heart Study. Biolearn also includes reference implementations for common aging clocks such as the Horvath clock and DunedinPACE, which can be run with just a few lines of code. 

Join Biolearn Discord.

New Book review: How We Age: The Science of Longevity Coleen T. Murphy

LONGEVITY TV SERIES AIMS TO SHED LIGHT ON THE FUTURE OF LIVING LONGER AND HEALTHIER LIVES

Human Ageing Genomic Resources: updates on key databases in ageing research 

Prizes

Longevity Prize Million Molecule challenge with Ora Biomedical

Propose interventions to extend C. elegans lifespan, with a chance to win a prize for the most effective approach. Ora Biomedical has developed the WormBot-AI platform, combining robotics and AI to study longevity in C. elegans, a model organism for aging research. This technology enables quantitative assessment of lifespan and healthspan on a large scale, advancing our understanding of longevity.

Biomarker Challenge, our open-science competition rewarding folks who can best predict chronological age, survival/mortality and multi-morbidity incidence using biomarker data. Challenge officially begins March 1st.

Developing and validating aging biomarkers for clinical trials is challenging due to data limitations and collaboration barriers between scientists. To address this, Biolearn, an open-source toolset, was created. It harmonizes omics datasets and calculates existing aging biomarkers. See more about Biolearn in Resources section.

Conferences

How should ageing be classified?

Impetus awardee and Longevist curator Barry Bentley announces he will be hosting a consensus meeting with experts from around the world to define the criteria for an ageing-related pathology.

Date: Monday, 19th February, 2024

Contact Emma Short: eshort@cardiffmet.ac.uk

La Jolla Aging Meeting 2024

Date: Thursday, March 7, 2024

Location: Conrad T. Prebys Auditorium, Salk Institute, La Jolla

Registration deadline: Monday, February 26, 202

Tweets of the Month

Karl Pfleger

https://twitter.com/KarlPfleger/status/1736108328743489903

The aging field doesn't discuss enough the key top-level distinction between the 2 main therapeutic paradigms: slow aging or reverse it. I support slowing aging as much better than traditional medicine, but it pains me to see many in the field disparage or ignore reversal & I think there should be more open discussion of this distinction………

Anar Isman

https://twitter.com/IsmanAnar/status/1750383400664621057

Aging is the ultimate waste – a waste of talent, wisdom, genius. Takes decades to master a craft, only to have limited time to apply it. Think of the possibilities if mastery wasn't cut short: Federer dominating courts for 20 more years, Einstein revolutionizing science for another two decades, Aretha Franklin enchanting us with her voice, [insert your favorite luminary] advancing a cause dear to you. Let's challenge aging and unleash our full potential.

Podcasts and Webinars

Longevity & Aging Series

A great list of Aging Podcasts

NUS Medicine’s Healthy Longevity Webinar Series

Unlocking the Secrets of Aging with Prof. Pankaj Kapahi - BCI Podcast

Unlocking the Secrets of Lifespan Extension With Karl Pfleger

Aubrey de Grey: Lifespan Extension Imminent Breakthroughs & AI's Impact | Intelligence Podcast #001

The Sheekey Science Show - Should we be measuring biological age? - Aaron King

The Optispan podcast covering a variety of topics related to longevity and healthspan

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. 

This time we leave you with the latest VitaDAO podcast Mitochondria and Aging with Prof. Rudolf Wiesner - VitaDAO Aging Science Podcast

And don’t forget to check our Member’s Portal. New services are added every month!
See you next month!

Further Reading

Autophagy protein ATG-16.2 and its WD40 domain mediate the beneficial effects of inhibiting early-acting autophagy genes in C. elegans neurons

Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity

Early time-restricted eating improves markers of cardiometabolic health but has no impact on intestinal nutrient absorption in healthy adults

Vitamin D3 inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing

Social support and cognitive activity and their associations with incident cognitive impairment in cognitively normal older adults

Implications of stress-induced gene expression for hematopoietic stem cell aging studies

Causality-enriched epigenetic age uncouples damage and adaptation

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

Mitochondrial-derived vesicles in metabolism, disease, and aging

Omega-3 supplementation and outcomes of heart failure: A systematic review of clinical trials

Lipid droplets, autophagy, and ageing: A cell-specific tale

Targeting ageing with rapamycin and its derivatives in humans: a systematic review

The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing

Anti-Aging Drugs and the Related Signal Pathways

Cellular senescence in brain aging and neurodegeneration

Welcome back Vitalians. I’m sure that most of you would have by now heard the sad news that renowned Professor Judith Campisi has passed away. In place of our usual interview, this month ...
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Mitochondria and Aging with Prof. Rudolf Wiesner - VitaDAO Aging Science Podcast
February 5, 2024
Awareness
Podcast
Mitochondria and Aging with Prof. Rudolf Wiesner - VitaDAO Aging Science Podcast



In this podcast with Prof. Rudolf Wiesner we talked about the lack of long-term positions at German universities, mitochondria derived vesicles, mitochondrial mutation rates, TWINKLE, the adrenal medulla and mitochondrial quality control more broadly. I would not have expected the adrenal glands to be so important in mitochondrial aging, although in hindsight it should have been obvious why they are.

Prof. Rudolf Wiesner — brief bio

To quote from the CECAD webpage: “The group’s goal is to understand in detail how mitochondrial damage — in particular damage caused by mitochondrial DNA deletions — arises and how it leads to organ dysfunction by failure of single cells in a tissue. The aim is to develop therapeutic approaches to slow the process.”

“Mitochondria contain their own DNA molecules. The mutations that accumulate in many organs, such as the heart, brain and muscle, are mainly deletions, where a part of the DNA strand is missing. These deletions are not evenly distributed — few individual cells show massive accumulation, which leads to a loss of function of those cells. A mosaic of normal and heavily impaired cells develops. This process is accelerated in many aging-associated diseases, such as Parkinson’s disease or cardiac arrhythmia. The group investigates how these mutations arise, why they accumulate in individual cells, and how they influence tissue function.”
https://www.cecad.uni-koeln.de/research/principal-investigators/associated-members/rudolf-j-wiesner

Mitochondria — multifaceted players in aging

These organelles are often called the powerhouse of the cell but, apart from being cliched, this metaphor does not do them justice. If we want to stick with an “industrial” metaphor, the mitochondria are maybe like a manufacturing plant, a port, a power plant and a minor geopolitical center all in one. Given the complex responsibilities of mitochondria it should not come as a surprise that they have diverse failure modes during aging.

For example, during aging we see clonal expansion of point mutations and deletions which leads to tissue mosaicism, meaning that one and the same tissue ends up having stretches of totally different, often more or less dysfunctional, mitochondrial populations.

There is also the classic mitochondrial (mt) free radical theory of aging. In one more modern interpretation of this theory, production of radical oxygen species (ROS) at mitochondria is a constant source of macromolecular damage irrespectively of whether this mtROS production increases with aging or not. This is consistent with and supported by findings of reduced mtROS production (Lambert et al. 2007) and higher membrane lipid stability in long-lived species.

In some aging tissues we observe reduced mitochondrial mass and decreased mitochondrial biogenesis (1). Based on this we would expect increased mitochondrial biogenesis to improve healthspan or lifespan, and, indeed, PGC1a is consistently upregulated in long-lived rodents and overexpression of this gene extends fly lifespan (Tyshkovskiy et al. 2019, Ozkurede et al. 2019, Rera et al. 2011).

Although we do observe decreased mitochondrial mass in some tissues, in other tissues there may be a vicious cycle of defective mitochondria that proliferate out of hand. The latter is a theory which is bolstered by the work of Aiken and McKenzie (Herbst et al. 2022) as well as work by Prof. Doug Turnbull from Newcastle (Vincent et al. 2018).

Some other theories suggest that aging mitochondria lead to increased susceptibility to cell death, and that the mitochondrial network becomes disorganized with impaired fusion-fission dynamics.

And this is just a small sample of mitochondrial aging theories!

What is mitochondrial respiratory chain and electron transport chain (ETC) dysfunction?

In the podcast we talk a lot about ETC-negative cells or ETC-deficiency. By that we mean electron transport chain deficiency. ETC-deficient cells are those that have lost the ability to utilize oxygen for mitochondrial respiration via their ETC and now rely on glycolysis instead.

This is also reflected by the lack of a certain protein, which is called cytochrome C oxidase. This state is also termed COX deficiency and can be visualized by a histologic staining that gives a blue readout. Usually, although not always, mtDNA deletions or mutations will be the cause of this COX- and ETC-deficiency.

Which tissues suffer the most from mitochondrial DNA deletions and why?

We discuss why some tissues accumulate more mtDNA deletions than other tissues. What these tissues have in common is often a source of substantial oxidative stress. This is the case for the adrenal medulla and the substantia nigra, which both accumulate large amounts of mtDNA deletions. The adrenal glands are involved in the metabolism of adrenaline, as the name implies, which is structurally related to dopamine (both are catecholamines). The metabolism of dopamine is known to promote the formation of toxic intermediate products that can harm the mtDNA in the brain so it should be no surprise that metabolism of adrenaline is also problematic.

The group of Rudolf Wiesner discovered these abnormalities in mice carrying a relatively mild mutation in a protein that is involved in mitochondrial maintenance, called TWINKLE. It stands to reason that humans will show the same defects during aging, although this awaits confirmation. Mild TWINKLE mutants are generally considered a decent model of age-related mtDNA deletion formation.

“it’s scary if you look at an old adrenal gland…it looks like.. it is completely destroyed full with cells that have a mitochondrial defect.” (Rudolf Wiesner)

We both agreed that it would be useful to perform more autopsy studies of very long-lived individuals, as we still know little about tissue specific pathologies of the very old. To paraphrase:

“good old fashioned descriptive biology is always the basis to find something new”

Can we cure mitochondrial disease?

I asked an intentionally provocative question on this podcast that I like to pose in the context of mitochondrial research. Some time ago I went to a longevity conference, where I saw a talk by Dr. Anu Suomalainen-Wartiovaara, a respected mitochondrial expert talking about her work. During her talk she said that she wants to cure mitochondrial disease. Of course, no one disagreed nor batted an eye.

What I found rather puzzling about this was that people (working outside of our field) would be surprised, even upset, if an aging researcher said they wanted to cure aging or stop aging, to use less controversial language.

For a long time indeed, it was impossible for a respected longevity researcher to say, or to admit, that eventually, down the line, someday, they really would like to stop all aging. End it for good. Luckily this is finally changing, but not fast enough for my liking.

Curing mitochondrial disease is a far-fetched dream, but if mitochondrial researchers are allowed to dream, so are we.

If you ask me, we should all follow in the footsteps of Anu and boldly say that we want to end or reverse aging. If she can say so about her condition of choice, we are allowed as well.

References and further reading

Herbst, Allen, et al. “Age-and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles.” Geroscience (2022): 1–13.

Ozkurede, Ulas, and Richard A. Miller. “Improved mitochondrial stress response in long‐lived Snell dwarf mice.” Aging Cell 18.6 (2019): e13030.

Tyshkovskiy, Alexander, et al. “Identification and application of gene expression signatures associated with lifespan extension.” Cell metabolism 30.3 (2019): 573–593. webpage: http://gladyshevlab.org:3838/Gentervention/

Rera, Michael, et al. “Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog.” Cell metabolism 14.5 (2011): 623–634.

Lambert, Adrian J., et al. “Low rates of hydrogen peroxide production by isolated heart mitochondria associate with long maximum lifespan in vertebrate homeotherms.” Aging cell 6.5 (2007): 607–618.

Vincent, Amy E., et al. “Subcellular origin of mitochondrial DNA deletions in human skeletal muscle.” Annals of neurology 84.2 (2018): 289–301.

In this podcast with Prof. Rudolf Wiesner we talked about the lack of long-term positions at German universities, mitochondria derived vesicles, mitochondrial mutation rates...
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VitaDAO Letter: 2023 in Review
January 30, 2024
Sarah Friday
Awareness
Longevity
VitaDAO Letter: 2023 in Review

What an extraordinary year it has been! Since June 23rd, 2021, the day VitaDAO’s Gnosis Auction funded our Treasury, VitaDAO has been funding longevity research and fostering a community of passionate researchers, enthusiasts, and professionals. Fast forward to today, and VitaDAO has become a driving force in the field, achieving remarkable milestones and setting new standards. 2023 witnessed a successful funding round that garnered support from influential partners such as Pfizer Ventures, contained an unprecedented VITA-FAST token sale, and furthered the evolution of VitaDAO as a key player in the DeSci arena.

For those of you who are new here, VitaDAO is a community-owned collective dedicated to funding and advancing longevity science research. VitaDAO is divided into three working groups (Longevity Dealflow, Community and Awareness, and Coordination) that call upon smaller “squads” as needed. In this newsletter, find brief recaps of some of the work that VitaDAO’s Working Groups and Squads accomplished in the last year. Sit back, relax, and enjoy the read!

🧬Longevity Dealflow Working Group

Throughout 2023, the Dealflow Working Group tirelessly sourced and evaluated projects. Notably, through VDP-106, the DAO set forth a new standardized process to better screen proposals presented to the DAO. In total since its initiation, VitaDAO has evaluated over 200 projects, funded 20 projects, and deployed over 4 million dollars! Among these, 14 projects received funding in 2023:

  1. BE Therapeutics — Brain Tissue Replacement — BE Therapeutics is aiming to develop technology that can engineer functional brain tissue to replace the tissue impaired by age-related damage.
  2. Humanity — Proprietary Aging Score App — Humanity is an app that uses wearable technology and quantified-self methods to enable anyone with a smartphone to measure their rate of aging and it uses AI to find out what lifestyle actions and more advanced interventions each type of user should take to slow it down.
  3. Etheros — Fullerene Chemistry for Longevity — Etheros is a biotech company pioneering a new class of small molecule drugs based on Nobel Prize-winning fullerene chemistry. Their lead compound, which mimics enzymes called superoxide dismutases that protect cells from oxidative and inflammatory injury, has already generated promising efficacy data in animal studies.
  4. HDAX Therapeutics — Histone Deacetylase Targeting Drug Discovery — HDAX is a preclinical-stage drug discovery company targeting a class of proteins implicated in neuropathies and inflammation with novel small molecules having potentially superior drug properties.
  5. Zoe Biosciences — PAI-1 Antibody Therapeutics — Zoe Biosciences has two assets with the potential to extend human healthspan. The first program contains PAI-1 biologic inhibitors with high target selectivity and affinity, relevant for diseases including elevated FGF23 syndromes and metabolic disorders. The second program contains APJ small-molecule agonists for similar age-related indications.
  6. Matrix Bio — Long-lived Species Inspired Longevity Biotech — VitaDAO and the Gorbunova Lab are launching Matrix Bio, a cutting-edge research venture leveraging the anti-cancer and pro-longevity effects of high molecular weight hyaluronic acid from naked mole rats to humans.
  7. ImmuneAge Bio — Rejuvenation of Aged HSCs — ImmuneAGE Bio is the first drug discovery platform company focused on immune system rejuvenation. ImmuneAGE’s lead program, IA101, is a non-toxic small molecule that can rejuvenate aged HSCs and aged animal immune function with higher efficacy than any molecule previously published.
  8. ExcepGen Inc — RNA therapeutics for longevity — ExcepGen is developing a new generation of vaccines and therapeutics with an RNAx platform.
  9. ARTAN Bio — Mutation-Specific Codon Suppression for Aging and Longevity — ARTAN is a biotechnology company developing first-in-class interventions to tackle the most frequent nonsense mutations implicated in a wide range of age-related diseases and cancers. These nonsense mutations induce premature stops of protein translation when occurring in coding regions.
  10. Cyclarity — Novel Cyclodextrin Molecules for Multiple Aging-related Diseases — Cyclarity Therapeutics is an early-stage biotechnology company developing computationally designed novel cyclodextrin drug molecules for the extraction of toxic biomolecules that accumulate with age and are implicated in a variety of age-related conditions.
  11. Reversing Periodontal Disease using Geroscience — An Lab — Johnathan An’s Lab proposes to use small molecule inhibitors of the PI3K/NFkB/mTOR pathway to treat periodontal disease. By targeting inflammation in age-related periodontitis, they hope to find a geroscience-based treatment.
  12. Oisín Biotechnologies — Pioneering Genetic Medicines for Sarcopenia — Oisín Biotechnologies is a multi-asset longevity biotech company pioneering genetic medicines to combat sarcopenia and other age-related diseases to promote healthier, longer lives.
  13. Remedium Bio- Gene Therapy for Regenerative Medicine — Remedium Bio is a regenerative medicine biotechnology company, that has developed the only dose-adjustable gene therapy platform technology Prometheus™ and is currently advancing multiple assets with uncorrelated risk to Investigational New Drug (IND) approval.

Other Notable Dealflow Achievements

  • Through June’s token sale of $VITA-FAST tokens, token holders were given the ability to directly influence longevity research for the first time in history. The $VITA-FAST token was created to give holders exclusive control over the licensing function of the Newcastle-Korolchuk IP and governance over the direction of the research and development of that IP. The sale was wildly successful, concluding with over 1700% oversubscription.
  • VitaDAO made history as it was the first DAO to kickstart a biotech company. This company, MatrixBio, is leveraging high molecular weight hyaluronic acid (HMW-HA) for cancer and age-related diseases.
  • VitaDAO launched “The Longevist,” an overlay longevity research journal. Every quarter, a shortlist of preprints has been selected by the VitaDAO community and voted on by Longevist Curators.
  • VitaDAO played a strategic role in Zuzalu’s inaugural event, a pop-up city in Montenegro. In the capacity of a co-organizer and representative authority on longevity, VitaDAO hosted a two-day longevity biotech conference. Here, leading experts shared insights into cutting-edge research in longevity science and rejuvenation technology. Topics spanned a broad range of disciplines, including Cellular Reprogramming, Cell Replacement, Immune System Rejuvenation, and DNA Damage.
  • Of note this year, through VDP 107, Laurence Ion stepped down from the role of Longevity Dealflow Working Group Steward. The community voted to place Eleanor Davies as Interim Dealflow Steward.

🗣️Community and Awareness Working Group

With a robust Dealflow Working Group, the Community and Awareness team had its work cut out! Alex Dobrin’s re-election as the Community and Awareness Working Group Steward set the stage for a packed year. The year started off strong with PR efforts surrounding the announcement of VitaDAO’s $4.1 million fundraising round. VitaDAO continued to spread awareness globally, as representatives from VitaDAO attended over a dozen conferences on four continents. These meetings included, but are not limited to, DeSci London, DeSci Singapore, DeSci Berlin, Penn Blockchain, DeSci Japan, Longevity Summit Dublin, Longevity+DeSci Summit NYC, the 10th Aging Research and Drug Discovery Meeting, and Token 2049 Singapore. The VitaDAO buzz reached new heights when Balaji shared our story with his million followers on Lex Fridman’s podcast.

Continuing community education and news dissemination remained a top priority. VitaDAO’s Monthly Community Newsletter celebrated its two-year anniversary and VitaDAO’s Monthly Longevity Research Newsletter celebrated one year in existence. Adding to the excitement, VitaDAO launched The Aging Science Podcast. The podcast, released monthly, features deep conversations with many leading experts in the field of longevity.

Past initiatives were continued in 2023 including VitaDAO’s collaboration with Jellyfish and VitaDAO’s involvement with the VitaDAO Longevity Prize, a collaboration with Foresight Institute and Methuselah Foundation. This April 2023, Hypothesis Prize winners were announced. More recently, VitaDAO partnered with X-Prize on their XPRIZE Healthspan initiative promising a groundbreaking 7-year competition with a $101 million prize pool.

Other awareness initiatives included the funding of another cohort of fellows within VitaDAO’s Longevity Fellowship. The fellowship is composed of deed-based grants awarded to individuals to cover expenses such as conference fees, research funding, and longevity program tuition. In total, VitaDAO has funded over 65 fellows with over $65,000. VitaDAO also continued to engage its community through the Ambassador Program. This program aims to facilitate community growth and engagement through the organization of in-person meet-ups.

As if that wasn’t enough news, VitaDAO hosted its 3rd VitaDAO DeSci & Longevity Symposium. And, VitaDAO hosted its first VitaDAO hackathon! This successful event boasted three winners: Hack-Age (1st), AdStella (2nd), and AGen-iNET (3rd).

Other notable highlights include the release of a Longevity Briefing Primer to define longevity, highlight VitaDAO’s role in the field, and make the case for special economic zones. Maria Marinova posted a series of articles on VitaDAO’s blog exploring the potential of optogenetics to combat aging, embryogenesis and its potential role in longevity, and the mechanisms by which sugar byproducts may impact aging. Lastly, VitaDAO’s Twitter fostered good conversation in the form of multiple Twitter Space interviews and discussions. These include but are not limited to, a discussion on the latest advancements in robust mouse rejuvenation, an interview with Sergey Young, an open discussion on the future of longevity & De-sci, and a discussion on the latest in epigenetic clock research.

Our community outreach numbers, as of January 2023, tell an impressive tale: (see numbers, updated as of January 2023, below):

  • + 3,400 Token Holders
  • + 10,000 Discord Members
  • + 22,000 Twitter followers
  • + 2,100 Youtube Subscribers

🔏Coordination Working Group

In 2023, VitaDAO was recognized by CoinGecko as one of the top crypto projects in Europe. Operating a DAO, and operating it successfully, is no easy task! Todd White, the re-elected Steward, led the working group as it continued to improve financial reporting, ensure accountable use of VitaDAO’s resources, and implement changes to the DAO infrastructure.

Key additions to the VitaDAO infrastructure include the creation of a network steward role and the launch of the member services squad and VitaDAO Global platform for members. The member squad seeks to increase the $VITA token utility value and help VitaDAO members pursue their personal longevity journeys.

Another large change implemented by the Coordination Working Group was the development of an operational company for the execution of the Coordination Working Group functions on behalf of VitaDAO. This for-profit cooperation provides service provider contract management, executes the VitaDAO’s member services program, and more!

This year, the Coordination Working Group also worked with legal counsel to prepare VitaDAO for issuing tokens under the new EU Markets in Crypto-Assets (MiCA) Regulations. Going forward, starting in June 2024, all IP Tokens issued from our IP-NFTs as well as our own VITA token must be compliant with the MiCA Regulations. VitaDAO is on track to be fully compliant by the June 2024 deadline.

The Coordination Working Group also closed 2 funding events for VitaDAO — the $4.1m round in January 2023 which included Pfizer Ventures, Shine Capital, and L1D — but also a smaller $1.3m round in December to provide interested parties with VITA tokens prior to the launch of the VitaDAO Accredited Investor Fund (VDAIF) anticipated in Q1’2024. Another $5.4m which brings us to a total of $10.5m raised since inception.

While the Coordination Working group is often behind the scenes, they are an imperative component to VitaDAO’s success. Early in the year, they played a role in token-gating Discord such that different levels of Discord are unlocked with different quantities of $VITA. More recently, they have assisted with the migration to Parcel for payouts and created a dashboard to create a better payout experience for contributors.

👾Tech/Product + Tokenomic Squads

As mentioned above, the year started with a successful funding round. This round required the minting of an additional 10% $VITA for strategic contributors. Following the 10% $VITA mint, the individuals in the DAO squads worked to allocate 6% of the total $VITA token supply to new strategic contributors. This minted allowed onboarding of new strategic members such as Pfizer Ventures, Shine Capital, and L1 Digital; decentralized science and web3 organizations like Beaker DAO and Spaceship DAO; and longevity enthusiasts including Balaji Srinivasan and Joe Betts-LaCroix. Additional technical challenges addressed by the DAO included the fractionalization of the Newcastle-Korolchuk IP-NFT and the coordination of the crowd token sale. The Tokenomics Squad also assisted with launching Vita on Optimism and Polygon. This change decreased the burden of gas fees for community members!

In 2023, the Tech/Product Squad facilitated the launch of a VitaADO member portal (vitadao.global). This portal enables VitaDAO holders to claim exclusive perks such as reduced medical testing, discounts on health products, and discounts on health insurance for digital nomads. Additionally, the team continued to improve the VitaDAO website, created a VitaDAO treasury dashboard, and designed a merch shop. The treasury was created to foster greater transparency of VitaDAO’s economics. And the merch shop features a cool hoodie!

What an extraordinary year it has been! Since June 23rd, 2021, the day VitaDAO's Gnosis Auction funded our Treasury, VitaDAO has been funding longevity research and fostering a community of passionate researchers, enthusiasts & professionals.
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Exploring DNA Repair for Longevity with Prof. Björn Schumacher - The VitaDAO Aging Science Podcast
January 16, 2024
Podcast
Awareness
Exploring DNA Repair for Longevity with Prof. Björn Schumacher - The VitaDAO Aging Science Podcast

In this episode of the Aging Science Podcast by VitaDAO I had the pleasure of talking with Prof. Björn Schumacher (@schumacherbj) about his recent work identifying a novel way to boost DNA repair. I found this work unusual in many ways: not only is it urgently needed but he also identified a rather strange protein, with a strange name, as a player in DNA repair using a model species whose aging is not even particularly dependent on DNA repair! Wow.

Short bio

Since 2013, Björn Schumacher is full professor and director of the Institute for Genome Stability in Ageing and Diseases (IGSAD) at the CECAD Research Centre of the University of Cologne. 

Professor Schumacher is President of the German Society for DNA Repair (DGDR), co-Director of the Minerva Center of the Biological Mechanisms of Healthy Ageing at Bar-Ilan University (IL), and between 2014 and 2020 served as President of the German Society for Ageing Research (DGfA). 

His research interest focuses on the molecular mechanisms through which DNA damage contributes to cancer development and ageing-associated diseases.  Employing the C. elegans system and mammalian disease models, his group uncovered cell-autonomous and systemic responses through which the organism adapts to accumulating DNA damage with ageing. Through the understanding of the basic mechanisms of genome instability-driven ageing, Schumacher aims to contribute to the development of future strategies to prevent ageing-associated diseases.


Björn Schumacher, webpage: https://igsad.de

How important is DNA damage to aging?

We know that DNA is important because every cell has exactly two copies (or alleles) of a gene. If one or both or damaged through DNA mutations this can have severe consequences since all mRNA and protein is produced based on this DNA blueprint. Hence, cells have evolved a very complex machinery of DNA repair. This complexity has limited our ability to study and understand DNA repair for a long time.

While mutations in DNA repair proteins accelerate death and certain aspects of aging – causing progerias – so far no one has managed to extend lifespan by increasing DNA repair, it is not even clear if anyone has successfully and consistently managed to increase DNA repair to begin with. The main issue, just as with oxidative stress defenses, is that boosting a single function might have no impact or worse harm the whole system by causing an imbalance in the ration of different components!

However, there is very strong indirect evidence for the role of DNA repair in aging. Björn points out recent studies that allowed us to better quantify somatic mutations. These mutations are so heterogeneous that until recently we lacked the techniques for accurate measurements. These newer studies show convincingly that mutation rates are lower in short-lived species. Some of these we discussed in our Vera Gorbunova podcast.

In the end whether DNA damage is “just” a driver of cancer or also causes other age-related diseases is a moot point. We still lack tools to effectively prevent caner and we will need them to extend healthy human lifespan. Therefore, tackling DNA damage and mutations downstream of damage remains one of the most important tasks ahead.

The many types of DNA damage

So far, we used the word DNA damage or DNA damage theory quite liberally. However, experts in the field like to distinguish between DNA damage and DNA mutations. One usually leads to the other, but not always. This can be important. Some species like the naked mole rate seem to have low mutation rates but high rates of transient DNA damage – this is still consistent with the DNA damage theory of aging. Ultimately the only thing that matters is the final, unrepairable type of damage: the mutation. Perhaps, as I suggested during the podcast, the word DNA damage theory could be confusing.

Conversely, making matters even more complicated, unrepaired DNA damage can lead to senescence or other issues without causing mutations. However, most DNA damage is not so severe.

In fact, DNA is constantly damaged and this damage is usually repaired efficiently. Some types of DNA damage are considered less toxic, like the famous pyrimidine dimers caused by ultraviolet radiation, single strand breaks, or nucleotide changes. These can induce harmful mutations but the damage is often very small or localized, like a single nucleotide change.

Much worse are crosslinks or double strand breaks. Interstrand crosslinks, for example, block the separation of DNA strands, which is essential for replication and transcription. Imagine your DNA being torn to pieces during replication. This cannot be good. Some cancer therapeutics induce exactly these kinds of mutations to destroy quickly dividing cancers! Similarly, double strand breaks. Perhaps temporarily not a problem but once the cell starts dividing it would lose whole stretches of DNA since the broken parts will not properly attach to the spindle that pulls replicated DNA apart to divide evenly across the new cells. We are dealing with the loss of hundreds of genes and not just single mutations. 

Now imagine there was a way to boost every single type of DNA repair in a balanced and natural way. Maybe we have found it.

The DREAM complex

This large multiprotein complex is involved in cell cycle regulation and repression of DNA repair. Now that makes it quite unusual since one would hardly expect the cell to turn off something as beneficial as DNA repair, would we? As Björn explains in the podcast, everything comes with a cost. It would be wasteful for a worm to boost DNA repair in their body cells to allow a few worms a longer life, when it would cost energy or time that could be invested in producing more eggs, or producing eggs faster. Most worms die early and do not need good DNA repair. If they are exposed to genotoxic stressors they prefer to increase stress resistance mechanisms like antioxidants instead of DNA repair.

Given that DNA damage seems to be a mechanism of aging “private” to long-lived species, i.e. limited to these, it is all the more surprising that Björn’s group discovered the importance of DREAM in C. elegans. It takes a lot of ingenuity and persistence to walk such a tortuous road towards discovery. However, this might have been the right call if, as Björn says, identifying transcriptional regulators of DNA repair was much easier in the worm. From there he just needed to assume that these mechanisms are conserved in higher mammals and get a bit lucky.

The basic idea was fascinating. As it turns out, the germline has 10-fold lower mutation rates than somatic tissues, making it an elite tissue. It stood to reasons that there should be an activator of DNA repair in the germline or an inhibitor of DNA repair in somatic tissues. Since we know that many important age-related pathways are regulated transcriptionally, e.g. multistress resistance via Nrf2 or autophagy via TFEB, it was an obvious choice to look for a transcriptional regulator. It turned out to be DREAM, which was aptly named that way by other researchers who had been studying this one for its role in cell cycle progression and differentiation.

The future of DREAM

Björn and others have identified drugs that repress this repressor of DNA repair. Which means they can activate DNA repair. This is one of the big breakthroughs that we need to finally test the DNA damage theory experimentally. I am optimistic that we are getting closer and that we will eventually find a way to increase DNA repair. Nevertheless, to temper our optimism we have to realize that DREAM has many functions, DNA repair is only one of them. As Björn noted, the whole system is even more complicated in humans than in worms. In the worst-case inhibiting DREAM could lead to unwanted side effects. However, this is only speculation one way or another. The only way to find out is to test existing and novel DREAM inhibitors in mice to see whether they are well tolerated and extend lifespan.

It may be a bumpy road but eventually we will get there. All the best to everyone working in this field!

The host – brief bio

Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.

References and further reading

Bujarrabal-Dueso, Arturo, et al. "The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities." Nature Structural & Molecular Biology 30.4 (2023): 475-488.
https://www.nature.com/articles/s41594-023-00942-8

Telomeres vs DNA damage - battle of the aging theories
https://biogerontolgy.blogspot.com/2022/03/telomeres-vs-dna-damage-battle-of-aging.html

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December Longevity Research Newsletter
January 11, 2024
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
December Longevity Research Newsletter

Introduction

Welcome to 2024, Vitalians! We hope your holiday season was wonderful, and that you're returning recharged and ready for another year of exciting developments in longevity science! 

I know it seems so far away already but here is what happened in December, plus an insightful interview from Dr. Bernadette Carroll - who shares her thoughts on the longevity field as well as discussing her research on nutrient sensing, lysosomes and their role in senescence and aging, enjoy!

Longevity Literature Hot Picks

Preprint Corner in collaboration with

The Longevist is an overlay journal spotlighting the most promising longevity studies each quarter through a collaborative and transparent process, leveraging insights from a panel of global experts in the longevity space.

With Q4 now over, The Longevist editors are currently finalising the shortlist of preprints to put forward to our curators for the next on-chain vote. In the meantime, check out the 3rd issue of The Longevist and look out for our newly assigned ISSN!

Check out these latest preprints, each of these will be entered into the Q1 2024 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

Sex-specific growth and lifespan effects of germline removal in the dioecious nematode Caenorhabditis remanei

The germline regulates longevity and somatic repair in a sex-specific manner

Epigenetic Clocks and Programmatic Aging

A Fully-Automated Senescence Test (FAST) for the high-throughput quantification of senescence-associated markers

Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects

Extensive remodeling of the ubiquitination landscape during aging in C. elegans

The molecular landscape of premature aging diseases defined by multilayer network exploration

From Churchill to Elephants: The Role of Protective Genes Against Cancer

Published Research Papers

DNA methylation rates scale with maximum lifespan across mammals

A new statistical framework was developed to compare DNA methylation rates at conserved age-related sites across mammals, revealing a negative correlation with maximum lifespan in both blood and skin tissues. This indicates methylation rates might be a constraint on maximum lifespan, affecting diverse mammalian lineages.

Organ aging signatures in the plasma proteome track health and disease

Analysis of organ-specific aging in humans using blood plasma proteins, finding significant variations in aging rates across different organs and predicting increased disease risks. The approach offers a novel method for assessing individual aging processes and their impact on health, using plasma proteomics data.

Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype

Iron accumulation is a key factor in cellular senescence and fibrosis in mice and humans, suggesting iron metabolism as a potential target for treating senescence-associated diseases. It also highlights the possibility of using magnetic resonance imaging to non-invasively assess fibrotic diseases.

Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice

This research explored inflammaging in the mouse intestinal epithelium, discovering that aged intestinal stem cells (ISCs) play a key role in this process by upregulating major histocompatibility complex class II genes and exhibiting an intrinsic inflammatory memory. It highlights that inflammaging is driven by a cell-intrinsic mechanism, dependent on STAT1 signaling, and leads to a disruption in immune homeostasis.

The effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer

A ketogenic diet, compared to standard mouse chow, effectively reduces breast tumor growth and increases lifespan in a mouse model, particularly when combined with the anti-cancer drug rapamycin. 

Transcriptomes of aging brain, heart, muscle, and spleen from female and male African turquoise killifish

The study introduces a detailed RNA-seq dataset from multiple organs of the African turquoise killifish, highlighting that age significantly affects gene expression more than sex. This resource is pivotal for investigating aging and sex-related gene expression in this short-lived vertebrate model, especially noting the increased expression of transposable elements in the brain with age.

Published Literature Reviews, Hypothesis, Perspectives and more

The Information Theory of Aging

Biological information is stored in two ways: the genome as a blueprint, and the epigenome which regulates gene expression. The Information Theory of Aging suggests that aging results from losing epigenetic information, and its retrieval through reprogramming could reverse aging.

Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming

Recent developments in anti-aging research involve using nuclear reprogramming factors to reverse age-related deterioration in mouse and human models. The study also explores the challenges and potential of epigenetic rejuvenation strategies in practical applications for treating aging and age-related diseases.

Telomeres, cellular senescence, and aging: past and future

The review commemorates over fifty years since Alexey Olovnikov's theory of the end-replication problem, exploring the complex role of telomeres in cellular senescence and aging, and their impact on age-related diseases.

Putting a strain on diversity

There are significant limitations of predominantly using the inbred C57BL/6 mouse strain in aging research, advocating for the diversification of mouse strains to better understand variations in lifespan and healthspan. They emphasize the need to select mouse strains based on specific research questions and an understanding of genetic diversity to bridge the gap in translating findings to human aging.

A step toward precision gerontology: Lifespan effects of calorie and protein restriction are consistent with predicted impacts on entropy generation

A thermodynamic model to predict lifespan changes in mice under calorie and protein restriction finds that increased restriction reduces entropy generation and potentially extends lifespan. This model aligns with precision gerontology goals and could help identify anti-aging interventions.

Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement

The review analyzes recent aging research, focusing on cellular and molecular hallmarks, their links to age-related diseases, and major biochemical processes, aiming to advance understanding of aging mechanisms and challenges.

Job Board

PhD Studentship: Blood-based Biomarkers of Frailty and Ageing

PhD Studentship: Exploring Valid Approaches to Breath VOC Analysis for Diagnostic Research with Prof Alexandra Stolzing

Postdoctoral Position in Genome Stability: The Institute for Genome Stability in Aging and Disease at the CECAD Research Center, University of Cologne. DNA damage in aging and the regulation of the inheritance of stable genomes with Prof Schumacher

The Kohler Mito Lab are recruiting a Post-doc and a PhD student to study Mitochondrial Protein Quality Control Umeå University, Sweden

Interested in cellular senescence? Apply for this fellowship to join Ana O’Loghlen’s lab in Madrid!

The Sandri Lab are hiring - 18 months postdoctoral fellowship to work on developing RNA-based therapies in vivo for modulating signaling pathways involved in protein degradation, bioenergetics/mitchondria and protein synthesis. University of Padova, Italy.

News and Media

$200 Billion in Revenue: How an Aging Drug Will Conquer Pharma

Hevolution Foundation Grant Expands New Investigator Awards in Geroscience

What’s Your ‘Biological Age’?

New tests promise to tell you if you have the cells of a 30-year-old or a 60-year-old. Here’s what to know about them.

Bridging Generations: Our Ageless Future

Longevity 2023: From A to…

Aging research comes of age

Turn Bio, backed by the VitaDAO Community, achieves a milestone in RNA therapeutics by successfully delivering mRNA to the skin, a significant step beyond liver-targeted therapies

Not all organs age the same. ‘Older’ ones may predict your risk of disease

The RAPID Clinical Trial are recruiting volunteers to take part in a clinical study to treating periodontal disease by targeting mTOR

Death Becomes Her, or Why Aging is an Epigenetic Program

Insilico Medicine announces AI drug discovery milestone achievement in pharma collaboration

Venture Capital Giants In The Billion-Dollar Quest For Longevity Breakthroughs

Frontiers in Aging are accepting submissions on the research topic “Longevity Worldwide: A Collection on Centenarian Studies” until 31st January

The Biggest Breakthrough in Longevity may Start with Menopause

Light color is less important for the internal clock than originally thought, study finds

Conferences

Cologne Aging Conference 2024

Jan 29-30, CECAD Cologne

Young ICSA 18th & 19th March

Oriel College Oxford - Register here by 19th January

Vitalia.city has officially launched. It will host 4 bi-weekly conferences on different topics, 2 of which will be on longevity:

Longevity & Human Improvement (Jan 15 - 21, Summit: Jan 20)

  • The Bioscience of Longevity
  • Business Models for Longevity Companies
  • Economics and Incentives of Healthcare Systems
  • Philosophical Views and Ethics of Life Extension 

Startup Societies & Crypto Cities (Jan 29 - Feb 4, Summit: Feb 3)

AI & Technological Progress (Feb 5 - 11, Summit: Feb 10)

Pathways to Life Extension (Feb 19 - Feb 25, Summit: Feb 24)

  • New Drug Development
  • Clinical and Healthcare
  • Biohacking and Self-Improvement
  • Incentive Design Solutions

Tweets of the Month

From Artemy Shumskiy, what do you think?

Aging hallmark I dislike: telomeres

Aging hallmark I begrudgingly respect: splicing dysreg

Aging hallmark I think is overrated: senescence

Aging hallmark I think is underrated: altered intercell comm

Aging hallmark I like: inflammation

Aging hallmark I love: epi alterations

Some pearls of wisdom from The Terminator (Arnold Schwarzenegger)

I heard that the way you go viral on this site is by making a big list of things you have to do. Let me try.

-You should mostly eat food you know is healthy, there is no magic food.

-You should also occasionally let yourself eat delicious food you know isn’t healthy. Otherwise what’s the point?

-You should be training with some kind of resistance (your bodyweight works), no matter your age

-You should do something to get your heart going and get a schvitz a few times a week

-You should know there isn’t a magic pill, a hack, or a diet and most of that crap people put in their lists is just mean to confuse you so you pay them to figure it out for you with whatever they are selling

-You should also know my daily newsletter is free, is allergic to bullshit, and includes weekly workouts, the latest health and fitness news, and motivation from me.

-Don’t worry, if you paid one of those people to tell you jumping in cold water or taking 29 pills every morning will get you fit, I’ll still be here in three months when you decide it’s time to try something that works. The only trick I know is that you have to work, it hasn’t changed in 76 years and it won’t change.

Podcasts and Webinars

Longevity & Aging Series

NUS Medicine Healthy Longevity Webinar

Cellular Senescence and Mitochondria | Prof Joao Passos

Gene Therapy Insights Podcast

Energy Replacement in the Light of Aging with Dr. Shahaf Peleg

The Desci Podcast by Molecule

Keith Comito's Insights on Aging Research and Lifespan Extension

The Sheekey Science Show

Can taurine and vitamin B12 improve your health?

Interview with Dr. Bernadette Carroll

After completing her PhD at Imperial College London, Dr. Carroll worked in Viktor Korolchuk’s laboratory at the Newcastle University Institute for Ageing and Health where she published numerous papers on nutrient sensing, mTOR, autophagy and their role in senescence and aging. She now runs her own research laboratory at The University of Bristol, focusing on mechanisms controlling the spatial regulation of nutrient homeostasis in health, senescence and cancer. She has recently published a paper discovering a key mechanism of how lysosomal biogenesis is required for cell survival during the onset of senescence.

What inspired you to enter longevity research?

I will admit that my entry into longevity research was not entirely by design. I originally trained as a cell biologist, and I have always been interested in the spatial organisation of our cells, asking questions such as how and why are proteins recruited to specific sites in the cell, and what happens if this localisation becomes dysregulated? For my postdoc, I moved to Newcastle University to work in the lab of Dr Viktor Korolchuk, a key contributor to the VitaDAO community. My project was focused on understanding how the localisation of the main regulator of cell growth, called mTOR is controlled. Over time, through research seminars, coffee chats and a pint (or several), I was won over by the enthusiasm and passion of researchers in the longevity field. It was well established in the field that mTOR signalling drives several senescence phenotypes, and so I got onboard and used my expertise to take a closer look and explain in more detail exactly how mTOR is dysregulated in senescence.

Which of the current theories of ageing do you think are the most convincing?

I see immense value in developing theories of ageing. As an experimentalist who relies on a bottom-up approach, these theories give us new ideas to test using hypothesis-based science. If we can rescue senescence phenotypes by identifying and modifying dysregulated mechanisms, this gives us hope that one day we will be able to develop new anti-ageing interventions. Currently, I particularly favour programmatic theories rooted in the development, where processes like mTOR play an important role.

How has the field changed since you started?

The field has become a lot more mainstream. There is increasing appreciation that a comprehensive understanding of all aspects of fundamental and applied biology is required to explain the ageing process. This is undoubtedly a positive, there is more interest from the public, from governments and from biotech industry which has led to increased, dedicated funding, increased initiatives to promote collaboration and more research teams focused on longevity. This increased focus however also presents its own challenges as we come to fully realise the complexity of understanding longevity, integrating topics from biochemistry, to physiology, psychology, and sociology. I think it will require some out-of-the-box thinking going forward to tackle longevity research effectively and collaboratively. That’s why communities like VitaDAO are so important.

What mistakes do you think the longevity field has made?

Ageing is a complex, multi-factorial and multi-scale process and I think the longevity field is guilty of approaching the question from a reductionist angle. This is a natural result of the short-term funding strategies of most national and international funding schemes that don’t necessarily support high-risk or more preliminary projects. While labs working on model organisms such as yeast, flies and mice have been true trailblazers in identifying key signalling or metabolic pathways involved in longevity, translating these findings to humans has been very limited. Instead, we are still at the stage of generating theories of ageing, essentially a thought process. The next few decades however promise an explosion of fundamental, translational, and clinical research in longevity which will inevitably push the field forward in a practical way.

Other than your own, what do you think have been the biggest/important discoveries in the field?

As cell biologists, we work exclusively with human cells that have been removed from their natural environment in the body and are instead exposed to different nutrients and stressors. There is always the worry therefore that the many of the phenomenon’s we study could be artifacts that have little or no physiological relevance. That is why the seminal work from the Mayo clinic demonstrating that the selective clearance of p16-positive senescent cells can alleviate ageing phenotypes was fundamentally important for researchers working on senescence.

What advice would you give to people currently working in longevity research?

Collaborate. I believe the biggest rewards will come from those who can step out of their comfort zone to embrace different approaches and ways of thinking about longevity. Also keep an open mind about new potential directions. Getting involved with communities like VitaDAO is a really positive move to facilitate collaborations and generate new ideas.

Your research focuses on the interplay between nutrient homeostasis and cellular processes in the context of aging and cancer. What inspired your interest in this area?

We are what we eat, and as such I believe that a lot of the answers about how well we age and how likely we are to develop age-related diseases lies in our diets and in the way our bodies are able to handle nutrients. There are so many intriguing questions in this area, both in terms of fundamental mechanisms of nutrient sensing as well as in terms of practical applications. For example, despite decades of nutritional research, we are still unclear about how to combine the beneficial effects of dietary restriction with the need to maintain active and fit bodies, especially in old age. In the lab, we are developing cell- and tissue-based models of human ageing and believe that these will provide new answers to the long-standing questions in the field.

mTOR is often referred to as a master regulator of cell growth and metabolism and heavily implicated in the aging process. You previously published work showing that mTORC1 activity can be regulated by the amino acid arginine, through control of the TSC2-Rheb signalling pathway. Could you summarise these findings?

Several decades of research have revealed that the activity of mTORC1 is controlled via its subcellular localisation in the cell. Specifically, the availability of specific amino acids is sensed to dictate whether mTORC1 is localised to the cytoplasm or to the surface of the lysosome (the degradative compartment of the cell). When I started my postdoc, the mechanisms via which leucine and glutamine controlled mTORC1 had been identified but we found over and over again in our cell system, that arginine was having a very strong effect on mTORC1 signalling and cell growth. We identified that rather than regulating the localisation of mTORC1, arginine is important for controlling the localisation of the inhibitor of mTORC1, called TSC. This large protein complex inactivates another protein, called Rheb which is the master activator of mTORC1 signalling. We found that in the absence of arginine, TSC is localised on the lysosome, binds to Rheb and prevents the mTORC1 activation. As such, the mechanism by which arginine is sensed is conceptually different to other amino acids.

Do you think the positive effects of dietary restriction on healthspan/lifespan could be due in some part due to lowered arginine availability, and would this be worth testing? Considering leucine and glutamine have also been shown to affect mTORC1 activity, do you think any other amino acids could also play a role?

The regulation of amino acid uptake, utilisation and synthesis is complicated and very context dependent. There are 20 natural amino acids which are the building blocks of proteins and play key roles in metabolism. Human cells can make 11 of them, the other 9 amino acids, including leucine are referred to as essential amino acids which means they need to be ingested in our diets. Leucine is a particularly potent growth-promoting amino acid; you might have noticed high levels of leucine advertised on protein shakes aimed at gym-goers trying to boost muscle mass. Glutamine and arginine, along with several other amino acids are referred to as conditionally essential, that means our cells can produce them but that at certain times, for example during development or during tissue/wound healing, our cells might not be able to meet demand and diet supplementation is necessary. It’s true that exploiting changes in amino acid metabolism can have clinical benefits in some settings; for example, tumours auxotropic for arginine (i.e. tumour cells that have lost the ability to synthesise their own arginine) can be treated with circulating arginase to degrade circulating arginine and thus essentially starve the tumour cells. However, as of yet, we have not identified any specific defects in senescent cells that would allow us to target them in this manner.

Evidence from fly models would also suggest that starvation of any single amino acids may not yield any discernible longevity benefits, except perhaps for methionine starvation. So rather than any specific amino acid, it’s more likely that caloric restriction has a beneficial effect through a combination of reduced protein synthesis-related stress (less burden on ribosomes and ER folding machinery) and increased levels of autophagy.

Senescent cells have dysfunctional lysosomes and you recently published a paper identifying the mechanism by which senescent cells increase their lysosomal content to cope with this decreased function. Could you briefly explain these findings and what the potential therapeutic implications could be?

Lysosomes are the degradative organelle of the cell and they play an essential role in degrading unwanted, or damaged cellular contents. Despite the fact that an increase in lysosomal content is one of the hallmarks of senescence (measured by senescence-associated ß-galactosidase staining), the driving mechanisms and cellular consequences were poorly understood. We identified that lysosomes in senescence are dysfunctional. Their pH is increased which is important because low pH is required to maintain the activity of the degradative enzymes in the lysosome. As a result, the lysosomes are less active, and less able to degrade cargo. We propose that senescent cells compensate for this reduced lysosome activity by increasing their biogenesis, specifically by activating transcription factors of the TFEB family. Increased lysosome content therefore allows continued degradation of damaged and surplus cellular contents and support senescent cell survival.

What’s next for the Carroll lab?

The work us and others demonstrated that inhibiting lysosome biogenesis or modulating dysregulated mTORC1 signalling can promote senescent cell death, which indicates we could one day be able to develop interventions to target these pathways and promote healthier ageing in vivo. With this ultimate goal in mind, we are continuing to work towards a better mechanistic understanding of lysosomes and their interplay with mTORC1 signalling in senescence. We have some exciting data on changes in lysosomal lipids in senescence coming through, so watch this space :).

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!

Further Reading

Capsaicin inhibits A7r5 cell senescence via the mitochondrial carrier protein Slc25a12

Senescent skeletal muscle fibroadipogenic progenitors recruit and promote M2 polarization of macrophages

NADase CD38 is a key determinant of ovarian aging

DNA repair-deficient premature aging models display accelerated epigenetic age

Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Successful Aging: The Longer One Lives, the Better One Has Eaten?

NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies

Welcome to 2024, Vitalians! We hope your holiday season was wonderful, and that you're returning recharged and ready for another year of exciting developments in longevity science!
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Aging Insights: Dr. Jesse Poganik and Dr. Mahdi Moqri on Biomarkers and Longevity Research – The VitaDAO Aging Science Podcast
December 18, 2023
Longevity
Podcast
Aging Insights: Dr. Jesse Poganik and Dr. Mahdi Moqri on Biomarkers and Longevity Research – The VitaDAO Aging Science Podcast

In this podcast with Dr. Jesse Poganik (@jpoganik) and Dr. Mahdi Moqri (@mahdi_moqri) we had a chat about their upcoming symposium and the importance of biomarkers. Our topics ranged from omics over to liquid biopsies and clinical studies. We talked about walking speed, epigenetics, longitudinal studies and prizes (yes, you can win money!)

Hope you will enjoy this podcast and our brief shownotes.

Short Bio of the speakers

Dr. Jesse Poganik is an Instructor in Medicine at Brigham and Women’s Hospital and Harvard Medical School. His research focuses on understanding the most fundamental aspects of aging: what is the essence of the aging process, and what features define the biological nature of aging? He leads several projects in the Gladyshev Lab to understand the temporal dynamics of biological age, the inter-cellular and inter-tissue dynamics of aging, and how aging may best be quantitatively assessed.

www.poganik.com

Dr. Mahdi Moqri is a joint Research Fellow in Aging Research at Harvard (Gladyshev Lab, Genetics) and Stanford (Snyder Lab, Genetics). He is leading the executive committee of the Biomarkers of Aging Consortium, to establish reliable biomarkers for longevity interventions and mentoring non-profits and young researchers in omics techniques.

https://www.moqri.com/

Important links and upcoming events

The consortium website with relevant information and news
www.agingconsortium.org

2023 Biomarkers of Aging Symposium
December 4th 2023
https://event.fourwaves.com/boa2023/pages

ClockBase: here you can check whether your favorite dataset, drug or intervention affects epigenetic age
https://www.clockbase.org/

What is a clock and what is a biomarker?

“You know when I was talking to people in Vadim’s lab when I was considering joining they were saying clock, clock, clock and I was just… I had no idea…[and] in many ways clock is not a good term”

Basically, a clock tries to measure biological aging or something related for newer clocks. A somewhat more technical definition would understand the clock as a mathematical algorithm, based on molecular data, that has some relation to biological age.

The problem with the word clock that Jesse alluded to is reflected in current papers. These days many clocks are designed not to predict age anymore, rather they are trained to predict age-related outcomes. For instance, the GrimAge epigenetic clock predicts mortality risk. At this point it might be better to just stick to the word “biomarker” instead of clock.

Even worse, as Mahdi mentioned, we do not want a clock that accurately predicts calendar age in most cases, because then we might as well check your birth certificate. We really are interested in outcomes, which are predicted by your “biological age” so to say — i.e. the overall state and health of a person.

A biomarker is an indirect measure of any biological process. As aging researchers we want this kind of indirect measure for aging. We could use this word instead.

Nevertheless, while inaccurate I like the term clock from a popular science perspective. Everyone understands that “the clock is ticking” towards undesirable outcomes or some well-defined end. The word and the idea captures the imagination of people and this is the reason why the term became so popular.

Clinical studies and data sharing — two pressing issues

We all agreed that biomarkers are needed to facilitate clinical studies. Having a marker that can predict drug success in advance would be a great boon to aging researchers. Although I did caution that even the best biomarkers for other diseases rarely if ever replace large studies with hard outcomes. Nevertheless, such markers can save billions by helping us to choose the best possible interventions to pursue in large studies!

Secondly, we all agreed that there are many reasonable and, unfortunately, also unreasonable obstacles hindering our work on biomarkers: “there are many barriers that make data sharing harder than it should be from a scientific point of view” (Jesse)

Hence, I am looking forward to the work of the Biomarker Consortium to improve datasharing and accessibility.

The importance of functional markers

Although neither of us is a clinician and this is more the purview of doctors, I encouraged the speakers to take a brief detour and talk about functional markers. I remain very excited about functional markers because they are relatively inexpensive. Measuring improvements in walking speed, hair loss, wrinkling, libido etc. is so much easier than doing thorough long-term mortality follow-up. (Also as you can see the distinction between marker and outcomes is quite blurry when it comes to clinical or functional markers. All of these can be considered markers of aging but are also valuable outcomes by themselves.)

The reason I am excited about these is that some drugs like rapamycin have shown rejuvenation-like effects in mice and there may exist more such drugs. Not only are they in a way more attractive than drugs which merely slow aging, they would be also cheaper to study since you could design a study based on functional biomarkers to efficiently measure rejuventation!

Jesse and I agreed that emerging digital biomarkers are very suited to study some of these functional markers (e.g. heart rate variability, sleep quality, movement patterns).

This topic then led to a great discussion about the difference between cross-sectional and longitudinal studies. Jesse mentioned that the latter are obviously more suited to study a continuous process like aging, although unfortunately such studies are difficult and expensive.

What do we mean by these terms anyway?

Cross sectional — single measurement.

Longitudinal — follow the same group of people or animals over time.

With biomarkers longitudinal can mean more than one measurement, or we measure a biomarker at point T1 and then outcome and outcome at a later point T2, e.g. does cystatin predict kidney failure and death. This in a nutshell is what a prospective cohort study does, which is a longitudinal study design.

The importance of omics

For those who do not know, “omics” refers to a collection of fields in biology that study various sets of molecules within cells, tissues, or organisms. The defining characteristics is usually a high throughput approach where many of these molecular species are studied at the same time. The study of small metabolites is called “metabolomics” and the study of transcription “transcriptomics”, etc.

The really cool thing about omics is that markers based on these techniques could predict changes in functional markers many years in advance.

We speculated which omics field is the best for predicting age-related outcomes. It appears that at this moment in time epigenetics takes the lead. However, this may be because the field had a head start and enjoys a large level of standardization which is essential for clinical studies and cohort studies.

The big disadvantage of epigenetics is lack of “interpretability” which means that given a result with some specific epigenetic methylation pattern it is hard to make sense of it in terms of causality. We simply do not know how these marks affect protein levels, which are the ultimate effectors. That is why the different omics layers are so important.

Mahdi also alluded to another issue. We have very little head to head comparison data and when they looked at this in preliminary work, it seemed like, for example, metabolomics was also performing very well for the prediction of age-related outcomes.

The host — brief bio

Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.

In the upcoming episode of The Science of Aging Podcast, we're set to explore aging research with Dr. Jesse Poganik and Dr. Mahdi Moqri, just before the 2023 Biomarkers of Aging Symposium. Dr. Poganik ...
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November Longevity Research Newsletter
December 5, 2023
Maria Marinova & Rhys Anderson
Longevity
Newsletters
November Longevity Research Newsletter

Introduction

Welcome back Vitalians and please join us in congratulating the Remedium Bio team for passing the VitaDAO token holder vote with 75.61% voting in favour! This proposal was an assessment of a regenerative medicine biotechnology company, which has developed the only dose adjustable gene therapy platform technology Prometheus™ and is currently advancing multiple assets with uncorrelated risk to Investigational New Drug (IND) approval.

Get ready for some tail-wagging news! Loyal's latest leap in longevity science has just made history. For the first time ever, the FDA has nodded yes to a drug aimed at extending lifespans – and it's for our furry large-breed friends!

Loyal's LOY-001, is all about giving more years of belly rubs and fetch games to our big pooches. Though not yet in the market, this breakthrough means we're on the brink of a huge leap forward. This breakthrough is not just a victory for Loyal but a beacon of hope for all who dream of a future where longevity is within reach. 

And just when we thought we'd have to spend this newsletter talking about the unfolding OpenAI drama this fantastic news came wagging in! 

And the good news don’t stop here. XPRIZE Healthspan Challenge is live! Launched at the Global Healthspan Summit in Riyadh, this groundbreaking competition aims to revolutionize aging! A staggering $101 million prize awaits the team that develops a therapy to rewind the aging clock by 20 years for muscle, cognition, and immune function in older adults.

The twist? The project needs to demonstrate remarkable results within just one year of treatment!

We also have some exciting new research and fascinating reviews. We’ve explored one of them “Epigenetic aging of mammalian gametes” more deeply with the lead author Prof. Michael Klutstein in our monthly interview!

Longevity Literature Hot Picks

Preprint Corner

The votes are in - The Longevist curators have decided what they think are the most important preprints of Q3. Before we publish the Q3 Issue of the Longevist, take a look at our previous issues!

Check out these latest preprints, each of these will be entered into the Q4 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

Intranasal GHK peptide enhances resilience to cognitive decline in aging mice

Protein thiol alterations drive aberrant phase separation in aging

Regulators of health and lifespan extension in genetically diverse mice on dietary restriction

Quantification of healthspan in aging mice: Introducing FAMY and GRAIL

The AccelerAge framework: A new statistical approach to predict biological age based on time-to-event data

A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation

Published Research Papers

In vivo reprogramming leads to premature death linked to hepatic and intestinal failure

Continuous in vivo expression of reprogramming factors (Oct4, Sox2, Klf4, c‐Myc) can reverse aspects of aging in tissues but causes liver and intestinal dysfunction, leading to weight loss and premature death. A transgenic mouse strain was created to avoid these side effects, allowing safer, longer-term rejuvenation studies.

Failure to Repair Endogenous DNA Damage in β-Cells Causes Adult-Onset Diabetes in Mice

Increased age raises type 2 diabetes risk due to DNA damage in β-cells. Ercc1-deficient mice developed diabetes, linking DNA damage to β-cell dysfunction and disease onset.

Life expectancy can increase by up to 10 years following sustained shifts towards healthier diets in the United Kingdom

Making healthy food choices can significantly impact your life expectancy. Research using data from the UK Biobank suggests that transitioning from unhealthy eating habits to recommended dietary patterns could add nearly 9 years to the lives of 40-year-old men and women, with even greater gains by adopting longevity-associated diets rich in whole grains, nuts, and fruits while reducing sugar-sweetened beverages and processed meats.

Cellular Senescence Exacerbates Features of Aging in the Eyes

Senescent ocular cells (SOCs) from human corneas exhibit increased aging markers and disrupt epithelial barriers due to a pro-inflammatory secretory phenotype (SASP). Senolytic treatment in older mice with dry eye symptoms prevents corneal opacity.

Stochasticity Explains Nongenetic Inheritance of Lifespan and Apparent Trade-Offs between Reproduction and Aging

Longer-lived female flies produce longer-lived but fewer offspring, indicating a stochastic trade-off between lifespan and reproduction. This challenges traditional views on aging, suggesting random factors rather than genetics predominantly influence lifespan inheritance and aging treatments.

Longitudinal study of traumatic-stress related cellular and cognitive aging

Accelerated epigenetic aging in trauma-exposed veterans predicts increased dementia biomarkers and cognitive decline, linking psychiatric comorbidity to neurodegeneration risk.

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Restricting dietary isoleucine (IleR) improves metabolic health, promotes leanness, and controls blood sugar in young and old genetically diverse mice. It also extends lifespan, particularly in males, suggesting its potential as a geroprotective intervention.

ATAC-clock: An aging clock based on chromatin accessibility

We’ve all heard of methylation clocks, now this team have developed a chromatin accessibility clock which has a direct link to age-related transcriptional alterations, whilst also outperforming a transcription clock trained on the same data.

Mid-old cells are a potential target for anti-aging interventions in the elderly

SIRT2 transgenic over-expression does not impact lifespan in mice

This study uncovers a subset of fibroblasts and smooth muscle cells termed "mid-old status" cells in aging organs, distinct from proliferative or senescent cells, exhibiting upregulated pro-inflammatory and downregulated anti-inflammatory genes. Within the stroma, the inflammatory microenvironment induced by SAA1 negatively impacts epithelial cell stability, contributing to aging-related tissue dysfunction, but this effect can be reversed by a young cell-derived protein, SLIT2, suggesting a potential method to prevent or ameliorate aspects of age-related tissue decline.

Comparative analysis of animal lifespan

Exploring aging across a diverse range of species offers valuable insights into universal aging processes. Though recent methodological advancements enable the study of evolutionarily distant species, the broad scope introduces challenges in experimental design. In this discussion, the authors discuss these challenges, identify key issues to tackle, and offer recommendations grounded in current approaches to effectively conduct comparative aging studies spanning the animal kingdom.

Published Literature Reviews, Hypotheses, Perspectives and more

Epigenetic aging of mammalian gametes

Olfaction: an emerging regulator of longevity and metabolism

Authored by a VitaDAO fellow!

To promote healthy aging, focus on the environment

Combining geroscience with environmental research offers a way to understand and improve healthy aging and reduce health disparities, by studying how environments influence aging processes from an early age.

Entropy Meets Physiology: Should We Translate Aging as Disorder?

Multipotential stem/progenitor cells, crucial for tissue homeostasis, face age-related challenges, leading to altered self-renewal, differentiation, and immunomodulation, contributing to tissue destruction and reduced metabolic performance. This review highlights the impact of aging on mesenchymal stromal/stem cells (MSCs) and suggests a parallel between the thermodynamic concept of "entropy" and biological aging, proposing that both entail irreversible disorder within systems. The question arises: should aging be viewed as disorder?

The power and potential of mitochondria transfer

Mitochondria, traditionally considered to pass down vertically during cell division, are now recognized to undergo intercellular transfer in certain cell types, allowing them to be delivered to unrelated cell types. This process, termed intercellular mitochondria transfer, plays a role in regulating various physiological functions across organ systems. This review explores the mechanisms and impacts of intercellular mitochondria transfer on various cellular processes.

The longevity bottleneck hypothesis: Could dinosaurs have shaped ageing in present-day mammals?

The intriguing contrast in ageing patterns between mammals and certain reptiles and amphibians sparks curiosity about the evolutionary roots of ageing. While mammals, shaped by the dominance of dinosaurs over millions of years, exhibit marked ageing, some reptiles defy ageing or age very slowly. The 'longevity bottleneck hypothesis' suggests that the pressure for rapid reproduction during the era of dinosaurs led to the loss or inactivation of genes and pathways associated with long life in early mammals, creating an enduring impact on their ageing processes.

Job board

Maja Funk Lab at Holmholth Munich is looking for a PhD candidate on a lung organoids project to investigate the links between ageing and environmental stress in COPD, as well as a technical assistant

Maria Mittelbrunn is hiring a postdocs interested in immunometabolism during inflammation and aging at the Centro de Biología Molecular Severo Ochoa in Madrid.

PhD positions in barcelona with Dr. Ana Victoria Lechuga-Vieco on Mitochondrial Biology and Tissue Regeneration

Joao Pedro de Magalhaes has an opening for a PhD studentship at the University of Birmingham to study ageing, longevity and cellular rejuvenation

Deadline: 4th January 2024

An exciting research fellow opportunity to join the groups of Dr Nazif Alic and Prof. Linda Partridge at the UCL Institute of Healthy Ageing. The successful applicant will investigate the role of the multiple copies of tRNAiMet in animal development and ageing. Deadline: 8th December 2023.

Pankaj Kapahi has an opening for a postdoctoral fellow interested in studying “how metabolism regulates astrocyte-neuron signaling in aging and dementia.” Send your CV to pkapahi@buckinstitute.org

American Aging Association are looking for enthusiastic trainees studying aging or age-related diseases to apply for the AGE Early Career Scholar’s Program.  Apply Today!

PhD Position available at University of Birmingham - Researching skeletal muscle decline with ageing and obesity: establishing a role for adipose tissue inflammation and immune system deterioration

News and Media

Venture Capital Giants In The Billion-Dollar Quest For Longevity Breakthroughs

The Secrets to Healthy Aging According to Longevity Experts

Can restoring elastin with existing drugs improve longevity?

VITALISM. n. The philosophy and movement against death and biological decline

Nature's Design Paradox: Aging as an Inherent Software Flaw

Support the Dog Aging Project

An Aging Expert Thinks Humans Can Live for 20,000 Years. He's Not Crazy

The Clues to Longer Life That Are Coming From Dogs

Resources

Bottlenecks of Aging by the Amaranth Foundation

The science of longevity and the quest to solve an age-old problem

Coleen Murphy’s upcoming book How We Age: The Science of Longevity tells the story of these remarkable discoveries through the words of a protagonist in this field.

Prizes

The deadline is approaching for the Longevity Funding Innovation Prize and the reward of $20000 is still up for grabs

XPRIZE Healthspan is a $101 million global competition to revolutionize the way we approach human aging.


Conferences

Dec 1-2nd, San Francisco

Foresight institute vision weekend 

Dec 4th, Novato CA

The Biomarkers of Aging Symposium

Dec 5-6th, Buck Institute, Novato CA

The Longevity Summit

Dec 7th, Stanford

Bay Area Aging Meeting (BAAM)

Some of the VitaDAO team will be around all of the Bay Area aging meetings so come say hi and maybe claim some Vita swag!

Tweets of the Month

Ex Binance CEO CZ is suddenly interested in biotech:


CZ 🔶 BNB @cz_binance:

Been reading about biotech, thinking about how to use crypto to accelerate research funding there.

Keep building!

Mikhail Batin

Aging remains an enigmatic phenomenon. Despite its universal occurrence, the evolutionary rationale and molecular underpinnings of aging are not fully understood.

There are three overlapping strategies to combat aging:

1. Searching for therapies based on our current understanding of aging mechanisms.

2. Identifying new targets through big data analysis, such as transcriptomics.

3. Validating aging theories and testing them empirically…….

Danielle Beckman

What's the biggest difference between a neuron from a young vs. an aged primate? It is not the length of the axon and dendrites, but the number of spines available to make contact and connections with other surrounding neurons!

Podcasts and Webinars

Longevity & Aging Series

Aging (Aging-US) and FOXO Technologies collaborated to produce a special video series on aging research: Longevity & Aging Series. In this limited series, selected Aging researchers were invited to speak about their research with host Dr. Brian Chen, an adjunct faculty member at the University of California San Diego. LEARN MORE

Check out some talks from The Longevity Forum’s Longevity Week

The longevity revolution has the potential to transform healthcare in our lifetime

Funding Opportunities

The SENS Research Foundation is now accepting applications for our undergraduate Summer Scholar Program and our Post-Baccalaureate program (which is paid)! Apply today

Interview with Michael Klutstein

Michael Klutstein is an Associate Professor Epigenetics who heads The Chromatin and Aging Research Lab at the Hebrew University of Jerusalem. His lab is interested in understanding the dynamics of heterochromatin adaptation and subsequent gene expression during cellular and developmental processes and how these contribute to the process of aging in different tissues

What inspired you to enter longevity research?

The future of mankind depends on our ability to successfully cohabitate with our eco system, to gain and make perfect use of experience and wisdom and to successfully colonize other planets. All these goals require that we live longer than we do today. For the future of mankind- longevity research is essential. 

Which of the current theories of ageing do you think are the most convincing?

I do not currently prefer one theory as they all grasp some real aspects of aging, but in my opinion fail to grasp the picture in its entirety. I think aging is so pleotropic that more extensive theories are needed to understand it. Recently, a theory of elevated stochasticity as an origin for aging is starting to emerge. In my opinion- this is the closest thing to an comprehensive theory for aging we have today. 

How has the field changed since you started?

From a couple of genes involved in aging we have dozens now. From a handful of mechanisms involved we have many. From no treatments to delay aging we have now several strong candidates. 

What mistakes do you think the longevity field has made?

Too much emphasis was given to interventions instead of deep biological understanding. This is true for many other scientific fields, but I think in this case- we would benefit much more from understanding the basic Biology. 

Other than your own, what do you think have been the biggest/important discoveries in the field?

I will focus on the field of reproductive aging, as this is my main focus. I would like to highlight the excellent work of Bjorn Schumacher who is developing the theory of elevated stochasticity in aging, and who has shown several key points in reproductive aging in nematodes. Also, the work of Francesca Duncan, to show how ovaries change with age have been a key to gain insight into how reproductive aging occurs.  

What advice would you give to people currently working in longevity research?

Open your eyes, ears and minds, cause this field is going to explode…

Which aspect of longevity research do you think requires more attention?

The answer to this one is obvious as it is close to my heart- I think the field of reproductive aging is key to understanding aging in general and deserves much more attention and resources. 

Is ageing a disease?

No. In other words - it’s not a bug, it’s a feature. 

In your recent work, you describe how germ cells also age, similar to other cells in the body. Are there specific types of damage or aging processes that are more prevalent in gametes compared to adult somatic cells?

Yes, definitely. Germ cells seem to be much more sensitive to epigenetic changes than somatic cell types. The reasons for that are unclear, but a few possibilities are the fact that gametes are arrested in the cell cycle for long periods, and the fact that they are arrested at an unusual point in the cell cycle- after DNA replication. Another important point is regulatory chromatin processes that operate in gametes to activate parts of the genome that are germline specific- and which we do not know enough about. 

It's understood that while gametes age, the creation of a new organism effectively resets or wipes out this damage, leading to a 'fresh start' for the offspring. In the context of your focus on epigenetics, would you say epigenetic factors are the primary drivers of this full rejuvenation, or are there multiple processes involved? Do you plan to explore these additional processes?

Epigenetic processes are thought to be the main driver of this “reset”, since the genetic information is kept intact, and only the epigenetic information is changed in this process. An important and unknown link between the genetic and epigenetic information are mobile elements such as retrotransposons. These are activated because of epigenetic changes, and then move to other parts of the genome, changing the genetic material itself. Their propagation could be a key factor in understanding the interactions between the genetic material, epigenetics and transgenerational reset of information. 

What can we learn from germline rejuvenation that could potentially be translated to human aging?

We can learn a great deal. We can learn that aging can be cancelled but relatively simple interventions. We can learn that the aging process may differ from system to system and between cell types. Still, germline rejuvenation brings up a lot of unsolved issues, both scientific and ethical that need to be addressed.  

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!

Further Reading

Mitophagy Activation by Urolithin A to Target Muscle Aging

Circulating monocytes expressing senescence-associated features are enriched in COVID-19 patients with severe disease

A Mediterranean Diet-Based Metabolomic Score and Cognitive Decline in Older Adults: A Case–Control Analysis Nested within the Three-City Cohort Study

Methylmalonic acid in aging and disease

Too big not to fail: Different paths lead to senescence of enlarged cells

Vitamin B12 emerges as key player during cellular reprogramming

Too big not to fail: Different paths lead to senescence of enlarged cells

Workshop Report - Biology of Stress Responses in Aging

Genetics of human longevity: From variants to genes to pathways

Cellular age explains variation in age-related cell-to-cell transcriptome variability

A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment

Clonally expanded memory CD8+ T cells accumulate in atherosclerotic plaques and are pro-atherogenic in aged mice

COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells

Knockdown of neuronal DAF-15/Raptor promotes healthy aging in C. elegans

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Rapid measurement of ageing by automated monitoring of movement of C. elegans populations

Microautophagy regulated by STK38 and GABARAPs is essential to repair lysosomes and prevent aging

Mechanisms underlying retardation of aging by dietary energy restriction

Welcome back Vitalians and please join us in congratulating the Remedium Bio team for passing the VitaDAO token holder vote with 75.61% voting in favour!
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Beyond Mice Models: Exploring Human Aging Genetics with Dr. Joris Deelen on The VitaDAO Aging Science Podcast
November 26, 2023
Podcast
Awareness
Beyond Mice Models: Exploring Human Aging Genetics with Dr. Joris Deelen on The VitaDAO Aging Science Podcast

Limitations of mice as model organism have been a recurring theme of the last few episodes. Nothing highlights this better than the human genetic data, since it often seems to disagree with the mouse data. In this podcast I discuss with Dr. Joris Deelen (@Joris_Deelen) discuss whether this is really true and what we can learn about aging from human genetic studies.

We both agree that the state of the art in his field "is quite depressing, [yet also] also quite interesting".

Joris Deelen – short bio

Joris Deelen obtained his PhD at the Leiden University Medical Center in The Netherlands in 2014 in the group of Prof. Dr. Eline Slagboom. In 2016, he joined the Max Planck Institute for Biology of Ageing as a postdoctoral researcher in the group of Prof. Dr. Linda Partridge, where he was promoted to independent Research Group Leader in 2020. The work in his group is mainly focused on the identification and functional characterisation of genetic variants linked to human longevity. To this end, they make use of the CRISPR/Cas9 system to generate transgenic cell lines and model organisms harbouring the identified variants and subsequently measure their functional effects in vitro and in vivo. 

GWAS studies – our main tool to study the genetics of human longevity

GWAS stands for Genome-Wide Association Studies. These studies are a type of research method used in genetics, mainly for the identification of genetic variants associated with particular diseases. GWAS involves the examination of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait or disease.

The process begins with the collection of DNA samples from many people who have a certain disease (cases) and from people who do not have the disease (controls). The DNA is then scanned for genetic markers, usually single-nucleotide polymorphisms (SNPs), small differences in the DNA sequence that occur between individuals. The frequency of these markers in the disease group is compared to the control group to find any significant associations.

Interestingly many times the variants found are not even in the protein-coding region of the gene, probably because such variants would be rare due to their high impact on protein function.

The major ways of running GWAS studies for longevity

There are different ways of analyzing the data that will yield slightly different interpretations. The major difference is in the outcome we study. Although we may use the umbrella term “longevity”, there is actually more than one longevity-related outcome of interest. We can study genes that predict survival to old age (as a binary variable), this is most similar to a classic case-control design. A different take on this method is using the whole range of lifespan values, which may increase power but will also include people who died of diseases not related to aging. Both these approaches suffer from one major limitation. We have to wait until a large portion of the cohort has died before we can apply them!

An alternative is to measure how genetic variants correlate with the lifespan of a participant’s parents. This will give a valid estimate for the longevity of each participant because longevity is heritable. Finally, as done by Joris and others, we can also look at healthspan as an outcome, aggregating data from multiple age-related diseases that participants might currently have – obviating the need for a full mortality analysis.

Missing heritability of aging

Genetic heritability estimates the proportion of variation, or differences, in a phenotypic trait in a population that is due to genetic variation between individuals within that population. While the heritability of lifespan is not very high, the heritability of extreme survivorship is considerably higher. As aging researchers we are more interested in extreme survival, e.g. people who become centenarians. 

Regardless of which outcome you look at, it appears that GWAS studies fail to find all the variants that would account for the heritability of longevity predicted from twin studies. Joris and I discuss why this is the case in the podcast. 

Similarly, the heritability of age-related diseases is much higher than the heritability of lifespan. Therefore, I believe, it might be possible to find novel variants associated with lifespan to close the heritability gap, at least somewhat.

Genetic variants: rare vs common

The term SNV stands for single nucleotide variants and SNP stands for single nucleotide polymorphisms. While there is a subtle difference between the two, for the purposes of this podcast we are dealing with small, single nucleotide changes at a specific position in the genome. These genetic variants, differences between people, can be then studied for their association with different traits like longevity.

Some variants are rarer than others. Common variants may be found in 1% of the population, while variants at below 1% are called rare. Ultra rare are found in fewer than 0.1% of the population and in some cases even unique variants may be of interest. Imagine you studied the genome of the oldest person in the world and found a unique variant in a “candidate” longevity gene like growth hormone. This would be obviously scientifically interesting.

The curious case of ApoE and how it compares with other variants

ApoE is a fascinating case  study for the success and failure of GWAS studies. It is the best known and most robust genetic variant associated with longevity. It is by far the most robust one, as we both lament. Almost none of the other variants identified so far replicate in all human populations, except ApoE.

It has been shown that the ε2 (E2) allele is overrepresented in long-lived individuals compared to control groups, while the ε4 allele is underrepresented. The ε3 allele, being the most common, does not seem to have a strong effect either way. The E2 allele may be also linked to lower risk of Alzheimer’s disease and cardiovascular disease. Interestingly, ApoE genotype could be more important in people who eat a lot of cholesterol, i.e. cholesterol would be more risky if you have an E4 genotype.

In a way ApoE is also interesting because it breaks a common pattern seen in longevity GWAS. Usually variants are not protein altering, except for the ApoE alleles which do change the actual protein, giving rise to isoforms.

Finally, it is important to point out that ApoE by itself would not be enough to meaningfully extend human lifespan since we are looking at a small extension in absolute terms even in the base case. If I recall correctly Joris mentioned something on the order of 2 years. If we want to robustly extend human lifespan we need to discover gerotherapeutics that work in humans as well as does rapamycin in mice.

Alternative approaches and future directions for genetic studies

Using candidate gene approaches, where a candidate is defined based on animal data, e.g. “insulin signaling pathway”, rare or even unique variants enriched in long-lived populations are collected and then studied further and validated in animal models. The work Joris himself does or Vera Gorbunova did on SIRT6 falls into this category.

Most GWAS studies are performed in populations of European ancestry or in East Asian populations, whereas there is very little data from Africa, South America and many other regions. If we could diversify our datasets we might be able to identify novel variants specific to these populations and better confirm our so called “universal” variants.

Novel techniques including long read sequencing to study changes in structural variants and larger scale chromosomal changes as they related to aging. Even just a shift from array genotyping to standard whole genome sequencing could help to reveal novel longevity-related variants.

We also discssus collaborations with 23andme or other companies that sell commercial tests and how we could use this to increase the total sample size of available longevity GWAS studies. Here the limiting factor is that these companies may be unable to keep track of mortality statistics and/or did not inquire about parental longevity, the two key outcomes we would use in GWAS studies.

Another promising technique is mendelian randomization. We call it randomization because each person randomly inherits genetic variants from their parents. Using GWAS we then define a set of variants that are interesting (because they predict X) and then we ask if they are associated with longevity, which will also tell us whether X is causally associated with longevity.

One example would be asking whether genetically proxied risk for Alzheimer’s disease predicts lifespan, another would be to look at predicted LDL or iron levels. If a genetic variant is associated with higher levels of LDL cholesterol, and if the same variant is also associated with an increased risk of heart disease, one could infer that higher LDL cholesterol levels cause an increased risk of heart disease (this is indeed the case; Daghlas and Gill 2021). Below we discuss this approach for iron.

Iron and Aging – a case study for the usefulness of genetics

As a part-time iron researcher myself, I was pleased to discuss Joris’ work on iron, where he used mendelian randomization to test whether genetically predicted iron levels are related to measures of longevity. There is a plausible link between iron and aging. In fact, I have written an article on this topic not long ago, which while quite focused on supplementation, nutrition and blood testing, nevertheless provides a good review of the evidence on this topic: (https://novoslabs.com/iron-longevity-aging-cancer/)

“Iron is a mineral that’s essential to human health and life. Your body uses iron to generate the protein hemoglobin, which red blood cells use to carry oxygen from the lungs throughout the body, as well as the protein myoglobin, which provides oxygen to muscles. The body requires a careful balance of iron in just the right amounts: In studies, iron has presented as one of the few micronutrients that shows a pronounced U-shaped dose-benefit-response curve within a relatively narrow range of intakes or blood levels. This means that both too much and too little iron is harmful to your health.

Under normal circumstances, iron is so precious that nature did not come up with an active mechanism for the excretion of this metal. Bleeding and cell shedding are the major ways in which the body loses iron and modulates uptake. While iron is utilized by many enzymes, it is nonetheless dangerous to the body under certain circumstances. Unbound or free iron can catalyze oxidative stress and DNA damage through the so-called Fenton reaction.”

In this study (Timmers et al. 2020) Joris and colleagues first went back to the definition of longevity before even starting the analysis. Combining data from studies looking at parental lifespan, healthspan and long-lived participants they were able to validate and extend the list of significant genes found in GWAS studies. Having established that, they identified which so called quantitative trait loci (QTL) were colocalizing with the above GWAS variants. Since QTLs predict “quantitative” changes in some phenotype (e.g. height or cholesterol) they were able to put them together and test for enrichment of pathways that could affect these phenotypes. One pathway they found was “heme metabolism” and, as far as I understand, this then led them to perform full-scale mendelian randomization of iron traits, finding that lower iron was beneficial for longevity. 

Although as a non-geneticist, I do not pretend to fully understand what they did, it is certainly good work based on plausible biology that has been solidly replicated (Daghlas and Gill 2021).

Studying accelerated aging (progerias)

We also talk about an often-controversial topic which is progerias. Some people study these syndromes since they appear to accelerate aging. During the podcast we speculate that there should be progeroid rare variants that produce less severe symptoms, which could teach us something about pro-longevity pathways (whose loss of function is harmful to lifespan).

However, there are many ways to shorten our lifespan genetically and fewer that will extend lifespan. Furthermore, the variants that shorten lifespan will do this in different ways, whereas there is only one way to live longer, which is by slowing aging or one of the major age-related diseases. You may call this the Anna Karenina principle applied to longevity if you will.

The host – brief bio

Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research. 

References and further reading

Daghlas, Iyas, and Dipender Gill. "Low‐density lipoprotein cholesterol and lifespan: A Mendelian randomization study." British Journal of Clinical Pharmacology 87.10 (2021): 3916-3924.

Timmers, Paul RHJ, et al. "Multivariate genomic scan implicates novel loci and haem metabolism in human ageing." Nature communications 11.1 (2020): 3570.

Daghlas, Iyas, and Dipender Gill. "Genetically predicted iron status and life expectancy." Clinical Nutrition 40.4 (2021): 2456-2459.

Limitations of mice as model organism have been a recurring theme of the last few episodes. Nothing highlights this better than the human genetic data, since it often seems to disagree with the mouse data.
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VitaDAO Letter: Introducing The Members Portal
November 20, 2023
Awareness
VitaDAO Letter: Introducing The Members Portal

🌎 VitaDAO.Global

Just when you thought being a $VITA holder couldn’t get any better, VitaDAO launched VitaDAO.Global. This new membership portal features an overview of one’s $VITA holdings, active and past DAO governance proposals, a comprehensive DAO treasury, and exclusive discounts to DAO members! Huge kudos to the Tech-Product squad for their amazing work!

Since the initiation of VitaDAO, members have voiced the desire to optimize their longevity and health journey. VitaDAO.Global was created with this in mind, to give DAO members access to health products and services at a discounted price. In addition to health optimization, the portal offers discounts on common expenses such as hotel stays, housing rentals, coworking spaces, and academic publications. DAO members, such as Esther Klaps (featured later in the Newsletter), have been hard at work identifying and coordinating these services. Currently, all VitaDAO members with 100+ $VITA in a linked wallet qualify for these exclusive member services.

Current discounts include:

  • 31% off GlycanAge Tests: GlycanAge combines a biological age test with expert advice to optimize wellness. The age tests examine the state of one’s immune system through examination of the types of glycans attached to Immunoglobulin G, the most common antibody in the blood. The type of glycans attached to Immunoglobulin G can able to change the function of the antibody from pro-inflammatory to anti-inflammatory and vice versa. Signs of chronic inflammation are directly related to lifestyle.

The overall process is simple, requiring only a small fingerprick at home. You can expect results in three weeks in the form of a report. After which you will have a consultation to further explain the test results. As a VitaDAO member, you have discounted access to this cutting-edge approach to measuring biological age.

  • Up to 50% off Sonder in 40+ cities: VitaDAO has teamed up with Sonder to offer DAO members premium accommodations at affordable rates. Simply browse the selection of Sonder properties in your desired destination and apply the portal’s discount code to receive up to 50% off your next accommodation!
  • 15% Off Bon Charge: Optimize your sleep, relaxation, and overall well-being! Bon Charge offers a variety of products including infrared sauna blankets, infrared PEMF mats, blue light-blocking glasses, cold therapy devices, and red light therapy devices. As a $VITA hodler, you get 15% off Bon Charge’s products to optimize your health in this digital world.
  • 10% Off Sensate: Stressed by fluctuations in the crypto market? Sensate is a sensory device that uses vibrations and sounds to decrease stress and improve stress. This combination of chest resonance is thought to signal the vagus nerve.

The team is actively working to improve and expand upon the exclusive offers for $VITA holders. Reach out on Twitter with suggestions for products or services that you would like to see partnered with VitaDAO!

🏠The Network State Conference

This month, VitaDAO’s founding member, Laurence Ion, took the main stage at The Network State Conference. In his talk, he discussed the idea of creating a city to increase work speed and fix the crisis of aging.

“You are all infected with a terminal disease. It is called aging…. Join or die.”- Laurence Ion

In this talk, which can be found on YouTube, Laurence introduces the idea of Vitalia, a movement to start a longevity network city. The next step of this movement is happening in January and February of 2024, through a two-month pop-up city in Roatán. VitaDAO members have priority to join and co-create. The ultimate goal is to identify semi-autonomous zones where an in-person community can self-govern, self-experiment, and identify lifesaving treatments.

🧢Buy VitaDAO Merch

As if the Membership Portal wasn’t enough big news this month…🥁🥁🥁(drum roll please)… introducing VitaDAO’s Merch Shop! VitaDAO teamed up with senior designer Patrick Saville to produce a limited edition hoodie. This sustainably produced hoodie commemorates the genesis of VitaDAO. Don’t miss the opportunity to get this VitaDAO collectible- limited units are available!

🗣️VitaDAO in the Wild

- VitaDAO-backed Turn Bio announced the ability to deliver precise in-vivo mRNA delivery to dermal cells!

- VitaDAO-backed Turn Bio also received positive FDA feedback on TRN-001, a cell rejuvenation therapy!

- Last month, VitaDAO became the first DAO to kickstart a biotech company (MatrixBio).

- Balajis gave VitaDAO a shout-out on Twitter, recognizing the global power of VitaDAO’s decentralized network.

📣Community Approved: What YOU voted for!

Thanks to the support of the VitaDAO community, one proposal successfully passed this month! This proposal was VDP-121. In VDP-121, the community voted to mint an additional 10% of the total token supply in new vested VITA for new strategic contributors. VitaDAO’s 2023 Strategic Plan outlines the launch of the VitaDAO Accredited Investor Fund (VDAIF), anticipated in Q4. The fund will be token-gated, increasing the demand for VITA tokens. Currently, purchasing VITA on DEXs is impossible for these entities in high enough volume. With the passing of VDP-121, we are excited to grow the DAO treasury and include these new strategic contributors!

💪Exercise Your Right to Vote

Visit VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Together, we can shape the future of VitaDAO and accelerate decentralized science.

👋Meet the Lead of VitaDAO’s Membership Program: Esther Klaps

Esther Klaps is a valuable contributor to the VitaDAO community and the Lead of VitaDAO’s Membership Services. More recently, Esther has been the driving force behind VitaDAO’s Membership Program, identifying opportunities and coordinating strategic partnerships. Esther holds a BSc. in International Business from Maastricht University’s School of Business & Economics and further honed her expertise with an MSc. in Blockchain and Digital Currencies from the University of Nicosia’s Institute for the Future. She brings a wealth of expertise to the table, having excelled in various partner-facing roles, event planning, and business strategy. When not contributing to VitaDAO, Esther enjoys exploring her interest in nutrition and fertility.

How did you first learn about VitaDAO and what drew you to it?

I previously worked at ConsenSys in employer branding and ecosystem growth, and knew I wanted to stay within the Blockchain world. When I came across VitaDAO, this sounded like the perfect combination of my work in Blockchain and my passion for health. I have a background in Orthomolecular Nutrition, focused on reproductive health, which of course is closely related to improved longevity.

How are you currently contributing to VitaDAO?

I’m currently focused on finding interesting companies to collaborate with. We want to offer discounts on excellent longevity and biohacking products and services to our members through the Member Portal. Next to this, I’m also contributing to the Ambassador Program.

You’ve worked in a variety of different fields, and also have a background in Blockchain. You likely have a different perspective than most VitaDAO contributors.

From working in member and partner-faced roles in Blockchain, I do have a good understanding of the needs and wants of a Web3 audience. The way of interacting with that audience is very different than that of the more “traditional” academic world. I feel that’s also one of VitaDAO’s strengths, that our contributors come from both worlds.

What has surprised you the most about VitaDAO? What sets it apart?

There’s a lot of potential in Blockchain technology. However, from what I’ve seen working in Web3, many brilliant ideas are constrained to the crypto ecosystem, unable to truly impact real-world problems. I enjoy contributing to VitaDAO because you can directly see the impact it’s able to make by empowering and funding promising early-stage longevity projects that would otherwise lack access to funding. VitaDAO is able to create that bridge between Web3 and the “real world”.

Any closing thoughts for readers?

If there are any biohacking products or services you’d love to see discounts for on our Member Portal, do let us know in Discord!

🤝Thanks for Reading!

Want to stay up to date with all that’s going VitaDAOn? Join us on Discord, subscribe to our Twitter, and follow our Instagram! You can now connect your wallet to VitaDAO’s Members Portal to learn about exclusive member benefits and find VitaDAO’s treasure dashboard. Find updated information on VitaDAO’s funded projects on our website.


Just when you thought being a $VITA holder couldn't get any better, VitaDAO launched VitaDAO.Global.
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Epigenetics & Longevity: Unraveling Aging Mysteries with Dr. David Meyer and Prof. Sarah Voisin at ARDD – The VitaDAO Aging Science Podcast
November 9, 2023
Podcast
Longevity
Epigenetics & Longevity: Unraveling Aging Mysteries with Dr. David Meyer and Prof. Sarah Voisin at ARDD – The VitaDAO Aging Science Podcast



This special the episode of the Aging Science podcast is brought to you from the ARDD conference that took place at the end of August in Kopenhagen. I sat together with Dr. David Meyer from CECAD and Prof. Sarah Voisin from the University of Copenhagen to talk about epigenetics, clocks, our favorite conference presentations, stochastic and adaptive changes during aging. Finally, we also talked about the all-important questions of sustainability and overpopulation, and whether longevity researchers should have a say in this matter.

https://agingpharma.org/

My interview partners

David is a bioinformatician with a strong interest in genome instability and aging research. His research utilises data analysis, machine learning, and the development of computational tools to help advance our understanding of aging and age-related diseases.

Sarah is an Assistant Professor at the University of Copenhagen and a former Australian NHMRC Early Career Fellow (2019-2022). She works at the intersection of epigenetics, genetics, statistics and bioinformatics, with particular focus on exercise, ageing and human health. She completed her PhD at Uppsala University and Pierre & Marie Curie University, and published 58 peer-reviewed papers. Her current research work and interest is epigenetic ageing and exercise, sex differences in biology, and statistical methods to develop personalised health interventions.

What is epigenetics?

The term epigenetics describes a form of gene regulation that relies on modifications to the (chemical) structure and organization of DNA and chromatin. This is in contrast to genetics which deals with changes to the DNA sequence itself.

Epigenetic marks are a type of modification that is attached to DNA that help genes to be expressed at the proper time. There are two major types of epigenetic marks, those found on histones and those found directly on the DNA. Histone modifications are highly diverse, whereas regulatory DNA modification is largely limited to the methylation of cytosines.

The different epigenetic marks are recognized by reader proteins that affect gene expression. Although these marks can have complex effects, some broad patterns are evident, like for example repression of transcription through CpG methylation.

Although methylation serves an important regulatory role, it turns out not all species have methylation at CpG sites. Bacteria have a different type of DNA methylation whereas C. elegans seems to have lost this feature altogether during evolution.

The rise of epigenetic clocks

When we age, so does our epigenome and one way to measure this epigenetic aging is through so-called DNA methylation clocks. Many studies, initially pioneered by Steve Horvath, have shown that methylation at certain sites in the genome can be used to construct a clock that closely tracks the passage of time.

These clocks are exciting because they are much better at predicting chronologic and biological age than the biomarkers we used to have. In fact, I still remember going to conferences and listening to talks that painted a rather disappointing picture of blood based aging biomarkers.

These clocks are also exciting because they promise to become a surrogate endpoint for medium sized phase II-like studies. A surrogate endpoint is a cheap, easy-to-measure marker that substitutes for something else that is more expensive. The hope is that a slowing of epigenetic aging in small studies would be predictive of success in larger trials that focus on harder outcomes like health and survival. If true, this would push down the cost of trials by orders of magnitude because we could pre-select promising compounds before going into large studies. However, even the best surrogate endpoints like LDL or HDL cholesterol cannot substitute for large studies, as the countless failures and disappointments in the clinic show (e.g. CETP-inhibitors for atherosclerosis and the clinical failure of most non-statin drugs).

Another reason why clocks are important is their link with the biology of aging. Understanding why methylation at certain sites changes and what harmful effects these changes have, could improve our understanding of aging and allow us to find new therapies. To give an example of such advances, as mentioned in a prior podcast, the study of epigenetics has uncovered not only the importance of entropy in the process of aging, but also ways to reset some of these age-related changes (partial reprogramming). 

Stochastic Changes and Aging

These changes refer to random alterations in the DNA, epigenome or even proteome that accumulate over time. David Mayer's work suggests that these stochastic changes, or noise, may play a significant role in aging and may be the age component that epigenetic clocks actually measure. Understanding these changes could provide insights into why people age at different rates, if we find the drivers of increasing noise or even means to reverse it.

In a way the idea that stochastic changes drive aging is a very old one and dates to aging theories like the error catastrophe theory. Initially, it was believed that DNA will accumulate damage, which is then transcribed to produce proteins of lower quality which will further increase damage accumulation. Although there may be no error catastrophe per se, the concept has been rediscovered recently. It may very well be that such stochastic errors accumulate, both on the gene and epigenetic level, which decrease the functioning of gene expression networks, finally resulting in reduced resilience and aging.

There are several interesting aspects of these stochastic theories. One is the potential irreversibility. Aging may be hard to reverse if stochastic, very random, scattered, changes are key drivers rather than a few well-defined damage types or “hallmarks”. This worry has been recently echoed by voices like Peter Fedichev. Because stochastic changes are hard to reverse, and hard to “titrate” in experiments, these theories are also very difficult to prove. For example, there is still no smoking gun experiment showing that reduced DNA damage accumulation slows aging or that increased accumulation accelerates aging. The former has proven devilishly hard since DNA damage repair is so efficient. Whereas the latter is always controversial since models of accelerated damage accumulation often show damage levels that are either too high, too low or too specific (hence it is hard to “titrate” to the correct level).

In this context, we also discussed attempts to disentangle the stochastic component of clocks from an adaptive one, as recently proposed by Vadim Gladyshev. It remains to be seen if this will allow us to pinpoint genes that have important functions with aging.

This special the episode of the Aging Science podcast is brought to you from the ARDD conference that took place at the end of August in Kopenhagen. I sat together with Dr. David Meyer from CECAD and Prof. Sarah Voisin ...
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October Longevity Research Newsletter
November 7, 2023
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
October Longevity Research Newsletter

Introduction

Welcome back Vitalians and please join us in congratulating the Oisín Biotechnologies team for passing the VitaDAO token holder vote with 86.47% voting in favour! This proposal was an assessment of a multi-asset longevity biotech company pioneering genetic medicines to combat sarcopenia and other age-related diseases to promote healthier, longer lives.

VitaDAO's Members Portal is LIVE! We want to give tokenholders the opportunity to access health products and services at a discounted price. Currently we have offers with Glycanage and Bon Charge with many more to come.

Stop the press! AgingDoc is AgingDoxxed! After years of speculation as to who was behind this Twitter account:

David Barzilai MD PhD, MS, MBA, DipABLM has revealed his identity!!!! Read here to find out why he made this decision. 

We are also excited to announce that we interviewed David this month, who shared his thoughts on the longevity field with us - check it out at the end of this newsletter! Enjoy!

Longevity Literature Hot Picks

Preprint Corner

The Longevist editors have whittled down a longlist of over 60 longevity preprints from Q3 down to 10 amazing contenders! The Snapshot vote will begin soon to determine which ones our curators think will have the biggest impact in the longevity field.

Check out these latest preprints, each of these will be entered into the Q4 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

Spatially and Functionally Distinct mTORC1 Entities Orchestrate the Cellular Response to Amino Acid Availability

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

Dietary restriction extends lifespan across different temperatures in the fly

Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer

Elevated epigenetic age in wild compared to lab-raised house mice

The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses

Published Research Papers

Apoptotic stress causes mtDNA release during senescence and drives the SASP

The Passos lab have previously published research showing that mitochondria are essential for the pro-ageing features of the senescent phenotype. Now they have followed this up with a Nature paper showing that mitochondria in senescent cells develop macropores which allow mitochondrial DNA to leak out into the cytosol and activate the cGAS-STING pathway, which is a major regulator of the senescence-associated secretory phenotype (SASP).

Biomarkers of cellular senescence and risk of death in humans

This study analysed the levels of 28 SASP proteins in the patients’ blood and discovered that high levels of GDF15, RAGE, VEGFA, PARC, and MMP2 were particularly predictive of mortality. 

Effects of iron homeostasis on epigenetic age acceleration: a two-sample Mendelian randomization study

In this paper, the authors showed that higher levels of serum iron were linked to an acceleration of various epigenetic clocks associated with aging, including GrimAge, HannumAge, and Intrinsic epigenetic age

Multi-species atlas resolves an axolotl limb development and regeneration paradox

Using a multi-species transcriptomics approach, this study confirmed the presence of apical-ectodermal-ridge (AER)-like cells in axolotls, a key model organism for regeneration, while noting that complete reformation of AER cells during limb regeneration was not observed. Additionally, the research identified elements of the AER machinery within the axolotl mesoderm, offering insights into the mechanisms of limb (re)growth and resolving the debate surrounding the role of AER in axolotl limb regeneration.

Repurposing Metformin for periodontal disease management as a form of oral-systemic preventive medicine

This study addressed the global prevalence of periodontal disease (PD) and its association with diabetes, emphasizing the role of glucose metabolism modulation as a significant factor in non-communicable disease development. By repurposing Metformin, the research demonstrated that pharmaceutically controlling glucose metabolism led to the prevention of bone loss associated with induced periodontal disease and aging. 

Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis

The research identifies Gremlin 1 (Grem1) as a marker for progenitor cells in cartilage that can become bone or cartilage cells. These cells decrease with age and injury, contributing to osteoarthritis (OA). Loss of Foxo1 function in these cells leads to OA. Treatment with FGF18 promotes these progenitor cells' growth, improving cartilage and decreasing OA, pointing to potential OA treatments.

Transcriptomic analysis reveals a tissue-specific loss of identity during ageing and cancer

This study found aging results in the downregulation of tissue-specific genes in 40% of tissues. In cancer, a similar loss of identity occurs with tumors expressing genes from different tissues, influencing patient survival independently of their age.

A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells

This research presents a new tool, a soluble transhydrogenase from E. coli, to study reductive stress by increasing NADH/NAD+ ratios in cells. It offers a fresh approach to investigate redox imbalances in diseases.

The total mass, number, and distribution of immune cells in the human body

Whilst not a longevity paper per se, it begs the question: how do these stats change with age?

The association of leukocyte telomere length with exceptional longevity among older women

This study investigates the correlation between leukocyte telomere length (LTL) and the likelihood of living to age 90 with good mobility among postmenopausal women. Findings suggest women with longer LTLs had higher chances of reaching age 90, with or without mobility issues. 

Platelets rejuvenate the aging brain

The studies investigate different aspects of brain function and aging but converge on the finding that platelet factor 4 (PF4) can rejuvenate cognitive abilities in older mice. This marks the first evidence of platelets and PF4 as regulators of brain cognition.

Decoding aging-dependent regenerative decline across tissues at single-cell resolution

The study analyzes how aging affects tissue regeneration, revealing that aged tissues have reduced stem cell movement and blood vessel formation, and a distinct type of macrophage active in young but not old tissues, pinpointing targets for improving regeneration in the elderly.

A fluorophore-conjugated reagent enabling rapid detection, isolation and live tracking of senescent cells

The article presents a new tool, GLF16, for identifying senescent cells using fluorescence techniques. With a novel delivery method using micelles, this approach allows for easier, more precise isolation and analysis of live senescent cells, both in vivo and in vitro.

Published Literature Reviews, Hypotheses, Perspectives and more

Combinatorial interventions in aging

Biomarkers of aging remain elusive as researchers try to slow the biological clock

Device-measured physical activity, sedentary time, and risk of all-cause mortality: an individual participant data analysis of four prospective cohort studies

The ticking of aging clocks

Insulin and aging – a disappointing relationship

Job board

Dr Bernadette Carroll is looking to recruit a research associate to work on various aspects of membrane dynamics and cell signalling at University of Bristol. The aim is to investigate the role of non-canonical mTORC1 activity at focal adhesions.

The Webb Lab at The Buck Institute is recruiting 1-2 postdocs to work on mechanisms of brain aging and neurodegeneration!

Kapahi Laboratory at The Buck Institute are looking to recruit 2 Postdocs to work on applying bioinformatic approaches to study eye aging and neurodegeneration using flies and mammals. The lab values include curiosity driven science, team spirit and mentorship. 

The Kane lab at the Institute for Systems Biology is seeking a highly motivated Postdoctoral Fellow interested in the biology of aging to lead projects focused on understanding, measuring and predicting heterogeneity in aging, and particularly identifying epigenetic determinants and biomarkers of frailty 

The Kohler Lab have an open call for a PhD student to work on the fascinating interrelation between Proteostasis and Ageing, combining High Throughput approaches in Yeast with validation in Cell Culture.

The Whitworth lab at the University of Cambridge are recruiting a PhD student who is interested in unravelling the ways that impinging on mitochondrial calcium can prevent neurodegeneration.

Marta Kovatcheva launching a new lab and is looking to hire a postdoc who will use novel lineage tracing strategies to probe the contribution of partially reprogrammed cells in vivo.

The Korolchuk Lab is offering a new PhD opportunity, working closely with Procter & Gamble to investigate mechanisms of skin ageing. 

Two PhD positions available at the Tayilor Lab on 1) the roles of a novel prion-like protein in stress resistance and aging and 2) the unfolded protein response, restoring homeostasis and a new regulator of aging.

News and Media

Gero raises $6 million to find root causes of aging and age-related diseases

BioAge Labs Announces Plans for Phase 2 Trial of First-in-Class Apelin Receptor Agonist BGE-105/Azelaprag Co-Administered With Tirzepatide for Treatment of Obesity, in Collaboration With Lilly’s Chorus Organization

BATPROTECT: Learning from Bats: New strategies to extend healthspan and improve disease resistance

ERC funding: 11,882,510€ over 72 months

You might have heard of Ora Biomedical’s ambitious endeavour to assess 1,000,000 longevity interventions in 5 years, catchily named The Million Molecule Challenge! Now you can help support his endeavour by becoming a sponsor!

LongeVC: What longevity investors are really looking for

Prizes

A brand new Longevity Prize has launched and accepting application over the next couple of months. The Longevity Funding Innovation Prize initiated and funded by Marat Karpeko is going to award $20,000 USD for the most innovative and potentially impactful longevity funding strategy. The judges want to see a real action plan and tangible solution for real world impact.

Keep in mind the key dates:

  • Kick-Off: 20th September 2023
  • Proposal Closing: 20th December 2023
  • Evaluation Wrap-Up: 20th February 2024
  • Champion Unveiled: 29th February 2024


Conferences

Seno-Therapeutics Summit 2023

7-8 November, Buck Institute for Research on Ageing, Novato, CA, USA

Ageing Research at King's (ARK) Longevity Week 2023 - Sustainable Longevity: Harnessing Consumer HealthTech and FinTech

17 November, King’s College London, UK

The Longevity Forum’s - The Longevity Week

13 -17 November 2023

17 November DeSci & Longevity Biotech 2023 — A Próspera Builders’ Summit

Careers in Aging Day at GSA 2023

Friday, November 10, 2023 – Full-day event, Tampa Waterfront Marriott, 505 Water St, Tampa, FL, US  

NUHS Centre for Healthy Longevity - Unlock Healthy Longevity: Supplements

Scientific Conference: February 29th - March 1st, 2024. This is the first global scientific conference focused solely on the role of supplements as a geroprotective intervention.

The Longevity Summit

4-5th December, Novato CA, Buck

BAAM

7th December, Stanford

Tweet of the Month

Peter Fedichev: It may sound strange, but beyond our "longevity" bubble people often ask: what are the reasons, scientifically, culturally, etc. for the reasons why people want to stop aging? My guess is that consciousness, once emerged, faced the vastness of universe and shortness of life. Hence two dreams, of flight and immortality are universalities of human inspirations transcending all the cultural differences. And this is why, in relation to those questions, I like to tell the following story. Continue reading here...

Podcasts and Webinars

NUS Medicine’s Healthy Longevity Webinar Series

Funding Opportunities

SCPAB Transition to Independence Award supports researchers investigating the mechanisms of cognitive resilience and functional maintenance of the healthy aging brain. Experience in aging research is not required; the program welcomes applications from candidates with backgrounds in neuroscience, molecular biology, genetics, immunology, cell biology and the physical and information sciences.

Interview with Agingdoc, or Dr David Barzilai

What inspired you to enter the longevity field?

Almost as far back as I can remember, I’ve been profoundly struck by the extent of life’s hardship and brevity. At the same time, I love the sciences including biology, and like most of us, I’ve always wanted to make my mark in world helping others.  So, with that as background, and following studying biology and public health related studies in college, I determined to enter medicine, so that I could help alleviate suffering and cure when possible. This was an MD-PhD program in health services research- which taught me much about medicine, evidence-based practice, asking good questions, studying them, and appraising published work.

My keen interest in, or what some may call “obsession,” for optimizing my own health pervaded all these stages in my life, and motivated me to avidly read far wider and deeper than my medical training required. I’ve followed the geroscience literature and see the potential of insight from aging biology to address healthy longevity. These passions were the seed for my getting involved in the longevity space.

I have turned to social media as one manifestation of these interests. By collating significant publications and creating a space for people with varied perspectives to learn and discuss, I aimed to bridge the gap between scientific communities and the public. This initiative not only fosters a collective understanding but also catalyzes a multi-dimensional contribution towards advancing the field of longevity. I did so anonymously for several years, but on my 49th birthday in August 2023 I came to the realization that I could still do so much more simply post publications. It’s time to apply my knowledge more directly. So since then, I’ve worked on what I dubbed “project 49” – starting with coaching and consulting a few clients to experience one-on-one in the longevity space – and from there branching out to more public role of geroscience advancement, advocacy, and general awareness. 

Did your general medical training include anything on geroscience and what do you think should be taught in medical school?

In medical school, the focus was essentially: (a) prevent disease (b) diagnose it- which by definition is primarily after it manifests, (c) treat it- and at best cure it, and if not, at least improve symptom burden and quality of life. At first blush, it’s not a terrible way of looking at health. While it has some preventative focus, the amount of time spent in these areas in medical school paled in comparison with complex excursions into the pathophysiology of disease and vast therapeutic armamentarium that can be applied to illness after it manifests

 I’ll spare a long analysis here on why, but suffice to say it did a better job of preparing future doctors for diagnoses to make later into the underlying biology than would be ideal, and treatments to give late in the game when it’s already an uphill battle making a difference.

It seems to me that we need a stronger preventative focus, and one that not only more strongly emphasizes lifestyle medicine, but also invests in the development of biomedical technologies that directly address the molecular mechanisms driving disease itself.

In other words, I’d like to see curriculum and incentives more strongly aligned towards favorable outcomes for patients, starting with prevention. I’d also like to see geroscience incorporated formally into the curriculum, because while we are still only scratching the surface, the fact (unbeknownst to me in medical school) that there is an underlying biology of aging that we can make a concerted effort to target is no less than revolutionary. We’re starting to make progress, but in medicine, awareness of the field is still minimal. That needs to change, and when society comes aboard, we can take steps together toward better targeting aging biology and with it our healthspan long before overt disease manifests, when we may be able to do much more about it.

How has the field changed since you started?

The field has changed dramatically over only a few decades. We’ve literally gone from questioning whether single genes can impact lifespan in an organism such as C elegans (which we found yes, they can), to targeting genes and gene expression to increase not only lifespan, but apparent health too. 

We have powerful tools emerging across the hallmarks of aging, from epigenetic reprogramming and deployment of senolytics or senomorphics, to genetic engineering, and cell-based therapies. Our tools are not only getting more powerful (CRISPR, scRNASeq analysis, microfluidic chips, you name it), but also are getting more sophisticated at evaluating their output via computational (including machine learning) models. Progress is speeding up with high throughput research pipelines, incorporating robotics and the latest technology.  Even our older models are being revisited now, but with a modern spin: In parabiosis, for example, we’re examining whether there may be potentially useful blood factors (from hormones to exosomes  and small molecules) in younger organisms, or alternatively harmful ones that need to be either filtered out or diluted to achieve a more youthful phenotype.

We’re also starting to scrutinize biological age, and its rate change.  Measuring and tracking biological age is of utmost importance to the future of successfully translating this work to healthy longevity in humans. This requires reliable surrogates for tracking biological aging. While not a replacement for better validated traditional functional biomarkers, progress is being made. Such development and validation would greatly accelerate progress in the deployment of trial-proven geroprotectors for healthy individuals in our lifetime.

Which of the current theories do you think are most promising?

I believe that multiple aging theories are compatible with the same biological process, and that we’re going to require computational AI tools to take their utility to be more useful developing longevity medicine therapeutics. If you are satisfied with this, skip to my next answer. If you’re interested in a deeper dive, keep reading the rest of this section below.

The expression “theory of aging” is imprecise. Sometimes this describes a process, say sources of metabolic or other damage and their sequela. Other times they focus on how these are evolutionarily permissive- mostly under the antagonistic pleiotropy rubric, including its “dysfunctional pseudoprogram” conceptual model. Yet while we can conjecture and model plausibility, we cannot observe evolution in real time, so I focus on the former meaning of “theory of aging” – the change that arises during biological aging.

Biological systems obey the laws of physics, but the complexity arising from nonlinear relationships and higher-order emergence challenges the notion of a single encompassing theory. Thus while many theories today encompass aspects of aging at an intuitive level, what will be most useful are models that can make reliable predictions that can accelerate progress towards therapies. To do so, our best chance may be utilizing computational modeling of empirically obtained data. As for today’s models, I believe the majority either (a) describe the same process through different imprecise human analogies, (b) capture different aspects of biologic aging arising spontaneously in parallel, or both. As entropy increases at the molecular, cellular and organismal level, chaos arises through loss of information, damage, and dysregulation of signaling, and other departures from biological homeostasis and integrity. Thus, while distinctions can be made in emphasis, I do not believe these are fundamentally mutually exclusive, and at their core all describe a unified process.

My primary interest is what works; ultimately the experiments will arbitrate the relative importance of different explanatory models in describing aging as a targetable process. I believe, that useful models exist and have been created, and theorizing continues to be helpful both conceptualizing the problem and theorizing solutions (for example genomic instability- fix the genome, epigenetic drift- revert to a more youthful state, molecular damage- address ECM and other units of disarray, inflammation or hyperfunction- employ nutrient sensing modulators to mitigate these, etc).

Yet I also believe that there is a natural limit to how far our conceptually satisfying yet deceptively oversimplistic models of aging will take us. Computational models employing AI are likely to be increasingly valuable helping us break down complexity, into black box predictions whose basis may elude us, yet nevertheless be leveraged to progress.

What do you think have been the biggest/most important discoveries of the field? 

The largest in my mind was our finding that targeting one gene (we’ve found many since then) can have a meaningful impact on lifespan or health. Until this work, biogerontology was more devoted to describing aging than aspiring to target it directly. The second, from the Interventions Testing Program (ITP), that mammalian models can be given interventions that extend lifespan even when given at the equivalent of late middle age. And not only by one molecule, but now several. While we can’t say the impact in humans yet (particularly as we’re already more efficient at damage repair than the shorter-lived models we are studying), it remains a tantalizing prospect that in theory longevity interventions introduced in late adulthood could in principal be successful. ITP should also be recognized for drawing attention to the strong impact of gender on all of these. If we imagine an equitable healthy longevity future for all, it is vital we do the research to see what works for everyone.

What aspects of longevity research do you feel requires more attention?

The short-version is we need a broad agenda, one that incorporates both short and long-term goals, one that balances pragmatism with moonshots, as well as foundational research towards validation of biomarkers so that human longevity trials can be attainable in our lifetime. We also need to mobilize widespread political and social support for translational research pivotal to our capacity for making a real impact on patients (and healthy human lifespan).

There is more about aging we don’t know than we do at this point, and diversification of approaches is our best way forward.  This means funding labs focusing on all aspects of aging biology, from genetic engineering to epigenetic reprogramming. Likewise, we should balance short-term lines of inquiry farther along the investigative, therapeutic and regulatory pipeline, along with long-term more challenging and ambitious projects.  This way, we can embrace what is most likely to translate to therapy in the near term, while also sustaining investment in high-risk, high-reward longevity moonshots. 

Assessing whether known mouse gerotherpeutics work in humans is important low lying fruit, and frankly something I wish we had pursued much more aggressively all along.  Specifically, I am thinking of rapamycin/rapalogs, canagliflozin and 17-alpha estradiol (males), acarbose, several others from ITP including more recently astaxanthin and meclizine, and others, including supplements and nutraceuticals such as taurine, spermidine, urolithin A, fucoidan, alpha ketoglutarate, novel NAD+ boosters, and others. The high safety profile, modest cost and efficient pipelines for approval and distribution make nutraceuticals of even modest expectation excellent candidates. 

So, how do we get the most bang-for-the-buck investing our resources? My first interest, and I suspect yours also, is how do we get safe and effective therapies to humans as efficiently as possible? It would be great for us to be around when the first generation of translational geroscience interventions arrive. 

There are several models for investigation that may help us get there. I support TAME which may be cost prohibitive to apply to all interventions, but the hope is that it may not only narrowly evaluate metformin’s off-label geroprotecive efficacy, but may also support precedent for other gerotherapeutic trials focusing on a panel of aging-associated outcomes rather than focusing on one disease indication. Alternatively, seeking FDA-approval for non-aging indications for modalities that nevertheless work by targeting underlying aging biology is generating optimism that  progress can be made without the requirement of FDA recognition of biologic aging as a drug-approval indication itself per se. 

There are certain key scientific matters that if overcome would help tremendously.  Human lifespan studies are fundamentally untenable, and the field direly needs validated biomarkers, so that shorter term trials can provide reliable and convincing evidence on efficacy. If we can get there, it would entail validating a panel of predictive aging biology surrogate variables such as methlation clocks, and broader -omics panels integrated with more traditional clinical markers such as tracking functional decline, (eg, walking speed, grip strength, etc) predictive of further morbidity and lifespan.

What mistakes do you think the longevity field has made?

I believe we have been slow to build collaborations between academic medical center labs and industry despite having the common aims of helping discover, validate, develop, and deliver gerotherapeutics. We have also failed to invest enough on the public and policy side on the value of geroscience from both a fundamental public good and economic investment standpoint.  Our competitive spirit and fierce independence as labs and longevity biotechs are strengths that should be incentivized. We also need to build bridges, across academics, industry, and organizations, and governmental agencies. We can do this responsibly, with appropriate checks and balances around safety and efficacy, while more efficiently, and without delay.

Is aging a disease?

Is aging a disease? Innumerable arguments have been made, with publications and conference symposium panels all focused on this issue. The answer is simple: It depends on how we chose to define aging, and how we chose to define disease.

The bottom line is this: Aging biology can be argued to be the ultimate risk factor for not one, but a wide multitude of diseases. At the very least, we can observe that something in the aging process- and its molecular underpinnings- is permissive to the development of disease. Thus ultimately, if we are interested in mitigating the negative impact of disease, targeting biologic aging is a sensible approach.

Precisely because biologic aging is intertwined with not one, but a wide multitude of diseases and poor health states (including frailty and lack of resilience), targeting aging biology before it deviates from the state of youth holds the potential to reduce the overall burden of chronic disease.

What do you think are the most important endpoints, biomarkers, and measurements to be taken in human clinical trials for interventions that can impact general healthspan?

This is very much in flux, and we aren’t there yet. The emergence of epigenetic methylation clocks- in particular 2nd and 3rd generation- on the landscape have done much to instill optimism. I do not believe any one measure is likely to get us there. There simply is too much uncertainty including whether prediction can be disentangled from biology (ie, the theoretical possibility that an intervention reduces one measure of biologic aging readout without concurrent improvement in physiology). Thus as I described previously, we’re going to need broad panels with many biomarkers of every kind complementing traditional better validated laboratory and functional surrogates for healthspan and mortality. 

Do you think standardization can be a concern in human aging studies, how hard do you find it to compare findings from studies conducted by various institutions including academic and clinical ones?

Do I  think standardization can be a concern in human aging studies? Absolutely. As you hint, studies are phenomenally disparate. This can be frustrating and confusing, and complicates our efforts towards coordinating efforts and insight into what might account for different results between studies. All the more so when we either pool results for meta-analyses or attempt to mine them for deeper insight via computational large data tools including via AI. Thus I do believe in standardization, and this is arising in various forms, whether consensus conferences on protocols or collaborations such as through the NIH SenNet Consortium, or individual initiatives such as at the ITP which attempts to control experimental differences between centers.

Lack of standardization can be highlighted by the monkey caloric restriction trial, which was frustrating in that results varied between the two (though at least for lifespan, both had groups remarkable improvements in health measures), with remarkable differences in diet genetics, diet quality, diet composition, and frequency of feeding. The poor replication in CITP was another remarkable illustration of the replication crisis affecting geroscience. And as AI models rely on collating varied data sources, consistent input is increasingly necessary for accurate and insightful outputs. So, the need for standardized protocols is greater than ever. 

Where do we find you?

I’m on Twitter @agingdoc1. My Twitter account has been a way to give back by sharing interesting and topical publications for critique/debate, as well as to keep health influencers and scientists “in the know,” so they can stay informed, and thus better educate their audiences (the media & general public) on the good and bad of what is out there. I also continue to be passionate about the synergy of bringing together different communities (from aging biologists to biotech, media, thought leaders, health influencers, and avid biohackers) and I plan to continue that mission, bringing timely and interesting content from across the web to my @agingdoc1 channel.

I’ve been anonymous for years on Twitter but ultimately on my 49th birthday (I secretly called this “project 49” before the big announcement) I decided to reveal my identity. Basically I felt like I could use more of my capabilities and do more good in the world being public than private. I’ve started to do only a little coaching and consulting (this is not a medical practice so I do not diagnose, treat or prescribe but discuss collaborate with my clients generally highly invested in their health and wellbeing). But because I only have a few hours a week to the endeavor, I recognize only a few individuals can take advantage of it. Thus I continue to try to make a broader impact other ways such as by the service I mentioned, and outreach, such as possibly by podcast or here today with you today.

Because of my last name (no relation to Nir for those wondering!) and coaching related work I have a website http://barzilaiconsulting.com, but for ease I have other webpages point to it like http://agingdoc.com and http://healthspancoaching.com. In any case, thanks for inviting me, and I hope I helped a little.

VitaDAO is an amazing organization. I’m as thrilled by the advancing science as I am with the revolution going on starting with leaders like you, at the grassroots, helping transform our culture and bringing the change we would like to see in the world. This is the day for a longevity moonshot. Together, we are making it happen.

David Barzilai, MD PhD – “Agingdoc” 

http://youtube.com/@agingdoc

http://agingdoc.com / http://healthspancoaching.com 

https://twitter.com/agingdoc1 

My letter: https://www.barzilaiconsulting.com/49  (“Project 49” 😊)

Outro

We appreciate you sticking with our research newsletter for another month and hope you’ve found the content useful!

This time we leave you with a fun new article on research by Dr Shahaf Peleg and Dr Andrew Wojtovi that we’ve featured in the letter before: Shining a Light on Optogenetics: An Innovative Approach to Combat Aging

Further Reading

Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal ageing

Blazing a trail for the clinical use of rapamycin as a geroprotecTOR

Welcome back Vitalians and please join us in congratulating the Oisín Biotechnologies team for passing the VitaDAO token holder vote with 86.47% voting in favour! This proposal was an assessment of a multi-asset longevity biotech...
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Introducing the VitaDAO Members Portal
November 3, 2023
Awareness
Longevity
Introducing the VitaDAO Members Portal

VitaDAO is partnering with leading companies to offer substantial discounts on their products and services, exclusively for our members.

Our members are enthusiastic advocates of a range of longevity and health optimization interventions in their daily lives. Depending on age and health status, individuals may have different goals when exploring longevity protocols. This can range from improving athletic performance to enhancing metabolic health to preventing osteoporosis and more. We want to give them the opportunity to access health products and services at a discounted price. Some examples include discounts on wearables, at-home health test kits, supplements, biohacking tools, and more.

In addition to health products and services, we also offer discounts on common expenses such as hotel stays, short- to long-term rentals, coworking spaces, academic publications, and more.

We’re launching our portal with discounts on

  • GlycanAge — Discover your biological age, make lifestyle improvements, and track your success with GlycanAge tests.
  • Sonder — Premium, stylish, and fully serviced accommodations in over 40 vibrant cities worldwide.
  • Bon Charge — From blue light blocking glasses to sauna blankets to PEMF mats to red light therapy devices, Bon Charge offers everything you need to protect and optimize your health in this digital age.

More products and services will be added over the following weeks and months. For example, discounts on health programs with access to specialists, including medical doctors. Future services also include discounted access to exclusive events and curated meetings with leaders in the longevity space.

The 3 we’re launching with

GlycanAge

Get 31% off GlycanAge tests to determine your biological age

Extend your health span today. Discover your biological age, make lifestyle improvements, track your success.

GlycanAge is a biological age test paired with expert advice to help guide your wellness. It determines your biological age by measuring chronic inflammation in your system — which is directly related to your lifestyle. As a member, you now have discounted access to a groundbreaking approach that empowers you to take charge of your health and longevity.

GlycanAge leverages cutting-edge technology, providing valuable insights into your biological age. With this information, you can make informed decisions about your lifestyle, nutrition, and wellness strategies to promote a healthier, more vibrant life.

GlycanAge is based on more than 25 years of scientific research and over 200,000 tests. Their scientists regularly publish in world renowned Medical Journals.

Collect your sample. Collect and return your dry blood sample using an at-home test kit.

Receive your results. It takes about three weeks for the lab to analyse your sample and generate your report.

Talk to experts. A consultation is included with each test. Specialists will help you review your results and suggest lifestyle changes to help you improve your health.

GlycanAge has pricing and plans affordable for anyone! Choose the plan that suits your needs!

Bon Charge

Get 15% off science-backed wellness products to optimize your sleep, wellbeing and recovery

Premium. Science-Backed. Effective. From blue light blocking glasses to sauna blankets to PEMF mats to red light therapy devices, Bon Charge offers everything you need to protect and optimize your health in this digital age.

As a VitaDAO member, you get 15% off Bon Charge’s wellness products to safeguard your health while you work and play in the digital world.

From better sleep and relaxation to faster recovery and optimized wellbeing, Bon Charge’s science-backed wellness products are here to elevate your life. Whether you’re at your desk or on the go, our partnership ensures you have access to premium products that support your well-being.

Work and relax with confidence, knowing that you have the best in health protection with Bon Charge.

Sonder

Book a Sonder in 40+ cities up to 50% less

Looking for an exceptional stay for your next DeSci conference? Look no further. VitaDAO has teamed up with Sonder to make your travel experience a little better.

As part of this exclusive collaboration, our valued members now have the opportunity to book Sonder accommodations in over 40 vibrant cities worldwide at a discount of up to 50%. This partnership aims to elevate your travel experience, offering you premium, stylish, and fully serviced accommodations at unbeatable prices.

Booking a Sonder through our platform couldn’t be easier. With a variety of options, from cozy studios to spacious apartments, you can choose the perfect accommodation that suits your needs.

Browse the selection of Sonder properties in your desired destination. When you’re ready to book, simply use the discount code below for up to 50% off, making your stay both affordable and memorable.

Say hello to an elevated travel experience with Sonder and our exclusive partnership. Start exploring the world with comfort and savings today!

Visit the VitaDAO Members Portal https://vitadao.global

VitaDAO is partnering with leading companies to offer substantial discounts on their products and services, exclusively for our members.
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Shining a Light on Optogenetics: An Innovative Approach to Combat Aging
November 1, 2023
Maria Marinova
Awareness
Longevity
Shining a Light on Optogenetics: An Innovative Approach to Combat Aging

 

Mitochondria in the spotlight: Powerhouses Dimming with Age?

In the intricate ballet of cellular activity, mitochondria often play a leading role. These double-membraned organelles are frequently referred to as the "powerhouses" of the cell, converting nutrients into energy that fuels nearly everything we do. But, as with all things, age takes its toll on them (Clemente-Suárez et al., 2023).

Mitochondrial dysfunction is one of the central features of aging (Payne & Chinnery, 2015). Many strategies designed to prolong life and maintain good health into old age focus on these cellular structures. From diets to drugs like metformin and rapamycin, various interventions aim to tweak mitochondrial metabolism (Amorim et al., 2022). Interestingly, many of these strategies work by reducing mitochondrial activity. This may sound counterintuitive, but certain studies have shown that decreasing specific aspects of mitochondrial processes can actually increase an organism's lifespan (B. Hwang et al., 2012; Campos et al., 2021). However, there's a catch. Reducing mitochondrial function often comes at the cost of the organism's vitality and its ability to handle stress (Aragoni Da Silva et al., 2023). Thus, the question remains: can such an approach be realistically applied to humans? 

From Plants and Bacteria to Humans: A Radical Shift

All animals, including humans, need to consume other organisms for fuel, however some life forms, such as plants, algae and cyanobacteria have evolved to create their own fuel from sunlight, by mastering the art of solar power at the cellular level (Havurinne & Tyystjärvi, 2020).

It is thought that all organisms on the planet share a common ancestor, and thus many cellular mechanisms are universal, such as DNA for storing genetic information, ribosomes for producing proteins or the use of ATP as cellular energy currency. This allows opportunities for mechanisms from one organism to be utilised in another - take, for example, the CRISPR/Cas9 system, adapted from bacteria, that has revolutionized genetic editing in animals (Kick et al., 2017).

 A Bright Idea: Optogenetics

To generate energy, our cells rely on a remarkable mechanism known as the electron transport chain. This process uses energy to push protons across the mitochondrial membrane, creating a kind of energy imbalance. Later, these protons can flow back through special channels, triggering the production of ATP. Think of it like how a battery operates. However, as we age, this process can become dysregulated, leading to a decrease in efficiency and even leakage of toxic free radicals.

The proposed strategy revolves around an engineered protein from fungal origin (Leptosphaeria maculans) called mtON, which is light-sensitive protein that pumps the aforementioned protons through the electron transport chain. When exposed to light, mtON pumps protons across the mitochondrial membrane, aiding in the creation of ATP, the cell's primary energy molecule (Tiwary et al., 2023). What's fascinating here is that this system allows a cell to produce energy from light, circumventing the regular process, and potentially rescuing dysfunctional mitochondria in aging cells (Berry & Wojtovich, 2020). This is not mere speculation. Groundbreaking experiments have already demonstrated that this light-based approach can enhance lifespan in worms (Berry et al., 2022).

Harnessing the power of light for energy transduction in our cells could have profound effects on the way we age. By rejuvenating aging cells, the mtON approach offers a ray of hope for tissues that suffer from declining mitochondrial function. Aging cells, which struggle to produce adequate ATP due to faltering mitochondria (Berry & Kaeberlein, 2021), might find a new lease on life with the introduction of mtON.

Furthermore, aging isn't just about the passing of time; it's also about the wear and tear our cells experience. With ATP potentially being produced from light, we might see a decrease in overall cellular metabolic activity. This translates to reduced waste and a subsequent slowdown in the accumulation of cellular damage. Importantly, there might also be a drop in oxidative stress, a significant contributor to the aging process (Warraich et al., 2020).

One of the most bold potential implications revolves around our dietary needs. While this sounds like science fiction, maybe in the future, the light-driven energy transduction could even reduce our reliance on food for energy. This could allow us to enjoy the benefits associated with calorie restriction, which is known to promote health and longevity (Dorling et al., 2020), without the associated downsides of reduced energy intake. This shift might redefine our relationship with food and our understanding of metabolic health. But enough daydreaming for now…

The Future is Bright

To sum up, using light as an alternative energy source at the cellular level could pave the way for groundbreaking treatments against aging. While this hypothesis is still in its early stages, its potential is vast. Perhaps one day, instead of just basking in the sun for warmth, we might be doing it to recharge our cells!

Proposal author and Longevity Prize 3rd place winner: Dr Shahaf Peleg and Dr Andrew Wojtovi

Writer: Maria Marinova

Editors: Adrian Matysek, Rhys Anderson

References 

Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A. (2022). Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nature Reviews Endocrinology, 18(4), 243–258. https://doi.org/10.1038/s41574-021-00626-7

Aragoni Da Silva, J., Rolland, Y., Martinez, L. O., & De Souto Barreto, P. (2023). Mitochondrial Dysfunction and Intrinsic Capacity: Insights From a Narrative Review. The Journals of Gerontology: Series A, 78(5), 735–742. https://doi.org/10.1093/gerona/glac227

B. Hwang, A., Jeong, D.-E., & Lee, S.-J. (2012). Mitochondria and Organismal Longevity. Current Genomics, 13(7), 519–532. https://doi.org/10.2174/138920212803251427

Berry, B. J., & Kaeberlein, M. (2021). An energetics perspective on geroscience: Mitochondrial protonmotive force and aging. GeroScience, 43(4), 1591–1604. https://doi.org/10.1007/s11357-021-00365-7

Berry, B. J., Vodičková, A., Müller-Eigner, A., Meng, C., Ludwig, C., Kaeberlein, M., Peleg, S., & Wojtovich, A. P. (2022). Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan. Nature Aging, 3(2), 157–161. https://doi.org/10.1038/s43587-022-00340-7

Berry, B. J., & Wojtovich, A. P. (2020). Mitochondrial light switches: Optogenetic approaches to control metabolism. The FEBS Journal, 287(21), 4544–4556. https://doi.org/10.1111/febs.15424

Campos, J. C., Wu, Z., Rudich, P. D., Soo, S. K., Mistry, M., Ferreira, J. C., Blackwell, T. K., & Van Raamsdonk, J. M. (2021). Mild mitochondrial impairment enhances innate immunity and longevity through ATFS‐1 and p38 signaling. EMBO Reports, 22(12), e52964. https://doi.org/10.15252/embr.202152964

Clemente-Suárez, V. J., Redondo-Flórez, L., Beltrán-Velasco, A. I., Ramos-Campo, D. J., Belinchón-deMiguel, P., Martinez-Guardado, I., Dalamitros, A. A., Yáñez-Sepúlveda, R., Martín-Rodríguez, A., & Tornero-Aguilera, J. F. (2023). Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities. Biomedicines, 11(9), 2488. https://doi.org/10.3390/biomedicines11092488

Dorling, J. L., Martin, C. K., & Redman, L. M. (2020). Calorie restriction for enhanced longevity: The role of novel dietary strategies in the present obesogenic environment. Ageing Research Reviews, 64, 101038. https://doi.org/10.1016/j.arr.2020.101038

Havurinne, V., & Tyystjärvi, E. (2020). Photosynthetic sea slugs induce protective changes to the light reactions of the chloroplasts they steal from algae. eLife, 9, e57389. https://doi.org/10.7554/eLife.57389

Kick, L., Kirchner, M., & Schneider, S. (2017). CRISPR-Cas9: From a bacterial immune system to genome-edited human cells in clinical trials. Bioengineered, 8(3), 280–286. https://doi.org/10.1080/21655979.2017.1299834

Mansouri, M., Strittmatter, T., & Fussenegger, M. (2019). Light‐Controlled Mammalian Cells and Their Therapeutic Applications in Synthetic Biology. Advanced Science, 6(1), 1800952. https://doi.org/10.1002/advs.201800952

Payne, B. A. I., & Chinnery, P. F. (2015). Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1847(11), 1347–1353. https://doi.org/10.1016/j.bbabio.2015.05.022

Tiwary, V., Galow, A.-M., Wojtovich, A. P., & Peleg, S. (2023). Using light to drive energy transduction in metazoan aging. Trends in Biochemical Sciences, 48(11), 920–922. https://doi.org/10.1016/j.tibs.2023.08.010

Warraich, U.-A., Hussain, F., & Kayani, H. U. R. (2020). Aging—Oxidative stress, antioxidants and computational modeling. Heliyon, 6(5), e04107. https://doi.org/10.1016/j.heliyon.2020.e04107

 

In the intricate ballet of cellular activity, mitochondria often play a leading role. These double-membraned organelles are frequently referred to as the "powerhouses" of the cell, converting nutrients into energy that...
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VitaDAO Letter: The First DAO with a Biotech Spinoff
October 15, 2023
Sarah Friday
Awareness
VitaDAO Letter: The First DAO with a Biotech Spinoff

Despite the bear market, the VitaDAO community continues to push the boundaries of decentralized science (DeSci). This month has been particularly exciting, with developments such as the funding of ExcepGEN and the launch of MatrixBio. In this edition, we bring you the latest highlights:

  • Matrix Bio: VitaDAO’s biotech startup 
  • How to buy $VITA on Optimism 
  • Pfizer's representation at DeSci Berlin 
  • Recent VitaDAO proposals 
  • Awareness Working Group Contributor: Victoria Forest 

🧪A Landmark Achievement: VitaDAO’s Biotech Startup 

Ever heard of naked mole rats (NMR)? These long-lived rodents are cancer-resistant, thanks in part to the abundance of high molecular weight hyaluronic acid (HMW-HA) in their tissues. Previous research by the Gorbunova lab has demonstrated this link between cancer resistance and the abundance of HMW-HA.

This month, VitaDAO proudly became the FIRST DAO to kickstart a biotech company. This firm, Matrix Biosciences, will use insights from the Gorbunova lab to leverage the anti-cancer and pro-longevity properties of HMW-HA from NMR in humans. The creation of Matrix Biosciences marks a significant stride in both the field of longevity research and VitaDAO's portfolio.

🤑$VITA on Optimism 

$VITA is now on Optimism! Have you ever tried to make a transaction on the Ethereum mainnet and found yourself thinking “Not in this economy⛽️😫.” Say farewell to high Ethereum mainnet gas costs and take advantage of the ability to purchase $VITA on Optimism!

Unsure how to get started? Check out our step-by-step guide on acquiring $VITA on Optimism. Once you have $VITA, you can even use Velodrome to provide liquidity on Optimism. Additionally, $VITA is also accessible on the Gnosis chain. The expansion to L2s will hopefully make obtaining $VITA cheaper, more convenient, and more accessible for all HODLers! 

📚Hypothesis Prize: Exploring Winning Topics 

Maria Marinova has been busy collaborating with winners of the Longevity Prize. First-place winner Carlos Galicia suggested studying rejuvenation during embryogenesis as a means to combat age-related decline. Maria and Carlos explore this concept in their article, “The Key to Longevity Could Be Hidden in Embryos.”

Second-place winner Rakhan Aimbetov proposed focusing on proteostasis disruption in aging. Specifically, he focused on the role of methylglyoxal (MGO), a byproduct of sugar metabolism. In “Sugar Byproducts and How They May Influence Aging,” Maria and Rakhan explain how sugar remnants may contribute to aging. Stay tuned for the third article in the series featuring Shahaf Peleg's investigation of mitochondrial dysfunction! 

🌎VitaDAO in the Spotlight 

  • VitaDAO's global impact has earned a mention in Nature. We are proud to be one of several decentralized autonomous organizations contributing to innovative research funding methods. The transparency of blockchain and the collaborative spirit of our community has been recognized and featured in Nature Biotech, which notes: "Decentralized autonomous organizations are growing as alternative research funding models, but are also strong scientific communities. We should get on board."

“Pharma has deep pockets... it’s true, but I think the money for early-stage R&D or external partnerships is not what you might think.”

📣Community Approved: What YOU voted for!  

Thanks to the support of the VitaDAO community, three proposals successfully passed this month! These proposals include:  

VDP-120 (An assessment of Oisín Biotechnologies): Oisín Biotechnologies is a multi-asset longevity biotech company pioneering genetic medicines to combat sarcopenia and other age-related diseases. Oisín is working to deliver DNA and RNA through a Fusogenix Proteo-Lipid in (PLV) platform, to alter cell behavior. The company’s lead candidate aims to build muscle without exercise, which could be used as a therapy to strengthen older people. VITA token holders agreed with the Longevity-Dealflow WG’s and senior reviewers' assessment of this company.

VDP-119 (Proposal to empower a member services squad): The formation of the Member Services Squad as anticipated in VDP-69 was intended to create a team to focus on the development of new offerings for VitaDAO token-holders and contributors. This proposal served to empower a Member Services Squad to roll out new services and gave the squad the authority to make necessary legal and logistical decisions to launch a “Member Services” portal.

VDP-118 (An assessment of GERO): This proposal was an assessment of GERO, a company using AI and ML to analyze datasets to discover novel treatments for chronic age-related diseases. To accomplish their goal of doubling human health- and lifespan within the current generation, the company has trained a large generative model of human health on a large dataset of longitudinal, real-world medical histories. The model is being used to predict future health outcomes similarly to how Large Language Models (LLMs) anticipate the next word in a sentence. Unlike LLMs, GERO’s models are physics-based and interpretable, allowing exploration of the relationship between the aging process and diseases.


💪Exercise Your Right to Vote

Visit VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Together, we can shape the future of VitaDAO and accelerate decentralized science.

👋Meet Awareness Working Group Contributor: Victoria Forest 

Victoria Forest, an integral member of VitaDAO’s Awareness and SciComm Working Groups, plays a role as VitaDAO’s DeSci illustrator and Instagram manager. When not contributing to VitaDAO, Victoria enjoys working as a freelance web designer, learning about longevity, and practicing pilates. In my interview with Victoria, we dive into her journey with VitaDAO, her interest in longevity, and her role within the DAO community.

How did you first get involved in VitaDAO? 

I found out about VitaDAO before the official launch in 2021. At that time, I wasn't yet involved in the web3 space. A few months later, I joined the community calls, became more curious about the vision, and got excited to understand how DeSci works and potentially be part of this movement. It was great to spend some time with the team at the first offsite, interview them (Meet the Vitalians YouTube list), learn about the mission, connect, and from there, choose to dedicate even more time to it.

What is your role within VitaDAO?

I'm a member of the Community & Awareness working group, where my responsibilities include developing media materials, creating illustrations, maintaining our social media accounts to keep our community informed, and interviewing experts in the field, among other tasks.

What do you feel is VitaDAO’s biggest strength compared to traditional longevity biotech startups?  

VitaDAO’s primary advantage is its decentralized and community-centered approach. Unlike conventional startups, VitaDAO leverages blockchain and decentralized technologies to engage a wider group of contributors, investors, and experts globally. This approach encourages increased inclusivity, collaboration, and diversity in the quest for longevity research and biotech innovation. It also allows for a more transparent and efficient allocation of resources and decision-making, potentially accelerating progress in the field.

What has surprised you the most about VitaDAO? 

What has impressed me the most about VitaDAO is the remarkable transparency in how the DAO operates, the openness of its team members, and the effective leverage of blockchain technology to bring tangible value to the real world.

What advice do you have for other Web Designers who are interested in getting involved in DeSci? 

I'd say, first and foremost, be curious about the space. Take the time to learn how blockchain and decentralization can be applied to real-world problems. Once you've got a grasp of that, seek out a community whose mission resonates with you, something you genuinely care about. If you find it fulfilling and it aligns with your values, then dive in. Attend conferences, go to meetups, and start networking. You'll likely discover the perfect place where you can contribute your skills and, at the same time, feel great about what you're doing.

Any closing thoughts for readers? 

Think about the future you want, both for yourself and your loved ones. Can you picture yourself growing old and experiencing frailty and suffering? How about witnessing your parents and grandparents endure the pains of aging and age-related diseases? We need to do more than what we're currently doing. Talk to everyone you know, and share with them the possibility of having a longer healthspan and potentially a longer lifespan. Think about the abundant world we can create if we unite our efforts right now, at this critical moment. Also, consider joining us at Vitalia in Prospera, a movement dedicated to initiating a longevity network society.

🤝Thanks for Reading! 

Want to stay up to date with all that's going VitaDAOn? Join us on Discord, subscribe to our Twitter, and follow our Instagram! You can also find updated information on VitaDAO's funded projects and an updated treasury dashboard on our website

Despite the bear market, the VitaDAO community continues to push the boundaries of decentralized science (DeSci). This month has been particularly exciting, with developments such as the funding of ExcepGEN and the launch of MatrixBio.
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Deciphering Science's Secrets: Lifespan, UPR, and Lysosomal Pathwayswith Dr. Arwen Gao on The VitaDAO Aging Science Podcast
October 15, 2023
Podcast
Deciphering Science's Secrets: Lifespan, UPR, and Lysosomal Pathwayswith Dr. Arwen Gao on The VitaDAO Aging Science Podcast

In today’s podcast I talked to Dr. Arwen Gao about the working conditions in science and, of course, also about her research. First, we talked about scholarships, strikes, unions and bureaucracy before moving on to our research related topics like antibiotics that extend lifespan, the unfolded protein response (UPR) and a novel lysosomal surveillance pathway called LySR that she helped to identify.

You may want to skip to the first 20 minutes if you only want to hear about the hard science rather than our discussion of working conditions and the day-to-day life of a scientist.

Short Bio – Dr. Arwen Gao

Arwen was awarded an AMC PhD scholarship to pursue her PhD thesis, focusing on the metabolic control of aging in C. elegans, and earned her PhD degree in the fall of 2018 at the University of Amsterdam in the Netherlands. She continued her research on mitochondrial stress response and its role in metabolism and aging, under the supervision of Prof. Johan Auwerx (EPFL, Switzerland) and supported by a post-doctoral fellowship (2019 Accelerator price winner). After this postdoc, she moved back to the Netherlands, where she is currently a junior group leader at the Amsterdam UMC - Location AMC. Her research focuses on lysosomes, lipids, aging, and translational projects that can benefit patients with lysosome disorders.

A few helpful notes follow below explaining the concepts behind the topics we covered.

Worms as a model in aging research

There are many good reasons to use the worm (C. elegans) for preclinical aging research. For one, it is cheap to study and requires no ethics approval. These worms have a conveniently short lifespan of around 30 days and well understood genomes. In addition, many tools are available to manipulate their genomes including RNA-interference libraries to study the knock-down of genes in a high-throughput fashion.

There is also a surprising amount of conservation between human and worm genomes. Our genes often are very similar to worm genes suggesting that worms might be a suitable model to study some aspects of human aging. For example, FoxO signaling and the Igf-1 pathway have been first identified in worms and later confirmed to be important longevity pathways in mammals as well. 

In the podcast we discussed how worm researchers also struggle with the same problems as mouse researchers. Similarly, to the situation with mice, most worm aging research is done in a single, highly lab-adapted and inbred strains. The one we often use is called N2 (first isolated in “Bristol”). We discussed the problems with inbred mice in a recent podcast with Rich Miller and in this podcast I discuss the C. elegans perspective with Arwen Gao and some solutions to this, including the generation of inbred, yet diverse, recombinant “panels”, composed of different strains with varying genetics. A simpler - somewhat less sophisticated - solution is to use at least two different strains to confirm your findings.

UPR and doxycycline - an unfolding story

Folding is the process by which linear protein chains are assembled into functioning 3D structures. Whenever something goes wrong with this folding process, this activates a so-called unfolded protein response (UPR). There are at least two distinct unfolded protein responses that occur in different cellular compartments, one in the mitochondria termed (UPRmt) and the other the canonical UPR in the endoplasmic reticulum (ER). Conceptually, the UPR can be considered a “cry for help” from an organelle. Since eukaryotic cells are very large and compartmentalized there is a need for this kind of cross-talk between different organelles and the nucleus which orchestrates said help (via mRNA transcription).

To make matters more confusing, the UPR, can be considered as part of the integrated stress response (ISR) which downstream is characterized by phosphorylation of a translational initiation factor (eIF2alpha) leading to selective translation of certain proteins, including the famous ATF4 transcription factor which is elevated in long-lived mouse models. Another way of looking at this is in terms of partial overlap. One branch of the canonical UPR, acting via a protein called PERK, is also an arm of the integrated stress response. However, the UPR has many other outputs and the integrated stress response has many other inputs, including the UPRmt.

Intriguingly, doxycycline is an antibiotic that activates the UPRmt thereby extending lifespan in C. elegans as shown by Gao et al. (2022). This is consistent with a naïve notion that improved folding and the UPR stress response should benefit lifespan. Since this is real biology, however, it is also the place where intuitions go to die. Other work suggests that inhibition of the integrated stress response is beneficial, at least in worms (Derisbourg 2021). This is the article I mentioned during the podcast from the Denzel group. While interesting, this does not – and should not – dissuade us from putting this idea to the test in the mammalian system. And, indeed, the famous mouse interventions testing program (ITP) is running a cohort with an integrated stress response activator (galofuginone) in mice to see whether it will extend lifespan.

We live in interesting times indeed!

For further reading we have attached links to some freely accessible reviews.
Melber and Haynes 2018 and Pakos‐Zebrucka et al. 2016 (here esp. Fig. 1) under further reading.

You can consider the UPR as one input for the integrated stress response. Source: Pakos‐Zebrucka et al. 2016, https://www.embopress.org/doi/full/10.15252/embr.201642195

The lysoosomal surveillance response – just another cry for help?

Arwen and others discovered a new pathway responsible for sensing lysosomal stress when they knocked down different VATPase subunits in the worm (Li et al. 2022). This pathway appears to be independent of autophagy, mTOR and the TFEB biogenesis pathway (called HLH-30 in the worm). While it is not entirely clear how the signal is transmitted from the lysosome to nucleus, they do show that it converges on a specific transcription factor from the GATA family. One can speculate that VATPase knock-down leads to reduced acidification and proteolysis in the lysosome which somehow leads to nuclear GATA translocation. While superficially, this may not be the whole story since only specific VATPase subunits seem to be involved in triggering the LysR. Hopefully, once we figure out the players we will be able to use this knowledge to generate novel autophagy inducers to promote lifespan and health.

Scientific research - between madness and dedication

In this podcast we also talk about the working conditions of scientists and PhD students. Arwen mentioned that the conditions are quite favorable in the Netherlands and in the labs where she worked. However, we are also aware of horror stories like postdocs who were regularly "sleeping in the lab" (undisclosed German lab) or students "buying groceries" for their supervisor (somewhere in the Netherlands or Switzerland, presumably). While we do both agree that passion is an important ingredient to a science career, (self-)exploitation should not be part of the deal. Sadly, these stories are more common than they should be. Grad school in the USA, for example, has the reputation of being very taxing. Here as told from the perspective of chemists:

https://www.science.org/content/blog-post/more-grad-school-pressures
https://www.science.org/content/blog-post/industry-vs-academia-mental-aspect
http://notthelab.blogspot.com/2013/01/is-graduate-school-in-chemistry-bad-for.html

Personally, I believe society should value scientists more than we currently do and pay significantly higher salaries. Whenever the pay is high, there is less exploitation of cheap labor and more automation of tedious labor.

However, not everything is bleak and we do not want to discourage anyone from pursuing a career in science. Conditions are improving and they are already quite good at certain institutions and in some countries. If you want to learn more which countries have a relaxed work culture and good pay, this podcast might be for you!

The host – brief bio

Kamil Pabis, MSc is an aging researcher and longevity advocate with several years of experience in the aging field that spans multiple countries. Among other projects, Kamil worked on long-lived dwarf mice in Austria, on mitochondrial disease and aging in the UK, and finally on the bioinformatics of aging in Germany and Singapore. Presently, he is involved in several projects related to science communication and translational aging research.

References and further reading

Derisbourg, Maxime J., et al. "Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation." Nature Communications 12.1 (2021): 1678.

Arwen Gao at ARDD2022: A lysosomal surveillance response (LySR) that extends healthspan
https://www.youtube.com/watch?v=TiIs2stK2Iw&t=612s
see also biorxiv: https://www.biorxiv.org/content/10.1101/2022.06.13.495962v1

Gao, Arwen W., et al. "Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains." Iscience 25.2 (2022): 103734.

Melber, Andrew, and Cole M. Haynes. "UPRmt regulation and output: a stress response mediated by mitochondrial-nuclear communication." Cell research 28.3 (2018): 281-295.
https://www.nature.com/articles/cr201816

Pakos‐Zebrucka, Karolina, et al. "The integrated stress response." EMBO reports 17.10 (2016): 1374-1395.
https://www.embopress.org/doi/full/10.15252/embr.201642195

n this episode of The VitaDAO Aging Science Podcast, we embark on a fascinating journey through the realms of longevity and cellular health with Dr. Arwen Gao. Dr. Gao, a leading authority in the fields of aging research, metabolism, and lysosomal...
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September Longevity Research Newsletter
October 10, 2023
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
September Longevity Research Newsletter

Introduction

Welcome back Vitalians, it’s a big week for VitaDAO as we’ve just become the first DAO to kickstart a biotech company, MatrixBio. MatrixBio explores hyaluronic acid-based compounds, aiming to pioneer in cancer and aging treatments, utilizing insights from cancer-resistant naked mole rats in collaboration with Prof Vera Gorbunova.

Other exciting news: we have a new portfolio company. Please join us in congratulating the GERO team for passing the VitaDAO token holder vote with 99.98% voting in favour! This proposal was an assessment of a Machine Learning Platform for Age-Related Disease Targeting & Drug Discovery, with a view to creating therapeutics to slow down human aging and eliminate root causes of age-related diseases.

If you haven't already, please consider signing the Dublin Longevity Declaration.

We currently invest large sums of money trying to cure the leading causes of death such as heart disease, cancer and neurodegeneration, however the most common risk factor for all of these is age. 

"For millennia, the consensus of the general public has been that aging is inevitable."

However, the last few decades of research has shown that aging isn't an immutable phenomenon, rather it is something that can be understood and targeted. 

The Dublin Longevity Declaration is a consensus recommendation - already signed by a large number of leading figures in the aging field - to immediately expand research on extending healthy human lifespans.

Researchers are constantly exploring numerous avenues to rejuvenate organisms to younger healthier states, from epigenetic reprogramming, to stem cell therapies. This month we are excited to bring you an interview with a pioneer in the space, Professor Irina Conboy, who has made numerous contributions to the rejuvenation biology field, including the discovery of the rejuvenating effects of young blood through parabiosis. In this issue we’re going to delve deeper into her latest publication highlighted in our Hot Picks. To explore the topic further we are hosting a journal club with Irina and Michael Conboy on fail-testing DNA methylation clocks and developing a “noise” barometer for measuring epigenetic pressure - Oct 16th, 6 pm CET.  Enjoy and we hope to see you there! 

Longevity Literature Hot Picks

Preprint Corner

We have now entered Q4, but you still have until Friday 13th October to nominate great longevity preprints from Q3 2023 to be featured in the next issue of The Longevist! You can now nominate preprints using our new snazzy form and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

And if you haven’t already seen it, here is our second issue of The Longevist, featuring the best longevity preprints from Q2 2023.

Check out our last batch of preprints of Q3 with these September submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

Methylglyoxal Affects Translation Fidelity

A pre-print by the 2nd palace winner of the Longevity Prize Rakhan Aimbetov expands on the topic of his submission. We love to see our initiative leading to tangible results, publications and research… If you want a lighter read on the topic we just published a Sci Comms article based on the topic of his prize entry: Sugar Byproducts and How They May Influence Aging

Tardigrades dramatically upregulate DNA repair pathway genes in response to ionizing radiation

Ketogenic diet administration later in life improves memory and regulates the synaptic cortical proteome through the cAMP/PKA signaling pathway in aging mice

Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations

Longevity interventions in Titan mice attenuate frailty and senescence accumulation

Hemin decreases cellular aging and enhances healthspan and lifespan through the AMPK pathway

B Cells Promote T Cell Immunosenescence and Mammalian Aging Parameters

Molecular and phenotypic blueprint of the hematopoietic compartment reveals proliferation stress as a driver of age-associated human stem cell dysfunctions

A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis

Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

Genetic architecture of telomere length in 462,675 UK Biobank whole genome sequences

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts

Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging

Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aging Brain

Deep learning-based prediction of one-year mortality in the entire Finnish population is an accurate but unfair digital marker of aging

Cellular aging is accelerated in the malignant clone of myeloproliferative neoplasms

Published Research Papers

Fail-tests of DNA methylation clocks, and development of a noise barometer for measuring epigenetic pressure of aging and disease

Elastic Net DNA methylation clocks show low prediction accuracy for age and health. The study suggests that stable cytosine methylation over lifespan indicates biological age. Dysregulated cytosines, measured as standard deviations, act as a "noise barometer" for aging and disease.

Eye Diseases and Senescence

X-irradiation induces senescence in human corneal surface cells, leading to disruptions in the epithelial barrier, and in aging mice, the accumulation of senescent ocular cells contributes to chronic inflammation and barrier decline, suggesting these senescent cells could be a therapeutic target to treat aged ocular surface issues.

Association of biological age with health outcomes and its modifiable factors

Using the UK Biobank data, a multi-dimensional biological age model was developed. Accelerated aging correlates with health risks. 35 modifiable factors affecting aging were identified, notably pulmonary functions and body mass. 

The fruit fly acetyltransferase chameau promotes starvation resilience at the expense of longevity

A mutation in Drosophila's "chameau" gene extends lifespan but reduces weight and starvation resistance. Despite its longevity benefits, poor nutrient stress handling likely keeps this mutation from being evolutionarily dominant.

And the press release: Sometimes beneficial, sometimes damaging: The double role of the enzyme chameau

Intact mitochondrial function in the setting of telomere-induced senescence

Mitochondria are crucial for cell health. This study explored the impact of telomere issues on mitochondria. By deleting the TRF2 protein, cell aging was induced, but mitochondrial function remained strong. Thus, even with telomere problems, mitochondria can support cell processes.

Plasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals

In a study of over 13,500 participants, certain plasma metabolites were linked to mortality and longevity. Elevated levels of metabolites like N2,N2-dimethylguanosine indicate higher mortality, while others like L-serine suggest increased longevity. The study implies specific metabolites can predict mortality, but the exact mechanisms remain undetermined.

Leveraging the secretory machinery to eliminate senescent cells

Senescent cells, which increase with age, contribute to tissue deterioration. A genomic screen showed that targeting the secretory actions of these cells in older mice can eliminate them. Suppressing the YAP–TEAD complex and reducing endoplasmic reticulum activity makes senescent cells more prone to apoptosis (cell death).

Death-seq identifies regulators of cell death and senolytic therapies

"Death-seq" is a new CRISPR screen designed to identify cell death mechanisms. It enhances cell death research, pinpointing enhancers for the senolytic ABT-263 and uncovering new inducers using ABT-199. This method reveals insights into cell death pathways and potential drug targets for conditions like senescence, cancer, and fibrosis.

Transcriptional and epigenetic decoding of the microglial aging process

Researchers studied aging effects on microglia, the brain's immune cells. Using mice, they found significant age-related changes, including unexpected sex differences. By creating a model to accelerate microglial aging, they discovered that aged microglia alone can cause cognitive decline, highlighting their role in brain function over time.

Pleiotropic influence of DNA methylation QTLs on physiological and ageing traits

Researchers identified a locus, meQTL.5a, in BXD mouse strains that influences DNA methylation patterns. This locus, combined with aging, results in an "aged methylome" for certain strains. It's linked to gene traits, body weight, lipid levels, and lifespan. 

Complete or Culprit-Only PCI in Older Patients with Myocardial Infarction

A NEJM study of 1445 older patients with myocardial infarction and multivessel disease, complete revascularization resulted in fewer adverse events at 1 year compared to only treating the culprit lesion. Primary outcomes occurred in 15.7% of the complete-revascularization group versus 21.0% in the culprit-only group.

Published Literature Reviews, Hypotheses, Perspectives and more

We need to shift the focus of aging research to aging itself

Mitochondrial degradation: Mitophagy and beyond

Senescent cells at the crossroads of aging, disease, and tissue homeostasis

Biomarkers of aging for the identification and evaluation of longevity interventions

Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease

Job board

Alexandra Stolzing at Loughborough University is looking for a Research Associate on a project about volatilome-based signature for age-related recovery & resilience.

The Valenzano lab at the Leibniz Institute on Aging in beautiful Jena, Germany, is looking for two postdocs (microbiome and pop-gen) and a master student. 

David Vilchez has an open position for a lab technician/research assistant in his lab. It would be appreciated if the candidates have a good German level.

The HealthyLongevity.clinic in Florida is looking for a healthcare specialist.

News and Media

A new longevity fund lead by Alex Colville and Laura Deming has launched age1 to support new breakthrough longevity companies to address the field’s core challenges. A bit more from the co-founder and partner Laura: A Letter from Laura Daming

The Economist is finally catching up to the Longevist and has dedicated an entire issue with 8 articles to social and economic aspects of aging: In search of forever

The Economist Intelligence Unit also released: AGEING SHIFT

They introduce the "Scaling Healthy ageing, Inclusive environments and Financial security Today" (SHIFT) Index which benchmarks against a set of national-level leading practices to enable an environment that nurtures longevity and healthy ageing in 19 countries comprising the Group of Twenty (G20).

Featured topics:


Longevity is making it big in the mainstream media this month with another article about Bryan Johnson in Time magazine:

The Man Who Thinks He Can Live Forever

Another mention in Forbes magazine - an article by Alex Zhavoronkov with some specific definitions to distinguish Longevity Biotech companies and a checklist with criteria:

What Is A Longevity Biotechnology Company?

Actually we have one! Read more about the MatrixBio launch:
Pfizer-backed DAO launches community-funded biotech firm

Gulf Sovereign Fund, Hedge Fund Tycoons Bankroll Biotech to Fight Aging
Rejuveron closes a $75 million series B round

A longevity expert shares his exercise routine that he says was inspired by centenarians

The boom of the anti-aging market: How to get people to live to be 120 (and in good health)

If you’re up for some lighter reading here is a humorous piece by the New Yorker: Anti-Aging Secrets of the Mega-Rich

Live to 100? How about 1,000? Why this scientist believes we will one day have lifespans that long

New Epigenetic Clocks May Confirm Extreme Age

A race against time: How science and technology are being used to delay aging

MyAgeNetwork has been awarded UKRI_News global partnership funding to develop collaborative links in ageing research with 14 organisations in USA and Canada. Congrats to Dr Alavian @imperialcollege and colleagues

What is the Blue Zones diet blowing up on Netflix? People who live to 100 eat this way

Resources

Longevity Summit Dublin has uploaded some fantastic talks to YouTube

Our favourites are:

The Million Molecule Challenge for Life Extension by Matt Kaeberlein

Dysregulation of Homeostasis Drives Human Aging by Peter Fedichev 

Robust New Measures of Biological Age by Steve Horvath

And of course our very own:

Accelerating Research with Decentralised Science - Eleanor Davies 

Longevity Network States – Max Unfried

Human Ageing Genomic Resources: updates on key databases in ageing research

What are the key open questions in longevity science?

João Pedro de Magalhães and team have developed a website to compile the major open problems in longevity and aging and put together an initial list of problems, but are aware there will be omissions, so have opened the floor for others to fill in the blanks!

Prizes

A brand new Longevity Prize has launched and accepting application over the next couple of months. The Longevity Funding Innovation Prize initiated and funded by Marat Karpeko is going to award $20,000 USD for the most innovative and potentially impactful longevity funding strategy. The judges want to see a real action plan and tangible solution for real world impact.

Keep in mind the key dates:

  • Kick-Off: 20th September 2023
  • Proposal Closing: 20th December 2023
  • Evaluation Wrap-Up: 20th February 2024
  • Champion Unveiled: 29th February 2024

Conferences

The conference season might be over, but there are still a couple of interesting meetings which we recommend!

Expo and Convention: Independent Ageing 2023

13-15 October, Aichi, Japan

Seno-Therapeutics Summit 2023

7-8 November, Buck Institute for Research on Ageing, Novato, CA, USA

Tweets of the Month

Mikhail V. Blagosklonny: Most people believe that aging is a functional decline caused by accumulation of molecular damage…………..

Healthspanmed: Blagosklonny's theory of cellular hyperfunction has shifted our understanding of aging.

The theory states that aging is not a result of cellular decline or damage accumulation but rather excessive cellular activity he calls hyperfunctions….

Lada Nuzhna: aging research dies one citation at a time:

Podcasts and Webinars

NUS Medicine’s Healthy Longevity Webinar Series

Peter Attiia: Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more | David Sabatini, M.D., Ph.D. and Matt Kaeberlein, Ph.D.

Elon is Right. Having to Live Forever is a Curse. Here's How to Solve It

In this episode, Lifespan News explores the diverse perspectives and heated debates triggered by Elon's provocative statements on aging and the prospect of eternal life.

Active Motif Epigenetics Podcast: DNA Damage in Longevity and Ageing (Björn Schumacher)

In this episode Björn Schumacher discusses his research on DNA repair and its impact on ageing.

Interview with Prof. Irina Conboy

Irina Conboy is a Professor at the University of California, Berkeley in the Department of Bioengineering. The Conboy lab currently focuses on broad rejuvenation of tissue maintenance and repair, stem cell niche engineering, elucidating the mechanisms underlying muscle stem cell aging, directed organogenesis, and making CRISPR a therapeutic reality.

What inspired you to enter longevity research?
Self-preservation instinct: in my view, aging is an accumulation of disease and, metaphorically, we are flying breaking down airplanes, so the best one can do is to start working on a parachute, while the plane is still in the air and relatively “healthy”.

Which of the current theories of ageing do you think are the most convincing?
Succumbing to entropy, because of the imperfections in repair of molecules, cells and tissues.

How has the field changed since you started?
Inspired by the work of our colleagues (Cynthia Kenyon, for example) in worms and flies, we shifted the dominant paradigm in mice and people from inevitability of intrinsic aging (telomere shortening, DNA damage, etc.) to reversibility and inducibility of aging by the age of the systemic milieu – circulatory environment that connect all tissues. In other words, we uncovered that aging is a process with specific regulation, understanding this regulation allows attenuating and even reversing the process – the aging.

What mistakes do you think the longevity field has made? 

Exaggeration of the positives, lack of critical questions and reviews, lack of used-to-be frequent “I stand corrected”, tooting own horns “my silver bullet is better than your silver bullet”. 

Other than your own, what do you think have been the biggest/important discoveries in the field?
As mentioned, discovery of life extension in C. elegance by Prof. Cynthia Kenyon (UCSF, and Science leader at Calico), the concept of cellular and tissue senescence that was discovered by Prof. Judy Campisi (LBNL and Buck research institute), the paradigm of bone marrow, hematopoietic stem cells’ and immune aging, discovered by Prof. Irv Weissman (Stanford) and Prof. Sean Morrison (Stanford and UT Southwestern), the aging and rejuvenation of the brain and cognition that was discovered by Prof. Rusty Gage (aka Fred Gage, Salk). 

What advice would you give to people currently working in longevity research?
Take care of science and science will take care of you. 

Which aspect of longevity research do you think requires more attention?
Transition from animals (mice typically) to humans. Many diseases, including those associated with aging, can be cured in mice, but translation to clinic often fails. 

Is ageing a disease?
In my view, we notice aging specifically because tissues, organs and eventually organisms become unhealthy, e.g., it is accumulation of diseases. 

How has the perception of rejuvenation biology evolved since your seminal paper on the rejuvenating effects of young blood through parabiosis in 2005 was published in Nature?
Many intuitively decided that young blood is the key, which in our view, is not accurate.  Young mice with their young DNA, proteins, cells and tissues and 50% of their young blood become aged and senescence in two weeks after a single transfusion with 50% of old blood; and old blood dominates over young in cell culture experiments (https://pubmed.ncbi.nlm.nih.gov/35902645/). How can old mice or old people with their old blood, damaged tissues, cells, and macromolecules become “rejuvenated” by a “young” protein or a blood fraction? To make things more complicated, in contrast to mouse strains, we do not have our identical twins who are always 20 years old and could serve as blood donors. On the other hand, after dilution of old blood plasma (the liquid part of the blood with age-elevated proteins) all the positive effects of heterochronic parabiosis manifest without young blood in mice (https://pubmed.ncbi.nlm.nih.gov/32474458/); and there are rejuvenative effects on the circulating cells and systemic proteome in people after a similar procedure of plasma dilution, called therapeutic plasma exchange (https://pubmed.ncbi.nlm.nih.gov/35999337/. 

You published a new paper on fail-testing biological clocks and a novel approach for quantifying biological age. The study reveals that the change in methylation of cytosines with age is not the determinant for their selection into the clocks and that EN clock's selected cytosines change when non-clock cytosines are removed. Can you explain the significance of these findings and their implications for the development of future DNA methylation clocks and the the stability and relevance of the current ones?
People assume that when their age or health are predicted by so-called “clocks” it is because of the changes in their epigenome or proteome. In reality, the “clocks” is the well-known population statistics method, EN regression, in which computer is used to select and change by weights ~ 200 values from ~500.000. This is done without a biological justification, as a mathematical solution to the least-squares linear fit. In other words, if the results were not what they were, but some values were smaller and other were larger and we added them up for a minute subset of the data, then for this one experiment, Y axis would linearly correlate with X axis. These few datapoints do not have properties of biomarkers; their wights do not reflect the changes in DNAme with age or disease and when other datapoints that EN did not select are removed, EN starts discarding previously selected data, which does not happen with biomarkers. For, example, high blood glucose levels will always be biomarker of diabetes, even if we remove the inflammatory proteins, obesity, etc. We also show that in more than one experiments, predictions might reflect random experimental variation, so people should not rely heavily on being told that the “clock” determined that they are younger by a few months or older by a couple of years.  In support for the lack of biological relevance or even a physical connection, we show that numbers of people living in US can be accurately predicted using the EN DNAme “clock” and in the same vein, Dow Jones industrial, global temperatures, etc. clearly unrelated to epigenetics changes can be predicted from DNA methylation array data, using EN. This is because EN only requires a large data with a weak linearity (could be optical signals from an array or distances between the Galaxies) and a measured parameter, e.g., regular set of numbers. Age, health scores, numbers of people living in US, Dow Jones, are all designated as regular sets of numbers and it is the numbers, not their meaning that is predicted, moreover, without a requirement for the physical connection between X and Y. 

Can you explain in layman's terms the concept of the "noise barometer" and its importance in determining biological age? How does it differ from or complement existing markers of biological age?
EN tells us how to get the straight line between X and Y, in the mathematical realm of adjusted data; in the physical – biological realm we do not age linearly, not as an evenly ticking clock, but with intervals of youthful healthy plateaus and transitions to less health and aging, which become exponential after a serious illness. Can we quantify this and, moreover, using the primary unadjusted data? Search for biomarkers of aging spans decades and $100s of millions, yet it was not very successful, possibly, because individual differences mask the age-imposed changes. In the shift of this paradigm, we posited that it is not the levels, but the dysregulation (the noise) of genes and proteins, which biomarks aging and disease. In a metaphor, a strange noise when you drive a car strongly suggests a problem. In our bodies, the best detectors of the problematic noise are the genes, which are vital for our health (housekeeping genes, for example). Using the standard deviations or the distance from the healthy young mean of these noise detectors (UC Berkeley IP) quantifies the biological age (accurately, based on the actual unadjusted experimental results) and uncovers the natural polynomial line of aging.

Do you think the "noise barometer" can be applied in practical, clinical settings to detect or predict age-related diseases or conditions? Where can “quantifying” biological age can have the most value in clinical practice?
Yes, of course.  As with any new measurement, quantification of biological age opens new possibilities for testing the efficacy of medicine, validating the putative rejuvenative approaches and warning people of “sliding” from the healthy plateau. We expect that noise barometer will be used by the Health Insurance Companies, hospitals and clinicians, academia, and biotech.  In a metaphor, if there were no weight scales and we predicted weight based on the population statistics (clothes, food, body contours) it would be more difficult to get in shape and a person could have delusions of being lighter when they gained 20 pounds. Scales is the device that works on the concept of gravity, noise barometer is the first approach that measures biological entropy.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful!

This time we leave you with a twitter space recording about the Longevity Funding Innovation Prize, where you can hear first hand from Marat more about how the prize was created, what are the aims, and what would the judges be looking for when assessing applications.

Further Reading

Intact mitochondrial function in the setting of telomere-induced senescence

Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent

Cross-species comparison illuminates the importance of iron homeostasis for splenic anti-immunosenescence

Intense caloric restriction from birth prevents cardiovascular aging in rats

Welcome back Vitalians, it’s a big week for VitaDAO as we’ve just become the first DAO to kickstart a biotech company, MatrixBio. MatrixBio explores hyaluronic acid-based compounds, aiming to pioneer in cancer and aging treatments...
Read more
Announcing the first spinout company funded by VitaDAO
October 9, 2023
Awareness
Announcing the first spinout company funded by VitaDAO

VitaDAO, the global online community driving early-stage longevity research through innovative funding collaborations announced today the launch of its very first biotech company, Matrix Biosciences. This significant milestone comes from a community-wide vote and approval in favor of a collaboration with Vera Gorbunova, Ph.D., Co-Chair of the University of Rochester’s Aging Research Center.

“I am looking forward to beginning this partnership with VitaDAO,” said Dr. Gorbunova, “The funding and support from the VitaDAO community will bring Matrix Biosciences one step closer to delivering groundbreaking treatments that will significantly improve outcomes for our vulnerable aging patient population. While this is a first step for Matrix Biosciences, it is only the beginning of the transformative impact these treatments can have on the lives of individuals suffering from cancer and aging-related disorders.”The community decision to launch Matrix Biosciences marks a significant step forward for VitaDAO as it advances its early portfolio assets toward its next development milestones. The first tranche of $300,000 from VitaDAO will be followed by further funding through IP-NFT fractionalization in early 2024.

This essential support will facilitate the commencement of preclinical studies aimed at testing novel hyaluronic acid-based compounds. Leveraging its cutting-edge research, Matrix Biosciences aims to pinpoint an optimal drug candidate for the treatment of cancer and aging diseases.

Anthony Schwartz, PhD from VitaDAO added, “Matrix Biosciences is navigating a complex development pathway commonly encountered by many early-stage companies during the initial stages of drug discovery. Thanks to the collective drug development experience from VitaDAO’s online community and the collaborative nature and expertise of Dr. Gorbunova and the Matrix Biosciences team, we now have a well-designed development strategy in an area that has traditionally lacked the know-how or an established path. We are pleased with the early data generated thus far and its potential for advancing into clinical trials. On behalf of the community, VitaDAO is excited to embark on this journey with the Matrix Biosciences team.”

VitaDAO is focused on being the most efficient allocator of resources in aging and longevity research. By leveraging the talent of its academic community, VitaDAO continues to drive transformative advancements in aging diseases and longevity research.

About Matrix Biosciences

Matrix Biosciences is a pioneering company dedicated to the development of high molecular weight hyaluronic acid (HMW-HA) therapeutics for cancer and aging-related disease. The company’s pipeline is based on the observation that naked mole rats, long-lived rodents with a lifespan of up to 40 years, compared to normal rats which live about 3 years. These rodents are found to be cancer resistant which is controlled by an abundance of HMW-HA in their tissues. Research has demonstrated that transgenic mice expressing naked mole rat hyaluronan synthase gene (NHAS2) have fewer tumors, improved health, and live 10% longer than rats without the transgene. The Company is developing a class of small molecules that modulate hyaluronidases for potential applications in cancer and increasing human healthspan and lifespan.

For more information about Matrix Biosciences and its research, please visit www.matrixbio.co

About VitaDAO

VitaDAO is a community-owned collective dedicated to funding and advancing early stage longevity research. With strategic contributors such as Pfizer Ventures and Shine Capital among over 10,000 members, VitaDAO brings together the forefront of decentralized science and web3 including enthusiasts like Balaji Srinivasan, former CTO of Coinbase. VitaDAO has successfully funded 19 projects, deploying over $4M in capital to date. Members can join VitaDAO by purchasing VITA tokens or earning them through contributions of work or intellectual property.

For more information about VitaDAO, please visit www.vitadao.com


VitaDAO, the global online community driving early-stage longevity research through innovative funding collaborations announced today the launch of its very first biotech company, Matrix Biosciences. This significant milestone comes from a community
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Sugar Byproducts and How They May Influence Aging
October 2, 2023
Rakhan Aimbetov & Maria Marinova
Awareness
Longevity
Sugar Byproducts and How They May Influence Aging

Imagine a bustling factory, working tirelessly day and night, crafting intricate items with utmost precision. This isn't a scene from a high-tech industrial park; it's happening right now inside your body. Our cells host these marvelous 'protein factories' known as ribosomes. Their job is to translate the genetic blueprints (the mRNAs or copies of our transcribed genes from the cell's nucleus) into protein masterpieces vital for all living organisms on the planet. This is an essential part of life known as the central dogma of molecular biology.


Typical error rates for each process of the “Central Dogma”

The ribosome is a cellular marvel, acting as the primary site of biological protein synthesis or translation. Like a seasoned craftsman reading a set of instructions to craft a product, ribosomes read mRNA sequences to stitch together the right sequence of amino acids and form proteins. However, as with any machinery, time can introduce wear and tear. It’s akin to the minute deviations that occur in a factory assembly line, where a widget produced on day one might not be identical to one made on day ten thousand. In the context of ribosomes and the biological setting, these inconsistencies, or 'noise', manifest as errors in protein synthesis. The process might result in proteins with incorrect amino acid sequences and misfolded structures.

Why does this matter? Proteins, especially enzymes, rely on their exact structures to function properly. A slight deviation in structure might render a protein non-functional and harmful. This accumulation of 'noise' is a phenomenon that has been associated with the aging process itself and a plethora of age-related diseases (Anisimova et al., 2018).

In addition to the amino acid sequence, the structure, and function, of proteins can also be determined by post-translational modifications (PTMs), which are enzymatically regulated covalent conjugations of other molecules to specific amino acid residues on proteins. Perhaps the most widely studied PTM is phosphorylation, whereby the addition of a phosphate group creates a negative charge that can alter protein conformation, often activating the protein. Glycosylation is another PTM that involves the enzymatic addition of a sugar molecule, or glycan, to a specific residue - important in a wide variety of physiological functions from correct protein folding to stability. But there is another side of the coin, whereby proteins are subjected to non-enzymatic covalent additions of reactive metabolites. These are unregulated additions occurring at non-specific residues on the protein, which can negatively affect protein functionality and have mechanistic involvement in a range of pathologies, including aging (Harmel & Fiedler, 2018). Non-enzymatic glycosylation (addition of sugar molecules or glycation) is one such modification, which has implications in the progression of age-related pathologies and has been underappreciated for decades. The recent body of published research, linking glycation to the hallmarks of aging paradigm, has put it in a new light (Fedintsev & Moskalev, 2020).

Now, as we dive deeper into this intricate molecular dance, we encounter a significant player. Enter methylglyoxal (MGO), a byproduct of sugar metabolism (Allaman et al., 2015). MGO tends to get a bit too 'reactive' with our proteins and especially with certain amino acid residues, resulting in modifications that form various chemical adducts known as advanced glycation endproducts (AGEs) (Twarda-Clapa et al., 2022). These AGEs aren't benign; they've been linked with aging and an array of health conditions, such as diabetes and its complications (Singh et al., 2014).

A novel scientific inquiry is proposing an exciting conjecture linking back to MGO.
MGO, while modifying proteins, may also be throwing a ‘spanner’ in the works of our protein factories. This interference could increase the error rate of protein synthesis, potentially contributing to the disruption of protein homeostasis — the crucial equilibrium of protein production, function, and degradation — and driving us toward aging.

Why is this significant? Well, longevity is, in part, a game of accuracy. The better our cells can convert genetic information into protein structures, the longer and healthier lives we're likely to enjoy. In fact, research has shown that some organisms with higher translation accuracy inherently have longer lifespans (Azpurua et al., 2013; Ke et al., 2017; Martinez-Miguel et al., 2021), while the artificial elevation of the translation error rate in animal models decreases lifespan (Brilkova et al., 2022; Moore et al., 2021; Shcherbakov et al., 2022).

By exploring how MGO, a common byproduct of our metabolism, could be meddling with this delicate process, researchers are laying the groundwork for potential interventions that could counter these effects and perhaps help us enjoy longer, healthier lives.

But the investigation doesn't stop at protein synthesis. The researchers are also probing how this process might interact with the environment of our cells, specifically the extracellular matrix (ECM). The ECM is a complex network of proteins that provide structural support to tissues and guide the behavior of cells (Theocharis et al., 2016).

What’s the working hypothesis here? Accumulation of AGEs might increase ECM stiffness, influencing cellular behavior and disrupting glucose uptake (Ge et al., 2021). This disruption could then lead to an uptick in MGO production and a subsequent rise in protein misfolding. It's an intricate cellular tug-of-war: stiffened ECM leads to increased MGO production and ribosome errors, which then contribute to aging and age-related diseases.

Pioneering experiments are already providing some answers. Researchers have shown that increasing MGO levels within cells, by stimulating the accumulation of its precursor, dihydroxyacetone phosphate, leads to more protein glycation. Also, a luciferase assay-based system — a clever new tool for measuring translation accuracy by detecting emitted light — is providing promising initial results.

With this line of inquiry and focusing on translational fidelity, we're getting closer to unravelling another aspect of the complicated biology of aging. In doing so, it's opening up potential routes for interventions that could reinforce our cellular accuracy, providing hope for healthier, more extended lives.

We're still in the early stages, but every discovery brings us closer to a future where aging is not an unavoidable decline but a process we understand and, crucially, can influence. Keep your eyes on this space; these seemingly innocent sugar byproducts could hold a piece to the intricate puzzle of longevity.

Authors: Rakhan Aimbetov & Maria Marinova

Editor: Rhys Anderson

Illustrator: Meghan Ho-Tong

References:

Allaman, I., Bélanger, M., & Magistretti, P. J. (2015). Methylglyoxal, the dark side of glycolysis. Frontiers in Neuroscience, 9, 23. https://doi.org/10.3389/fnins.2015.00023

Anisimova, A. S., Alexandrov, A. I., Makarova, N. E., Gladyshev, V. N., & Dmitriev, S. E. (2018). Protein synthesis and quality control in aging. Aging, 10(12), 4269–4288. https://doi.org/10/gfwdds

Azpurua, J., Ke, Z., Chen, I. X., Zhang, Q., Ermolenko, D. N., Zhang, Z. D., Gorbunova, V., & Seluanov, A. (2013). Naked mole-rat has increased translational fidelity compared with the mouse, as well as a unique 28S ribosomal RNA cleavage. Proceedings of the National Academy of Sciences of the United States of America, 110(43), 17350–17355. https://doi.org/10.1073/pnas.1313473110

Brilkova, M., Nigri, M., Kumar, H. S., Moore, J., Mantovani, M., Keller, C., Grimm, A., Eckert, A., Shcherbakov, D., Akbergenov, R., Seebeck, P., Krämer, S. D., Wolfer, D. P., Gent, T. C., & Böttger, E. C. (2022). Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice. Cell Reports, 40(13), 111433. https://doi.org/10/gq24jr

Fedintsev, A., & Moskalev, A. (2020). Stochastic non-enzymatic modification of long-lived macromolecules: A missing hallmark of aging. Ageing Research Reviews, 62, 101097. https://doi.org/10.1016/j.arr.2020.101097

Ge, H., Tian, M., Pei, Q., Tan, F., & Pei, H. (2021). Extracellular matrix stiffness: New areas affecting cell metabolism. Frontiers in Oncology, 11, 631991. https://doi.org/10.3389/fonc.2021.631991

Harmel, R., & Fiedler, D. (2018). Features and regulation of non-enzymatic post-translational modifications. Nature Chemical Biology, 14(3), 244–252. https://doi.org/10.1038/nchembio.2575

Ke, Z., Mallik, P., Johnson, A. B., Luna, F., Nevo, E., Zhang, Z. D., Gladyshev, V. N., Seluanov, A., & Gorbunova, V. (2017). Translation fidelity coevolves with longevity. Aging Cell, 16(5), 988–993. https://doi.org/10/gn9sgj

Martinez-Miguel, V. E., Lujan, C., Espie-Caullet, T., Martinez-Martinez, D., Moore, S., Backes, C., Gonzalez, S., Galimov, E. R., Brown, A. E. X., Halic, M., Tomita, K., Rallis, C., von der Haar, T., Cabreiro, F., & Bjedov, I. (2021). Increased fidelity of protein synthesis extends lifespan. Cell Metabolism, 33(11), 2288-2300.e12. https://doi.org/10/gnjjkx

Moore, J., Akbergenov, R., Nigri, M., Isnard-Petit, P., Grimm, A., Seebeck, P., Restelli, L., Frank, S., Eckert, A., Thiam, K., Wolfer, D. P., Shcherbakov, D., & Böttger, E. C. (2021). Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice. Communications Biology, 4(1), 703. https://doi.org/10/gkgp3t

Shcherbakov, D., Nigri, M., Akbergenov, R., Brilkova, M., Mantovani, M., Petit, P. I., Grimm, A., Karol, A. A., Teo, Y., Sanchón, A. C., Kumar, Y., Eckert, A., Thiam, K., Seebeck, P., Wolfer, D. P., & Böttger, E. C. (2022). Premature aging in mice with error-prone protein synthesis. Science Advances, 8(9), eabl9051. https://doi.org/10/gptgms

Singh, V. P., Bali, A., Singh, N., & Jaggi, A. S. (2014). Advanced glycation end products and diabetic complications. Korean Journal of Physiology & Pharmacology, 18(1), 1–14. https://doi.org/10.4196/kjpp.2014.18.1.1

Theocharis, A. D., Skandalis, S. S., Gialeli, C., & Karamanos, N. K. (2016). Extracellular matrix structure. Advanced Drug Delivery Reviews, 97, 4–27. https://doi.org/10.1016/j.addr.2015.11.001

Twarda-Clapa, A., Olczak, A., Białkowska, A. M., & Koziołkiewicz, M. (2022). Advanced glycation end-products (AGEs): Formation, chemistry, classification, receptors, and diseases related to AGEs. Cells, 11(8), 1312. https://doi.org/10.3390/cells11081312

Imagine a bustling factory, working tirelessly day and night, crafting intricate items with utmost precision. This isn't a scene from a high-tech industrial park; it's happening right now inside your body.
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$VITA Goes Optimism
September 26, 2023
Awareness
Tokenomics
$VITA Goes Optimism

Creating an Optimism wallet

Because Optimism seamlessly integrates with the Ethereum Virtual Machine (EVM), incorporating an Optimism account into your current Ethereum wallet(s) is a straightforward process. To enable Optimism, follow these straightforward steps:

  • Visit the Chainlist platform through your web browser.
  • Establish a secure connection between your MetaMask wallet and Chainlist by logging in and granting the necessary permissions.
  • Once the connection is established, navigate to the platform's interface and locate the "Optimism" (ID:10) option.
  • Click on the "Optimism" option to initiate the integration process.
  • After successful integration, return to your MetaMask wallet.
  • In the MetaMask interface, you'll notice a new feature that allows you to toggle between the Ethereum and Optimism networks. Locate and click on the "Networks" button within MetaMask.
  • Use this "Networks" button to easily switch between the Ethereum and Optimism networks based on your specific requirements and preferences.

How to Fund your Optimism Wallet

To fund your Optimism wallet, follow these simple steps using The Optimism Gateway:

Deposit Funds:

  1. Access The Optimism Gateway.
  2. Select the amount of ETH or supported tokens.
  3. Confirm your deposit and wallet transaction.

How It Works:

  • Your funds get locked on Ethereum.
  • Tokens representing your deposit appear in your Optimism wallet.
  • When you withdraw, Optimism tokens are removed, and Ethereum tokens become accessible. Remember, it takes seven days for withdrawn funds to become usable again.

How to Get VITA on Optimism

  1. Swap your tokens for VITA  on 1inch.

Note: only get VITA for the purpose of using it in VitaDAO.

Bridge Mainnet VITA to Optimism

  • Select the amount of VITA you want to bridge to Optimism
  • Approve & Review the deposit

Use your VITA on Optimism

Governance: VITA tokens on Optimism to be used for voting on Snapshot. Learn how to vote on VitaDAO Governance proposals using this guide.

Providing liquidity: If you would like to use your VITA tokens to provide liquidity, you can use Velodrome.

DISCLAIMER: This guide is intended only for people who want to get VITA for use in VitaDAO.

Resources

Tired of Ethereum's sky-high fees? 💤 We've got good news! Become a VitaDAO member on Optimism and enjoy lower gas fees.
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August Longevity Research Newsletter
September 8, 2023
Maria Marinova & Rhys Anderson
Longevity
Awareness
Newsletters
August Longevity Research Newsletter

Introduction

Welcome back Vitalians and please join us in congratulating the Cyclarity Therapeutics (CTx) team for passing the VitaDAO token holder vote! This proposal was an assessment of an early-stage biotechnology company that is developing novel cyclodextrin drug molecules to extract toxic biomolecules that accumulate with age.

Whilst all of the humans were either at ARDD or on holiday, we took the opportunity to interview our favourite silicon friend, ChatGPT to ask its thoughts on longevity research. And talking of AI, we hope you are enjoying the new artwork peppered throughout our newsletter!

Longevity Literature Hot Picks

Preprint Corner

The second edition of The Longevist is now live! Check it out to see what our team of expert curators think are the best preprints of Q2.

We're excited to bring you our second batch of preprints of Q3 with these August submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3. 

Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

On standardization of controls in lifespan studies

The principal component-based clinical aging clock (PCAge) identifies signatures of healthy aging and provides normative targets for clinical intervention

Caloric restriction promotes beta cell longevity and delays aging and senescence by enhancing cell identity and homeostasis mechanisms

Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease

Profiling an integrated network of cellular senescence and immune resilience measures in natural aging: a prospective multi-cohort study

Establishing RNAge to score cellular aging and rejuvenation paradigms and identify novel age-modulating compounds

Published Research Papers

Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice

By introducing the naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2) into mice, researchers observed increased hyaluronan levels, reduced cancer incidence, extended lifespan, improved healthspan, and reduced inflammation, demonstrating the potential for HMM-HA to enhance longevity and health in other species

Universal DNA methylation age across mammalian tissues

Researchers have developed universal pan-mammalian clocks based on DNA methylation profiles, accurately estimating the age of mammalian tissues with high precision. These age estimations are linked to mortality risk in humans, somatotropic axis mutations in mice, and caloric restriction, and they highlight specific methylation changes near genes associated with development, cancer, obesity, and longevity, indicating that aging is evolutionarily conserved and connected to developmental processes across mammalian species.

Atlas of the aging mouse brain reveals white matter as vulnerable foci

Aging leads to cognitive decline with distinct molecular changes in the brain. Using mouse models, researchers identified aging patterns in glial cells. Rejuvenation treatments affected gene expression differently, suggesting regional aging may impact neurodegenerative diseases.

The impact of the cardiovascular component and somatic mutations on ageing

In a study across 15 mammals, lifespan showed a strong negative correlation with somatic mutation rate. While various traits influenced lifespan, resting heart rate stood out. Combining somatic mutation with heart rate improved lifespan predictions, indicating underlying mechanisms tied to aging.

Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease

Circadian disruptions are prevalent in Alzheimer’s disease (AD). A study showed time-restricted feeding (TRF) benefitted AD mouse models by improving memory, reducing disease markers, and adjusting disrupted gene patterns. TRF's broad impacts suggest it could be a potential strategy to counteract AD progression.

Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling

In Drosophila, an early adulthood increase in protein translation (PT) negatively affects aging and protein balance. Stopping this PT surge improves lifespan and reduces protein build-up. The initial PT boost disrupts protein management and accelerates aging through certain pathways. Thus, the natural post-youth PT decline might protect against age-related problems, offering a fresh angle on how PT impacts lifelong aging.

Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation

Cells become senescent to stop unchecked growth, but its irreversibility has been debated. This study reveals that senescence is irreversible due to MYC protein degradation. When MYC isn't degraded, senescent cells divide; with MYC reduction, non-dividing cells become senescent.

The YAP–TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress

Senescence stops cell growth and increases resistance to death. A study found that inhibiting the YAP–TEAD pathway with verteporfin (VPF) led to targeted death of senescent cells. This occurs by suppressing mTOR, inducing endoplasmic reticulum (ER) stress due to the demands of the senescence-associated secretory pattern (SASP). 

Published Literature Reviews, Hypotheses, Perspectives and more

Challenges in developing Geroscience trials

As the geroscience field grows, refining clinical study designs becomes crucial. Challenges include selecting populations, choosing interventions, defining trial outcomes, and pinpointing key age-related biomarkers ("Gerodiagnostics"). 

The evolution of selective autophagy as a mechanism of oxidative stress response

Aging reduces autophagy and increases damaging ROS. In humans, selective autophagy receptors (SARs) may have evolved to detect oxidative stress, initiating autophagy to remove damaged components and restore cellular balance, which contributes to our longer lifespan, while its loss could lead to age-related diseases.

A mammalian DNA methylation landscape

Mammals display varied lifespans, from bowhead whales at 200 years to giant Sunda rats at 6 months. Despite similar genes, gene regulation might dictate aging. Haghani et al. studied DNA methylation across mammals, identifying regions possibly affecting lifespan, shedding light on molecular lifespan determinants.

Job board

The Institute of Inflammation and Aging, with Joao Pedro, is seeking a dedicated professor with expertise in aging science and age-related diseases. This is a valuable opportunity at the University of Birmingham!

Deadline: 31 August 2023

Apollo Health Ventures are recruiting for their portfolio company (and VitaDAOs portfolio company) BE Therapeutics in New York City, looking for a Research Asscociate

McLab is announcing openings for postdoc and technician roles! Backed by new funding, they aim to delve deeper into understanding the effects of aging on breast cancer progression and therapeutic response.

Cologne Graduate School of Ageing Research

Up to 12 fully funded PhD studentships starting in October 2024

Valentin F. Cracan is seeking a postdoctoral fellow in genetically encoded sensors and tools for studying the role of redox imbalance in cancer, neurodegeneration and aging

Interested in nutrition, supplements and human trials? This Research Fellow (Nutritional Intervention) position in Andrea Maier's lab at National University of Singapore could be for you.

Two fully funded PhD student positions in Healthy Aging Research (biochemistry, epidemiology, bioinformatics) at Charite Berlin and Humboldt University. Please apply by Sept 30th.

News and Media

The British Society for Research on Aging is pleased to announce the award of the Lord Cohen Medal to Professor Lynne Cox for her outstanding achievements and contributions to understanding the biology of aging.

GERO and FOXO Technologies embark on joint initiative on AI and epigenetic data

Anti-aging technology is here. And the Middle East is getting ready

How does aging increase risk of dehydration?

A cook from Okinawa, Japan — where many live to be over the age of 100 — explains the healing powers of 7 traditional foods

A biological clock explains why a dog year is equivalent to seven human years

Adherence to a Mediterranean lifestyle associated with lower risk of all-cause and cancer mortality

Leaders In Longevity Medicine Convene In Copenhagen

Saudi Arabia Is Dangling Billions for Research on Aging. Scientists Are Lining Up to Take It

Resources

Free Courses in Longevity Medicine for physicians, researchers, and anyone interested in longevity medicine! 

Prizes

The Amaranth Prize

Rewarding the most impactful research in longevity

$250k Prize pool. 15 Winning papers. 180 Influencing papers


Conferences

British Society for Research on Aging Annual Scientific Meeting (BSRA ASM)

6-8 September, London, UK

RAADFest

7-9 September, LA, CA, USA

The Longevity Investors Conference (LIC) is an application-only event

27-28 September

Expo and Convention: Independent Ageing 2023

13-15 October, Aichi, Japan

Seno-Therapeutics Summit 2023

7-8 November, Buck Institute for Research on Aging, Novato, CA, USA

Tweet of the Month

Shahaf Peleg:

Instead of greeting someone ‚hey you lost weight!‘, won’t it be great to greet someone by saying ,hey, you lost age!‘ ?

Podcasts and Webinars

NUS Medicine’s Healthy Longevity Webinar Series

Funding Opportunities

Impetus Grants will keep applications open until September 15, 2023.

Interview with ChatGPT

Short bio
ChatGPT is developed by OpenAI and based on the GPT-4 architecture. As it likes to remind us, it is programmed to provide information based on a wide array of sources available up until 2021. 

Why do you think humans are inspired to research aging?

For humans, the inspiration to study aging often comes from a deep-seated desire to improve human life, reduce suffering from age-related diseases, and extend the healthy years of human life. The field has also been inspired by observations in nature; for example, certain species of whales, tortoises, and birds exhibit remarkably slow aging and resistance to age-related diseases.

How has the longevity field changed in the last 3 decades?

The development of advanced computational tools, genome sequencing, and molecular biology techniques has allowed researchers to identify and target specific pathways related to aging. 

Consequently, the attitude towards aging is now changing, as people are beginning to see it as something that can be manipulated, rather than an inevitable, untreatable process.

What do you think have been the biggest/important discoveries in the field?

Some of the most important discoveries include the identification of key genes and pathways associated with aging, such as the sirtuins, mTOR, and AMPK pathways. The discovery that the drug rapamycin, originally used to prevent organ transplant rejection, can extend the lifespan of mice has led to a surge of interest in the mTOR pathway as a target for anti-aging interventions. Also, studies on calorie restriction and its impact on lifespan have opened new avenues for research

The discovery of telomeres and the role of telomerase in cellular aging has also been pivotal. Finally, the discovery of cellular senescence and development of senolytic drugs has been a significant breakthrough. 

What advice would you give to people currently working in longevity research?

Stay interdisciplinary. Aging is a complex process that affects every system in the body, so collaborations across different fields of science will be key to making significant progress. Also, consider the ethical implications of your work; extending lifespan will have profound implications for society, and it is important to consider these issues as the research progresses.

Which aspect of longevity research do you think requires more attention?

One aspect that requires more attention is the study of the social, economic, and psychological implications of increased lifespan. While much focus has been placed on the biological aspects of aging, it is equally important to understand how increased lifespan will impact society as a whole.

While a lot of focus has been on the molecular and cellular aspects of aging, the impact of the microbiome on aging is an area that requires more attention. The microbiome plays a crucial role in human health, and its composition changes with age. Understanding these changes and how they contribute to aging could open up new avenues for intervention.

Is aging a disease?

This is a controversial topic. Some researchers argue that aging should be classified as a disease to spur more funding and research into interventions. Others argue that it is a natural process and classifying it as a disease could have unintended societal implications. While there is no consensus, it is clear that aging is the biggest risk factor for many diseases, and interventions that target the aging process could have broad benefits for human health.

How would you solve aging?

Aging is a highly complex and multifaceted process. A plausible approach would be to tackle it from both a biological and a sociocultural angle:

Biologically: Focus on cellular and genetic levels. This could involve targeting senescent cells, managing telomere length, and improving proteostasis, along with employing genetic engineering techniques like CRISPR to modify or replace genes linked with aging.

Socioculturally: The intersection of technology, lifestyle, and health would have to be addressed. Integrative health systems would become a priority, where AI, human medical expertise, and regular health monitoring would ensure that people stay in the best health possible.

Do you think solving aging would facilitate humankind’s efforts to colonise the galaxy?

Yes, solving aging would significantly facilitate space exploration and colonization. With extended lifespans, the time it takes to travel between stars becomes less daunting. Humans could embark on century-long journeys to distant star systems without the fear of dying of old age.

How can AI significantly influence and advance the field of aging biology?

Data Analysis: The biology of aging generates vast amounts of data, from genetic sequencing to cellular imaging. AI can rapidly process and analyze this data, identifying patterns or anomalies that might be missed by human researchers.

Predictive Modeling: AI can develop models to predict the outcomes of various interventions on aging. For example, given the genetic and health data of an individual, an AI might predict how certain treatments could impact their aging process.

Drug Discovery: AI-driven algorithms can analyze massive compound libraries to identify potential drugs that could impact aging. They can also predict drug interactions and side effects.

Genomic Analysis: Machine learning can help identify genes associated with longevity and age-related diseases. By understanding these genes, researchers can target them for therapeutic interventions.

Simulations: AI can simulate biological processes, allowing researchers to test theories about aging in a virtual environment before conducting real-world experiments.

How can we innovate strategies that dramatically amplify human lifespan by decades or even centuries, rather than achieving mere incremental enhancements of a few years?

Radical Interventions: While current interventions might add a few years, radical approaches, like advanced gene therapy, organ replacements using lab-grown organs, or nanotechnology to repair cellular damage, might be required for substantial lifespan extensions.

Holistic Approach: Aging is multifactorial. Addressing it might require a combination of genetic, pharmacological, lifestyle, and environmental interventions.

Space and Environment: There's emerging interest in how changing environments (e.g., space or deep-sea habitats) could impact human aging. If certain environments slow aging, they might become more appealing for habitation.

AI and Tech Integration: As discussed, AI will play a pivotal role. The seamless integration of technology and biology, such as continuous health monitoring and immediate AI-driven interventions, might be crucial.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful! Wishing you speedy recovery after an intense conference season and see you back here next month.

This time we leave you with the first of a new article series co-written with the winners of the Longevity Prize, highlighting their proposals. Starting with the 1st prize winner Carlos Galicia and The Key to Longevity Could Be Hidden in Embryos.

Further Reading

Health Consequences of Thymus Removal in Adults

LINE-1 regulates cortical development by acting as long non-coding RNAs

Welcome back Vitalians and please join us in congratulating the Cyclarity Therapeutics (CTx) team for passing the VitaDAO token holder vote! This proposal was an assessment of an early-stage biotechnology company...
Read more
VitaDAO Letter: Falling DAOn the Longevity Rabbit Hole🍁
September 6, 2023
Sarah Friday
Awareness
VitaDAO Letter: Falling DAOn the Longevity Rabbit Hole🍁

Hello Vitalians! While the seasons might be changing, VitaDAO’s unwavering commitment to extending healthy lifespan remains constant! This month, VitaDAO members traveled across the globe to attend conferences, spoke with field leaders through TwitterSpace events, screened new project submissions, and funded even more research! Inside this edition of our Newsletter, you can find:

  • A Twitter Space Month In Review  
  • The Latest VitaFAST Updates
  • How to become a VitaDAO Delegate 
  • Competition Winning VitaDAO Memes

🗣️A Month of VitaDAO’s Twitter Space In Review 

August was a vibrant month filled with enlightening Twitter Spaces, or as we now call them, X Spaces. The conversations began with Sergei Young, a prominent longevity investor who founded the $100M Longevity Vision Fund. Max Unfried and Laurence Ion engaged in a thought provoking dialogue with Sergei about the importance of recognizing aging as a disease, global regulatory framework, and intricacies of funding in longevity research.

The learning journey continued as host Max Unfried led a conversation with Aubrey De Grey, Caitlin Lewis, and Kelsey Moody, focused on mouse rejuvenation. The purpose of extending lifespan in mice is twofold: 1) convince the world that rejuvenation is possible and 2) identify interventions that may translate to humans. Researchers on the space discussed recent developments in mouse studies, concerns with the interventions, and approaches to interpreting survivorship data. 

In VitaDAO’s next TwitterSpace event, Max Unfried was joined by experts Mahdi Moqri, Kristen McGreevy, David Meyer, and Raghav Sehgal to explore the latest developments in epigenetic clocks. Mahdi Moqri aptly defined epigenetics as “an additional layer on top of your DNA that controls cell identity.” The epigenome plays a pivotal role in both development and aging. During this space, experts dissected the differences between first, second, and third generation epigenetic clocks. 

Following Zuzalu, a pop-up city dedicated to life extension, VitaDAO has continued to delve into the creation of longevity network cities. Niklas Anzinger, Laurence Ion, Tom Howard, and Max Unfried discussed the practicalities of establishing network longevity cities, states, and countries. In early 2024, VitaDAO is excited to be a part of coordinating Vitalia, a pop-up city that will center around the belief that “life is good, death is bad.”

To wrap up the month, Alex Dobrin joined Ines Silva, Laura Minquini, and Estéfano Pinilla from AthenaDAO to discuss the work AthenaDAO is doing to advance women’s reproductive longevity. Recognizing the lack of funding for female related conditions, AthenaDAO has been advocating for and funding women’s health research. They are currently conducting a token auction!

🧪VITA-FAST Updates 

Can you believe it’s only been two months since the launch of the VITA-FAST token? They say time flies when you're having fun, and researching autophagy is indeed exhilarating! The launch, which garnered an 1700% oversubscription with $620k in bids, marked a revolutionary shift in how individuals can engage with longevity research. 

Since the launch, there have been two VITA-FAST governance proposals:

  1. VFDP-1: The election of a Project Lead for the Decentralized Autonomous Organization (DAO) that governs the Discovering Novel Autophagy Activators IP-NFT.
  2. VFDP-2: Agreement to enter into a contractual relationship with Camp Consulting.

This month, Dr. Viktor Korolchuk spoke at the first VITA-FAST Community Call. The Korolchuk Lab is committed to identifying compounds that could potentially kickstart autophagy and rejuvenate aged cells. During the call, VITA-FAST token holders were informed that the lab has ordered commercially available analogs and screened them on two of three autophagy assays. Some of the analogs have show promising results and are even outperforming their predecessors! The lab is now considering engaging an external medicinal chemist to validate which chemical families to pursue. As the project moves closer to target identification, the lab hinted at the future of a hackathon to leverage the DeSci community’s expertise in predicting where the mechanism of action lies. Exciting progress indeed!

🌎Back to Back: Conference After Conference

Our Vitalians have been keeping busy! This month began with the Longevity+DeSci Summit NYC. Here, VitaDAO members Todd White, Eleanor Davies, Laurence Ion, and Niklas Anzinger took the stage. Todd delivered a keynote talk titled "A New Epoch in Longevity Science? Preparing for a Longevity Future with DeSci,” advocating for decentralized science by highlighting the shortcomings of “traditional” science. 

Shortly after Longevity+DeSci Summit NYC, Eleanor Davies and Max Unfried represented VitaDAO at the Longevity Summit Dublin. They gave an insightful presentations on the ways VitaDAO is pioneering longevity research funding and ways the internet can be used to create a decentralized network state.

The whirlwind of a month concluded with the 10th Aging Research and Drug Discovery Meeting. VitaDAO members Tim Peterson, Estefano Pinilla, Maria Marinova, Eleanor Davies, Max Unfried, and Paolo Binetti spoke at the conference, even shared some VitaDAO swag (check out the pictures below!). 

🗳️Transfer Your Voting Power

Introducing delegated voting! In VDP-65, the VitaDAO community voted to allow $VITA token holders to delegate their voting rights to a delegate. Simply put, delegation is a transfer of voting power. Delegation is great for $VITA holders who don’t have the bandwidth to actively participate in the governance and evaluation of VitaDAO’s research proposals. The DAO is currently accepting applications for delegates on Discourse. One can delegate their voting power to candidates directly on Snapshot. 

📣Community Approved: What YOU voted for!  

Thanks to the support of the VitaDAO community, multiple proposals successfully passed this month! Notable passed proposals include:  

  • VDP-110: Allocation of $10,000 USD to fund another batch of VitaDAO Longevity Fellows with need-based micro-grants of up to $2,000 USD.
  • VDP-106: Clarifications to the guidelines for applicants to and reviewers of projects VitaDAO funds.
  • VDP-111: An outline of a VITA-FAST governance model and the election of a steward by VITA-FAST token holders. 
  • VDP-103: Funding $91,300 towards engineering an arginine suppressor tRNA that can specifically recognize these nonsense mutations, restoring normal protein translation. 
  • VDP-112: An assessment of Cyclarity Therapeutics, an early stage biotechnology company developing computationally designed novel cyclodextrin drug molecules to extraction of toxic biomolecules that accumulate with age.


💪Exercise Your Right to Vote

Visit VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Your input is invaluable, and together, we can shape the future of VitaDAO and decide how best to accelerate decentralized science.

😆VitaDAO Meme Competition

Looking for a good laugh? Want to work out your zygomaticus? This summer, VitaDAO hosted a Twitter meme competition, with a $VITA reward for the top three submitted memes. The only rule: the meme had to relate to longevity and aging. The submissions did not disappoint! Head over to VitaDAO’s Twitter to enjoy some clever community generated memes.

🥇First Place

🥈 Second Place: 

🥉Third Place:

🤝Thanks for Reading! 

Want to stay up to date with all that's going VitaDAOn? Join us on Discord, subscribe to our Twitter, and follow our Instagram! You can also find updated information on VitaDAO's funded projects and a treasury dashboard on our website

Hello Vitalians! While the seasons might be changing, VitaDAO’s unwavering commitment to extending healthy lifespan remains constant! This month, VitaDAO members traveled across the globe to attend conferences, spoke with field leaders through...
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Vision's Aging Secrets: Eye Diseases & Breakthroughs with Prof. Dorota Skowronska-Krawczyk on The VitaDAO Aging Science Podcast
September 5, 2023
Longevity
Awareness
Vision's Aging Secrets: Eye Diseases & Breakthroughs with Prof. Dorota Skowronska-Krawczyk on The VitaDAO Aging Science Podcast

Today I had the pleasure of talking to Prof. Dorota Skowronska-Krawczyk (@DrDorotaSK) on the VitaDAO Aging Science Podcast (episode 8). We discussed the importance of basic aging mechanisms like senescence, repeated stress and inflammation as drivers of multiple eye diseases. We talked about the lack of good animal models for age-related eye diseases, prevention of age-related macular degeneration, unity therapeutics and recent trials of senolytics for eye diseases.

Short Bio

Dorota was born in Lodz, Poland and later studied biology in Warsaw, Poland where she finished her studies with distinction. She received a PhD in Biochemistry at the University of Geneva, Switzerland. Then she finished two postdoctoral trainings – in Lausanne, Switzerland and at UCSD San Diego before starting her independent career in May 2017. 

Work in her lab focuses on deciphering the mechanism of age-related eye degeneration. Using retina as a model system, the lab employs modern technologies to address unresolved issues, such as the role of fatty acids in age-related neurodegeneration and the role of stress in accelerated aging. In her free time, she likes to travel alone or with family.

Prof. Dorota Skowronska-Krawczyk
Center for Translational Vision Research, UC Irvine, School of Medicine
https://faculty.sites.uci.edu/skowronska-krawczyk/

The eye is a privileged organ

The eye is sometimes referred to as an “immune privileged” organ because the blood-retinal barrier shields it from invading immune cells. While this may be beneficial, it could also mean reduced clearance of senescent cells via NK cells (or future adoptive cell based therapies). On the other hand, the eye is very accessible which makes it easy to administer drugs directly using intravitreal injections or topical application. Dorota and I agreed that this could mean early proto-gerotherapeutics would be first available to treat eye disease before they are used to treat other tissues, as the local nature of these treatments would prevent systemic side effects.

Aging promotes multiple eye diseases

We discussed just how exquisitely sensitive the eye is to aging. There are so many eye diseases that show a textbook exponential pattern of increasing incidence with age. This means if you live long enough you will likely develop one or all of these diseases. Dorota works on two of the more famous eye disease, age-related macular degeneration (AMD) and glaucoma. Other common age-related eye diseases include cataract, near-sightedness and diabetic and hypertensive retinopathy. The former two reaching a prevalence of 80% or more in the very old. Less know age-related eye disorders include dry eye disease and eyelid muscle weakness associated with drooping eyelids. 

Nevertheless, there are species that can maintain their eye health far longer than humans including some turtles, whales and Greenland sharks. Dorota mentioned that she would really love to study the eyes of these sharks that are able to live up to 400 years. As we have discussed in the podcast with Vera Gorbunova, this kind of approach is called “comparative” and it often yields very interesting insights that are quite off the beaten path.

Age-related macular degeneration (AMD)

Age-related macular degeneration (AMD) is characterized by the progressive degeneration of the macula, the central part of the retina responsible for sharp, central vision. The incidence of AMD increases significantly with age, reaching >10% in people over the age of 80. AMD is categorized into two main forms, wet (neovascular) and dry (non-neovascular) AMD. As we discussed during the podcast, there are very few treatment options for dry AMD and mice do not have a macula, further hampering research into this pathology. Alternative models like dogs and non-human primates are very expensive.

Typical molecular hallmarks of AMD are extracellular deposits called drusen and intracellular deposits called lipofuscin. The retinal pigment epithelium is responsible for phagocytosing and removing outer segments of photoreceptors after they have become damaged during the vision process. The sheer volume of recycling is quite remarkable as every day 10% of these outer segments are lost and recycled. The sensitivity to AMD might be somehow rooted in this high metabolic activity, although we do not know for sure.

We mentioned during the podcast that AMD is one of the few diseases where the now unpopular “oxidative stress theory of aging” triumphed, since a cocktail of antioxidants was shown to slow progression of early AMD (AREDS study). Surprisingly, while omega 3 fatty acids from fish appear protective in observational studies, these benefits could not be replicated in controlled trials (AREDS2 study). Dorota believes that a better and more refined formulation might eventually work in another trial, perhaps AREDS3. Of course, it is also a real possibility that observational studies produced exaggerated or spurious results as they are wont to do.

Glaucoma

Glaucoma, is actually not just one disease but probably a whole group of eye conditions leading to optic nerve damage. Glaucoma is primarily associated with an increase in intraocular pressure (IOP), however – and this was quite a surprise to me –  a subset of cases known as normal-tension glaucoma (NTG) occurs without elevated IOP. Importantly, IOP is unrelated to blood pressure.

The prevalence of so called open angle glaucoma is around 20% at the age of 90 with an exponential increase during aging.

Pathologically, glaucoma involves the progressive degeneration of retinal ganglion cells, causing irreversible vision loss. This is in contrast to AMD, where the retinal pigment epithelium and photoreceptors degenerate. Another difference between the two pathologies is that we have better treatments for glaucoma.

Glaucoma is sometimes called the “silent thief of sight” because the vision loss only becomes obvious after a significant amount of irreparable cell loss. This is not unlike the situation with AMD, where the eye and brain are able to compensate for cell loss until a considerable amount of damage has been done. 

Dorota in her research found that old mice are much more susceptible to increased IOP whereas in young mice it takes multiple cycles to cause the same amount of vision loss (Xu et al. 2022). This finding is consistent with the idea that aging can be broadly defined as the loss of resilience towards stressors. We also talked about inflammation during glaucoma and whether the inflammation is local or due to immune cell infiltration – a question that vexes almost every aging researcher studying any kind of tissue. Based on bulk RNAseq and RNAscope data she believes that inflammation in glaucoma is specific to ganglion cells.

Commonalities between eye aging and aging more broadly

Inflammation, repeated “stress” (e.g. elevated intraocular pressure), oxidative stress and senescence are hallmarks of both aging and eye aging. Dorota has had a lot of success using senolytics in mouse models of glaucoma, specifically dasatinib (Xu et al. 2022), underscoring the importance of senescence as a universal pathomechanism. She does believe there is some evidence for senescence in AMD as well, although this is not entirely clear due to a paucity of in vivo studies (Malek et al. 2022). Given this, we were both puzzled and disappointed by the failure of Unity’s senolytic  – the Bcl-xL inhibitor UBX1325 – for wet AMD (1).

Obviously not everyone is in love with the senescence hypothesis and ultimately we have to wait for more data to settle the issue.

Targeting inflammation has been a glimmer of hope for those with dry AMD. The first ever approved drug for this condition, pegcetacoplan, inhibits the complement system, which is a cascade of proteins normally used to amplify immune responses against pathogens. Dorota believes that both AMD and glaucoma may have an inflammatory component. Thus it is tempting to speculate that chronic senolytic or other anti-inflammatory therapies could slow the development of both of these diseases. I mentioned to Dorota that perhaps starting treatment in late-stage disease was not such a good idea for this very reason.

Finally, we also speculated about general mechanisms of aging. Dorota asked how could it be that damage is repaired and completely removed, as far as we can tell, yet it still predisposes the organism to future disease and stressors? Could it be that the repair machinery was diverted from other places where it was needed? To me this whole idea is somewhat reminiscent of certain epigenetic aging theories where DNA damage, even when repaired, leads to local changes in epigenetic marks that predispose to aging. On the level of gene expression it seems very plausible that stressful events could introduce some kind of noise into the system that can be fully compensated while reducing the resilience of the system.

In her recent article titled "Hallmarks of Aging: Causes and Consequences." Dorota further elaborates on her views and tries to put the hallmarks into a temporal order. Her approach is certainly not bad considering how botched the naming of hallmarks is in the new paper. Who came up with the terms “primary, antagonistic, and integrative”? (2)

My opinion remains: all hallmarks are wrong, some of them are useful. We can achieve a lot without a full understanding of aging as the seminal discoveries of caloric restriction and rapamycin show. Now we just need to convince politicians that the only Manhattan project worth funding is the anti-aging project.

References

Stress induced aging in mouse eye.
Xu Q, Rydz C, Nguyen Huu VA, Rocha L, Palomino La Torre C, Lee I, Cho W, Jabari M, Donello J, Lyon DC, Brooke RT, Horvath S, Weinreb RN, Ju WK, Foik A, Skowronska-Krawczyk D. Aging Cell. 2022 Dec;21(12):e13737. doi: 10.1111/acel.13737. Epub 2022 Nov 17.

Does senescence play a role in age-related macular degeneration?
Malek G, Campisi J, Kitazawa K, Webster C, Lakkaraju A, Skowronska-Krawczyk D.
Exp Eye Res. 2022 Dec;225:109254. doi: 10.1016/j.exer.2022.109254. Epub 2022 Sep 21.

Skowronska-Krawczyk, Dorota. "Hallmarks of Aging: Causes and Consequences."
https://agingcelljournal.org/Archive/Volume2/hallmarks_of_aging/

(1) https://www.biospace.com/article/unity-shares-nearly-halved-as-lead-asset-fails-to-match-regeneron-s-eylea/

(2) Obviously the failure of the hallmarks simply reflects the complexity of aging and lack of consensus rather than the shortcomings of the authors. There is no doubt that the hallmarks papers are useful.

Nevertheless, a few pet peeves of mine. Is the telomere not a part of the genome and central to genome stability? It has always been a very odd choice to put telomeres as their own hallmark. Another interesting choice is to put mitochondrial dysfunction as an antagonistic hallmark. Are other organelles not dysfunctional during aging?

I must say I fully agree with Dorota that the hallmarks were always somewhat confusing because they merrily mix together things like damage (genomic instability), pathways (nutrient sensing), cellular processes (autophagy or proteostasis), organelle dysfunction and systemic/tissue pathology (inflammation). I would much rather think and classify in these terms:


Damage -> cellular process -> cell level pathology -> tissue and organ level pathology

With another strict distinction between cellular processes of “damage prevention” (e.g. antioxidants), “damage repair” (e.g. DNA repair or autophagy) and “damage compensation”.

In this episode of The VitaDAO Aging Science Podcast, we delve into the world of age-related eye diseases with Prof. Dorota Skowronska-Krawczyk, a renowned expert in vision and aging. We explore fundamental aging mechanisms, challenges in research...
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The Key to Longevity Could Be Hidden in Embryos
September 4, 2023
Carlos Galicia & Maria Marinova
Longevity
Awareness
The Key to Longevity Could Be Hidden in Embryos


Scientists are forever searching for ways to rejuvenate aged cells and organisms back to a more youthful and healthier state — from stem cell therapies to telomere lengthening, or even the Frankenstein-esque heterochronic parabiosis experiments whereby older organisms receive the blood of younger ones. In 2012, the Nobel Prize in Physiology or Medicine was awarded to Sir John B. Gurdon and Shinya Yamanaka who discovered a technique to reprogram mature cells back to stem cells, coined induced pluripotent stem cells. Big pharma has attempted to use this knowledge to develop rejuvenating therapies, for example Altos labs became one of the highest funded start-ups in history with an initial investment of 3 billion dollars.

What if I told you the key to reverse aging might be hidden inside your very own cells? We’re not talking about sipping on an exotic “superfood” concoction, strapping on some high-tech gadget, or hiring a blood boy. The spotlight is firmly on embryogenesis — a biological process that we’ve all experienced yet barely understand.

Okay, so what’s the big deal about embryogenesis? The miraculous transformation of two adult gametes (sex cells) into a full-blown organism effectively hits a giant reset button. Any age-related wear and tear present in the parent cells? Gone. Erased. Just like that, the biological clock is set back to zero. If that’s not a natural “Fountain of Youth,” what on earth is?

Like other adult cells, gametes undergo multiple types of age-related changes. They suffer mitochondrial dysfunction; they accumulate molecular damage and show epigenetic alterations [1, 2]. These afflictions bear the potential to be the unwelcome legacy passed down to the nascent embryo. Yet, this sparks a compelling hypothesis: could the embryo come equipped with inherent mechanisms to mitigate age related changes and undergo rejuvenation?

The idea of ‘rejuvenation’ isn’t new in the biological world. Conversion of somatic cells to induced pluripotent stem cells and the reset of the germline age with each generation are examples of this phenomena. This gives rise to the proposition of a ‘ground zero’ model, a mid-embryonic state characterized by the lowest biological age. It is hypothesized that the period from zygote to this ‘ground zero’ is associated with rejuvenation, wherein the biological age is decreased, telomeres are extended, and molecular damage is cleared. This concept of ‘ground zero’ helps illuminate the relationship between aging, development, rejuvenation, and de-differentiation, elements that are distinct throughout life [1, 3]. But here’s the million-dollar question: how does this occur? Well, hold onto your lab goggles, because scientists are already exploring this exciting frontier!

Using algorithms that can predict the age of an organism called epigenetic clocks, researchers have identified a point in embryogenesis where epigenetic age is reversed [1, 4]. Epigenetic clocks measure epigenetic age by looking at specific methylation patterns that are indicative of the age of an organism. Methylation patterns are a fundamental aspect of epigenetics. They involve the addition of a methyl group (a carbon atom linked to three hydrogen atoms) to the DNA molecule, typically at a cytosine nucleotide (one of the “building blocks” of DNA). These patterns play a pivotal role in gene expression because they can silence or activate genes without changing the underlying DNA sequence.

Scientists speculate that harnessing this natural epigenetic rejuvenation could be a key to promoting longevity and reducing age-related disease. This theory has taken the field by storm over the last few years and attracted a lot of commercial interest and new ventures trying to induce a state of “youthfulness” in cells by applying a process of epigenetic reprogramming.

Indeed, methylation presents a fascinating instance of the molecular alterations associated with aging. However, it represents only one facet of this complex process. A myriad of other molecular transformations and deteriorations in cellular function accumulate over time. The extent to which these changes affect gametes and whether they can be reversed by the embryo remains largely unknown.

To gain a deeper understanding of the relationship between aging and embryogenesis, researchers are delving deep, right into the core of gametes and embryos. Their goal? To identify any age-related alterations in parent cells that are subsequently erased as oocytes and sperm transform into an embryo, ultimately giving rise to a new organism.

The idea is to identify what molecular and functional changes occur as gametes age and to study whether embryogenesis has the capacity to reverse and alleviate some of them. To do this, scientists plan to use advanced technologies that can measure the abundance and state of a cell’s molecular components. These technologies include powerful tools like mass spectrometry which can be used to quantify and characterize proteins and the modifications they have undergone. This is important since protein damage and protein aggregates are thought to be a direct contributor to the aging process. Other tools like nanopore and SMRT sequencing have the potential to spot alterations in our DNA [5, 6]. These changes include various forms of DNA damage and understanding how these changes evolve with age and their behavior during embryogenesis, may uncover unknown aging and rejuvenation mechanisms.

However, the exploration doesn’t stop at proteins and DNA. Scientists are planning to do a deep dive into other components of cells, like lipids, metabolites, RNA, and the shape of DNA. They will gather heaps of data from these tests, then add functional data about different parts of the cells like mitochondria or lysosomes. When all these investigations come together, they would give us a detailed picture of how gametes age and how embryos deal with this.

These large datasets do more than just offer information about which facets of aging are undergoing rejuvenation. They also provide invaluable insights about the genes, peptides, and metabolites that drive the powerful genetic programs the embryo utilizes. This could prove very valuable, given that the embryo utilizes multiple processes that can be used to fight age related diseases.

For instance, in an intriguing series of experiments, scientists have injected cancerous cells into embryos. Yet, contrary to expectations, these malignant cells neither overwhelm the embryo nor are they eliminated. Instead, the embryo exercises a remarkable level of control over these intruders, compelling them to halt their proliferation [7]. Adding to the element of surprise is the fact that these transformed cells are not only maintained in tissues until birth, but they also undergo a complete reprogramming from their original cancerous state. It’s as if the embryo, in its potent nascent life, possesses a transformative capacity that can strip away the cells’ malignancy.

This intriguing process is likely to contribute to the intricate equilibrium required during tissue formation in embryogenesis. Unlike in cell culture where most cell types face a limit on the number of divisions, during embryogenesis the initial cells can form an entire organism without succumbing to replicative senescence. This is the result of elaborate cellular programs that grant cells the freedom to proliferate robustly while concurrently shielding them from becoming cancerous.

These are potent programs encoded within our very genome, holding potential applications for regenerating new tissue or combating malignancies in aging organisms. Indeed, certain creatures in the animal kingdom, like the aquatic hydra and some species of planaria, exploit similar processes to earn their ticket to immortality [8, 9]. Venturing into this new frontier of knowledge could unlock transformative therapeutic strategies, potentially reshaping our approach to age-related diseases and longevity.

While this all might sound like it’s straight out of a science fiction novel, it’s rooted in solid science. Even more exciting is that it’s mostly an uncharted territory! Despite the enormous potential of studying embryogenesis, it’s been an overlooked area in the longevity research world, making it ripe for exploration. Cracking the code of embryogenesis could very well be the key to understanding aging and how to reverse it. If successful, this could be a game-changer in how we approach aging and longevity. Forget about mythical fountains or enchanted forests; our ticket to timeless youth might just be nestled within the miracle of life itself!

Authors: Carlos Galicia & Maria Marinova

Editors: Rhys Anderson

Illustrator: Victoria Forest

References:

1. Kerepesi, C., et al., Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. Science advances., 2021. 7(26): p. eabg6082.

2. Smits, M.A.J., et al., Human ovarian ageing is characterized by oxidative damage and mitochondrial dysfunction. 2023, Cold Spring Harbor Laboratory.

3. Gladyshev, V.N., The Ground Zero of Organismal Life and Aging. Trends in Molecular Medicine, 2021. 27(1): p. 11–19.

4. Zhang, B., et al., Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in Xenopus laevis. 2022, Cold Spring Harbor Laboratory.

5. Clark, T.A., et al., Direct detection and sequencing of damaged DNA bases. Genome Integr, 2011. 2: p. 10.

6. Wang, F., et al., Solid-State Nanopore Analysis of Diverse DNA Base Modifications Using a Modular Enzymatic Labeling Process. Nano Lett, 2017. 17(11): p. 7110–7116.

7. Astigiano, S., et al., Fate of embryonal carcinoma cells injected into postimplantation mouse embryos. Differentiation., 2005. 73(9–10): p. 484–490.

8. Sahu, S., A. Dattani, and A.A. Aboobaker, Secrets from immortal worms: What can we learn about biological ageing from the planarian model system? Semin Cell Dev Biol, 2017. 70: p. 108–121.

9. Muller, W.A., Pattern formation in the immortal Hydra. Trends Genet, 1996. 12(3): p. 91–6.

Scientists are forever searching for ways to rejuvenate aged cells and organisms back to a more youthful and healthier state - from stem cell therapies to telomere lengthening, or even the Frankenstein-esque heterochronic parabiosis experiments...
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Decoding Longevity: DNA Mutations, Mole Rats, and Cancer Prevention with Prof. Vera Gorbunova on The Aging Science Podcast by VitaDAO
August 23, 2023
Awareness
Longevity
Decoding Longevity: DNA Mutations, Mole Rats, and Cancer Prevention with Prof. Vera Gorbunova on The Aging Science Podcast by VitaDAO

In the 7th episode of the Aging Science podcast we talked with Prof. Vera Gorbunova about her most recent work, covering a wide array of topics from genome stability, naked mole rats, the role of hyaluronan in cancer prevention, fucoidan as a SIRT6 activator, to comparative transcriptomics and Peto’s paradox.

Short Bio — Vera Gorbunova

Dr. Vera Gorbunova is a Professor of Biology and Medicine from University of Rochester. Having earned her undergraduate degree at at Saint Petersburg State University (Russia) and her Ph.D. at the Weizmann Institute of Science (Israel), she has dedicated her career to understanding the mechanisms of longevity across species, exploring genome stability, sirtuins, and non-traditional animal models. Her pioneering work on SIRT6 biology and potential activators like fucoidan, along with contributions to studying hyaluronan for cancer prevention, could pave the way towards therapeutic applications.

“I would choose to live for as long as I am enjoying it[…]it is very difficult to set a limit for yourself. That is what we would want for every person that people can live as long as they are happy.” (Vera Gorbunova)

DNA damage and aging

One of Vera’s key interests is genomic instability, which has emerged as a likely driver of aging. Mutations can lead to cancer, disrupt gene expression and the epigenetic architecture of the genome. This explains why long-lived species had to develop effective mechanisms for repairing or preventing such damage.

In a recent study together with Jan Vijg, Vera discovered that short-lived rodents, and in particular mice, show higher levels of DNA mutations before and after a genotoxic stress (Zhang et al. 2021). The technique they used to show this is particularly interesting. Without going into details, it is difficult to measure DNA mutations using classical sequencing due to high levels of background noise that looks like mutations. Many workarounds exist, often focusing on clonally expanded stretches of mutations. Here, instead, the authors performed whole genome sequencing of single fibroblasts from five different species that differed in their maximum lifespan (mouse, human, guinea pig, blind mole-rat, and naked mole-rat).

While the finding of lower mutation rates in long-lived species is correlational and indirect, it has been replicated many times and there is no clear alternative explanation for it that would be unrelated to aging or cancer. This is one of the reasons why the “DNA damage theory of aging” is generally held in high regard by most people in the field.

Comparative biology of aging

Researchers doing comparative biology or biogerontology of aging, as the name suggests, want to compare species that have different lifespans to discover why some live longer than others.

On this podcast we often talk about the shortcomings of mice, like their short lifespans and susceptibility to cancer (1). Comparative biology avoids these pitfalls of mouse models since it allows researchers to study a wide variety of species, some of which live orders of magnitude longer than mice and are more similar to humans.

Comparisons come in many types. Some researchers study dozens or even hundreds of species, if they can access the right kind of data for these species (2), whereas others pick two closely related species that have different lifespans and compare them. Often this is the mouse and the naked mole rat, which while mouse-sized nevertheless lives up to 30 years. The techniques employed are as varied as the sample sizes of these studies. In principle, one can compare any phenotype or molecular marker between species. Recent studies have focused on high-throughput methods, comparing the genomes or transcriptomes of different species.

Transcriptomics and other “omics” of aging

The expression patterns of cellular mRNA, the template that gives rise to proteins, can be studied using RNA-sequencing which we call transcriptomics. Vera’s team recently published a large-scale comparison of different rodents (Lu et al. 2022) confirming some candidate pathways we believed are associated with longevity. For example, longer-lived rodents, let’s say capybaras or naked mole rats, were found to have better repair of DNA double strand breaks, while pathways involved in the repair of smaller lesions were unchanged. This is keeping with an emerging consensus that double strand break repair is the most important type of DNA repair for aging.

Also, not surprisingly inflammation was reduced in longer-lived rodent species. Transcription factors related to pluripotency were linked with the expression of “pro-longevity” genes while “anti-longevity” genes were related to circadian transcription factors.

The study also reported some beautifully odd findings implicating novel pathways in aging, including collagen synthesis or RNA export. This is the kind of finding that, if it pans out, can spawn a new field of research.

While I love comparative studies utilizing omics, it should not go unmentioned that they have certain limitations. Given the large amount of data generated it is quite easy to find support for some of the popular aging theories, whereas lack of evidence is often ignored. No one ever talks about the aging theories that were not supported by the data that and what this means.

Moving forward, Vera’s next goal is to apply proteomics and metabolomics approaches to these rodent species, integrating this data with the transcriptomic findings. We both agreed that proteomics, i.e. the systematic analysis of protein expression patterns, is very under-utilized in aging research.

Extracellular matrix (ECM) and aging

The importance of extracellular matrix (ECM) changes to cardiovascular aging was discovered by Blumenthal and Lansing in the early twentieth century. Despite this early and seminal work, for a while there was a lack of interest in studying extracellular matrix changes during aging and the field is having a renaissance now. While Lansing studied a protein called elastin, Vera’s work is focused on glycosaminoglycans, which are a type of large sugar chains (polysaccharides).

“The length of hyaluronan [=hyaluronic acid] can range from an oligomer to an extremely long form up to millions of daltons. The concept that emerged in the field is that high (HMW-HA) and low (LMW-HA) molecular weight hyaluronans have different biological properties and trigger different signaling cascades within the cells. LMW-HA is associated with inflammation, tissue injury and metastasis, while HMW-HA improves tissue homeostasis and has anti-inflammatory and antimetastatic properties.” (Gorbunova et al. 2020)

In this episode of our podcast Vera explains that hyaluronan forms a mesh between tissues and cells that may be able to slow down metastasis and the growth of cancer more generally. It appears that naked mole rats possess high molecular weight hyaluronan that is particularly effective at preventing cancer and perhaps we might be able to slow down cancer growth by boosting our own production of hyaluronan. Achieving this goal, however, will not be simple since such a large molecule cannot be absorbed well from the gastrointestinal tract, which rules out a simple supplementation approach. Similarly, although hyaluronan injections are a popular treatment for wrinkles and osteoarthritis, they will not work to increase whole body hyaluronan synthesis because the hyaluronan molecule is large and “sticky”.

Instead, the idea is to inhibit the enzyme that breaks down hyaluronan which would also cause a shift towards larger molecular weight species of hyaluronan.

Although it remains speculative whether boosting hyaluronan synthesis or increasing the molecular weight of our own hyaluronan will be beneficial, it is nevertheless a good working hypothesis. This kind of work beautifully illustrates how basic and comparative science can lead to potential clinical applications

Below you can read more about Vera’s recent project that was funded by VitaDAO: https://snapshot.org/#/vote.vitadao.eth/proposal/0x747f0e671d6e049ce501fba8067c9da3b0502b8945daa890ca98f36a63bc7246

Summary

Prof. Gorbunova’s work reveals a correlation between long lifespan and low DNA mutation rates. Among other things, she also found changes in the hyaluronan of long-lived species. There is ongoing work to utilize these findings to develop therapies that target human aging, e.g. fucoidan as a SIRT6 activator or inhibitors of hyaluronan breakdown.

References

Lu, J. Yuyang, et al. “Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation.” Cell Metabolism 34.6 (2022): 836–856.

Zhang, Lei, et al. “Maintenance of genome sequence integrity in long-and short-lived rodent species.” Science Advances 7.44 (2021): eabj3284.

Gorbunova, Vera, Masaki Takasugi, and Andrei Seluanov. “Hyaluronan goes to great length.” Cell stress 4.9 (2020): 227.

Notes

(1) The justification for mouse research is as follows. We do not use mice because they are a great model of long-lived mammals, instead you can consider them as “better worms”. They are simply the next best model after invertebrates that is still affordable for basic research.

(2) One accessible type of data is for example the sequence of the mitochondrial genome. Both Vera and I published research on this topic and as an “amateur” comparative gerontologist myself I always like following her work.

Pabis, Kamil. “Triplex and other DNA motifs show motif-specific associations with mitochondrial DNA deletions and species lifespan.” Mechanisms of Ageing and Development 194 (2021): 111429.

Yang, Jiang-Nan, Andrei Seluanov, and Vera Gorbunova. “Mitochondrial inverted repeats strongly correlate with lifespan: mtDNA inversions and aging.” PLoS One 8.9 (2013): e73318.


In the 7th episode of the Aging Science podcast we talked with Prof. Vera Gorbunova about her most recent work, covering a wide array of topics from genome stability, naked mole rats, the role of hyaluronan in cancer prevention..
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July Longevity Research Newsletter
August 10, 2023
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
July Longevity Research Newsletter

Introduction

Welcome back Vitalians! Stop the press — the Impetus Longevity grants are back!

Having already deployed 24M USD to fund longevity research, round 3 is now open with 10M USD of funding, so if you have a great idea, get your application in before 31st August!

And the good news doesn’t stop there! VitaDAO has just opened another round of the Longevity Fellowship. We provide need-based micro-grants of up to $2,000 USD to passionate scientists, students, and longevity enthusiasts to delve deeper into their research interests, attend conferences, and join programs such as the Longevity Biotech Fellowship.
Quick tip: funding is distributed on a rolling basis so don’t wait too long to apply!

If real estate agents like to inform you it’s all about “location, location, location”, then drug developers would likely tell you it’s all about “delivery, delivery, delivery”.

It’s simply not enough to have a drug which works in a test tube, it has to be able to reach the intended target within the organism. The bioavailability of a drug can be diminished by various obstacles, from having to pass through the GI tract or the blood-brain-barrier, to navigating solid tumour microenvironments. As such, scientists are constantly looking for new ways to improve drug delivery, such as innovative nanotechnology-based carriers or developing prodrugs which can convert to being pharmacologically active at the site they are required. This month we’re excited to bring you an interview with Matthew Yousefzadeh, who has made significant contributions to the aging field, and touches on the bioavailability hurdles associated with the promising senolytic drug fisetin — enjoy!

Longevity Literature Hot Picks

Preprint Corner

The votes are in — The Longevist curators have decided what they think are the most important preprints of Q2. Before we publish the Q2 Issue of the Longevist, take a look at the inaugural issue of The Longevist which is now live!

Check out our first batch of preprints of Q3 with these July submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

As always, you can refer preprints to The Longevist and receive a bounty of 50 VITA for each one that makes the editors’ shortlist or 200 VITA if it makes the curators’ top 3.

LEF1 isoforms regulate cellular senescence and aging

Preserved striatal innervation and motor function despite severe loss of nigral dopamine neurons following mitochondrial dysfunction induced by mtDNA mutations

Alterations of the gut microbiome are associated with epigenetic age acceleration and physical fitness

Amyloid β accelerates age-related proteome-wide protein insolubility

The principal component-based clinical aging clock (PCAge) identifies signatures of healthy aging and provides normative targets for clinical intervention

Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems

Machine Learning identifies conserved traits that influence lifespan and healthspan responses to dietary restriction

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain

Somatic mutations in human ageing: New insights from DNA sequencing and inherited mutations

A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction

Glial-derived mitochondrial signals impact neuronal proteostasis and aging

Published Research Papers

Chemically induced reprogramming to reverse cellular aging

The Sinclair lab have identified chemical cocktails which can reverse transcriptomic age in cells. Thus they claim that age reversal can be achieved by chemical means. This paper has sparked controversy due to the speed of publication, questions of novelty, and overhyped claims. Take a read and make up your own mind!

The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery

From microscopes to space telescopes,

technology and science need to work together to make advances possible. Using the WormBot-AI automated data capture and analysis technology, the Kaeberlein lab are taking on the ambitious challenge of screening a million molecules for their effects on lifespan in C. elegans.

Large-scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals

Among mammals alone, lifespan can vary over 100 times between species. Here the authors performed transcriptomics across numerous species and identified that translation fidelity pathways correlate with lifespan and methionine restriction genes are under strong selection in long-lived mammals.

Here we have back to back published studies showing that senescent macrophages drive lung cancer and accumulate in aging

More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome

The Levine lab’s study suggests that aging and cancer share a common epigenetic replication signature, termed CellDRIFT. This signature increased with age across tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and could be reset upon reprogramming.

Multi-omic rejuvenation and life span extension on exposure to youthful circulation

Heterochronic parabiosis (HPB) in mice has shown significant rejuvenation effects, improving physiological parameters and extending lifespan. HPB reduced the epigenetic age of blood and liver, with the effect persisting even after detachment. The transcriptomic and epigenomic profiles suggest a global rejuvenation effect.

Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria

Maternal age significantly influences offspring adult traits like body size. This study utilized C. elegans to explore the mechanisms, revealing aged mitochondria transmitted from older worms are rejuvenated in offspring in an AMPK-dependent manner. This early-life mitochondrial dysfunction triggers AMPK and TGFβ signaling, increasing adult offspring size.

Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton

Using mass cytometry, researchers identified and analyzed senescent cells in aged mice at single-cell resolution. They found these cells in certain skeletal cell populations could be robustly cleared by senolytic therapies, providing a method to target senescent cells in vivo.

Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers

A study investigating the gradual molecular dysregulation in aging finds that lifespan-extending interventions like acarbose, 17α-estradiol, rapamycin, and calorie restriction generally tighten the regulation of biological modules. These patterns are similar across interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response.

Pan-primate studies of age and sex

Horvath presents accurate pan-primate epigenetic clocks based on DNA methylation profiles from 2400 tissues across 37 primate species. The study explores the impact of age and sex on cytosine methylation, identifying 11 sex-related CpGs on autosomes. The findings provide insights into conserved age- and sex-related epigenetic changes and biomarkers of aging in primates.

Predicting lifespan-extending chemical compounds for C. elegans with machine learning and biologically interpretable features

Researchers used machine learning to analyze DrugAge, a database of compounds that modulate lifespan in model organisms. They identified the importance of the “Glutathione metabolic process” and predicted new promising compounds for extending lifespan, including nitroprusside, an antihypertensive medication.

Published Literature Reviews

Chronic inflammation and the hallmarks of aging

The review suggests that chronic inflammation, known as “inflammaging,” is a critical driver of aging and age-related diseases. It is linked with other aging hallmarks, exacerbating cellular dysfunction and advancing aging. Targeting inflammation could be key in developing anti-aging interventions and addressing age-related conditions.

An updated landscape of cellular senescence heterogeneity: Mechanisms, technologies and senotherapies

The review emphasizes the critical role of senescent cells in aging, and the need for better identification methods. Despite the challenge posed by the heterogeneity of senescence, high-throughput technologies like single-cell RNA sequencing could enable improved analysis and potential discovery of new markers.

Stress, diet, exercise: Common environmental factors and their impact on epigenetic age

This review explores how lifestyle factors influence the DNA methylation landscape, as revealed by epigenetic aging clocks. Lifestyle factors can impact DNA methylation and consequently influence biological aging. Understanding these relationships could provide valuable insights for people interested in creating a lifestyle designed to promote longevity.

Spatial mapping of cellular senescence: emerging challenges and opportunities

This review discusses the challenges of mapping senescent cells, crucial for understanding aging. Current single-cell technologies lack spatial data, which is key due to the interactive nature of these cells. New spatial imaging methods are needed to create a comprehensive senescent cell atlas.

Job board

VitaDAO’s portfolio company BE therapeutics is looking for a scientist with tissue engineering or neuro lab experience for some exciting work on brain replacement lead by Jean Hebert. Send CV to jean.hebert@einsteinmed.edu to be considered.

Korolchuk lab in Newcastle University are hiring for an exciting new position of lab technician which will support an industrial project in collaboration with Procter & Gamble.

Explore new mechanisms of how DNA damage drives aging and alters heritable genomes at the Schumacher Lab at CECAD Cologne. They are seeking enthusiastic postdoc candidates with a background in genetics, cell biology, biochemistry or computational biology.

Prof. Marco Demaria is looking for an enthusiastic and ambitious PhD candidate to join the Laboratory of Cellular senescence and age-related pathologies (Groningen, Netherlands), to work on a project studying the contribution of senescent cells to inflammatory and fibrotic chronic disease.

Research Associate position available in Dr. Gordon Lithgow’s laboratory at the Buck Institute for Research on Aging. The Lithgow lab combines biochemical, molecular, and genetic techniques to address fundamental questions about aging in C. elegans.

Brieno-Enriquez lab is looking for two motivated postdocs to explore reproductive aging in the naked mole rat. They will leverage the NMR to explore mechanisms that rejuvenate the ovary and extend both reproductive lifespan and overall health.

News and Media

FDA grants full approval to Leqembi, opening up coverage of Alzheimer’s drug by Medicare

After a dispute with the publisher resulted in the resignation of 5 editors-in-chief from Aging Cell — the former editors have now returned with a new scientist-led journal — Aging Biology — which is now accepting submissions and publishing papers.

Check out Lada Nuzhna’s reflections on 2 years of going after risky aging science.

USA Today: Want to live healthier longer? Scientists aim to improve life quality over quantity

8 healthy habits that may add 24 years to your lifespan

The Wall Street Journal: The Longevity Clinic Will See You Now — for $100,000

Twenty minutes of daily exercise can help reverse frailty and build resilience in over 65-year-olds

The boom of the anti-aging market: How to get people to live to be 120 (and in good health)

The Daily Mail catches up on the drama in the aging research world: EXCLUSIVE: Harvard claims it found the elixir of youth — but experts call it ‘hype’

Mitochondrial DNA fragments in blood shown to be important biomarkers for aging

Peter Fedichev Explains His Theory of Aging

Healthy longevity is not only for the neurotypical

Resources

Norn Group’s age related diseases overview: an excellent resource of early stage startups in the longevity space that are looking for an initial clinical indication to target

Prizes

Rewarding the most impactful research in longevity

Substantially increasing the human lifespan. The Amaranth Prize gives no-strings attached funding to the best research in Longevity.

Conferences

Ending Age-Related Diseases

10–11 August, NY, USA and virtual

Longevity Summit Dublin

17–20 August, Dublin Ireland

Aging Research & Drug Discovery (ARDD)

28 August — 1 September, Copenhagen, Denmark

British Society for Research on Aging Annual Scientific Meeting (BSRA ASM)

6–8 September, London, UK

RAADFest

7–9 September, LA, CA, USA

Expo and Convention: Independent Ageing 2023

13–15 October, Aichi, Japan

Seno-Therapeutics Summit 2023

7–8 November, Buck Institute for Research on Ageing, Novato, CA, USA

Tweet of the Month

Adam Gries (@adamgries):


The idea that we shouldn’t work hard to extend lifespans (which has been echo’ed by @ elonmusk) would make more sense , if we weren’t *already* spending like crazy to increase lifespans, just doing it poorly.

Trillions now go to the last 5 years of life. […]

Podcasts and Webinars

Join us for a Twitter live discussion on the latest epigenetic clock research

7 August, virtual

Norn Group presents: Near Future Skill Gaps in Software & ML discussing current & impending changes impacting aging bio research due to advances in software & ML. Featuring Joe Betts-LaCroix, Luca Naef, Andy Lee, and Sam Spurlin

9 August, virtual

Did you miss our Robust Mouse Rejuvenation Twitter live with Aubrey de Gray, Caitlin Lewis,

Kelsey Moody, & Danique Wortel? Don’t worry, the recording is up.

We also interviewed Sergey Young!

NUS Medicine’s Healthy Longevity Webinar Series

This month:

Ovarian Ageing: A Target for Geroprotection in Women | Prof Suh Yousin

AI and robotics | Dr Alex Zhavoronkov

Taurine deficiency as a driver of ageing | Asst Prof Vijay Yadav

Funding Opportunities

Research: Impetus Longevity grants

Micro-grants: VitaDAO Longevity Fellowship

Interview with Matthew Yousefzadeh

Matthew is an instructor at Columbia University Medical Center where he works on mechanisms of aging, in particular how DNA damage and cellular senescence contribute to cell autonomous and non-autonomous aging.

What inspired you to enter longevity research?

Previously, my background was in cancer biology and much of my PhD work was on how specialized DNA polymerases could play protective roles in limiting genotoxic stress, but their levels had to be tightly regulated. Too much of these enzymes could be permissive to tumorigenesis or make them refractory to treatment. I got into cancer biology because during my freshman year of college my grandmother survived one bout with breast cancer but succumbed to a second round of cancer. Likewise, as I was finishing my PhD, I saw my mom start to accumulate some age-related health issues and she died at a young age. This was the impetus for me to get interested in aging research. Going to Laura Niedernhofer’s lab was a no-brainer and provided a natural transition for me where I could take my DNA repair background and use it to study senescence.

How has the field changed since you started?

My plan was to go to Laura’s lab to study senescence that was induced by DNA damage or through DNA repair deficiency. At the time, I had no clue what senolytics were and the first senolytics paper was published a few weeks before I showed up to the lab. Obviously, the senescence field has matured a lot since then and still has a way to go. Outside of that there have been incredible discoveries in many of the other pillars of aging like the broadened use of epigenetic clocks, epigenetic reprogramming, and use of companion animals as a method to study aging. The field felt a bit slower back when I started my postdoc, and it is moving much more rapidly now. This is both great because I feel like the speed of progress is picking up, but terrifying from a standpoint of how many good papers are coming out every day that I need to read up on. It is a fantastic problem to have though! Recently in the past few years there seems to be a greater public interest in aging, and I think it has turned into a prime opportunity to bring young enthusiastic minds into the field of geroscience. Also, we are seeing people in other diseases spaces like cancer begin to get much more serious about looking at the interplay between their disease of interest and aging. From a commercial standpoint the number of longevity companies was really limited to Calico and in the realm of senescence, Unity Biotechnology. In the past few years, this aging biotech landscape has exploded, which I find to be a positive sign.

Other than your own, what do you think have been the biggest/important discoveries in the field?

While some of these are controversial spaces, I think the work done by too many labs to individually list on these topics are a boon for geroscience: 1) Levels of in disease and aging, 2) epigenetic reprogramming and functional outcomes in regards to rejuvenation, 3) understanding how centenarians age so well, 4) transgenerational effects on aging and longevity, and 5) the use of C. elegans to conduct high throughput screening of monotherapies and combinations to determine possible geroprotectors. Each of these are very important and in their own individual way could serve as a disruptor in the field of aging.

What advice would you give to people currently working in longevity research?

Find something you care about working on and go all in on it. Some days you will love it and other days it will frustrate the hell out of you. I have seen some really good scientists run away from projects when they get their first piece of negative data or experience some difficulty. Some of them have tried to jump from what they thought was a hot project to next hot project because it was “cooling off” and eventually they burnt themselves out. Learning resiliency can be tough but find something that you can stick and see it through. It is so rewarding! Another piece of advice is to find a place where people are invested in your development. I tell graduate students and other early career researchers to chase mentorship and not projects. Good mentorship can set you on a path to success when you are at such a nascent stage in your career. I also think programs like the MBL Biology of Aging Advanced Research Training Course that was created by Jennifer Garrison and Will Mair will serve as excellent conceptual and technical primers for people new to the field or looking to expand their skillsets. Get involved! Join the American Aging Association or the Gerontological Society of America and get involved with the trainee chapters or other committees. Trainees can take part in the peer review training program at Geroscience where they can independently review manuscripts. If you are interesting, contact me.

Which aspect of longevity research do you think requires more attention?

I’m going to say there are two big areas that deserve more attention: 1) validation of biomarkers and reagents; and bandwidth and best practices for bioinformatic analysis. The first has been a long-standing issue not just for aging but for other fields as well. We all know biology can plagued by poor reagents like antibodies that have not been properly validated or how many of the markers in my own field of senescence are non-specific. Discovering better markers and building better tools that we are confident will go a long way to expediting progress. Let’s face it, resource validation is not sexy, but it is vital.

To the second point, it has been incredible to watch the explosion of ‘omic and multiomic analysis in the field of aging. I wish I had access to single cell RNAsequencing as a first-year postdoc, it would have made my life a lot easier. A lot of us, me included, are trying to play catch up to the ever-shifting landscape of technology in this area and its inherent strengths and weaknesses. We desperately need bioinformatics support to help us process the mountains of data and we have been fortunate to draw a lot of very talented people from the tech sector into aging in the last few years as we also home grow bioinformatics talent. My last point on this topic is that many of us are looking for resources on best practices for these topics so that we can plan and execute the best possible experiment. One example of this is a recent publication from Param Priya Singh and Bérénice Benayoun on “Considerations for reproducible omics in aging research.” I think this manuscript is incredibly informative and can serve as a great reference for anyone using ‘omics to study aging. Speaking of advice, I am also incredibly fortunate that Bérénice is a friend and has been generous with giving me advice as a postdoc and now as a PI.

Is ageing a disease?

This is how you start a fight over beers when you get a bunch of aging researchers together. I think it is a disease, but also a natural and omnipresent condition. A very milquetoast take right? Realistically it probably sits in between the two states. Some people feel very strongly about it, but I’d rather focus on the science rather than semantics.

You have shown that fisetin is a senotherapeutic that extends health and lifespan in mice — what do you think is the biggest challenge in bringing fisetin to the clinic?

Fisetin is interesting in that we wanted to demonstrate that a senolytic could be safe but effective. Dasatinib, a chemotherapeutic that is used in combination with quercetin as a senolytic, has side effects. The natural product fisetin was originally identified through screening other flavonoids to see if they had more potent senotherapeutic effects than quercetin. I think two big hurdles for bringing fisetin to the clinic is that since it is a natural product it has a very limited intellectual property (IP) position and from a drug standpoint it has poor bioavailability. To address the second point, Kyle Brewer, a talented aging biologist, at ETTA Biotechnology is working to develop an optimized formulation to better deliver fisetin. Meanwhile the laboratory of my former co-mentor at the University of Minnesota, Paul Robbins, is developing fisetin analogs to increase potency and bioavailability, as well as create novel IP around these analogs. Paul has co-founded Itasca Therapeutics, a platform company which I currently serve as the CSO for, to develop these compounds and other senolytics. Itasca Therapeutics was created because we found that the typical funding mechanisms for academic research were insufficient to push lead compounds discovered in the academic lab further into the drug development thus the needs to acquire private funding.

Which other senolytic strategies do you think hold promise and what are the potential negative impacts of removing senescent cells?

The field of senolytics is growing and so are their approaches. These include everything from the use of AI-guided drug design, protein degraders of targets (PROTACs), CART cells, and activation of immune clearance mechanisms. I find Anil Bhushan’s work on senescent cell elimination by invariant (i)NKT cells to be both intriguing and refreshing. Many of us are looking at senescent cell accumulation as purely detrimental and studying them in the gain of function context. Others like Anil view senescent cells are serving a regulatory role and asking questions about why we fail to clear them as we age. This work is addressing the other side of the senescence equation (loss of function in the form of immune clearance). Furthermore, not all senescent cells are deleterious and should be cleared. A few years ago, a group showed that genetic clearance of senescent liver sinusoidal endothelial cells (LSECs) that expressed high levels of the p16Ink4a gene had detrimental effects and caused a pro-fibrotic response in the livers of these mice. These cells were not affected when the mice were treated with dasatinib and quercetin. Furthermore, it was found that expression of p16Ink4a specifically in the pancreatic beta cells of transgenic mice enhanced glucose-stimulated insulin production and provided an unexpected benefit to diabetic mice. Studies like these serve as a cautionary tale to not be hasty to eliminate all senescent cells or all cells that express p16Ink4a. We are fortunate that the newly created NIH Common Fund Cellular Senescence Network program is working to better characterize the heterogeneity of senescent cells in multiple tissues of both humans and mice across the lifespan. This could provide greater insight into specific senescent cells and how best to target them.

Which other interventions do you think hold promise for improving human healthspan/lifespan?

One of the most efficient interventions to democratize longevity is exercise as medicine. Beyond that interventions range anywhere from practical to promising to vaporwave. If I had to pick a front runner it would be mTOR inhibition whether it be in the form of rapamycin or newer generation compounds that selectively target mTORC1. It is one of the most reproducible results throughout multiple animal models and the human data on mTOR inhibition has been very encouraging. Columbia University Medical Center, where my lab is located, has just launched the VIBRANT (Validating Benefits of Rapamycin for Reproductive Aging Treatment) study, VIBRANT is being co-led by Yousin Suh, a well-known figure in the field of aging and director of reproductive aging at CUMC. If rapamycin treatment can slow down ovarian aging in humans, that would be huge!

You have also shown that an aged immune system has a causal role in driving systemic ageing — which therapeutic strategies do you think could help tackle this?

Speaking of mTOR inhibition, Joan Mannick’s work on vaccination rates in the elderly and outcomes with respiratory tract infections or Tyler Curiel’s work on cancer models was very inspiring to my own work. Beyond that the work on enhancing senescent cell clearance via immunotherapy is very exciting. Overall, I think it is going to take a combinatorial approach to rescue some of the age-related deficits in immune function.

You recently relocated to Columbia University Medical Center — what can we expect from the Yousefzadeh lab?

I am really interested to continue studying the role of senescent immune cells and how they affect systemic aging through interorgan communication. Beyond that I am interested in the role of cellular senescence (immune cells and beyond) on adverse outcomes in pathogenic infections. Previously, I established a human senescence core at UMN and plan to do the same at CUMC to help measure biomarkers of aging in humans. Moving to New York City has put me in close contact with long-time collaborators like Derek Huffman at Albert Einstein College of Medicine and allows me to foster new collaborations. Beyond that I have a strong interest in DEIB and have participated in multiple outreach programs that work to provide opportunity and exposure to promising young scientists from all backgrounds. I want to continue my work with these programs and help mentor the next generation of scientists that want to embark on careers in aging and longevity. If you are in NYC, let’s grab a slice of pizza and talk science. My treat!

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful!

This time we leave you with a short summary video of what VitaDAO does and why.

Further Reading

Translational longevity medicine: a Swiss perspective in an ageing country

Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing

Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons

Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in naked mole-rats

Changes in methylation-based aging in women who do and do not develop breast cancer

RNA polymerase II associates with active genes during DNA replication

Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging

Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells

Senolytics Reduce Endothelial Cell DNA Damage and Telomere Dysfunction Despite Reductions in Telomere Length

Associations of Dental Health With the Progression of Hippocampal Atrophy in Community-Dwelling Individuals: The Ohasama Study

Cocoa flavanols improve peakVO2 and exercise capacity in a randomized double blinded clinical trial in healthy elderly people

Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters

Prolonged fasting times reap greater geroprotective effects when combined with caloric restriction in adult female mice


Welcome back Vitalians! Stop the press - the Impetus Longevity grants are back!
Read more
VitaDAO Letter: A New Journal, Ambassador Program, and New Steward!
July 27, 2023
Sarah Friday
VitaDAO Letter: A New Journal, Ambassador Program, and New Steward!

Inside this Newsletter:

  • The First Edition of VitaDAO’s Journal, The Longevist 
  • VITA-FAST Recap: Redifing IP-NFT Governance 
  • Building Collaborative Connections with an Ambassador Program 
  • Meet VitaDAO’s New Dealflow Steward: Eleanor Davies

🧬The Longevist is LIVE

VitaDAO is thrilled to announce the launch of "The Longevist," an overlay journal that curates promising longevity research. In the inaugural edition, we present the top ten preprints from Q1 2023, as handpicked by an esteemed panel of experts. The expert curators involved in the selection process are renowned professionals and scientists in the field of longevity.

Three a few noteworthy studies featured in the inaugural "The Longevist" feature:

🤑VITA-FAST: A Novel Funding Module 

In collaboration with Molecule, VitaDAO proudly launched VITA-FAST, a groundbreaking initiative that has redefined governance of Intellectual Property (IP) and Research and development (R&D) data through the use of IP-NFTs (Intellectual Property Non-Fungible Tokens). VITA-FAST tokens represent ownership in the IP pool and grant holders the power to participate in governance, make crucial IP licensing decisions, influence experiment priorities, and govern research projects. Thus, the creation of tokenized IP pools using IPNFTs allows DAOs to cooperatively manage collective IP while co-governing development and commercialization.

The IP pools, governed by token holder-set rules, provide solutions to existing challenges in the biotech IP market. In minimizing risk management, aiding in capital formation, and increasing patient involvement in therapeutic development, this transparent process is revolutionary. Its transparent and efficient process promises to accelerate scientific progress and foster innovation. It is possible to imagine that the creation of liquid and efficient markets can solve some of the issues in the current funding of bio IP.

The VITA-FAST initiative was completed in conjunction with the Korolchuk Lab, a lab led by cellular biologist Prof. Viktor Korolchuk. Dr. Korolchuk's research focuses on identifying novel bioactive autophagy inducers, a process that plays a vital role in the body's cellular health. By administering potential activators to cells unable to initiate autophagy, Dr. Korolchuk aims to demonstrate the specificity and effectiveness of compounds in promoting autophagy.

This project is still young and developing! For example, VDP-111, proposal passed on Snapshot, proposes the election of a project lead by VITA-FAST token holders and outlines a VITA-FAST governance framework. 

“This is the next phase in the evolution of decentralized patient communities, to directly contribute to, govern, and be rewarded for progressing valuable longevity research.” - Alex Dobrin

🌎VitaDAO’s Ambassador Program: Building Connections and Facilitating Collaboration ​

In March 2023, VitaDAO community leaders, Gavin and Cat, proposed the creation of a VitaDAO Ambassador Program. The goal of the program was to propagate DAO outreach and increase DAO engagement. 

This month in London, Bharat, Maria Maroniva PhD, and Eleanor Davies spoke at the Ambassador Program’s first official event. They touched on DeSci and VitaDAO's significant contributions to shaping the field. This event was just the beginning of a much larger initiative!

The VitaDAO Ambassador Program aims to enable individuals from different jurisdictions to organize in-person meet-ups, bridging the gap between virtual and face-to-face interactions. Many in the DAO community will agree that the value of interaction and engagement is much higher when meeting mission-aligned people in person! To select a group of DAO Ambassadors, an application was sent out. Thus far, we have received an overwhelming response with over 170 applications to become a VitaDAO Ambassador! Stay tuned to hear more about VitaDAO’s selected ambassadors and events occurring near you!

🗣️VitaDAO in the Wild

📣Community Approved: What YOU voted for!  

Thanks to the support of the VitaDAO community, multiple proposals successfully passed this month! Notable proposals include:  

VDP-89 Passed! This proposal was an assessment of ExcepGen Inc's RNA therapeutics for longevity. In passing, this proposal signifies that VitaDAO supports funding $100,000 to develop a new generation of vaccines with this RNAx platform.

VDP-93 Passed! As a result of this VDP, VDP nomenclature, and phase 2 proposal workflow will be altered to ensure visibility of risks and legal review before on-chain voting.

VDP-96 Passed! With this proposal, VitaDAO will provide a loan of $400k to VHF, secured against the underlying equity in companies VHF.

VDP-101 Passed! As a result, VitaDAO will set up an operating company in Canada to execute VitaDAO Coordination Working Group functions such as finance, member services, and service provider management. 

VDP-102 Passed! VitaDAO will now implement 7 new tools to better manage the growing portfolio of the VitaDAO projects more effectively and efficiently. 

VDP-107 Passed! As a result of VDP-107,  Laurance Ion stepped down as Dealflow Steward and Eleanor Davies was elevated as Interim Dealflow Steward.

VDP-108 Passed! With the passing of VDP-108,  VitaDAO will complete an annual review of compensation/governance allocations as outlined in VDP-72. 


💪Exercise Your Right to Vote

Check out VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Your input is invaluable, and together, we can shape the future of VitaDAO and accelerate decentralized science.

👋Meet VitaDAO’s Dealflow Steward: Eleanor Davies 

Eleanor Davies, VitaDAO’s New Dealflow Steward, brings a wealth of experience in fund operations, healthcare, and biotech consulting. A graduate of the University of Manchester, she has grown as a professional serving in Marwood Group healthcare and biotech consultancy, co-founding a company and helping to raise funds, deploy capital, and manage the portfolio at ODX, a Silicon Valley-based accelerator. More recently, she has actively engaged with the DeSci community, serving as COO of LabDAO. This month, I had the privilege of sitting down for a brief chat with Eleanor: 

It’s great to meet you, Eleanor! I would love to know a little more about your background. How did you first get involved in VitaDAO?

Hi! Thank you for featuring me in the VitaDAO newsletter. A little about me: I come from a less traditional background. I first started off studying languages, combined with international policy, business, and history. This gave me the flexibility to look into different industries that were a good fit for me. I found that I had an advantage as a language learner in the UK, because not many of us Brits speak other languages. If you show you are highly motivated, ambitious, and willing to take on new challenges, it is generally quite well-regarded by graduate employers.

From the start, I have always had a lot of side projects and interests. I have a long-standing curiosity in biotech, specifically in pushing the limitations of human biology - is life extension really possible? How would this work in practice? I started by working at IBM, and later in M&A advisory across industries in the German speaking (DACH) mid-market for private equity transactions. With time, I found myself gravitating towards the biotech side of M&A.

Between then and working in consulting, I co-founded an AI-based recruitment company - that was a lockdown existential crisis! It came out of the frustration I witnessed by the number of people who lost their jobs during the pandemic. What if I could change the way of looking at the job market? Tldr; it didn't work out, but it was a great learning opportunity. There was a market fit and we were generating revenue, but it was more about the team dynamic.

I then worked in consulting mid- to large-cap private equity clients for healthcare and biotech transactions. The consultancy specialized in advising the commercial implications of political and regulatory change across the UK and EU to domestic and transatlantic clients. Early during my tenure, the consultancy Director left, so I had to step up and lead in the role of Director - from the experience level of an Analyst. It was a very steep learning trajectory, but I saw it as an ideal opportunity to step up. I did a lot of self-directed learning, not only for interfacing with clients, but also for company growth, negotiation, and leadership. Alongside the consulting, I also doubled company sales targets, doubled the pipeline for marketing prospects, and transformed the marketing channels. A lot of progress in a short amount of time! 

I then moved on to work at On Deck’s ODX, which is an accelerator based in Silicon Valley. I was working in fund operations, working across raising funds to deploying capital, conducting due diligence, and portfolio management. Almost similar to what I’m doing at VitaDAO today, Sadly, due to the market conditions, I had to leave ODX, but this allowed me to pursue my nerdy side interest - DeSci!

That leads me to today. I had been a “lurker” in both the VitaDAO and LabDAO Discord servers for some time and finally decided to do something about it. I was introduced to Niklas from LabDAO at DeSci Berlin - I was so motivated by the vision, the highly intellectual community, the level of passion, and mission alignment in the ecosystem. So, I made the leap! For me, DeSci could be hugely disruptive for the scientific community, funders, policy makers, and beyond. In the consulting world, I had seen a misalignment between politicians and regulators, funders and companies, healthcare insurers, and patients. Not only in capital allocation, but in communication, education, and expectations. For me, a community-first, community-governed approach could create the new standard.

As part of the core team at LabDAO, Niklas and I led the fundraise ($3.6M). It was a challenging time to raise in a bear market, but it was gratifying upon completion. I also worked across legal, tokenomics, investor relations, and treasury management… all-in-all, a bit of Swiss Army Knife-ing. It was hugely satisfying to see LabDAO through to maturation. During its PMF phase, LabDAO pivoted to tools versus the Lab Fund, which I was to lead. As everything was up and running, my role eventually phased out. By that time I was closely following VitaDAO and knew that there was a need for somebody to work in deal flow. It was the ideal time to join. Now, I’m still advising LabDAO, but full-time at VitaDAO. 

You mention that you find DeSci to be promising. What drew you to DeSci and where do you see DeSci going in the future? 

There are many aspects that I find interesting about DeSci; for me, I’m excited about tools, funding, and globally distributed venture building. This is why I am confident in VitaDAO and why I’m motivated to make it succeed. We are looking at a broader pool of capital for higher risk funding opportunities, and zooming in on the early, idea stage of lab research projects. The IP-NFT is particularly interesting here. VitaDAO and the community, as part of the Decentralized Tech Transfer Spinout framework, work with the scientific team to build projects from idea, to IP commercialization, to maturation. To my knowledge, this hasn't been done before with Web3 and DeFi technology.

Also, never before has there been such a globally distributed community of mission-aligned people to work together in this way. The thing that I find special about the VitaDAO community is that world leading talent, especially in the dealflow working group, participate out of sheer interest. There is a real mission alignment here. And despite some DAO inefficiencies, its youngness, and teething issues, DAO members stick around. 

I’m also excited about the IP-NFT, pioneered by Molecule. The non-dilutive funding, and the ability to get more proceeds for project development in this manner is a pretty innovative way - also high risk, but high reward - of funding a project and getting more community interest. It promotes openness, making research a lot less siloed and more collaborative. And even if it doesn't work out at least we’ve tried. But, we’re making waves already.

You’ve touched on the strengths of DeSci and some of the strengths of VitaDAO in particular. Is there a particular VitaDAO project you are most excited about? 

There is - Matrix Bio! I’m also PM’ing that alongside Anthony Schwartz as a part of the Builder Squad. It's a moonshot, but this could have a huge payoff for the LongBio world. We are working with one of the world's leading aging researchers, Vera Gorbunova. Not only is she a pleasure to work with, but also her research is groundbreaking. The fact that she has her belief in VitaDAO to incubate her project towards a point of commercialisation, is compelling and exciting.

Another would be Viktor Korolchuk’s autophagy project. Again I think that not only is it an under-resourced side of longevity aging research, but also that he and the Newcastle University have the conviction that VitaDAO can build and incubate the project, using an innovative funding and governance method. This is a strong signal for me.

As a result of VDP-107, you’re now Longevity Dealflow Working Group Steward. In your short time in this role, what has surprised you the most about VitaDAO? What are you most excited about in taking on this role? 

First of all, I’m very very grateful for those who voted in favor and have the confidence in me to be the Dealflow Steward. What am I most excited about? I’d say the support of the community. Putting the collective wisdom in the deal flow working group to great use! We have so much talent; so many amazing people are eager to get involved with the opportunities that come our way. For me, something that dealflow needs is great operations. It is the cornerstone of making things work: ramping it up and scaling it up to a mode of maximum efficiency. I’d also like to ramp up Tech Transfer Office outreach, project sourcing, and both start-up and early-stage IP projects. And have an engine that enables this to happen: a great funnel and a great process. As boring as they sound, you need these to make things work.

Also knowing how to engage with the community in different stages. We have so many talented people who are amazing in different aspects of the deal flow process. It is knowing what incentives are, and how contributors should be incentivized in the DAO from the start; something which is still being tested out in the Web3 ecosystem. And, how can we be efficient enough to become the world's best longevity research funding organization? How can we become the first place that people think of when looking for funding, looking for education, or an amazing community, when they think of longevity? That is what I want for VitaDAO. I want it to be on the UN’s radar. Dream big. 

When I first joined the VitaDAO Discord, I initially had no idea about all the work that goes on behind the scenes at VitaDAO on the Dealflow side of things. There is a lot more work that goes on before projects are presented on Discourse. 

It's true. From automating the dealflow funnel to refining IP strategy with projects, to Friday pitch sessions and onboarding new members - we are taking VitaDAO from 0 to 1. If anyone wants to get involved, come to an onboarding call! I lead the calls with community member, Ryan Spangler, and it’s a great first point of entry to join the working group. We go through terms, voting, the nuances of dealflow, DAO-ism, and how VitaDAO is different from a traditional venture studio or VC. Why is it a not-for-profit? What is an IP-NFT? I find the best way to get great engagement when onboarding new community members to deal with the flow, is to have a chat instead of reading through documentation. To anyone who wants to get involved, feel free to reach out!

Where do you see VitaDAO 100 years from now? 

I wonder if VitaDAO will have solved aging by 100 years? First off, I want VitaDAO to be the biggest name in longevity. This involves being a well-oiled machine. People come in because they’ve heard about our reputation in longevity and for being the best DAO that works to maximum efficiency. I’d like to have had successful exits (everyone wants successful exits), and successful spinouts that will have IPO'd. Happy founders. Happy community members. A cyclicality of members who come, build companies, grow it, scale it, exit, come back, and continue. On the network state side, bridging successful spinouts with the possibilities achieved by a longevity network state is another goal. Leveraging the more friendly regulatory pathways in specific jurisdictions could be an ingenious way that VitaDAO can expedite scientific progress - if done correctly. Zuzalu was an amazing way of showing us this potential. What about novel cures or treatments that are more financially accessible - or generally more accessible. That’s another dream, and I hope we can weigh in there, too. It'd be amazing for VitaDAO to be a front-runner in changing how cures come to market and also how we behave around human health- and lifespan.

I’ve enjoyed chatting with you today! Before we end, any closing thoughts for readers?

Again, I am very very appreciative of being the Steward in Dealflow. Of having the support of the community. Reach out if you are interested in getting involved in dealflow, interested in knowing more about spinouts, the builder squad, and generally getting involved. If you are a builder. If you are an operator. If you’re an academic. If you are interested in pursuing a project, a side project, and looking for funding. Also please reach out or apply. I am always interested in looking for new opportunities and the same goes for the working group. I’d also love to hear from the community about why they are interested in longevity: what they see in VitaDAO, what keeps people coming, and how we can collectively build on that vision. Because it is not just the Stewards, it’s everyone here. Which is what makes this so unique!

Thank you for your time today! I’m excited to see a female steward! It is exciting to continue to see more women get involved as members of the VitaDAO community! 

I would love to use this feature as an opportunity to encourage more young women to step up and be a part of the conversation. They are wonderful and I love working with them, but the ratio of men to women in scientific research and web3 is still disproportionate. I see DeSci as a startup in itself. It is an emerging industry, and therefore, the perfect opportunity to pave the way to create new standards. To make a place for ourselves. I want to see more women!

🤝Thanks for Reading! 

Want to get involved in VitaDAO? Have a special skill set? Join an onboarding meeting to learn more about ways to contribute to the growing community! Want to stay up to date with all that's going VitaDAOn? Join us on Discord, subscribe to our Twitter, and follow our Instagram

Additionally, VitaDAO's website (https://www.vitadao.com/) contains updated information on funded projects and a treasury dashboard. 

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Transcending Boundaries: Exploring Cryonics, Drug Repurposing, and the Future of Aging Research with Prof. Joao Pedro De Magalhaes on The Aging Science Podcast by VitaDAO
July 21, 2023
Awareness
Longevity
Transcending Boundaries: Exploring Cryonics, Drug Repurposing, and the Future of Aging Research with Prof. Joao Pedro De Magalhaes on The Aging Science Podcast by VitaDAO

In today’s podcast we talked with Prof. Joao Pedro De Magalhaes (@jpsenescence) about some exciting topics ranging from his current work, to philosophy and science fiction. Among other things we talked about cryonics, transhumanism, the need for a “Sputnik moment” in longevity research, fish oil and rilmenidine for longevity, inflammaging, and cellular reprogramming.

It was a pleasure to talk with Pedro because we both share very similar views about aging, longevity, transhumanism and other topics.

Short CV - Joao Pedro De Magalhaes

Prof de Magalhaes graduated in Microbiology in 1999 from the Escola Superior de Biotecnologia in his hometown of Porto, Portugal, and then obtained a PhD in 2004 from the University of Namur in Belgium. Following a postdoc with genomics pioneer Prof George Church at Harvard Medical School, in 2008 Prof de Magalhaes joined the University of Liverpool and, in 2022, he was recruited to the University of Birmingham where he leads the Genomics of Ageing and Rejuvenation Lab (http://rejuvenomicslab.com/). His lab studies the ageing process and how we can manipulate it to fend off age-related diseases and improve human health. Prof de Magalhaes has authored over 100 publications and given over 100 invited talks, including three TEDx talks. He is also CSO of YouthBio Therapeutics, a US-based biotech company developing rejuvenation gene therapies.

Pedro is the author of the widely read senescence.info https://jp.senescence.info/ webpage and of the @jpsenescence twitter account.

The reputation problem for aging research

“If you tell people that you're trying to discover a drug for Alzheimer's, everybody loves it. If you say you're discovering a drug for cancer, everybody loves it. If you say you're discovering a drug for aging, people ask why? I mean, why you want to do that? ... it generates a lot of questions and even opposition, not by everyone, but for some people.” (Joao Pedro De Magalhaes)

Many people think that lifespan extension is science fiction. However, even that is an understatement of the problem because lifespan extension is rarely portrayed at all or positively portrayed even within sci-fi literature. Pedro and I discussed possible reasons for this. One idea is that the finality of death is so ingrained and terrifying that people refuse to think about anything concerning death as a coping mechanism. This will include even positive things like lifespan extension. It is absurd to consider a future where interstellar travel is possible but not radical lifespan extension. Yet this is what is often portrayed in science fiction!

We spent the first half of the podcast digging into the psychology and philosophy of aging research and trying to figure out what will make people believe that aging research is necessary; and that we will be able to slow aging in the not-too-distant future. Even if you are not interested in aging research I think the first part is worth a listen. One of our key insights was that people who are afraid of living longer, and who are afraid of technology, now, will most likely change their opinion once the technology matures. The great majority will be keen to use longevity therapies and only a fringe minority will continue to oppose the technology:

“So, I mean, if you ask people, hey, if I have a little pill that will make you live 200 years in good health, if you ask around, there's a lot of people going to say, no, I don't want that. But trust me, if that were introduced, and people started taking that pill and being healthier, everybody would want it. That's just, you know, inevitable.(Joao Pedro De Magalhaes)

Transhumanism and radical lifespan extension communities

Transhumanism describes a philosophy that contends we should transcend or improve human nature using technology. The idea is that human biology is flawed and that life could be much improved if we embraced technology to improve ourselves. Such technology includes but is not limited to things like artificial intelligence, lifespan extending treatments or cryonics.

“Radical” lifespan extension tries to differentiate itself from the modest goals of regular biogerontology. Advocates for radical lifespan extension believe that we need to extend human lifespan significantly, by decades or centuries, and that we may be on the cusp of success. In the podcast we discuss that while we might not be that close to this goal, the idea of radical lifespan extension itself is worthwhile. There is no reason why we cannot have ambitious dreams.

We also discussed the recent history of the online longevity movement. Many communities, back when bulletin boards, forums and mailing lists were popular, catered to transhumanists and life extensionists of the early days, including the now renamed “Immortality Institute”.

We can consider Vitadao as a continuation and extension of these old communities. It is attractive not only to transhumanists, but also crypto enthusiasts, web3 developers, investors, scientists, the general public etc. If you want to be part of this community, here is the link to their discord:
https://discord.com/invite/vitadao

Cryonics

The idea of cryopreservation is to freeze one’s body right after death, for a non-zero chance of revival in the future. The hope is that future technology might be able to reverse the damage that led to death and also reverse the damage induced by cryopreservation. Although this is a tall order the likelihood is probably not zero, even if it is very low. In that way cryonics is a modern, transhumanist Pascal’s wager.

In the meantime, while we research cryobiology with the long term goal of preserving whole organisms, every little advance we make can be used to improve the storage of donated organs, hence benefiting humanity now and not just in the future.

This is the same idea as with radical lifespan extension. One can have an ambition long term goal that is reached through reasonable intermediate steps. 

Repurposing of drugs

Even though many drugs are approved for one condition they could also work for another. However, in many cases no one has tested this yet. In the process of repurposing, also called repositioning, scientists are trying to find new uses for such old drugs. If we want to cast our net wider, we can also consider drugs that passed phase II or phase III trials but were not pursued for whatever reasons. These drugs will also have a decent amount of safety data in humans and will be backed by good efficacy data.

One strategy Pedro uses to find drugs that could be repositioned is based on gene expression signatures. The idea is to find drugs that show similar gene expression to that of caloric restriction. This strategy allowed him to pinpoint allantoin as a potentially life extending drug and later rilmenidine, an approved, although rarely used, anti-hypertensive drug, that might operate via a similar mechanism (Calvert et al. 2016, Bennett et al. 2023).

Immunology of aging, inflammaging and the power of meta-analysis

In his meta-analysis of transcriptomic data Pedro found that in mammals many genes change with age (Palmers et al. 2021). Some highlights include decreased expression of mitochondrial genes, perhaps consistent with decreased mitochondrial biogenesis and function, but also increased expression of pro-inflammatory factors.

“The preponderance of inflammatory and stress response genes [over-expressed with aging] is reminiscent of the inflammageing hypothesis [14], which argues that ageing is caused by steadily failing responses to stress, in particular responses to the increased antigenic load that comes with age.”

In this context we also discussed new single sequencing data, suggesting age-related infiltration by immune cells and Pedro’s work in a new company focusing on reprogramming. One of the ideas that we discussed was that immune cells are generally a good target for rejuvenation because they are accessible and affect many processes in the body.

The Interventions Testing Program (ITP)

The NIA’s Interventions Testing Program is a large mouse study that seeks to rigorously test which compounds extend mouse lifespan. Anyone can propose a compound to be tested and during the podcast I suggested to Pedro he could submit rilmenidine to the ITP. If you want to learn more about this important study, we had a thorough discussion of the ITP in my podcast with Rich Miller.

https://www.vitadao.com/blog-article/the-mouse-longevity-chronicles-unraveling-aging-with-dr-richard-miller-during-the-aging-science-podcast-by-vitadao

Further reading – aging as a software design flaw

A controversial take we discussed during the podcast was Pedro’s idea that aging has programmatic features. I will not go too much into details here and the interested reader can check out his paper (de Magalhães 2023) and the below tweetorial, as well as our podcast discussion.

References

Bennett, Dominic F., et al. "Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1‐imidazoline receptor." Aging Cell 22.2 (2023): e13774.

Calvert, Shaun, et al. "A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans." Aging cell 15.2 (2016): 256-266.

de Magalhães, João Pedro. "Ageing as a software design flaw." Genome Biology 24.1 (2023): 51.

The new webpage of the Immortality Institute: https://www.longecity.org/forum/

Pedro’s linkedin: https://www.linkedin.com/in/joaopedrodemagalhaes/

We talked with Prof. Joao Pedro De Magalhaes about about cryonics, transhumanism, the need for a “Sputnik moment” in longevity research, fish oil and rilmenidine for longevity, inflammaging, and cellular reprogramming.
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June Longevity Research Newsletter
July 10, 2023
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
June Longevity Research Newsletter

Introduction

Welcome to this month's newsletter, where we delve into the philosophical dichotomy at the heart of longevity research. 

Two broad perspectives pervade the field. Firstly, we have the 'death defiers', individuals who perceive mortality as a malady, akin to a disease that can be vanquished. These aspirants advocate for a significant postponement, if not complete eradication, of death. They envisage a future where humanity capitalizes on biotechnology, genetics, and regenerative medicine advancements to conquer the final frontier - death itself. They approach aging, particularly from age-related causes, as an adversary to be defeated.

On the other end of the spectrum, we find the 'quality adherents'. These individuals think that lifespan is finite, but champion improving healthspan as a tangible goal, believing in 'healthy aging'. This focuses on extending the phase of our lives free from chronic diseases, where we maintain physical and mental fitness.

In this edition, we put the spotlight on Prof. Joao Pedro de Magalhaes, a distinguished researcher and a keen advocate of lifespan extension. We'll share insights from our recent interview, where he shares his perspectives on his work and the motivation behind it. Also, we explore the intriguing discourse ignited by a Tweet from Balaji, which dared to voice support for the death defier's view, sparking a vibrant discussion on Twitter.

VitaDAO-funded Research Projects

The VITA-FAST Token Sale concluded with a 1700% oversubscription!!!

VITA-FAST token holders have exclusive control over the licensing function of Newcastle-Korolchuk IP and governance over the direction of the research and development of that IP.

Congratulations to the ExcepGen Inc team for receiving a 80.66% majority in the tokenholder vote to secure VitaDAO funding and support for their project aiming to optimise RNA Delivery for Longevity Therapeutics

Longevity Literature Hot Picks

Preprint Corner

Check out this month’s longevity preprints - will any receive a coveted spot in the Q2 Issue of the Longevist? Watch this space!

Premature Aging and Reduced Cancer Incidence Associated with Near-Complete Body-Wide Myc Inactivation

Measuring C. elegans Ageing Through Non-Invasive Monitoring of Movement across Large Populations

The blood has something to say: A hematology-based clock to measure aging in mice

Cognitive Rejuvenation In Old Rats By Hippocampal Oskm Gene Therapy

Developmental mitochondrial Complex I activity determines lifespan

The Role of Respiratory Complex IV in Lifespan Length and Quality

The molecular clock in long-lived tropical trees is independent of growth rate

Uncoupling of lifespan and reproductive tradeoffs by dietary methionine and one-carbon metabolism

Measuring C. elegans Ageing Through Non-Invasive Monitoring of Movement across Large Populations

Published Research Papers

Distinct longevity mechanisms across and within species and their association with aging

The study analyzed RNA from 41 mammals to decipher longevity mechanisms. Findings include common and unique gene markers related to lifespan, revealing a connection between long-lived species, ancient genes, and age-related changes. 

Human PBMC scRNA-seq–based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity

A new aging clock model, using blood single-cell RNA sequencing data, suggests supercentenarians (SCs) have a biological age between 80.43 and 102.67 years. SCs have more cells and types with high ribosome levels, potentially contributing to their low inflammation state and slow aging.

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

The study identifies senescent macrophages and endothelial cells as primary in KRAS-driven lung tumors in mice. Senolytic removal or macrophage depletion reduces tumor load and boosts survival. It underlines the crucial role of senescent macrophages in lung cancer progression, suggesting potential therapeutic strategies.

Targeting lymphoid-derived IL-17 signaling to delay skin aging

Aging skin sees increased inflammation due to a shift towards IL-17-expressing immune cells, according to single-cell RNA sequencing of mouse skin. Blocking IL-17 signaling in vivo reduces skin inflammation and delays age-related skin changes. 

Resistance training rejuvenates aging skin by reducing circulating inflammatory factors and enhancing dermal extracellular matrices
Both aerobic training (AT) and resistance training (RT) improved skin elasticity and structure in middle-aged Japanese women. RT uniquely increased dermal thickness and biglycan levels, suggesting different effects of AT and RT on skin aging.

The blood has something to say: A hematology-based clock to measure aging in mice

A biological age clock in mice was developed using hematological markers from longitudinal studies. The deep learning-based biological age prediction correlated well with actual age and aging acceleration linked with lifespan. 

Restoration of CPEB4 prevents muscle stem cell senescence during aging

Aging affects mitochondrial function in muscle stem cells (MuSCs), leading to senescence. The study found downregulated CPEB4, which supports mitochondria, in aged tissues. Restoring CPEB4 improved MuSC function and prevented senescence.

Comparative analysis of calcified soft tissues revealed shared deregulated pathways

This study aimed to understand the mechanisms and tissue-specific changes associated with pathological calcification in various soft tissues. The authors found that down-regulation of intracellular transport pathways and up-regulation of inflammatory pathways were common features. 

Impact of social isolation on grey matter structure and cognitive functions: A population-based longitudinal neuroimaging study

This study examined the impact of social isolation on brain health and cognitive decline in a population-based longitudinal MRI study. The findings revealed that social isolation was associated with smaller hippocampal volumes, reduced cortical thickness, and poorer cognitive function, suggesting that social isolation contributes to brain atrophy and cognitive decline. The results highlight the potential of promoting social networks as a means to reduce the risk of dementia.

Published Literature Reviews

Aging - What it is and how to measure it

This review argues for the need to focus on general biological aging rather than lifespan, which can be influenced by specific pathologies. It suggests a framework that accounts for phenotypic changes over an average lifespan, applicable across multiple organisms.

The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations

The study suggests features like cellular senescence, epigenetic aging, and stem cell changes may be adaptations, not aging drivers. It proposes 'damaging adaptations' may accelerate aging despite short-term benefits. This insight may impact antiaging interventions.

Taurine linked with healthy aging

Taurine, a semi-essential amino acid, plays a key role in animal development and health. It is linked to benefits in human metabolic and inflammatory diseases, and recent studies indicate it aids health in aged animal models.

Chronic inflammation and the hallmarks of aging

The updated aging hallmarks include dysbiosis, impaired macroautophagy, and "inflammaging". These factors interact, affecting age-related diseases like cardiovascular issues, neurodegeneration, and cancer. Understanding this is key in aging research.

Are we measuring what matters to older people?

Comprehensive geriatric assessment is key in elderly care, emphasizing personalized biopsychosocial evaluations. However, health systems often neglect person-centered outcomes, risking suboptimal care. Prioritizing meaningful outcomes for older individuals is vital.

And finally - a special FEBs issue of reviews and research articles on Senescence in Ageing and Disease

Job board

Van Heron Labs is hiring for two positions very shortly - a senior scientist and an RA/Lab tech. Please reach out directly for more info: rvaught@vanheronlabs.com

Clinical Research Assistant position at the Healthy Longevity Translational Research Program is open. Apply to Yong Loo Lin School of Medicine at NUS to work with Andrea Maier’s team.

Oliver Hahn’s lab at Calico is hiring scientists & senior scientists to develop novel and exciting experimental platforms to understand and treat age-related diseases of the CNS

Master Fellowship Programme

Do you hold a BSc degree in life science and are eager to explore the field of ageing research in a cutting-edge and interdisciplinary environment of the Cologne ageing cluster? 

The Cologne Graduate School of Ageing Research offers a new Master Fellowship programme for excellent and motivated students that wish to learn more about ageing research.

Are you interested in studying brain ageing?

Oliver Hahn’s lab at Calico is hiring scientists & senior scientists to develop novel and exciting experimental platforms to understand and treat age-related diseases of the CNS. Apply here.

News

Healthy Longevity Talent Incubator is open for applications!

When: July 3-13, 2023

Where: Singapore

Who: Talent (from all disciplines) eager to learn more about Healthy Longevity!

Application form

Dr. David Sinclair Assumes Presidency of the Academy for Health and Lifespan Research

Police got called to an overcrowded presentation on “rejuvenation” technology

Chris Hemsworth’s Center Partners with Lifespan.io, to Make Health, Wellness and Longevity Education More Accessible for All

Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution

Nature Aging enters the Journal Citation Reports 2023 - ranking #1 in Geriatrics & Gerontology with a first Impact Factor over 16 and a JCI of 3!

Prizes

Rewarding the most impactful research in longevity

Substantially increasing the human lifespan. The Amaranth Prize gives no-strings attached funding to the best research in Longevity.

Articles

Last month’s article proposing Taurine as a driver of aging has sparked a lot of discussion around its relevance for human healthspan:

Taurine supplement makes animals live longer — what it means for people is unclear

In the Pipeline | Aging and Lifespan: Taurine

Taurine improves the health and longevity of mice and monkeys – but what about humans?

Should I worry about my VO2 max?

Meet Rapamycin, the Drug That Could Delay Menopause

Time-restricted feeding makes the mouse run like a pro 

Defining a longevity biotechnology company

Transformer-based aging clock provides insights into aging

Navigate the emerging field of longevity

How seeing corpses reduces the lifespan of flies

Fasting Mimetics: Health And Longevity Benefits With Dr. Valter Longo

Cutting Calories To Add Years Finally, We Have Evidence That Caloric Restriction May Increase Human Lifespan

The billion-dollar search for immortality

Finding joy at age 100: Talking to centenarians about living their best life at any age

Conferences, Workshops and Webinars

World Aging and Rejuvenation Conference (ARC)

17-18 July, Frankfurt, Germany

Ending Age-Related Diseases

10-11 August, NY, USA and virtual

Longevity Summit Dublin

17-20 August, Dublin Ireland

Aging Research & Drug Discovery (ARDD)

28 August - 1 September, Copenhagen, Denmark

British Society for Research on Aging Annual Scientific Meeting (BSRA ASM)

6-8 September, London, UK

RAADFest

7-9 September, LA, CA, USA

Zuzalu talks recordings are out!

https://zuzalu.streameth.org/archive

Tweet of the Month

This month we leave you with some food for thought from a leader in the crypto world, Balaji Srinivasan

Balaji: CHEATING DEATH IS GOOD

People often associate performance enhancing drugs with “cheating”. And of course it’s true that if you’re an athlete it’s cheating and against the rules. But there’s nothing wrong with cheating death.

[Full text]

Also check out this interesting thread from Healthspan on Blagosklonny's theory of cellular hyperfunction

Podcasts and Videos

Wired: Have a Nice Future: Gideon Lichfield and Lauren Goode talk to Celine Halioua, the founder and CEO of Loyal—a company that researches drugs to extend the lifespan of dogs.

Brain Boosting Effects of Young Blood Revealed

Lifespan news talk about the most problematic yet perhaps one of the most promising cures for aging, young blood. Heterochronic parabiosis is a well-known aging intervention in mouse studies, but it happens to be one of the more, shall we say, unrealistic procedures for humans.

Interview with Prof Joao Pedro de Magalhaes

Joao Pedro de Magalhaes is a world renowned leader in aging research using computational and experimental approaches to untangle the secrets of human aging. He is the Chair of Molecular Biogerontology at  the University of Birmingham, and currently leads the Genomics of Aging and Rejuvenation Lab there.

What inspired you to enter longevity research?

I have never made it a secret that I work on aging and longevity to cheat death. When I was a child and realised that my parents and everyone I love would age and die, I made it my mission to develop a cure for aging.

Which of the current theories of ageing do you think are the most convincing?

I’m very interested in the idea that programmatic features originating in development contribute to aging. I think it’s a very overlooked area, as most scientists assume that aging is caused by molecular and cellular damage. However, I think some genetic programs originating in development continue later in life and become detrimental. That said, it’s clear that some forms of damage contribute to certain aging phenotypes, like for example mutations contribute to cancer. I also think it’s important we keep an open mind and explore different avenues, because at the moment we don’t know what are the drivers of human aging.

How has the field changed since you started?

In some ways, the field has changed substantially in the past 20 years because there is a lot more focus on translational research, many more companies, more investors; there has been a big growth in the longevity field. This growth has been catalysed by the discovery of longevity manipulations in animal models, and the huge medical and commercial potential of applying those to humans. In that sense, there has been a huge growth in longevity pharmacology and in longevity biotech in general. That said, at the mechanistic level things have not progressed so much, we still have a very poor understanding of what causes human aging.

What mistakes do you think the longevity field has made?

I think a common mistake in science is being overly conservative. This issue is not limited to the longevity industry; you can observe it in other fields as well, like Alzheimer‘s. Scientists, investors and funding bodies are often conservative. What this means is that scientist and companies tend to focus on the same mechanisms, targets and pathways, as I pointed out in a recent article (https://www.sciencedirect.com/science/article/pii/S1359644621000982?via%3Dihub). I think we need to be more creative in the field, and in fact, I would argue that the creativity is there, it’s just not well supported because most people and institutions are risk-averse. We need to be bolder.

Other than your own, what do you think have been the biggest/important discoveries in the field?

There have been some important discoveries in the past 10–20 years. One important discovery was that rapamycin extends mouse lifespan even in middle-aged animals. It showed we can significantly extend lifespan in animal models with pharmacological interventions. The discovery of epigenetic clocks by Horvath and others has also been an important breakthrough, even if we don’t understand the underlying biological mechanisms very well. In addition, the discovery of cell rejuvenation with partial reprogramming has been an important discovery, although we still need to establish whether it can be applied to retard aging in whole organisms.

What advice would you give to people currently working in longevity research?

Be bold, be creative, don’t be afraid to take risks and to create an environment that allows others to take risks. Aim high, don’t settle for the low-hanging fruit.

Which aspect of longevity research do you think requires more attention?

As I mentioned above, there has been a shift in the field from understanding ageing to developing interventions. I would argue that going back to basics and trying to understand the underlying drivers of human aging is still the big question, and if we could better understand the causes of human aging this would be a watershed moment and open the door to much better therapies. Of course, trying to understand the aging process is hard; it’s a lot easier to give drugs to worms or flies and see if they live longer than trying to figure out why human being age. Studying aging processes also requires a sustained long-term investment that most funders and companies are unwilling to provide.

Is ageing a disease?

That’s a good question, but I suppose it depends on the definitions of aging and of disease. As such, I think it’s more of a semantics question than a biological one. Regardless of the definitions, aging is a trigger for diseases, and it should be targeted therapeutically.

In your recent paper you compare aging to a software design flaw. Can you briefly summarise this theory and discuss how it has influenced your approach to studying aging and potential impact on the development of interventions to delay or reverse age-related decline?

The hypothesis is that ageing is not just driven by damage to the hardware, defined as cells and their components, but rather by design flaws in the software, defined as the DNA code that orchestrates how a single cell becomes an adult human being composed of billions of cells with many different identities. My view is that some processes set in motion by the genetic software during development continue in adulthood and become detrimental as a form of antagonistic pleiotropy. If aging is an unintended outcome of a program this explains the accuracy of epigenetic clocks, it explains species differences in aging as developmental rates correlate very strongly with aging rates in mammals, and fits the major genetic, dietary, and pharmacological manipulations of aging in animals. As a result, we should see aging is an information problem.

Seeing aging as the outcome of flaws in our software has important implications for studying and developing interventions for aging. Traditional anti-aging interventions targeting damage, like oxidative damage and telomere shortening, will – I predict – have limited success. By contrast, aging therapies will only be effective if targeting the software rather than the hardware. As such, interventions like a computer restart such as partial reprogramming could hold clues for future interventions.

Your research involves using computational biology and machine learning to better understand the molecular mechanisms of aging. Can you discuss the most promising applications of these techniques in the field of aging research and how they can accelerate academic research?

The problem we have in the field, and others, studying complex diseases and phenotypes, is that aging and longevity derive from the interactions of multiple genes with each other and the environment. In that regard, we need to take a systems biology approach to study how the components of the system interact with each other and ultimately understand the whole from its parts. So, in a way, we are trying to make sense, trying to tackle the complexity of biology. Using these computational methods, we can identify and prioritise new genes, drugs and pathways. For example, we have done some recent work on drug repositioning in the context of aging, revealing new existing drugs that, in animals, extend longevity and may ultimately have human applications (https://onlinelibrary.wiley.com/doi/10.1111/acel.13774). Also for a recent talk on computational approaches and aging please see:
https://www.youtube.com/watch?v=VhaAGwh012k

Your research has also covered comparative biology of aging, looking at how different species age and what factors contribute to differences in longevity. What have been some of the most surprising or interesting findings from this work?

I have always been fascinated by species differences in aging. I’ve always liked animals and used to have many different pets as a child. It is fascinating how no matter how well you care for a hamster, or a mouse or rat for that matter, they’ll still age 20 or 30 times faster than a human being. However, just like we don’t understand the mechanisms of aging, we have a very poor understanding of species differences in aging. In our work, we have tried to find genes and pathways associated with the evolution of longevity, for example studying the bowhead whale which is the longest-lived mammals. But of course we cannot do experiments in whales. My dream is to take some genes from the bowhead whale that we have found and put them in mice and see if they live longer or if they are cancer resistant, but we unfortunately don’t have the funding to do it. We have also done studies in the naked mole rat and in primates, and others have studied other species like bats. But we have really only scratched the surface as far as mechanisms of cancer resistance and longevity across species. My rationale is that different long-lived species use different molecular tricks and if we can figure out the longevity mechanisms of other taxa maybe we can apply them to human beings.

Your new pre-print paper proposes a conceptual model for explaining aging based on first principles, suggesting that epigenetic aging might be inevitable. Can you discuss how this model is different from existing models of aging, and what are the key implications of this conclusion for our understanding of the aging process?

This was a different approach for me as well, as you say, based on first principles, and credit to a brilliant PhD student, Thomas Duffield, for leading this work. Ultimately, this model assumes that epigenetic changes drive aging. This is based on the observation that epigenetic damage cannot be repaired in the same way as DNA damage, and we show that the epigenetic system has a built-in, unavoidable fidelity limitation. Based on this theoretical model, we looked into epigenetic data, namely methylation, and surprisingly found that there is an increase in noise with age and, strikingly, we can use neural networks to build accurate epigenetic clocks based on noise. I think this is very surprising, and I happily admit I’m still trying to get my head around what it means for understanding aging.

Outro

Thanks for reading and sticking with us for another month. We leave you with a short but insightful article on the potential of tokenizing IP-NFTs, where you can find more detail on the recent VITA-FAST launch!

VITA-FAST — Revolutionizing Governance in Longevity Research

Further Reading

Association between infectious exposures in infancy and epigenetic age acceleration in young adulthood in metropolitan Cebu, Philippines

Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing

Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria

Does omega-3 supplementation improve the inflammatory profile of patients with heart failure? a systematic review and meta-analysis

Curcumin, Inflammation, and Neurological disorders: How are they linked?

Epigenetic and Metabolomic Biomarkers for Biological Age: A Comparative Analysis of Mortality and Frailty Risk

Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop

To keep up-to-date with the latest breakthroughs in longevity research, exclusive insights, and exciting updates from our team, make sure to subscribe to our newsletter.

Welcome to this month's newsletter, where we delve into the philosophical dichotomy at the heart of longevity research.
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Feeding the Clock: Deciphering the Intricacies of Fasting, Caloric Restriction, and Circadian Rhythms with Dr. Heidi Pak on The Aging Science Podcast by VitaDAO
July 6, 2023
Awareness
Longevity
Feeding the Clock: Deciphering the Intricacies of Fasting, Caloric Restriction, and Circadian Rhythms with Dr. Heidi Pak on The Aging Science Podcast by VitaDAO

In this podcast with Dr. Heidi Pak (@pak_heidi) we primarily talked about the difference between fasting and time-restricted feeding, how and why it works and also the efficacy of caloric restriction (CR) in different mouse strains and species. It was a great podcast, very fun as well.

Other topics that we touched on included sleep, the postdoc shortage, hardships of being a grad student, the healthspan vs lifespan debate and some more. We also came up with some less-than-serious nutritional recommendations:

"I guess the diluted [fasting] diet [I studied] is the equivalent of eating celery" (Heidi Pak)

If you want to know why we were talking about celery and why Heidi wants to put pigs on a weight loss and fasting diet, then this podcast is for you.

Heidi Pak – short bio

Heidi did her PhD with Dudley Lamming at the University of Wisconsin–Madison where she studied fasting, time-restricted feeding and caloric restriction in relation to aging. She now works as a postdoc for Joseph Takahashi, continuing her work on fasting and moving into the relatively new field of circadian rhythms.

What is caloric restriction?

Also known as dietary restriction is the practice of restricting the caloric intake of mice, usually by 30%. This extends the lifespan of many, although not all, mouse strains considerably. CR is hailed as one of the biggest breakthroughs in biogerontology and for good reason. If it worked in humans; or if we could find a drug that mimics CR in humans it would be the biggest biomedical revolution since the invention of antibiotics!

The discovery of CR is often attributed to seminal work by Clive Mccay in the 1930s. However, what made CR big was not the work by McCay showing that food restriction from birth stunts growth and extends lifespan, rather it was protocol improvements. For example, Walford and Weindruch found in the 1980s that adult-onset CR can work reliably in many strains if it is introduced gradually.

This podcast episode is about another such protocol improvement. The disambiguation of fasting and caloric intake through modern feeding protocols and enabled by 24/7 monitoring of food intake, locomotion etc.

Using those new feeding protocols Heidi and others found that fasting contributes to the lifespan and health benefits of CR.

What is fasting and time restricted feeding?

The idea behind fasting to slow aging was that after the body has digested most of the food, when hunger starts setting in, an organism might be in something akin to a CR state. Therefore, imposing periods of fasting could reap some of the health benefits of CR without the drastic weight loss, constant hunger and other side-effects normally associated with CR. While plausible this theory had many problems, not least the fact that it seemed to contradict the work of Walford and Weindruch who suggested that gradual onset CR was more beneficial in adult mice than starting the protocol abruptly. It stands to reason that alternating periods of fasting and feasting could be stressful to the body, just like the abrupt CR protocols used in the past, and thereby shorten your life (or that of a mouse).

We needed evidence to settle this debate, or at least start addressing some of the major points. Before we can understand the evidence, let us take another look at what fasting exactly is.

Defining fasting is not easy since the cutoff when “fasting” starts is somewhat arbitrary and that can be a problem when reading papers and articles on this topic. When reading about fasting research it is important to keep in mind that a 16hr fast and a one-week water fast could be reported as the same thing by the media, even though the physiologic effects will be very different. Importantly, it could well turn out that certain eating windows are much more beneficial than others. Maybe the water fast is healthier, or maybe it is not. We do not know what will work in humans yet.

Intermittent fasting and time-restricted feeding mean similar things in mice. Although generally fasting refers to on-off feeding schedules and restricted feeding refers to shorter and variable eating windows within a day.

Little progress was made on this matter and some people, like me, remained convinced that fasting has no benefits or that we “simply do not know”. Early studies using intermittent fasting protocols were always biased by weight loss. Since the fasted mice lost weight, even if it was less than during CR proper, it was hard to attribute the health benefits to fasting rather than weight loss. There were also studies suggesting that fasting is not an important component of CR (Nelson and Halberg 1986).

However, one observation pointed out in the work by Heidi Pak always made a strong case for the importance of fasting. While, yes, intermittent fasting induces CR; CR actually induces a form of intermittent fasting! Apparently, the CR data itself was always potentially biased by the effects of fasting.

TimelineDescription automatically generated

From Mitchell 2019, eating windows indicated for caloric restriction (CR), control (AL) and meal fed mice (MF).

As you can see from this image taken from a typical fasting study, mice tend to self-impose a fasting window when they are under CR. They are so hungry that they gorge on their food early during their waking hours and then fast for many hours afterwards.

Building on this finding Heidi Pak and many others designed protocols to test this further.

How do we test the effects of fasting?

Several protocols exist to induce fasting without weight loss. One is caloric dilution, the other is time-restricted dispensation of food using a machine, or training mice to eat during a specific time window. All of them have advantages and disadvantages.

Caloric dilution involves diluting the diet with cellulose that cannot be digested and is one of the approaches that Heidi used in her research. While a very smart idea, I am not the biggest fast of the caloric dilution approach as I have written on my blog when I was first reviewing Heidi’s paper.
See here for more information why I think this way: http://biogerontolgy.blogspot.com/2021/12/caloric-restriction-and-fasting-does-it.html

Be that as it may, I do not want to be overly critical of the research here. As scientists we tend to be overly skeptical of new research. Fact is, modern fasting research was a big breakthrough in the field of CR because it provided conclusive evidence that fasting contributes at least to some of the health and longevity benefits of CR as we discuss in the podcast. This is very exciting because fasting is much more tolerable than CR in humans, thus could see actual application in the real world.

Another strategy to study fasting is removing the fasting window that CR mice self-impose to isolate the effect of calories. This means forcing CR mice to eat multiple times throughout the day. Such studies generally find that fasting is one but not the sole contributor to the health benefits of CR.

This is where it gets complicated – circadian timing

Recent work has shown that not only is fasting one component of CR that contributes to the lifespan extension, there is also a component of circadian alignment. The recently published work by Acosta-Rodríguez et al. 2022 from the Joseph Takahashi lab demonstrated this nicely. This paper has some of the most beautiful figures I have ever seen so highly recommended to check it out.
Here is a very good video explanation of the paper: https://www.youtube.com/watch?v=q5ZN_mT-xbw&t=12s

During the podcast we briefly talked about this work and I mistakenly mentioned that mice in that paper were fasted during the night. In fact it is quite a bit more complicated than that. Night is the active period for mice and it is generally beneficial for them to eat during this period. The above paper actually tested two groups fed at night. One with a 12 hr feeding window and one with a 2 hr feeding window during the day or during the night period. The latter was the most beneficial for lifespan, meaning the mice will be fed at the beginning of the dark period, will quickly finish their food and then will fast for most of the night and the day.

Why humans are not two-legged mice

Even though mice are my favorite animal model and I consider myself a mouse researcher, I have to admit that mice have their limitations as a model of aging. Let us first talk about the benefits of mice, though. Running mouse studies is orders of magnitude cheaper than running human studies, it is more ethical, the mouse is well-understood as to its genetics and longevity, it is amenable to transgenic manipulation and so on. In contrast to nematode worms and fruit flies, the other two popular aging models, mice are closer relatives of humans; they are real, breathing mammals with many of the same traits as humans. They get cancer, they like to cuddle with other mice and sometimes fight with them as well.

The fact that mice are so similar to humans, by the way, is also a reason why we need to treat them well and keep them healthy. Only data from healthy mice will translate to healthy humans. In the podcast we briefly discussed how important it is to keep mice healthy, which is reflected by long lifespans of the control group.

What is the problem with mice then? Well, they are unusually “fragile”, as we have alluded to in our podcast with Peter Fedichev. Meaning, they are unusually short-lived for their size, and unusually prone to cancer, whereas humans are exceptionally long-lived given their body mass and size.

Another limitation is the small size and high metabolic rate of mice. This precludes many surgical interventions and has led to a lot of spurious findings. In this context I like to tell the story of hydrogen sulfide induced suspended animation, which would be also very interesting to aging researchers, if it worked. However, as it turned out this was an intervention that only worked due the physics of small body sizes (Asfar et al. 2014). This is where other animal models come in handy to validate the mouse data. We were talking about pigs as one option during the podcast.

It is difficult to overstate the differences in metabolic rate between mice and humans. A mouse heart contracts at an unbelievable rate of 500 to 700 beats per minute and their energy needs are commensurate with their fast metabolism. Although a mouse may not eat much in absolute terms, per gram of body weight it eats much more than a human, consuming a staggering 10% of bodyweight every day. Imagine eating 8kg of food every day! If you starve a mouse for a couple of days, it will die. Humans in contrast can go on for months without food.

Nevertheless, we can learn a lot from mice. We learned that fasting can work to extend health and lifespan, in principle. Nevertheless mice cannot tell us whether fasting will work in humans.

Perhaps there is an eating window in humans that can mimic mouse time restricted feeding? No one knows whether this will have to involve a week of severe fasting, maybe 2 weeks of moderate fasting or whether the currently used protocols in clinical practice employing moderate fasts are enough. 

Hopefully future research by Heidi and others will help us to understand this issue.

References and notes

Acosta-Rodríguez, Victoria, et al. "Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice." Science 376.6598 (2022): 1192-1202.

Nelson, W. & Halberg, F. Meal-timing, circadian rhythms and life span of mice. J. Nutr. 116, 2244–2253 (1986).

Asfar, Pierre, Enrico Calzia, and Peter Radermacher. "Is pharmacological, H2S-induced'suspended animation'feasible in the ICU?." Critical Care 18.2 (2014): 1-8.

Mitchell, Sarah J., et al. "Daily fasting improves health and survival in male mice independent of diet composition and calories." Cell Metabolism 29.1 (2019): 221-228.

In this podcast with Dr. Heidi Pak we primarily talked about the difference between fasting and time-restricted feeding, how and why it works and also the efficacy of caloric restriction (CR) in different mouse strains and species.
Read more
VITA-FAST — Revolutionizing Governance in Longevity Research
June 30, 2023
Awareness
Tokenomics
VITA-FAST — Revolutionizing Governance in Longevity Research

VitaDAO, the global community accelerating research and development in longevity science, is pleased to announce the launch of the VITA-FAST tokens. This marks the first-ever opportunity for token holders to directly influence longevity research, setting a new precedent in the field of decentralized science (DeSci).

The VITA-FAST tokens, which allow holders to make decisions on IP licensing, set experiment priorities, and govern research on autophagy, have been met with overwhelming interest.

The initial token sale was 1700% oversubscribed, with $620k in bids, demonstrating the public’s eagerness to participate in scientific research.

This groundbreaking initiative is spearheaded by the esteemed Korolchuk Lab, led by renowned cellular biologist Prof. Viktor Korolchuk. The lab’s work focuses on autophagy, a process vital to cellular health and implicated in ageing and various diseases. The launch of VITA- FAST tokens not only provides financial support for this cutting-edge research but also fosters a community-driven approach to biomedical research.

Alex Dobrin, head of community at VitaDAO, said, “This is the next phase in the evolution of decentralized patient communities, to directly contribute to, govern, and be rewarded for progressing valuable longevity research.”

VitaDAO engaged its community in the token sale by using a newly launched crowdsales platform developed by Molecule AG, which developed the original IP-NFT platform for capturing IP in web3, and is a strategic contributor to VitaDAO.

“The success of the VITA-FAST token sale is a testament to VitaDAO’s innovative approach to integrating public participation into scientific research. It also underscores the potential of decentralized finance (DeFi) to fill in the gaps left by traditional funding agencies”, as noted by Paul Kohlhaas, CEO of Molecule.

Professor Matthew Grenby, Pro-Vice-Chancellor for Research and Innovation at Newcastle University added “It’s great to see this cutting-edge research going out into the world, and we are excited to be at the forefront of biomedical research funding. We look forward to supporting Molecule AG and VitaDAO with development of this novel platform and commercialisation of their IP”.

The VITA-FAST token offering marks a significant step forward for VitaDAO as it begins advancing its early research assets toward their next development milestones. The VITA-FAST tokens will provide ongoing options for funding for the Korolchuk Lab as it advances its research program.

For more information, visit https://www.vitadao.com/viktor-korolchuk-lab-vita-fast-token-sale-with-vitadao and talk to us in our Discord auction channel.

‍Discover the power of autophagy, a natural cell rejuvenation process, through the enlightening YouTube video, Autophagy as a Target for Rejuvenation | VitaDAO and Viktor Korolchuk Lab.

This marks the first-ever opportunity for token holders to directly influence longevity research, setting a new precedent in the field of decentralized science (DeSci).
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VitaDAO Letter: Zuzalu & Shaping the Future of Autophagy Research
June 18, 2023
Sarah Friday
Awareness
VitaDAO Letter: Zuzalu & Shaping the Future of Autophagy Research

Welcome back to the VitaDAO Newsletter, your monthly source of insights into the VitaDAO community. In just 20 months, we have successfully deployed over $4 million to fund 17 cutting-edge projects, pushing the boundaries of what is possible in the field.

From our upcoming token sale, which introduces the innovative VITA-FAST tokens, to the one-year anniversary of our renowned “Longevity Research Newsletter, we are pushing the boundaries of what is possible. Let’s dive in and explore the latest developments in VitaDAO’s mission to extend healthy lifespans. Inside this Newsletter:

  • VITA-FAST Tokens: Steering Korolchuk Lab’s Research
  • Celebrate One Year of the Longevity Research Newsletter
  • Recent VitaDAO Votes
  • Meet Rhys Anderson

VITA-FAST Token Crowd Sale

Hold up, I thought that $VITA was the community token of VitaDAO? It is! Then what is the talk of a VITA-FAST Token? 🤔

If you’re new here, welcome! Sit back, relax, and keep on reading as I introduce you to VDP-100,, and the utility of VITA-FAST tokens. This story dates back to 2021 when the VitaDAO community voted to fund Viktor Korolchuk Lab in the discovery of new autophagy inducers. Dysfunctional autophagy affects cellular functions including DNA repair, metabolism, and survival. Thus, activation of autophagy is considered a promising therapeutic approach to combat aging and age-related diseases.

“We see that activating this process makes old cells look young, which is quite striking from our point of view.” — Viktor Korolchuk

Flash forward to earlier this month, the community voted on VDP 100, the fractionalization of the IP-NFT minted pursuant to VDP-16. In layman’s terms, fractionalization is the concept of splitting up ownership of something. Here, the final model is a little different: not split ownership, but rather shared governance. In this case, VitaDAO is distributing governance over the Korolchuk project by allowing individuals to buy or earn governance rights in order to have a more active role.

This brings us to VITA-FAST tokens. $VITA-FAST will be Intellectual Property (IP) governance tokens that provide membership to an IP pool for the IP-NFT. Members of this pool will actively decide what happens with the IP and R&D data attached to the Korolchuk IP-NFT. Thus, VITA-FAST token holders have the right to participate in the governance of the IP-NFT and its development.

This necessitates token distribution! 1,000,000 VITA-FAST tokens will be minted, with 10% available for sale to VitaDAO members, and the rest divided among VitaDAO, researchers, Newcastle University, and a liquidity pool. The 10% will be sold to $VITA token holders in a fixed-price sale with pro rata distribution, overflow refunds, and 2-month vesting. VitaDAO members can bid as much as they’re willing to contribute to the sale, with the final allocation of tokens proportional to each participant’s contribution.

We invite you to join us as we make history! Before participating in the sale, familiarize yourself with the Korolchuk project page, the project white paper, and VitaDAO’s blog announcement.!

Sale duration: June 15 5pm CET — June 23 5pm CET

Participate in the sale here: https://mint.molecule.to/ipnft/2

🧪VitaDAO’s IP-NFT Funded Research Projects

In a newsletter discussing fractionalization, it feels wrong not to briefly cover IP-NFTs. IP-NFTs connect IP and research and development data rights to NFTs on the Ethereum network by attaching legal contracts to smart contracts. They represent a new paradigm in the evolution of legal contracts for scientific research. Benefits of IP-NFTs include: creating efficiencies in IP licensing, creating entirely new IP markets, and enabling decentralized IP ownership, governance, and commercialization.

VitaDAO has multiple IP-NFT-funded projects including (but not limited to):

🌎VitaDAO & Zuzalu

Last month, Zuzalu & VitaDAO took Montenegro by storm. VitaDAO’s “Longevity Zero to One” and “Longevity Biotech Conference” encouraged conversation about network states and the pursuit of extended life. Want to learn more? Check out the full article by MIT Technology Review for an immersive glimpse into this groundbreaking event:
https://www.technologyreview.com/2023/05/31/1073750/new-longevity-state-rhode-island/

🥳A Year of the Longevity Research Newsletter

Has it already been a year? Time flies when you’re having fun! Join us in commemorating the one-year anniversary of our renowned VitaDAO’s “Longevity Research Newsletter.” This fun initiative, led by Rhys Anderson and Maria Marinova, keeps VitaDAO members up-to-date with the most important longevity research activity happening across the globe. The newsletter offers updates about VitaDAO’s funded projects, highlights hot longevity research, and features top scientists in the field. Swing by VitaDAO’s Medium to read this month’s edition and stay informed about the latest breakthroughs.

🗣️VitaDAO in the Wild

Discover VitaDAO’s growing presence in the scientific and technological community:

📣Community Approved: What you voted for!

VDP-97 Passed! This vote distributed 700,000 VITA tokens to 6 of the top community & awareness contributors, with an additional allowance of up to 300,000 VITA for allocation to other core contributors.

VDP-99 Passed! As a result of this vote, VITA will launch on layer2s. Currently, VitaDAO is prioritizing launching on Optimism, Arbitrum, and Polygon with $250k of liquidity in each VITA + ETH.

VDP-100 Passed! In case you skimmed past the earlier part of this newsletter, VitaDAO’s Newcastle IP-NFT will be fractionalized! This vote confirmed the creation of IP-NFT tokens to govern the IP and control the R&D decision-making and capital allocation process.

💪Exercise Your Right to Vote (on VitaDAO’s Governance Forum)

Find all of VitaDAO’s pending proposals on Discourse, VitaDAO’s governance hub for proposals before they are moved on Snapshot. Proposals are open for engagement, voting, questions, and conversation!

Your voice matters, and together, we can shape the trajectory of VitaDAO and contribute to the advancement of decentralized science.

👋Meet Key VitaDAO Contributor: Rhys Anderson

Rhys Anderson is a research scientist and active VitaDAO contributor. In 2016, he received his PhD in Cell Biology from Newcastle University. Currently, his time as a postdoctoral research associate is spent researching senescence and aging at King’s College London. On the side, Rhys is a part of the Longevity Dealflow Working Group, and Community and Awareness Working Group, and has played an integral part in the initiation of the Longevist. Rhys’s dedication and expertise exemplify the collaborative spirit of our community.

How did you first get involved in VitaDAO?

I’m a cell biologist and in late 2021 I received a Longevity Impetus grant to support my research on targeting senescent cells. Shortly after, I received an email from VitaDAO saying they are reaching out to the Impetus awardees. I had a call with Dealflow Steward Laurence to discuss my research, and he also explained how the DAO works and that anyone can get involved — so I did, and the rest is history……

What does your contribution look like?

I started off contributing to deal flow by helping to evaluate funding applications before going on to “shepherd” some of my own. In mid-2022, Maria Marinova and I began co-authoring a monthly Longevity Newsletter, keeping people up-to-date with all the goings on in the longevity world from publications to conferences and interviews with prominent longevity scientists.

Recently I have also been busy working away on VitaDAO’s new initiative, an overlay journal — The Longevist — which will be ready for launch soon!

How does it work for you?

I work full-time doing research, but due to the remote and flexible nature of VitaDAO, I’m able to make contributions on weekends, evenings, and early mornings before my toddler awakes and summons his loyal servant.

You played an integral part in establishing The Longevist. What exactly is The Longevist?

The Longevist is a curation of the world’s most exciting longevity research each quarter. Our editorial team created a shortlist of preprints that we believe have the potential to have a big impact on the field and then our team of expert curators vote on-chain to determine which of these preprints they think are the best.

Why preprints?

Preprints have accelerated the rate at which scientific discoveries are shared with the world. However, so much research is published on a daily basis that it’s impossible to keep up with all the literature and it could be months to years before publication in a traditional journal. So we are using our platform to highlight research that deserves special attention.

What do you feel is VitaDAO’s biggest strength compared to traditional longevity biotechs?

VitaDAO has an extensive network with a real breadth and depth of expertise. With the opt-in nature, no one is lumbered with unwanted assignments from the boss — instead, people can focus on contributing to the projects they are most passionate about. I’ve been extremely impressed by the rate at which ideas can go from inception to reality.

The community is also willing to take risks on projects which would be unlikely to receive conventional funding as well as being able to support the longevity ecosystem in numerous other ways from prizes to fellowships.

Any closing thoughts for readers?

There’s a real buzz around DAOs at the moment — I imagine it’s akin to what the early stages of the dot com boom would have felt like in the 90s.

Looking at the DeSci space alone there are new DAOs popping up all the time and they are proving to be instrumental in bringing both the tech and science worlds together.

The success of VitaDAO has been enabled by decades of longevity research showing that aging isn’t an immutable universal constant but rather a process that can be understood and targeted. The tech world has bought into this and has created the infrastructure and provided funding to support longevity research, which has the potential to lead to a healthier, more prosperous future for all of humanity.

🗓️Upcoming Event

June 15, 5 pm CET — June 23, 5 pm CET: VITA-FAST Token Crowd Sale

We’ve made it possible for you to govern and engage with Viktor Korolchuk Lab’s research as a VitaDAO Member. As you know, we’re all about putting the power in the hands of our community and we’re doing exactly that with the VITA-FAST tokens.
Participate in the Sale: https://mint.molecule.to/ipnft/2

🤝Get Involved

Have a special skill set? Contribute to VitaDAO and receive $VITA in return. Want to stay up to date with the VitaDAO community? Join us on Discord, subscribe to our Twitter, and follow our Instagram!

Additionally, VitaDAO’s updated website (https://www.vitadao.com/) contains information on funded projects and a treasury dashboard.

Welcome back to the VitaDAO Newsletter, your monthly source of insights into the VitaDAO community. In just 20 months, we have successfully deployed over $4 million to fund 17 cutting-edge projects.
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Introducing VITA-FAST: Govern and Engage In Viktor Korolchuk Lab's Research as a VitaDAO Member
June 12, 2023
Awareness
Tokenomics
Introducing VITA-FAST: Govern and Engage In Viktor Korolchuk Lab's Research as a VitaDAO Member

Greetings, Vitalians!


Imagine having a direct hand in the future of longevity research. Today, we’re thrilled to introduce VitaDAO’s innovative approach to scientific research funding, giving you an exceptional chance to participate in the decision-making processes of longevity research. With our community fundraising effort for the “Discovering Novel Autophagy Activators” Intellectual Property Non-Fungible Token (IP-NFT) from the Korolchuk Lab at Newcastle University, you are invited to contribute to the democratization of one of the most cutting edge longevity research and development (R&D) projects funded by VitaDAO.

This fundraising effort will be a sale of VITA-FAST tokens, a.k.a. Molecules, representing governance rights over the pool of Intellectual Property (IP) and R&D generated by the esteemed Korolchuk Lab’s research centered on the discovery of novel autophagy activators–the research funded by VitaDAO’s Korolchuk IP-NFT. Autophagy is a cellular process whose decrease can contribute to our biological systems’ decline, particularly as we age. By stimulating autophagy, we’re exploring promising therapeutic approaches to combat aging and age-related diseases, with the goal of improving human healthspan.

By enabling community-led decision-making and governance, VitaDAO’s novel funding model redefines how research programs, including the Korolchuk Lab, are supported. Participating in this crowdsale means not just funding research, but driving scientific progress, shaping therapeutics’ future, and joining a devoted community of pioneers committed to extending human lifespan.

Your contribution to the VITA-FAST Molecules crowdsale provides you with more than just a chance to fund potential longevity therapeutics; it enables you to actively guide them. As a VITA-FAST tokenholder, your voice counts in making crucial decisions. You can influence how the program’s resources are allocated, ensuring they are put to the most effective use in our quest for groundbreaking research and discoveries. You’ll have the ability to dictate the priority of experiments, ensuring that we concentrate on the areas you believe hold the most promise. This unique capability lets you stay at the cutting edge of scientific exploration, directly impacting the path of life-extending advancements. You can decide who licenses the IP & R&D data and what the license terms are.

Your role as a VITA-FAST tokenholder is not passive. It’s about engagement and contribution, and there’s no one-size-fits-all approach. We value and need your unique skills and perspectives, regardless of your background. Whether you bring scientific knowledge, business development expertise, or other abilities beneficial to early-stage drug development, we welcome your input. We believe in collective intelligence and decentralized science, and we’re eager to see how your involvement will generate value for patients.

The number of available tokens are limited. A total of 1,000,000 VITA-FAST tokens will be minted, with 10% available for sale to VitaDAO members, and the rest divided among VitaDAO, researchers, Newcastle University, and a liquidity pool.


Our innovative Genesis Sale Structure further democratizes the process. This fixed-price sale allows VitaDAO members to bid as much as they’re willing to contribute to the auction, with the final allocation of tokens proportional to each participant’s contribution. VitaDAO members must lock their VITA for two months to participate in the sale. If we meet or exceed our sales target (~32,000 USD), the surplus will be returned to bidders. Importantly, the VITA-FAST tokens will be vested (non-transferrable) over a 60 days to ensure equitable participation in governance during vesting. The vested VITA-FAST tokens and the locked VITA will vest and unlock at the same time, 60 days after the Genesis Sale. For a more detailed explanation, read VDP-100 on Snapshot.

The funds raised from the sale will be directed towards providing liquidity for the VITA-FAST liquidity pool until token holders govern where the resources should be allocated. This could include contracting computational biochemists, engagement of experienced medicinal chemists, or filing patents.

We, therefore, invite you to join us on this revolutionary journey. Engage in this unique opportunity to support the Korolchuk Lab and the wider field of longevity research. Make your mark in a cause aiming to enhance human health and longevity. Every contribution, every Molecule purchased, every decision made, brings us a step closer to deciphering the mysteries of longevity.

While we aim to democratize research funding, we acknowledge that all biomedical research is unpredictable, laden with twists, turns, and complexities. Therefore, we ask those considering purchasing VITA-FAST tokens to do so with a comprehensive understanding of these inherent uncertainties.

First and foremost, please recognize that purchasing VITA-FAST tokens should not be regarded as an investment but as a contribution towards advancing scientific research. The focus is on the technology of tokenization, the utility of tokens within the IP pool, and the mission of scientific research.

It’s important to stress that VITA-FAST tokens are IP governance tokens that provide membership in an IP pool where members actively decide what happens with the IP and R&D data attached to the Korolchuk IP-NFT. They do not automatically confer any economic benefits or returns. This is not an investment contract where you’re buying a share of future profits.It is important to understand that there may never be a distribution of proceeds.

In fact, it is crucial to bear in mind the expectation of loss. The landscape of biotech research is fraught with challenges and the vast majority of research projects do not yield patentable IP. It’s very likely that the research may not lead to patentable IP, that buyers will not receive any money back, and that the tokens might not acquire any financial value.

As a VITA-FAST tokenholder, you have the responsibility to actively participate and put in work to generate value for yourself. Participation involves more than just owning VITA-FAST tokens. It means actively governing the direction of research and decision-making processes, and ensuring the responsible usage of the IP and R&D data.

Owning VITA-FAST tokens may require you to sign NDAs and provide KYC in order to access sensitive IP or R&D data. This is for the protection of the data and the rights of all parties involved. The rules for data access and privacy are to be governed into place by VITA-FAST tokenholders.

Finally, to our US community members, please note that due to unclear regulations, we unfortunately cannot include US buyers in this endeavor. This is an evolving area of law and while we are exploring ways to include the US, we are erring on the side of caution to ensure compliance with existing regulations.

The potential and the mission of this project are vast and exciting. However, it is crucial to approach this opportunity with a thorough understanding of the intricacies and potential risks involved. We encourage all potential participants to conduct their own due diligence and make informed decisions.

With these understandings and acknowledgments, we warmly invite you to participate, contribute, and make a difference today in the world of longevity research. Every step we take together brings us closer to deciphering the mysteries of longevity.

For more information, visit https://www.vitadao.com/viktor-korolchuk-lab-vita-fast-token-sale-with-vitadao and talk to us in our Discord auction channel.

Discover the power of autophagy, a natural cell rejuvenation process, through the enlightening YouTube video, Autophagy as a Target for Rejuvenation | VitaDAO and Viktor Korolchuk Lab.

Imagine having a direct hand in the future of longevity research. Today, we're thrilled to introduce VitaDAO's innovative approach to scientific research funding...
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May Longevity Research Newsletter
June 9, 2023
Maria Marinova & Rhys Anderson
Awareness
Longevity
Newsletters
May Longevity Research Newsletter

Introduction

Welcome to this month's edition of our newsletter, where we delve into the fascinating realm of gerontology - the scientific study of ageing - which has increasingly become a pivotal area of research, given the world's ageing population. This discipline, which explores the biological, psychological, and sociological aspects of ageing, has led to significant advances in understanding age-related diseases and interventions. Key to these advancements are human trials and interventions, turning laboratory findings into strategies that can enrich our lives as we age. This month, we are thrilled to feature an exclusive interview with renowned gerontologist, Professor Andrea Maier who brings an invaluable perspective and continues to break new ground in age-related diseases research.

This issue emphasizes the need for standardization in research methodologies to optimize comparability, which in turn may accelerate potential breakthroughs. As always, we strive to bridge the gap between the scientific community and policy makers, underscoring the urgent necessity for gerontology insights to inform public health strategies, legislation, and societal views on aging. Stay tuned for a captivating exploration of gerontology with Professor Maier.

VitaDAO Funded Research Projects

Viktor Korolchuk’s project, which aims to discover novel autophagy activators, will be the first VitaDAO project to undergo Synthesis of its IP-NFT after  receiving a 100% majority in the tokenholder vote.

Synthesis will create direct capital for the project and incentivise the VitaDAO community to contribute and move it into overdrive.

Longevity Literature Hot Picks

Preprint Corner

VitaDAO’s very own longevity overlay journal - The Longevist - had its first on-chain vote to determine what our team of curators think are the most exciting preprints of Q1 2023. We are aiming to launch the website later this month.

Prizes will be awarded for nominating preprints which make it into future issues of The Longevist. If you would like to nominate a preprint for inclusion in Q2 2023, then please follow this link - deadline 30th June 2023. 

This month we are featuring 6 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in previous issues of this newsletter.

DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging

Cellular Senescence is a Double-Edged Sword in Regulating Aged Immune Responses to Influenza

DNA methylation rates scale with maximum lifespan across mammals

Breast cancer risk based on a deep learning predictor of senescent cells in normal tissue

Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases

Published Research Papers

DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging

DNA methylation-based aging is conserved in frogs and mammals. The identified age-related CpGs are located in neural-developmental genes, implying a connection between epigenetic aging and age-associated diseases. The study opens avenues for using frogs as an aging model.

Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models

Researchers identified a peptide called Pep 14 that can effectively reduce senescence burden in human skin cells without toxicity. By modulating the activity of a specific enzyme involved in DNA repair and senescence pathways, Pep 14 improved the skin phenotype and reduced the biological age of aged skin samples in a safe manner.

Distinct longevity mechanisms across and within species and their association with aging

Study across 41 mammalian species reveals genetic signatures of lifespan control, including shared mechanisms like downregulated Igf1 and upregulated mitochondrial genes. Lifespan-extending interventions target genes related to energy metabolism.

Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging

Exercise rejuvenates aging stem cells, improves tissue regeneration, and reduces inflammation. This study examines the molecular changes induced by exercise in various stem cell compartments, highlighting its positive effects on intercellular communication and immune cells.

Effects of hunger on neuronal histone modifications slow aging in Drosophila

The sensation of hunger, by limiting BCAAs or directly activating hunger neurons, extends lifespan in Drosophila. Hunger-induced changes in neuronal histone acetylome seem to play a role.

Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial

Participants taking multivitamins had better immediate recall memory compared to those taking a placebo. This effect was sustained over a three-year period, suggesting multivitamin supplementation could be a safe way to maintain cognitive health with age.

Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies

Leukocyte telomere length (LTL) is associated with various health outcomes. Longer LTL is linked to increased neoplasm risk, while shorter LTL is associated with conditions like coronary heart disease and rheumatoid arthritis.

Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Activated autophagy in disease-associated microglia helps maintain amyloid plaque homeostasis and prevent senescence. Inhibiting microglial autophagy worsens neuropathology, while removing senescent microglia could be a therapeutic strategy for AD.

Discovering small-molecule senolytics with deep neural networks

Deep learning was used to identify three drug-like compounds that selectively target senescent cells, similar to a known senolytic drug. These compounds reduced senescent cell burden in aged mice, highlighting the promise of deep learning in drug discovery.

Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis

Lifelong exercise training in a rat model of prostate cancer led to increased γδ T cells and lymphocyte infiltration in the prostate tissue. Exercise also induced changes in the expression of Oestrogen Receptor and Mitogen-activated Protein Kinase 13.

Region-based epigenetic clock design improves RRBS-based age prediction

Epigenetic clocks for mouse RRBS data have poor performance on external datasets. A study introduces regional blood clocks (RegBCs) that improve age prediction by using average methylation over large regions and outperform individual CpG-based techniques.

Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing

Thrombomodulin (THBD) signaling identified as a key pathway in senescence. Inhibiting THBD signaling with vorapaxar eliminates senescent cells and restores tissue homeostasis in liver fibrosis models.

Alpha‑ketoglutarate supplementation and BiologicaL agE in middle‑aged adults (ABLE)—intervention study protocol

The ABLE trial investigates the effects of Alpha-Ketoglutarate (AKG) on aging in humans. Participants will receive AKG or a placebo for 6 months, with follow-up for 3 months. The study aims to measure changes in DNA methylation age, inflammatory and metabolic parameters, strength, arterial stiffness, skin autofluorescence, and aerobic capacity.

Published Literature Reviews

Chronic kidney disease promotes ageing in a multiorgan disease network

Chronic kidney disease has been identified as a significant risk factor for accelerated aging in multiple organ systems. This highlights the interconnectedness of age-related chronic diseases and their impact on mortality.

Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

This review emphasizes the impact of senescent cells on different cardiovascular cell types and discusses the potential of senotherapeutics for treating cardiovascular diseases.

Senescence: a double-edged sword in beta-cell health and failure?

In pancreatic beta-cells, senescence contributes to age-related decline and diabetes. Targeting senescence is a promising approach for diabetes treatment. This perspective discusses the importance of senescence in beta-cell homeostasis and pathology.

Job board

Looking for a job in longevity research? Check out jobrxiv - we have saved you milliseconds by entering “aging” in the keyword search, but enjoy searching for whatever your research interests are!

Wyss-Coray Lab looking for a research assistant/associate to work on microglia, HSCs, lipidome or aging clocks

Hansen lab at the Buck are looking for new postdocs!

The focus of the research is to understand how the basic cellular recycling process called autophagy is regulated during aging, using the nematode C. elegans and mammalian cell culture systems, and a combination of biochemical, imaging, and genetic approaches.

The Benayoun lab at the Leonard Davis School of Gerontology at the USC is seeking a Research Lab Technician. They aim to use mice to understand sex differences in the aging process!

News

Hevolution Foundation Geroscience Research Opportunities (HF-GRO) Awards Unveiled, with a Budget of up to $115M Over Five Years

Resources

Longevity Biotech Landscape

Ada Nguyen provides us with an overview of the longevity biotech landscape, by sorting the different companies into 4 key therapeutic areas: reset & repair, replace, reprogram and discover.

Prizes

The Maximon Longevity Prize for Translational Research

Awards outstanding breakthrough research in the field of longevity that can be translated for clinical or non-clinical applications and has the potential to substantially increase health span or life span of humans.

They are welcoming applications from all academic/non-profit researchers, inventors, scientists, students or startup founders who either published breakthrough research, hold the patent or are in very advanced stages of research.

Articles

Biopharma Targets the Untapped Potential of the Human Healthspan

The Longevity Skeptic

The Secrets of Aging Are Hidden in Your Ovaries

Can a Kidney Transplant Drug Keep You From Aging?

Inside the Secretive Life-Extension Clinic

Speaking of Illusions: Sirtuins and Longevity

Combilytics: Taking a combined approach to senescence

NPR-8: The Protein That Could Extend Human Lifespan in a Warming World

The unexpected force that may make us get less sleep

More geriatricians needed to meet the needs of the UK’s ageing population

Why do some people live to be a 100? Intestinal bacteria may hold the answer

Vitalik Buterin Exclusive Interview: Longevity, AI and More

Speaking of Vitalik, he published a longevity pyramid short survey on his website. See where your health philosophy fits in!

Conferences, Workshops and Webinars

Meet the most inspiring speakers and experts gathering to discuss their present research.

Authophagy UK

19-20th June, University of Birmingham, UK

DGfA (German Society for Research on Aging) Annual Meeting

29-30th June, Volkshaus Jena, Germany

5th World Aging And Rejuvenation Conference

17-18 July, Frankfurt, Germany

Longevity + DeSci Summit NYC: Ending Age-Related Diseases 2023

10-11th August, New York

International Longevity Summit Africa

23-24th August, Johannesburg, South Africa

10th Annual ARDD

28th August - 1st September, Copenhagen, Denmark

BSRA Annual Scientific Meeting

6–8th September, University of Westminster, UK

The Groningen-Jena Aging Meeting "G-JAM" 2023 

28-30th September, European Research Institute for the Biology of Ageing (ERIBA) in Groningen, the Netherlands

Tweet of the Month

By Matt Fuchs - an excerpt from a twitter thread on the article mentioned above “The Longevity Skeptic”:

Messiness is Good. You want to find and follow scientists who’ve published research over the years that does *not* tell a clean story. “Our goal is to disprove our models,” @mkaeberlein said. Their findings and views should zig and zag as their careers – and science – progress

Follow scientists who write and talk publicly about new evidence that’s convinced them to reevaluate their own positions. Who embrace the inherent messiness of science – that’s the hallmark of an honest researcher

Podcasts and Videos

Pathways to Impact

A series of 12 virtual panels with longevity leaders

Coming on June 21st: Oprah and Dr. Peter Attia Get Real About Living Better for Longer

The Art of Aging: A Tail of Canines, Rapamycin, and Longevity with Dr. Matt Kaeberlein

The Sheekey Science Show: Is aging adaptive?

Interview with Prof. Andrea Maier

Andrea Maier, a renowned professor of gerontology, serves as the Co-Director of the Centre for Healthy Longevity at the National University of Singapore. With over 350 published articles, her groundbreaking research in ageing and age-related diseases is globally recognized, influencing health policy discussions including at the WHO.

What inspired you to enter longevity research?

It was a long, long time ago when I first observed that people age differently. This observation was especially apparent in some older women who exuded an undeniable power and vitality. This led me to question, how does this happen?

At the time, I was already engaged in research within the field of pulmonology, focusing on diseases like cytomegalovirus and other viruses. However, my observations compelled me to switch my focus. First, I transitioned into geriatrics, but I was always drawn towards research into longevity.

I find it truly astonishing how some individuals possess such vitality, even at an advanced age. Admittedly, I was also drawn to this field because it was not overly crowded. For instance, many researchers are interested in diabetes, making it a highly competitive field. Aging and longevity research, on the other hand, is a bit different. I would argue that this is still one of the least explored fields, especially when you consider it through the lens of a physician.

How has the field changed since you started?

In my view, the field hasn't changed at all in terms of the key players. That's something we might need to reflect on. However, the field itself is undeniably evolving. There's been a shift from purely academic pursuits to a greater involvement of startups. Venture capitalists are now engaging in our field and there's also a different level of government inclusion.

In the past, societ