The VitaDAO Blog

December Longevity Research Newsletter

December 20, 2022
Maria Marinova & Rhys Anderson

Introduction

As the end of the year is fast approaching we wanted to look back and appreciate all the effort and hard work of the researchers in the VitaDAO community - from students, postdocs and fellows to principal investigators who have been awarded VitaDAO funding - this month, in addition to our hotpicks, we bring you a collection of 2022 papers from our Vitalians.

We are fortunate enough to work with experts from across the aging field and in this issue we are delighted to share with you an interview with VitaDAO Steward, Asst. Prof @ WashU and BIOIO founder - Tim Peterson.

Longevity Literature Hot Picks

Aging is associated with a systemic length-associated transcriptome imbalance

https://www.nature.com/articles/s43587-022-00317-6

Transcript size matters. Transcriptome analysis reveals the length of the transcripts alone can account for most age related transcriptional changes in both mice and humans. There is lower abundance of long transcripts with age and the longest transcripts enrich for longevity related genes. Importantly this abundance issue could be counteracted by interventions like rapamycin, FGF21 and others.

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice

https://www.nature.com/articles/s41467-022-34515-y

We have discovered numerous interventions which extend lifespan, but do any of these actually affect the ageing process per se, or do they affect specific pathologies? This study performs deep phenotyping on numerous putative anti-ageing interventions (PAAIs) and finds that many have no effect on the ageing phenotype.

In vivo partial reprogramming by bacteria promotes adult liver organ growth without fibrosis and tumorigenesis
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(22)00379-2

The fascinatingly odd paper about bacteria with natural partial reprogramming capability in armadillos shows in vivo de novo organogenesis. This bacterial hijacking induced reprogramming to progenitor state and drove liver growth, with preserved function, architecture and without tumorigenesis.

Association of spermidine plasma levels with brain aging in a population-based study

https://pubmed.ncbi.nlm.nih.gov/36321615/

While other studies show that spermidine supplementation might be beneficial in healthy aging, this population-based study raises some concerns. Increased levels of spermidine in plasma can potentially be an early biomarker for AD as it showed association with advanced brain aging.

Manipulation of the diet–microbiota–brain axis in Alzheimer’s disease

https://www.frontiersin.org/articles/10.3389/fnins.2022.1042865/full

More and more evidence is uncovered that microbiome is connected to everything in our body, including the brain via the gut-brain axis. It is unclear if the altered microbiota in the gut is a cause, a consequence of AD or both via feedback loops, we do see that certain probiotic treatments can prevent AD onset. 

Rapamycin improves the quality and developmental competence of in vitro matured oocytes in aged mice and humans

https://www.aging-us.com/article/204401/text

Beneficial effects of rapamycin have been described across the body, and now even down to the oocyte level. Culturing oocyte cells from mice and humans in rapamycin supplemented medium increased in vitro maturation efficiency and oocyte quality as shown by reduced ROS, chromosome aberrations and DNA damage markers (γ-H2AX).

CSF proteome profiling across the Alzheimer’s disease spectrum reflects the multifactorial nature of the disease and identifies specific biomarker panels

https://www.nature.com/articles/s43587-022-00300-1

Cerebrospinal fluid (CSF) is the liquid filling the space in and around the brain. It may be used, this study suggests, as a biomarker and diagnostic for AD. Analysing the proteins from CSF samples can not only identify disease state, but even help scientists distinguish between mild cognitive impairment with amyloid, AD dementia and non-AD dementia.

Could aging evolve as a pathogen control strategy?

https://www.sciencedirect.com/science/article/abs/pii/S0169534722001987?dgcid=author

There are numerous theories as to why organisms age, with most suggesting ageing is either evolutionary programmed or an accumulation of damage. Here the authors propose the pathogen control hypothesis suggesting that “defense against infectious diseases may provide a strong selection force for restriction of lifespan”. 

Biological Age Predictors: The Status Quo and Future Trends

https://www.mdpi.com/1422-0067/23/23/15103

To validate the efficacy of longevity interventions, it will be important to develop robust biomarkers for ageing. Here the authors provide a thorough review on currently used ageing biomarkers and what the future may hold.

A Glb1-2A-mCherry reporter monitors systemic aging and predicts lifespan in middle-aged mice

https://www.nature.com/articles/s41467-022-34801-9

A new mouse model in which beta-galactosidase is tagged with a fluorescence marker. The authors observe an increase of this reporter signal with age and is associated with cardiac hypertrophy and decreased lifespan.

A short history of saturated fat: the making and unmaking of a scientific consensus

https://journals.lww.com/co-endocrinology/Fulltext/9900/A_short_history_of_saturated_fat__the_making_and.42.aspx

A thought-provoking review arguing that the supposed link between saturated fats and heart disease was based on poor evidence, yet it became an unchallenged dogma. This resulted in policy making which, even in light of evidence to the contrary, has become difficult to alter due to bias and financial conflicts of interest.

2022 Papers from the VitaDAO Community

LipidClock: A Lipid-Based Predictor of Biological Age https://www.frontiersin.org/articles/10.3389/fragi.2022.828239/full

Max Unfried is Vita core and a key member of VitaDAO Awareness. He’s also a PhD candidate in the labs of Brian Kennedy and Morten Scheibye-Knudsen. Here is some of his work on LipidClocks, which can predict survival curves in agreement with lifespan experiments.

Beer, wine, and spirits differentially influence body composition in older white adults https://onlinelibrary.wiley.com/doi/10.1002/osp4.598

Tovah Wolf is an active contributor and also a scientist and a consultant. A UK Biobank study from her team reveals that while beer and spirits could contribute to adipogenesis, however red wine may be protective of it. White wine even predicted higher bone density. Finally some good news, but we’d be very curious to see this teased apart and what mechanisms might be at play.

New hallmarks of ageing : a 2022 Copenhagen ageing meeting summary

https://ruj.uj.edu.pl/xmlui/handle/item/303202

Tomas Schmauck-Medina and Adrian Moliere are active contributors who not only published this summary of the ARDD conference in Aging but also an article on rapamycin for VitaDAO. They are students in the lab Evandro Fang, who was one of the recipients of Vita funding. Their team has been particularly productive so here are a few more papers from the lab:

Mitophagy and neuroinflammation: a compelling interplay

https://europepmc.org/article/med/35762540

WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP

https://www.tandfonline.com/doi/full/10.1080/15548627.2022.2052461

And even a book chapter - Molecular linkages among Aβ, tau, impaired mitophagy, and mitochondrial dysfunction in Alzheimer’s disease

https://www.sciencedirect.com/science/article/pii/B9780323899062000071

Clinical Trials Targeting Aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261384/

Nuclear morphology is a deep learning biomarker of cellular senescence

https://www.nature.com/articles/s43587-022-00263-3

Two impactful papers from the lab of our first funding recipient and Vita supporter Morten Scheibye-Knudsen. 

Short senolytic or senostatic interventions rescue progression of radiation-induced frailty and premature ageing in mice

https://elifesciences.org/articles/75492

Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient-induced pluripotent stem cell-derived retinal pigment epithelium cells

https://onlinelibrary.wiley.com/doi/full/10.1002/ctm2.759

NDP52 acts as a redox sensor in PINK1/Parkin-mediated mitophagy

https://www.embopress.org/doi/full/10.15252/embj.2022111372

Another one of our grantees, Viktor Korolchuk, has published numerous papers across the hallmarks of aging with a few highlighted examples here.

Clinical Trial Updates

BioAge Announces Positive Topline Results for BGE-105 in Phase 1b Clinical Trial Evaluating Muscle Atrophy in Older Volunteers at Bed Rest

https://www.businesswire.com/news/home/20221205005201/en/BioAge-Announces-Positive-Topline-Results-for-BGE-105-in-Phase-1b-Clinical-Trial-Evaluating-Muscle-Atrophy-in-Older-Volunteers-at-Bed-Rest

BioAge is pleased to announce positive topline Phase 1b data showing that their apelin receptor agonist BGE-105 was able to attenuate muscle atrophy in healthy volunteers aged ≥65 years following 10 days of bed rest. 

Funding Opportunities

British Society for Research on Ageing

https://bsra.org.uk/funding/

1. Small Research Grant (equipment & publication costs)

2. Travel Grant (attending biology of ageing conference)

3. Summer Studentship (for undergraduates)

Scholarship for the Longevity Biotech Fellowship

https://www.longbiofellowship.org/scholarships

VitaDAO funded a $2k grant for people who can't afford, but would greatly benefit from attending https://longbiofellowship.org - its a non-profit community for people to come together to build, join, or invest in revolutionary longevity biotechnology projects.

Job board

The Kane lab at the Institute for Systems Biology is seeking a highly motivated Postdoctoral Fellow

http://isbscience.hrmdirect.com/employment/job-opening.php?req=2101816&&#job

The research project focuses on understanding, measuring and predicting heterogeneity in aging, and particularly identifying determinants and biomarkers of frailty. And apparently “postdoc salaries in Washington can't be beat!” ISB pays postdoctoral fellows on a scale based upon experience: $65,478 - $91,711 annually

Deciduous Therapeutics are looking to hire a research scientists and associates

https://www.deciduoustx.com/careers/

Deciduous Therapeutics are an early stage company working on endogenous immune activation to treat age-related diseases, via senescent cell elimination. Based in San Francisco (on site role)

News

Congratulations to Marco Demaria for being appointed Editor in Chief of npj Aging!

https://www.nature.com/npjamd/

The Longevity Biotech Fellowship

https://www.longbiofellowship.org/

The Longevity Biotech Fellowship (LBF) is a non-profit community for people to come together to build, join, or invest in revolutionary longevity biotechnology projects. LBF kicks off their first cohort in Jan 2023.

Peter Attia’s long-awaited longevity book “Outlive: The Science and Art of Longevity” will be released on 28th March 2023

https://peterattiamd.com/outlive/

Available to pre-order now wherever books are sold.

Cajal Neuroscience launches with $96M Series A, tackling Alzheimer's and Parkinson's

https://endpts.com/cajal-neuroscience-nets-96m-series-a-and-is-looking-to-go-after-neurodegeneration-targets/

Articles

Why is progress in biology so slow?

https://www.sam-rodriques.com/post/why-is-progress-in-biology-so-slow

A thought-provoking article on why Biology research is slow compared to other fields such as AI. The reasons proposed are: speed, knowledge and talent.

Funding science through blockchain technology and cryptocurrencies

https://from.ncl.ac.uk/funding-science-through-blockchain-technology-and-cryptocurrencies

A blog post from Newcastle University TTO Matt Abbott on Viktor Korolchuk’s VitaDAO-funded project

You may have heard about NAD but not really know what it is

https://post.news/article/2I5moQs7DrHbuc00sDLMQbuiTdY

A brief introduction to nicotinamide adenine dinucleotide (NAD) by Prof. Charles Brenner

Sarcopenia: What a Waste

https://neo.life/2022/12/sarcopenia-what-a-waste/

“Like memory loss, sarcopenia was traditionally seen as a normal part of aging, but is now recognized as a disease. It still lags far behind dementia in terms of research funding and everyday familiarity, partially because it’s ill-defined and poorly understood.”

Conferences and Webinars

Ageing Research at King's (ARK) Longevity Week event

https://www.kcl.ac.uk/events/longevity-week-2022-data-driven-longevity

You can see all recorded taks here:

https://www.youtube.com/@ageingresearchkings9013

Featuring our very own, newsletter co-author and research associate at King’s College London, Rhys Anderson

https://www.youtube.com/watch?v=FWC8M5lgq5c

DeSci London

15th-16th January - The Francis Crick Insitute, London, UK

https://www.desci.london/

Don't miss the 1st ever DeSci London Conference! Vitalik Buterin will be joining via Zoom to share his thoughts on DeSci.

Travel grants available: 

https://docs.google.com/forms/d/e/1FAIpQLSfDY2PJfAka82ick6NB-K3UFEyt1UrJ45naANim33U4lGDJPg/viewform

Drugs that slow ageing in mice | Prof Richard A. Miller

https://www.youtube.com/watch?v=UPqstwgr7x0

Podcasts and Videos

Evelyne Bischof: 100 Questions with Longevity Legends

https://www.youtube.com/watch?v=RjUg_VAwuZg

Infinite Monkey Cage Podcast: Can we cure ageing?

https://www.bbc.co.uk/sounds/play/p0dcn524

Peter Attia: Chris Hemsworth on Limitless, longevity, and happiness

https://peterattiamd.com/chrishemsworth/?utm_source=twitter&utm_medium=social&utm_campaign=221212-pod-chrishemsworth&utm_content=221212-pod-chrishemsworth-tw

Translating Aging: Hacking the Complex System of Aging (Peter Fedichev, GERO)

https://podcasts.apple.com/ua/podcast/hacking-the-complex-system-of-aging-peter-fedichev-gero/id1569628505?i=1000590133981

Longevity Tweet of the Month

Prof. Charles Brenner:

“animals have homeostatic functions that allow them to repair themselves

their capacity to do so declines after they reach reproductive prime

if you want to quantify aging, quantify repair capacity

if you want to test aging interventions, test maintenance of repair capacity”

https://twitter.com/CharlesMBrenner/status/1588549823183015937

Longevity Resources

Join Talent Bench - a database from the Norn Group (who brought us the Impetus Longevity Grants) to help people of all levels build out labs, companies, and careers!

https://norn.group/talent-bench

Longevity Apprenticeship Journal Club

https://docs.google.com/document/d/16edJ1vw5mfHKC2IQmcj-T73OjDLL8FK-mn7pxV375Lc/edit#

The Norn Group provides another public resource intended for people trying to learn about ageing biology. This document is the culmination of their year-long journal club from their Longevity Apprentices.

And here’s another journal club, written by Morgan Levine on Michael Rose’s early work on fecundity/longevity selection

https://www.nature.com/articles/s41576-022-00560-y

Interview with Tim Peterson

Tim Peterson has made some significant contributions to our understanding of longevity, especially in elucidating mechanisms of how the mammalian target of rapamycin (mTOR) protein functions. Tim is currently an assistant professor at Wash U, founder of BIOIO, and a VitaDAO Steward.

What inspired you to enter longevity research?

Several things. Aging encompasses most of human health, so everyone would benefit from the research. It's universal. It is a hard problem. 

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

That there are multiple causes.

How has the field changed since you started?

A move away from silver bullet thinking to a greater appreciation of how complicated biological networks are.

What mistakes do you think the longevity field has made?

Focusing on specific explanations as to why people age and get disease (Amyloid hypothesis, etc). Also I think categorising molecular biology into the hallmarks of aging has ossified our thinking.

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

Yamanaka reprogramming and CRISPR seem to be the most impactful discoveries.

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

We need more people developing therapies. There’s always more knowledge to gain, but I feel like not enough people are trying to translate the knowledge to therapies.

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

Aging is a decline in function. Most small molecules inhibit function. For these reasons I don’t think small molecules will have a significant effect on lifespan. We need combination therapies involving manipulating multiple genes, such as epigenetic reprogramming. We wrote about it recently on our VitaDAO blog post titled “Synthetic Vitality”.

Is ageing a disease?

I get that this matters to the FDA, but I’m not sure I have much to add to this debate other than people should have more rights to try new medicines.

You have made some significant contributions to our understanding of the role of the mTOR pathway in ageing. Do you think rapamycin treatment is likely to be a successful longevity intervention for humans?

Any single agent is unlikely to make a significant effect. Even rapamycin, which is a best case scenario seems to max out at ~20%. 20% is phenomenal and the world will benefit, but we can do better.

What do you think is the biggest challenge in bringing rapamycin to the clinic to treat and prevent age-related diseases?

I think it’s coming. Some rapalogs look promising!

You have developed some novel senolytic drugs – which disease indications do you intend to target first and why?

We feel our senolytics should work in ALS and we have the tools and team to test them there, but we admit ALS is a challenging indication.

Which other interventions do you think hold promise for improving human healthspan/lifespan? 

Epigenetic reprogramming. Anything that would have synergistic effects.

You and VitaDAO have recently launched a new reviewing platform – The Longevity Decentralised Review (TLDR) (https://longevity.review/). Could you explain what this platform is and why people should get involved? 

TLDR is an on-demand peer review service. We built it to help people get feedback on their work ahead of submitting to journals. We also wanted to provide an option for peer review while people are waiting at journals. We want to separate peer review from journal brand.

VitaDAO have had an impressive 2022 with over 3 million USD allocated to fund projects, along with new initiatives such TLDR, The Longevity Fellowship, and The Longevity Prize. What does 2023 have in store for VitaDAO?

Besides funding hopefully ~10 projects, we are going to be fractionalizing IP-NFTs, and are launching an on-chain overlay journal, The Longevist.

Outro

Thanks for reading and staying with us until the last issue of the year! We hope to see you again next year and as always, feel free to reach out with requests on what you’d like to see explored or featured here, even any new year resolutions for the newsletter are welcome. 

We wish you a happy holiday season and hope you enjoy a well deserved break!

Further Reading

The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis

https://link.springer.com/article/10.1007/s00125-022-05824-0

The Significance of NAD+ Biosynthesis Alterations in Acute Kidney Injury

https://pubmed.ncbi.nlm.nih.gov/36411195/

mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters

https://www.nature.com/articles/s41467-022-34890-6

https://twitter.com/marc_dema/status/1594712799124529155

Cell division drives DNA methylation loss in late-replicating domains in primary human cells

https://www.nature.com/articles/s41467-022-34268-8

Molecular mechanisms of exercise contributing to tissue regeneration

https://www.nature.com/articles/s41392-022-01233-2

Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin

https://www.nature.com/articles/s43587-022-00308-7

Interaction of aging and Immunosenescence: New therapeutic targets of aging

https://www.sciencedirect.com/science/article/pii/S1567576922008815

Consumption of coffee and tea with all-cause and cause-specific mortality: a prospective cohort study

https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-022-02636-2

High-confidence cancer patient stratification through multiomics investigation of DNA repair disorders

https://www.nature.com/articles/s41419-022-05437-w

Watch this fun video telling the story behind the paper: https://www.youtube.com/watch?v=hLXsIveTbpc

Recommended Reading