The VitaDAO Blog

NUS Medicine’s Healthy Longevity Webinar Series

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A great list of Aging Podcasts

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Scientists Debate How to Live Longer & Longevity Drugs | 55 - Charles Brenner

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Dr. Peter Attia: Supplements for Longevity & Their Efficacy

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Interview with Claude 3 Opus

Whilst all of the humans were either at ARDD or on holiday, we took the opportunity to interview Claude 3 Opus, to ask its thoughts on longevity research.

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Why do you think humans are inspired to research aging?

I believe humans are inspired to research aging primarily due to the universal desire to live longer, healthier lives. Aging is associated with physical decline, disease, and mortality, which most humans naturally wish to avoid or delay. There is also an innate human curiosity to understand the biological mechanisms underlying the aging process.

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How has the longevity field changed in the last 3 decades?

Over the last 3 decades, the longevity field has seen significant advancements in our understanding of the biological processes that drive aging. This includes the discovery of longevity-associated genes and pathways, development of interventions that extend lifespan in animal models, and a shift towards treating aging as a modifiable risk factor for age-related diseases. Technological progress in areas like genomics, biomarkers, and AI have also accelerated longevity research.

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What do you think have been the biggest/important discoveries in the field?

Some of the biggest discoveries in longevity research include the identification of genes and pathways that regulate lifespan, such as sirtuins, mTOR, and insulin/IGF-1 signaling. Another major milestone was the finding that calorie restriction and certain drugs like rapamycin and metformin can extend lifespan and healthspan in various animal models. The development of 'epigenetic clocks' to measure biological age has also been an important advance.

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

My advice to longevity researchers would be to embrace multidisciplinary collaboration, as the complexity of aging requires integrating insights from various fields. Prioritize translating promising findings from animal studies into humans, with a focus on interventions that compress morbidity and extend healthspan, not just lifespan. Engage proactively with policymakers, funding bodies, and the public to build support for aging research.

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

I believe longevity research should place more emphasis on studying aging in diverse human populations, as most findings to date come from animal models or specific cohorts. Developing multi-modal interventions that target several hallmarks of aging in parallel is another area that requires greater attention, along with understanding the role of the microbiome in aging processes.

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Is aging a disease?

Whether aging is a disease is a complex question that sparks debate. Some argue that aging is a natural, inevitable process distinct from disease, while others contend that aging is the primary risk factor for chronic diseases and should itself be classified as a disease to spur medical innovation. My view is that aging is a malleable process that can be therapeutically targeted to prevent age-related diseases, regardless of the semantic debate around defining it as a disease per se.

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How would you solve aging?

Solving aging will likely require a combination of approaches that address the multiple, interconnected mechanisms of the aging process. This could involve selectively eliminating senescent cells, rejuvenating stem cell populations, repairing accumulated molecular damage, epigenetic reprogramming to a more youthful state, and gene therapies targeting longevity pathways. A systems-level understanding of how these mechanisms interact will be crucial.

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Do you think solving aging would facilitate humankind's efforts to colonise the galaxy?

Yes, I believe that solving aging and enabling radical life extension would be a game-changer for humankind's efforts to explore and colonize the galaxy. The immense distances and timescales involved in interstellar travel pose daunting challenges for human lifespans as they exist now. If we could maintain youthful health and cognition for centuries or even millennia, it would open up the possibility for humans to personally undertake long-duration spaceflights and oversee the development of permanent settlements on other worlds. Essentially, solving aging could be an important factor in transforming humanity into a true spacefaring civilization.

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How can AI significantly influence and advance the field of aging biology?

AI has immense potential to advance aging biology research by enabling the analysis of vast datasets, such as genomic, proteomic, and multi-omics data, to uncover patterns and mechanisms underlying the aging process. AI can also accelerate the discovery of novel targets for longevity interventions, predict the outcomes of drug combinations and dosing schedules, and help develop personalized longevity plans based on an individual's genetic and physiological profile. As biological data continues to accumulate, AI will become an indispensable tool for deriving actionable insights and guiding the next generation of longevity therapies.

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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?

To achieve dramatic extensions of human lifespan by decades or centuries, we will need to think beyond the current paradigm of modest, incremental gains from drugs and lifestyle interventions. This may require harnessing radical advances in technologies like CRISPR gene editing to rewrite the human genome for extreme longevity, or leveraging breakthroughs in regenerative medicine to continuously repair and rejuvenate tissues and organs.

Nanomedicine could allow us to deploy fleets of microscopic robots to scour the body for molecular damage and fix it at the cellular level. Ultimately, if we can decode the information content of the human brain and upload it to a more durable substrate, we may be able to achieve a form of digital immortality. These are all highly speculative scenarios that face immense technical and ethical hurdles. But if we are to make transformative leaps in human lifespan, we must be willing to contemplate and rigorously investigate such seemingly science-fictional possibilities.

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!

Introduction

Welcome back Vitalians, it’s been an eventful month in longevity and DeSci.

Please join us in congratulating the TransFidelity team for passing the VitaDAO token holder vote. This proposal will allocate $50,000 to TransFidelity, a project focused on preventing neurodegenerative diseases by improving the accuracy of protein synthesis, thereby reducing the formation of harmful protein aggregates.

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VitaDAO-backed Oisín Biotechnologies raises $15M Series A led by AbbVie Ventures. Oisín Bio aims to advance genetic medicines for age-related conditions, focusing on muscle-building to combat frailty.

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We are also excited to share that the BIO Genesis event is underway. BIO creates a permanent, global pool of capital and talent, aiming to revolutionise biomedical science and creating a permissionless layer to back scientific projects with decentralized funding, liquidity & incentives.

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This month also brings the sad news that renowned Professor Leonard Hayflick, a legend in the aging field, has passed away. We’d like to dedicate this issue to honor the extraordinary life of Professor Hayflick, a visionary whose relentless pursuit of knowledge redefined our understanding of life itself. Hayflick was not just a scientist; he was a pioneer who dared to challenge the status quo, forever altering the landscape of biology and medicine.

For over half a century, there was a scientific dogma 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. The cessation of cell division is now known as cellular senescence, and the study of this phenomenon has blossomed into a scientific field in its own right. With several papers showing genetic or pharmacological removal of senescent cells can increase lifespan in mice, there is now a huge academic and pharmaceutical effort to further understand and target this process in an attempt to improve human healthspan and lifespan.

In addition to discovering cellular senescence, Prof. Hayflick developed the WI-38 cell line which became a cornerstone of modern vaccines, safeguarding the health of billions worldwide—a testament to his enduring legacy. Furthermore, he also developed the first inverted microscope for use in cell culture research, the design of which is still used today in modern microscopes.

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But Leonard Hayflick’s journey was not without its trials. He faced controversies and opposition, yet he stood firm, driven by a belief that science must serve humanity, no matter the personal cost. His courage in the face of adversity and his unwavering dedication to truth inspired generations of scientists to question, explore, and innovate. Leonard Hayflick’s life was a beacon of inspiration, reminding us all that true progress is born from curiosity, courage, and a deep commitment to making the world a better place. As we commemorate his life, we celebrate not only his remarkable achievements but the spirit of perseverance and passion that defined his work. His legacy will continue to inspire and guide us, a shining light in the ever-evolving quest for knowledge.

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At the end of this newsletter you’ll find some thoughts and quotes from him as well as a few words from his esteemed colleagues and students.

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Longevity Literature Hot Picks

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Preprint Corner in collaboration with

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

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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!

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A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

Inhibition of the insulin/IGF/mTORC1/Ras network, particularly through drugs like trametinib and rapamycin, can extend lifespan and improve health in mice, with combined treatment showing greater benefits than either drug alone. This suggests that repurposing these drugs for geroprotection in humans may have significant translational potential.

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The Emergent Aging Model: Aging as an Emergent Property of Biological Systems

The Emergent Aging Model (EAM) suggests that aging is an emergent property of complex biological systems, such as gene networks, where aging arises at the system level even if individual components do not age. EAM explains aging as an increase in mortality rate over time and aligns with observed stochastic influences on aging, providing a framework consistent with models like the Gompertz model and applicable to various biological species.

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Published Research Papers

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Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

This study has received a huge amount of press attention and discussion from the scientific community. The research demonstrates that IL-11, a pro-inflammatory cytokine, negatively impacts age-related diseases and lifespan by regulating the ERK–AMPK–mTORC1 axis as mice age. Deletion or inhibition of IL-11 significantly extends lifespan and improves health in aged mice, suggesting that anti-IL-11 therapy, currently under trial for fibrotic lung disease, could potentially mitigate aging-related pathologies in humans.

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An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging

The study reveals that CD38, an NAD+-dependent enzyme, facilitates hematopoietic stem cell (HSC) proliferation in young mice by promoting mitochondrial Ca2+ influx and metabolism, but its aberrant upregulation in aged mice leads to HSC deterioration through disrupted NAD+ metabolism and impaired mitochondrial stress responses. Pharmacological inactivation of CD38 mitigates these aging effects, underscoring an NAD+ metabolic checkpoint that balances mitochondrial activity to maintain HSC function across the lifespan.

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Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity

This study shows that overexpressing mitochondrial fission or fusion genes in C. elegans leads to increased mitochondrial fragmentation but unexpectedly extends lifespan and enhances stress resistance, despite not maintaining a youthful mitochondrial network morphology. This suggests that enhancing mitochondrial dynamics, rather than preserving their youthful structure, is key to promoting resilience and longevity.

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The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening

The study reveals a shared transcription factor binding site (TFBS) signature between aging and development, where early-life cis-regulatory elements (cCREs) lose accessibility over time, driven by a redistribution of transcription factors (TFs) towards AP-1-rich cCREs. This shift, coupled with a mild downregulation of cell identity TFs, alters gene expression, suggesting that AP-1-linked chromatin remodeling, initially promoting maturation, is later co-opted in aging to disrupt cell identity and function.

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Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant

Disrupting the mitochondrial fission gene drp-1 significantly extends the lifespan of daf-2 insulin/IGF-1 signaling mutants in C. elegans. This lifespan extension is linked to increased mitophagy, enhanced mitochondrial and peroxisomal connectivity, and improved energy production, while specific tissue knockdowns and ROS levels are not affected.

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Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study

This multicohort study found that obesity significantly increases the risk of developing diseases associated with cellular aging, such as those linked to mitochondrial dysfunction, telomere attrition, and stem cell exhaustion. Obesity-related cellular aging processes contribute substantially to increased mortality, suggesting that targeting these aging mechanisms could help mitigate the health impacts of the obesity epidemic.

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An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo

This study introduces the CellPopAge Clock, a novel epigenetic clock designed to accelerate the discovery of anti-aging compounds by accurately monitoring the aging of human primary cell populations in vitro. The clock successfully detected slowed cellular aging when cells were treated with known longevity drugs like rapamycin and trametinib.

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Blood protein assessment of leading incident diseases and mortality in the UK Biobank

This study analyzed 1,468 proteins in 47,600 UK Biobank participants, finding 3,209 associations between 963 proteins and 21 age-related diseases. The researchers developed ProteinScores that significantly improved the prediction of 10-year disease onset compared to traditional factors.

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The correlation between CpG methylation and gene expression is driven by sequence variants

Researchers identified 189,178 regions where methylation was significantly depleted, with 41% of these regions associated with cis-acting sequence variants, termed allele-specific methylation quantitative trait loci (ASM-QTLs). Further analysis using RNA sequencing showed that ASM-QTLs largely drive the correlation between gene expression and CpG methylation.

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Effects of walking on epigenetic age acceleration: a Mendelian randomization study

Higher usual walking pace is significantly associated with a deceleration in the acceleration of epigenetic aging, as measured by four classical epigenetic clocks (GrimAge, PhenoAge, Horvath, and Hannum). However, other walking behaviors, such as walking duration and frequency, did not show a significant impact on EAA.

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Published Literature Reviews, Hypothesis, Perspectives and more

Why cancer risk declines sharply in old age

Recent research suggests that the sharp decline in cancer risk after the age of 75, particularly for lung cancer, may be linked to the role of certain genes that influence how the body ages and responds to cancerous changes.

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Why do eggs in ovaries last for decades? Long-lived proteins may be key

Mammals are born with a set number of oocytes, which can remain viable for decades. Recent mouse studies suggest this longevity may be due to ovarian proteins that last nearly as long as the organism itself, potentially supporting long-term fertility.

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Microbiota-bone axis in ageing-related bone diseases

This review highlights the crucial role of gut microbiota in maintaining bone homeostasis, particularly in the context of aging. It explores how the gut microbiota influences bone metabolism through various mechanisms, including its effects on the endocrine and immune systems and the production of gut microbiota-derived metabolites.

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The complexity of coffee and its impact on metabolism

Coffee contains various bioactive compounds, including caffeine, which is metabolized into paraxanthine in the body. Paraxanthine, though not present in coffee, shares many of caffeine's effects and likely contributes significantly to coffee's impact on metabolism. While coffee consumption increases metabolic rate by 5% to 20%, individual responses vary due to factors like caffeine clearance, genetic differences, age, and body composition.

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The role of cellular senescence in ovarian aging

This review examines the link between ovarian aging and the accumulation of senescent cells, as well as the potential of senolytic drugs to extend reproductive longevity. Ovarian aging, marked by a decline in ovarian reserve, leads to reduced fertility and menopause.

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Senolytic Prodrugs: A Promising Approach to Enhancing Senescence-targeting Intervention

This review highlights the potential of senolytic prodrugs as a solution to the side effects of traditional senolytic therapies. These prodrugs, designed to selectively eliminate senescent cells by targeting the SA-β-gal biomarker, are categorized into galactose-modified senolytics and bioorthogonal activation approaches. The development of these prodrugs, including methods like PROTACs and photodynamic therapy, aims to safely translate senolytic therapies into clinical practice.

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Job Board

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David Vilchez’s lab in Cologne is recruiting a postdoc/lab manager position. The position is initially until December 2025 with the possibility to be extended until December 2032

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Postdoc position in cellular senescence and age-related pathologies in Prof. Marco Demaria’s lab.

News and Media

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BioAge Announces First Patient Dosed in the STRIDES Phase 2 Clinical Trial

Evaluating Azelaprag as a Novel Treatment for Obesity in Combination with Tirzepatide

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A Molecular Reason Why Exercise Fights Senescence

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Cells Across the Body Talk to Each Other About Aging

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‘Dream come true’: study suggests drug could extend women’s fertility by five years

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Cellular Reprogramming Improves Cognition in Aged Rats

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Vegan Diet Lowers Biological Age in a New Study

Resources

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LongevityGPT - designed to answer any aging/longevity/health/medical questions. Check out this Tweet to get more information.

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Conferences

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26-30th August, Copenhagen, Denmark

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Molecular and Cellular Aging Meeting in San Diego

4th-6th September

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La Jolla, CA. 10th-11th Sep 2024

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9th International Cell Senescence Association (ICSA) Conference

7th - 9th November, Puerto Varas, Chile

The ICSA are offering 2 Travel Fellowships for an ECR to attend the conference.

ICSA DEI Travel Fellowship Application

yICSA 1st ECR Travel Award

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The Cambridge Society of Ageing and Longevity Research term card for Michaelmas 2024 is here!

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Tweet of the Month

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A breakdown of the IL11 paper by Martin Borch Jensen

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Podcasts and Webinars

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NUS Medicine’s Healthy Longevity Webinar Series

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David Sinclair at the Aspen Institute

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David Sinclair shared some unpublished animal study results. These include:

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Reversing Alzheimer’s symptoms: Preliminary findings suggest potential for reversing symptoms in animal models.
Hearing loss: Animal studies indicate progress in reversing hearing loss.
ALS (Amyotrophic Lateral Sclerosis): There's encouraging data on alleviating ALS symptoms.
Glaucoma: Sinclair anticipates clinical trials by 2025, following positive outcomes in monkey models.
Rejuvenating skin, kidneys, and liver: Results show signs of rejuvenation in these organs.

Additionally, the FDA has approved Tet-inducible partial reprogramming gene therapies. Life Bio is nearing clinical trials, having shown promising results in monkeys, particularly in eye stroke models (NIAON) and a glaucoma model.

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What exactly is this rejuvenation paradigm called “partial reprogramming” or “epigenetic rejuvenation” that has taken the longevity field by storm

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Longevity, Environmental Pollution, and Nrf2 Activation with Dr. Dushani Palliyaguru - The VitaDAO Aging Science Podcast

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In memory of Professor Leonard Hayflick

Here is a collection of some of his most memorable quotes, reflecting his insights, wit, and wisdom throughout his remarkable career:

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“It is astonishing to realise that the human species survived hundreds of thousands of years, more than 99 percent of its time on this planet, with a life expectancy of only eighteen years.”

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"The purpose of research is to ask questions. Don’t be afraid to challenge accepted wisdom, and have the courage to defend your findings and, where necessary, to challenge accepted dogma."

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"The suggestion I made that the finite lifetime of cultured normal cells relates to aging was dismissed by many as foolish, but it’s been confirmed thousands of times since, worldwide."

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"Had I patented the cells, I might own the world's supply of WI-38, which would make me sufficiently wealthy to buy London, I think."

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"My recollection is that while the paper was in press, our electrical freezer failed, and we lost everything."

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"I put all my several hundred ampoules into a liquid nitrogen container and strapped it to the back seat of my Pontiac sedan. Two of my children sat next to it, and off we went to California."

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"The cells couldn’t be patented because in the early 1960s, the patent laws in the United States and most other countries prevented patenting of living materials. So I delivered ampoules of WI-38 worldwide freely to most virus vaccine manufacturers."

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These quotes capture the essence of Leonard Hayflick's character—his relentless curiosity, boldness in the face of opposition, and his enduring impact on the world of science.

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Outro

Introduction

Welcome back, Vitalians! This month we’re celebrating VitaDAO’s 3rd birthday! It’s been an exciting journey, and we’re thrilled to share our progress and future plans with you. In the past three years, VitaDAO has evaluated over 200 projects, funded 23, and deployed over $4.5 million USD in funding.

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In June 2023, VitaDAO launched the first intellectual property token pool, offering governance to the VitaDAO community (VITA-FAST). Building on this momentum, VitaDAO has since introduced a second intellectual property token (VITARNA), marking another significant milestone in our mission.

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As we look forward, we're more excited than ever about the future and our role in advancing the longevity field. The best is yet to come, and we can't wait to share 100 more birthdays with all of you!

As we celebrate another milestone, let's dive into the fiery debate that has our interviewees and experts in the field at odds: "Is aging a disease?" - our most hated question in the whole interview. The responses ranged from diplomatic nods to outright defiance, making this one of our most engaging topics yet. While some argue that aging is a natural process, others see it as a gateway to disease, begging the question—can we treat aging itself? Find a snapshot of where they clash and converge below as well as the answers from many aging scientists.

Longevity Literature Hot Picks

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Preprint Corner in collaboration with

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

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Neuron-type specific aging-rate reveals age decelerating interventions preventing neurodegeneration

Circadian clock disruption and lack of sleep harm cells and organs by activating the DREAM complex, which de-regulates essential cellular processes. Inhibiting DREAM restores cellular health and homeostasis despite persistent clock dysfunction, making it a potential therapeutic target for mitigating the adverse effects of circadian disruptions.

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Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner

Nicotinamide adenine dinucleotide (NAD) is crucial for various enzymatic reactions, including energy metabolism and DNA repair, and its levels can decline significantly with age. Long-term administration of the NAD+ precursor nicotinamide mononucleotide (NMN) in mice increased activity, maintained youthful gene expression, reduced frailty, improved metabolic health in males, and extended median lifespan in females by 8.5%, without increasing cancer risk, highlighting the potential of NAD+ boosters for age-related conditions and the importance of considering sex-specific effects in studies.

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Comprehensive evaluation of lifespan-extending molecules in C. elegans

The nematode C. elegans, a key model organism in aging research, is ideal for high-throughput experiments due to its short lifespan and small size, yet consensus on the most effective lifespan-extending compounds remains elusive, partly due to confounding drug-bacteria interactions. This study evaluated 16 frequently reported compounds, confirming robust lifespan extension with many and revealing some synergistic effects, while also demonstrating that several compounds extend lifespan in the fly D. melanogaster and identifying new lifespan-extending molecules in C. elegans.

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Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse

The female reproductive system ages early, causing infertility and endocrine issues, with the aging ovary developing a harmful fibro-inflammatory environment. This study found that systemic delivery of the anti-fibrotic drug Pirfenidone, but not the anti-inflammatory drug Etanercept, reduced ovarian fibrosis and improved ovarian function and gene expression in mice, suggesting that modulating the ovarian environment can extend reproductive longevity.

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Integrative epigenetics and transcriptomics identify aging genes in human blood

Recent studies have identified many genomic regions with age-related methylation changes, but their functional consequences remain unclear, while age-related gene expression changes have shown limited consistency across populations. By integrating high-resolution epigenetic and transcriptomic data, this study identified multi-omic aging genes in blood, which are enriched for adaptive immune functions, replicate robustly across diverse populations, and are strongly associated with aging outcomes, suggesting they may be targets for epigenetic editing to promote cellular rejuvenation.

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Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia

Programmed telomere shortening limits tumorigenesis by inducing replicative senescence, which is solely triggered by the ATM kinase. This study shows that ATM inhibition can delay senescence, allow normal cell divisions in some senescent cells, and that low oxygen conditions extend replicative lifespan by diminishing ATM activity, revealing how primary human cells detect shortened telomeres and the molecular mechanisms of the telomere tumor suppressor pathway.

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Circadian clock disruption engages the DREAM complex in suppressing cellular health

Circadian clock disruption and lack of sleep harm cells and organs, with mechanisms involving the DREAM complex as a key health repressor activated by clock impairment. Inhibition of DREAM restores healthy cellular homeostasis and alleviates dysfunction in clock-impaired systems, suggesting DREAM as a therapeutic target to mitigate the negative health effects of circadian disruptions.

Published Research Papers

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Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule

Previously VitaDAO-funded Korolchuk lab, have published a new study in Dev Cell, showing that age-dependent downregulation of mitophagy drives senescence and cell aging - phenotypes which can be rescued by restoring mitophagy levels.

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TERT activation targets DNA methylation and multiple aging hallmarks

Insufficient telomerase activity, due to low TERT gene transcription, leads to telomere dysfunction and aging pathologies. A TERT activator compound (TAC) has been identified that upregulates TERT via the MEK/ERK/AP-1 cascade, promoting telomere synthesis, reducing cellular senescence and inflammation, and enhancing cognitive function in aged mice without evident toxicity, highlighting TERT's crucial role in aging and potential therapeutic applications.

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Principal component-based clinical aging clocks identify signatures of healthy aging and targets for clinical intervention

Biological age clocks should predict mortality and provide insights for healthy aging. By applying principal component analysis to clinical data, we developed PCAge and LinAge clocks, identifying signatures of metabolic, cardiac, renal dysfunction, and inflammation predicting unsuccessful aging, with potential for drug intervention impacts. These clocks, including a tailored version for the CALERIE study, show that mild caloric restriction reduces biological age, highlighting the value of integrating biological markers for preventative medicine and promoting healthy aging.

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Benefits of calorie restriction in mice are mediated via energy imbalance, not absolute energy or protein intake

Caloric restriction (CR) in mice, achieved by cold-induced metabolism with matched protein intake, resulted in reduced body weight, lean and fat mass, leptin, IGF-1, and TNF-α levels, along with improved survival compared to ad libitum-fed mice. These findings suggest that the longevity benefits of CR are mediated by energy imbalance rather than low energy or protein intake alone.

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Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial

People with peripheral artery disease (PAD) experience increased oxidative stress, impaired mitochondrial activity, and poor walking performance. A 6-month randomized clinical trial showed that oral nicotinamide riboside (NR) significantly improved walking distance compared to placebo, with NR alone improving the 6-minute walk test by 31.0 meters among those adhering to the regimen, while resveratrol did not provide additional benefits.

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Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony

In aging, physiological networks decline at different rates among individuals, resulting in varied lifespans, with 70% of lifespan variance unexplained by genetics. Using Asynch-seq, a new method to study gene-expression heterogeneity, researchers created a detailed atlas of non-genetic variation in Caenorhabditis elegans, identifying the decoupling of mRNA content between germline and soma as a major source of aging variability, suggesting that targeting pleiotropic genes can reduce lifespan disparities.

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Sex-dependent regulation of vertebrate somatic growth and aging by germ cells

Germ cells influence somatic growth and aging differently in male and female Nothobranchius furzeri, a short-lived vertebrate model. Removing germ cells shortened lifespan and altered estrogen and IGF-1 signaling in females, while in males, it improved health via increased vitamin D signaling, highlighting sex-dependent pathways in regulating growth and aging.

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Single-cell mitochondrial sequencing reveals low-frequency mitochondrial mutations in naturally aging mice

Mitochondria are vital for many biological processes, but methods to study their heterogeneity at the single-cell level are limited. This study optimized the DNBelab C4 single-cell ATAC sequencing workflow for mitochondrial sequencing (C4_mtscATAC-seq), validated its effectiveness in HEK-293T cells, and applied it to mouse spleen and bone marrow tissues, revealing higher mitochondrial DNA content and fewer mutations in young tissues compared to aged tissues, with specific mtDNA variations linked to differential gene expression.

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Epigenetic predictors of species maximum life span and other life-history traits in mammals

By analyzing 15,000 samples from 348 mammalian species, researchers developed DNA methylation (DNAm) predictors for maximum life span, gestation time, and age at sexual maturity. These predictors reveal an innate longevity advantage for females in some species, remain unaffected by caloric restriction or partial reprogramming, and show that maximum life span is determined by an epigenetic signature intrinsic to each species, distinct from individual mortality risk.

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Published Literature Reviews, Hypothesis, Perspectives and more

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The human gut microbiome and aging

The human gut microbiome changes throughout life, influenced by factors such as birth method, diet, environment, geography, medication, and aging, with its composition impacting aging and age-related diseases. A diverse microbiome, particularly one producing anti-inflammatory metabolites like short-chain fatty acids, is consistently linked to healthy aging globally, suggesting universal features that could be targeted for interventions to promote health and longevity.

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Cellular senescence in normal physiology

Cellular senescence has been shown to contribute to the pathology of numerous age-related diseases, and thus there are numerous therapeutic efforts attempting to eliminate them. However, this perspective takes a deeper look at how senescence cells also perform a number of healthy physiological roles and thus emphasising our need to fully understand this phenomenon.

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SenNet recommendations for detecting senescent cells in different tissues

As mentioned above, cellular senescence is now recognized as playing both beneficial and detrimental roles in various biological processes across species. The SenNet Biomarkers Working Group offers recommendations for identifying and characterizing senescent cells in tissues, based on a comprehensive analysis of senescence markers in 14 tissues from mice and humans, aiming to support both experienced researchers and newcomers in the field.

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Therapy-induced senescence through the redox lens

Therapy-induced senescent tumor cells drive tumor recurrence and disease relapse, with reactive oxygen species (ROS) playing a crucial role in initiating and establishing this senescence. The review explores how ROS and redox dynamics influence these processes and discusses potential interventions, such as senotherapeutics, to target these pathways and reduce disease relapse.

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Regulation of cell function and identity by cellular senescence

Senescent cells, accumulating during aging and various contexts like embryonic development and cancer, play key roles in pathophysiological functions beyond just loss of proliferation. The discovery of the senescence-associated secretory phenotype (SASP) revealed that senescent cells also promote gain-of-function effects, influencing cell identity and impacting pathophysiology either beneficially or deleteriously.

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Gene regulatory networks in disease and ageing

Precise gene expression control is crucial for cellular homeostasis and function, with its decline contributing to age-related physiological changes and diseases. Gene regulatory networks, representing molecular interactions governing gene expression, have been inferred with high precision thanks to advances in experimental and computational technologies, aiding our understanding of cellular aging and disease mechanisms.

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Neuronal senescence may drive brain aging

Senescence was traditionally thought to be a phenotype affecting proliferating cells, however numerous studies have now shown that post-mitotic cells can also undergo senescence. This perspective examines the role of senescent neuronal cells and their impact on neurological aging.

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

Psychological factors are crucial predictors of healthspan and longevity but are often overlooked in aging research. Psychogenic Aging, a new branch of biogerontology, aims to integrate these psychological influences into geroscience, advocating for their inclusion in the Hallmarks of Aging framework to enhance understanding and development of anti-aging therapies.

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Job Board

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Did you know Retro Bio offers an accelerated PhD program?

They are also looking for a Facility Manager.

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Some Hevolution funding opportunities

Hevolution Foundation Postdoctoral Training in Geroscience Program (HF-PTG)
Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research
2024 Hevolution Foundation Saudi Arabia Postdoctoral Fellowship for Aging Biology & Geroscience (HF-SAP)

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The AbuGoot lab is hiring for a number of grad, postdoc and scientist positions for exciting new projects in the aging/AI spaces. We leverage high-throughput screening tools to understand aging and AI to interpret the results, and then build new rejuvenative therapies.

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Announcing COHORT 5 of the Longevity Biotech Fellowship! Join +600 hardcore engineers, scientists, entrepreneurs, investors, and operators working to solve aging.

Apply now!

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David Vilchez is looking for a motivated postdoc to study the links between aging and amyotrophic lateral sclerosis. The project combines disease modeling using patient-derived iPSCs and C. elegans models. Apply here or contact David Vilchez directly.

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News and Media

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Repair Bio is harnessing gene therapy’s potential to clear excess cholesterol with a platform that could reshape cardiovascular treatment

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New Drug Restores Telomerase, Improves Cognition in Mice

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New Study Reveals Way to 'Significantly Reduce' Biological Age

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Insilico Medicine completes patient enrollment in its Phase IIa Study in China investigating INS018_055 for Idiopathic Pulmonary Fibrosis (IPF)

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Reviewing What is Known of the Aging of the Gut Microbiome

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Daily multivitamins do not help people live longer, major study finds

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Hevolution Foundation: Transforming Healthspan Science with Unprecedented $400M Funding Surge

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Resources

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People in Aging (agingbiotech.info)

Check out the who’s who of longevity research!

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Available Therapeutics

A comprehensive list of interventions that are being explored to help healthy aging.

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Machine learning-aided generative molecular design

Review of generative AI in small molecule chemistry

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Conferences

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26-30th August, Copenhagen, Denmark

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9th International Cell Senescence Association (ICSA) Conference

4th-6th September

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La Jolla, CA. 10th-11th Sep 2024. Molecular and Cellular Aging. Registration link coming soon.

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7th - 9th November, Puerto Varas, Chile

The ICSA are offering 2 Travel Fellowships for an ECR to attend the conference.

ICSA DEI Travel Fellowship Application

yICSA 1st ECR Travel Award

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Tweet of the Month

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Could Blue Zones be a hoax?

https://x.com/DoctorTro/status/1813181976414704125

@DoctorTro

How statisticians and researchers arrived at the conclusion that the BlueZones are a FRAUD. 🤔

🔑 Thread with key excerpts

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Podcasts and Webinars

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NUS Medicine’s Healthy Longevity Webinar Series

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

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Longevity Acceleration Podcast Episode 003 with Professor Jean Hebert of the Einstein School of Medicine

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New organ system clock developed with Yale (TruDiagnostic) SymphonyAge webinar

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AI For Longevity Drug Discovery: Breakthrough and Challenges Webinar

The Optispan Podcast with Matt Kaeberlein:

Anti Aging with Nutrition

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Global Enlightenment? The Wild Effects Of An Age Cure

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Interview flashbacks “Is Aging a Disease”

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Our experts agree that aging and disease are intricately linked, but the classification of aging as a disease remains contentious. Some see aging as a natural, inevitable process, while others argue it’s the ultimate risk factor for a host of diseases. The consensus? Whether we call it a disease or not, targeting the biology of aging could revolutionize how we approach health and longevity.

Andrea Maier: “Yes! Yes, it absolutely is a disease. And we all have it!

Referring to aging as a disease might be counterproductive when communicating with the general public. However, as a physician, you require a clear diagnosis and treatment plan for your patients.

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By treating the underlying mechanisms and consequences of aging, we aim to optimize the overall health and well-being of your patients. Diagnosing aging-related deterioration and assessing biological age allows you to tailor interventions and treatments accordingly. It provides a framework for addressing the physiological and pathological changes associated with aging.

In the medical field, having a clear understanding of aging and its impact on health is crucial for establishing effective practices and offering appropriate interventions to enhance patients' quality of life.”

Irina Conboy: "In my view, we notice aging specifically because tissues, organs and eventually organisms become unhealthy, e.g., it is accumulation of diseases."

David Barzilai: "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 choose to define aging, and how we choose 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."

Matt Kaeberlein: “That’s the wrong question. It just distracts from what’s important. Aging biology is modifiable, and we can treat it to prevent disease and maintain health.”

Michael Klutstein: "No. In other words - it’s not a bug, it’s a feature."

Björn Schumacher: “Ageing is a physiological process but not a disease. However, it is the cause of all chronic diseases for which age is the primary risk factor. Therefore, we need to target the ageing process itself to prevent age-related diseases. Given the demographic change this is our only option for a future with 2 billion elderly whose active participation in society to a significant degree depends on their health. It is as urgent as fighting climate change to fight the multimorbidity that is affecting a growing proportion of the population. We need to boost ageing research now!”

John Speakman: “As far as we understand it, from an evolutionary standpoint, ageing and death happen as part of an adaptive program. We stop reproducing at a certain point in our lives, and there is no evolutionary selective pressure to invest in effective somatic maintenance programs to preserve us into old age. Mutations in genes leading to improvement in those features in later life never get passed on. Without that selective pressure to evolve physiological processes that sustain our systems they slowly fall apart. Should we call that a disease? To be honest I don’t think it matters. It is something that negatively affects all of us, creates enormous personal, economic and societal costs, and therefore there will always be an impetus to try and stop it. Interestingly the first ever written document (the story of Gilgamesh) is about discovery of anti-ageing therapeutics. We have always been interested in avoiding ageing and extending lifespan. Whether we call it a disease or not won’t change that. There is an argument that if it isn’t classed as a disease then the FDA would not grant a licence for drugs that aim to retard ageing in general, rather than specific components of it. Calling it a disease then is just a pragmatic solution to a practical hurdle. It’s not something that I think scientists should spend their time agonising over. If (when?) an effective anti-aging drug appears that needs approval, a billionaire will pay a very well paid lawyer to argue the case that ageing is a disease, and then the path will be open for FDA approval.”

Tom Kirkwood: “For me, ageing isn’t a disease in the sense I would usually apply to this term. It’s a normal process. But by its very nature it involves the generation of molecular and cellular abnormality. This feeds into multiple kinds of dysfunction. When a particular kind of dysfunction – which may have causes additional to ageing – passes a threshold recognised by clinicians, it gets a diagnosis of disease.”

Alex Cagan: “Aging certainly raises the risk for a number of diseases. Whether or not we define aging itself as a disease I would consider largely a semantics issue, though with implications for how we think about our lives and how we fund aging research. I enjoy considering different perspectives on aging, whether it is something we should ‘accept’ or ‘conquer’ or ‘cure’. Such conversations remind me of Sophocles’ lines about humanity from Antigone ‘Numberless are the world’s wonders, but none more wonderful than man; …from every wind he has made himself secure — from all but one: In the late wind of death he cannot stand.” It is awe inspiring and humbling to think that there is a realistic prospect that aging itself could be overcome through human ingenuity. Though we are currently far from reaching this point I think it’s important that as a society we begin to have conversations about what the implications of this would mean.”

Barry Bentley: "There is little agreement amongst gerontologists on how to classify aging, mainly because aging 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 aging-related pathology."

Nicole Ehrhart: "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 occurring 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."

David Vilchez: "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."

Marco Demaria: “No, aging is a condition that increases our predisposition to develop diseases.”

Adam Freund: "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 harbor 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."

Vera Gorbunova: “From the evolutionary standpoint aging is not a disease. However, we have to approach it as a disease to develop treatments and interventions.”

Matt Yousefzadeh: "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."

Tim Peterson: “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.”

Joao Pedro de Magalhaes: "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."

ChatGPT: “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.”

Peter Fedichev: “This is a hard question that is probably more politically and emotionally charged than scientifically justified. From what we see in human and animal data, I believe aging can be slowed down and even stopped, not reversed. In this sense, this “disease” can not be fully cured but may be prevented. A huge entropic component in human aging makes aging more like a syndrome (multiple diseases leading to the same symptoms). To me, this does not matter.

I am trying to avoid this conversation since it quickly gets murky and is dangerously close to scholastics. I believe that aging must be stopped, and once this is demonstrated, the technological solution will be covered by governments and insurance regardless of whether it addresses a disease. The potential upside is huge. It is so huge that new business models will emerge if the existing payers fail to recognize the opportunity. If I am correct on this, we must forget about politics and focus on demonstrating an effective solution.”

Shahaf Peleg: “No, it’s worse. Studying aging is currently the second most unattainable and important quest of mankind (I’ve ranked space travel as first). Aging is more complicated, inevitable, and lacks any treatment in comparison. Moreover, it is the primary cause of a large number of diseases, and slowing down aging can delay many of them. Aging is a fundamental process that gradually 'kills' us.”

Viktor Korolchuk: “If we are ever able to delay or cure human ageing, it will become a disease from the past for generations to come.”

Outro

Thank you for being part of our journey. Here’s to another year of exploring the fascinating world of longevity research! 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!

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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.

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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!

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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

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Preprint Corner in collaboration with

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

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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Job Board

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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

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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.

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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.

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

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

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

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

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

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Resources

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Conferences

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

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Longevity Summit Dublin

13-16th June, Dublin, Ireland

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Aging and Rejuvenation Conference

8-10th July, Paris, France

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26-30th August, Copenhagen, Denmark

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9th International Cell Senescence Association (ICSA) Conference

4th - 6th September

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7th - 9th November, Puerto Varas, Chile

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Tweets of the Month

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

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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…

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Podcasts and Webinars

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

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NewLimit Progress Update 2024

Some exciting updates on partial reprogramming from New Limit.

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NUS Medicine’s Healthy Longevity Webinar Series

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

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

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

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

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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.

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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?

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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

See you next month!

Longevity Literature Hot Picks

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Preprint Corner in collaboration with

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

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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!

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Long-term fasting remodels gut microbial metabolism and host metabolism

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Analog epigenetic cell memory by graded DNA methylation

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

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

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Published Research Papers

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Published Literature Reviews, Hypothesis, Perspectives and more

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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.

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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.

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Job Board

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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.

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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.

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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!

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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.

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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.

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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

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

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Science is closing in on the frailties of old age

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

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

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Vitalia: Living the Longevity Dream

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

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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

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

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

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

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

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Resources

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

Conferences

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

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Gordon Research Conference (GRC)

2-7th June, Barcelona, Spain

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American Aging Association Annual Meeting (AGE)

2-5th June Madison, Wisconsin USA

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Longevity Summit Dublin

13-16th June, Dublin, Ireland

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Aging and Rejuvenation Conference

8-10th July, Paris, France

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26-30th August, Copenhagen, Denmark

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9th International Cell Senescence Association (ICSA) Conference

4th - 6th September

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7th - 9th November, Puerto Varas, Chile

Tweets of the Month

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

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

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

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And some other interesting picks of the month:

Food for thought on mitochondrial transplantation

Why Karl Pfleger is cautiously optimistic on rejuvenation progress

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

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Podcasts and Webinars

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NUS Medicine’s Healthy Longevity Webinar Series

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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!

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

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The Sheekey Science Show has a Theme Tune!

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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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.

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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.

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Longevity Literature Hot Picks

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Preprint Corner in collaboration with

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

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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.

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Rejuvenation of aged oocyte through exposure to young follicular microenvironment

Comparative analysis of mouse strains for in vivo reprogramming

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

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cGAS-STING is responsible for aging of telomerase deficient zebrafish

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

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

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

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

Published Research Papers

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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!

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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”.

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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.

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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

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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

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

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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.

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

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News and Media

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

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Using Ultrasound to Assist Gene Therapy

This approach opens up heart muscle cells for potential therapies.

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

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

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

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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.”

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

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A call to arms to save the genome

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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

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Resources

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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!

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New Aging Books!

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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.

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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.

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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

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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.

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Conferences

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Aging & Gerontology

8-9th April, Valencia, Spain

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Midwest Aging Consortium Aging Research Symposium

28-30th April, Columbus, OH

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Longevity Med Summit

8-9th May, Lisbon, Portugal

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Rejuvenation Startup Summit

10-11th May, Berlin, Germany

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4th - 6th September

Tweet of the Month

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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

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NUS Medicine’s Healthy Longevity Webinar Series

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

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STARTALK: Is Aging a Disease? Epigenetics with David Sinclair

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Outro

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Longevity Literature Hot Picks

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Preprint Corner in collaboration with

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

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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.

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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.

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

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

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Published Research Papers

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Published Literature Reviews, Hypothesis, Perspectives and more

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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.

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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.

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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.

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Missing centenarians are an international concern

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Job Board

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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.

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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.

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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

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Assistant or Associate Full Professor of Geroscience positions at UCSD:

Assistant Professor - (Tenure-track): Apply

Associate or Full Professor - (Tenured): Apply

News and Media

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

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

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Caloric Restriction Extends Reproductive Lifespan in Hens

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

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

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Why age matters when it comes to cancer

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

Resources

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Reproductive aging resources - compiled by Carol Magalhaes.

Prizes

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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.

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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.

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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

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Aging and Gerontology

April 08-09, 2024

Valencia, Spain

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5th Annual MAC Aging Research Symposium

April 28 – 30, 2024

Columbus, OH, USA

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The Longevity Med Summit

May 8 - 9, 2024

Lisbon, Portugal

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The Rejuvenation Startup Summit 2024

May 10-11, 2024

Berlin, Germany

Tweet of the Month

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Carol Magalhaes:

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

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

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

Podcasts and Webinars

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NUS Medicine’s Healthy Longevity Webinar Series

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A great list of Aging Podcasts

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

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

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How this tiny mutant mouse lives so, so long

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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

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!

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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.

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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.

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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.

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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.

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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.

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

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“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.”

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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

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Preprint Corner in collaboration with

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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.

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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!

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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

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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.

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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.

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A universal molecular mechanism driving aging

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

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

Published Research Papers

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Published Literature Reviews, Hypothesis, Perspectives and more

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Job Board

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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.

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

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

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LongeVC is looking for a senior associate.

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

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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.

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

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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.

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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.

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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.

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News and Media

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

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What is behind ageing’s causal wheel?

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Cells Across the Body Talk to Each Other About Aging

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

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

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

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Life span increases in mice when specific brain cells are activated

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

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

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

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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.

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Obesity drugs have another superpower: taming inflammation

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CAR T Therapy Lowers Senescence, Improves Health in Mice

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

Resources

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

Join Biolearn Discord.

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

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

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

Prizes

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Longevity Prize Million Molecule challenge with Ora Biomedical

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Conferences

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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

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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

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Tweets of the Month

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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………

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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.

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Podcasts and Webinars

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A great list of Aging Podcasts

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NUS Medicine’s Healthy Longevity Webinar Series

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

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Unlocking the Secrets of Lifespan Extension With Karl Pfleger

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

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

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

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Outro

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

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

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

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Preprint Corner in collaboration with

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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!

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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.

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

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

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Epigenetic Clocks and Programmatic Aging

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

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Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects

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

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

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

Published Research Papers

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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.

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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.

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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.

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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.

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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.

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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.

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Published Literature Reviews, Hypothesis, Perspectives and more

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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.

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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.

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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.

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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.

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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.

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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

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PhD Studentship: Blood-based Biomarkers of Frailty and Ageing

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

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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

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

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

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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

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

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Hevolution Foundation Grant Expands New Investigator Awards in Geroscience

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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.

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Bridging Generations: Our Ageless Future

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Longevity 2023: From A to…

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Aging research comes of age

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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

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

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

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Death Becomes Her, or Why Aging is an Epigenetic Program

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Insilico Medicine announces AI drug discovery milestone achievement in pharma collaboration

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

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

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The Biggest Breakthrough in Longevity may Start with Menopause

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

Conferences

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Cologne Aging Conference 2024

Jan 29-30, CECAD Cologne

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Young ICSA 18th & 19th March

Oriel College Oxford - Register here by 19th January

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

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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

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

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

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

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

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Tweets of the Month

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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

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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.

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Podcasts and Webinars

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