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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Aging and Rejuvenation Conference

13-16th June, Dublin, Ireland

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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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Aging and Rejuvenation Conference

13-16th June, Dublin, Ireland

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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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Cellular Senescence and Mitochondria | Prof Joao Passos

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NUS Medicine Healthy Longevity Webinar

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Gene Therapy Insights Podcast

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

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The Desci Podcast by Molecule

Keith Comito's Insights on Aging Research and Lifespan Extension

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The Sheekey Science Show

Can taurine and vitamin B12 improve your health?

Interview with Dr. Bernadette Carroll

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

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What inspired you to enter longevity research?

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

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

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

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How has the field changed since you started?

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

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What mistakes do you think the longevity field has made?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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What’s next for the Carroll lab?

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

Outro

Interview with Michael Klutstein

Michael Klutstein is an Associate Professor Epigenetics who heads The Chromatin and Aging Research Lab at the Hebrew University of Jerusalem. His lab is interested in understanding the dynamics of heterochromatin adaptation and subsequent gene expression during cellular and developmental processes and how these contribute to the process of aging in different tissues

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What inspired you to enter longevity research?

The future of mankind depends on our ability to successfully cohabitate with our eco system, to gain and make perfect use of experience and wisdom and to successfully colonize other planets. All these goals require that we live longer than we do today. For the future of mankind- longevity research is essential.

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

I do not currently prefer one theory as they all grasp some real aspects of aging, but in my opinion fail to grasp the picture in its entirety. I think aging is so pleotropic that more extensive theories are needed to understand it. Recently, a theory of elevated stochasticity as an origin for aging is starting to emerge. In my opinion- this is the closest thing to an comprehensive theory for aging we have today.

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How has the field changed since you started?

From a couple of genes involved in aging we have dozens now. From a handful of mechanisms involved we have many. From no treatments to delay aging we have now several strong candidates.

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What mistakes do you think the longevity field has made?

Too much emphasis was given to interventions instead of deep biological understanding. This is true for many other scientific fields, but I think in this case- we would benefit much more from understanding the basic Biology.

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

I will focus on the field of reproductive aging, as this is my main focus. I would like to highlight the excellent work of Bjorn Schumacher who is developing the theory of elevated stochasticity in aging, and who has shown several key points in reproductive aging in nematodes. Also, the work of Francesca Duncan, to show how ovaries change with age have been a key to gain insight into how reproductive aging occurs.

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

Open your eyes, ears and minds, cause this field is going to explode…

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

The answer to this one is obvious as it is close to my heart- I think the field of reproductive aging is key to understanding aging in general and deserves much more attention and resources.

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Is ageing a disease?

No. In other words - it’s not a bug, it’s a feature.

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In your recent work, you describe how germ cells also age, similar to other cells in the body. Are there specific types of damage or aging processes that are more prevalent in gametes compared to adult somatic cells?

Yes, definitely. Germ cells seem to be much more sensitive to epigenetic changes than somatic cell types. The reasons for that are unclear, but a few possibilities are the fact that gametes are arrested in the cell cycle for long periods, and the fact that they are arrested at an unusual point in the cell cycle- after DNA replication. Another important point is regulatory chromatin processes that operate in gametes to activate parts of the genome that are germline specific- and which we do not know enough about.

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It's understood that while gametes age, the creation of a new organism effectively resets or wipes out this damage, leading to a 'fresh start' for the offspring. In the context of your focus on epigenetics, would you say epigenetic factors are the primary drivers of this full rejuvenation, or are there multiple processes involved? Do you plan to explore these additional processes?

Epigenetic processes are thought to be the main driver of this “reset”, since the genetic information is kept intact, and only the epigenetic information is changed in this process. An important and unknown link between the genetic and epigenetic information are mobile elements such as retrotransposons. These are activated because of epigenetic changes, and then move to other parts of the genome, changing the genetic material itself. Their propagation could be a key factor in understanding the interactions between the genetic material, epigenetics and transgenerational reset of information.

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What can we learn from germline rejuvenation that could potentially be translated to human aging?

We can learn a great deal. We can learn that aging can be cancelled but relatively simple interventions. We can learn that the aging process may differ from system to system and between cell types. Still, germline rejuvenation brings up a lot of unsolved issues, both scientific and ethical that need to be addressed.

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Outro

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Introduction

Welcome back Vitalians and please join us in congratulating the Oisín Biotechnologies team for passing the VitaDAO token holder vote with 86.47% voting in favour! This proposal was an assessment of a multi-asset longevity biotech company pioneering genetic medicines to combat sarcopenia and other age-related diseases to promote healthier, longer lives.

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VitaDAO's Members Portal is LIVE! We want to give tokenholders the opportunity to access health products and services at a discounted price. Currently we have offers with Glycanage and Bon Charge with many more to come.

Stop the press! AgingDoc is AgingDoxxed! After years of speculation as to who was behind this Twitter account:

David Barzilai MD PhD, MS, MBA, DipABLM has revealed his identity!!!! Read here to find out why he made this decision.

We are also excited to announce that we interviewed David this month, who shared his thoughts on the longevity field with us - check it out at the end of this newsletter! Enjoy!

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Longevity Literature Hot Picks

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Preprint Corner

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The Longevist editors have whittled down a longlist of over 60 longevity preprints from Q3 down to 10 amazing contenders! The Snapshot vote will begin soon to determine which ones our curators think will have the biggest impact in the longevity field.

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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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Spatially and Functionally Distinct mTORC1 Entities Orchestrate the Cellular Response to Amino Acid Availability

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The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

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Dietary restriction extends lifespan across different temperatures in the fly

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Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer

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Elevated epigenetic age in wild compared to lab-raised house mice

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The circulating proteome and brain health: Mendelian randomisation and cross-sectional analyses

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Published Research Papers

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Apoptotic stress causes mtDNA release during senescence and drives the SASP

The Passos lab have previously published research showing that mitochondria are essential for the pro-ageing features of the senescent phenotype. Now they have followed this up with a Nature paper showing that mitochondria in senescent cells develop macropores which allow mitochondrial DNA to leak out into the cytosol and activate the cGAS-STING pathway, which is a major regulator of the senescence-associated secretory phenotype (SASP).

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Biomarkers of cellular senescence and risk of death in humans

This study analysed the levels of 28 SASP proteins in the patients’ blood and discovered that high levels of GDF15, RAGE, VEGFA, PARC, and MMP2 were particularly predictive of mortality.

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Effects of iron homeostasis on epigenetic age acceleration: a two-sample Mendelian randomization study

In this paper, the authors showed that higher levels of serum iron were linked to an acceleration of various epigenetic clocks associated with aging, including GrimAge, HannumAge, and Intrinsic epigenetic age

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Multi-species atlas resolves an axolotl limb development and regeneration paradox

Using a multi-species transcriptomics approach, this study confirmed the presence of apical-ectodermal-ridge (AER)-like cells in axolotls, a key model organism for regeneration, while noting that complete reformation of AER cells during limb regeneration was not observed. Additionally, the research identified elements of the AER machinery within the axolotl mesoderm, offering insights into the mechanisms of limb (re)growth and resolving the debate surrounding the role of AER in axolotl limb regeneration.

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Repurposing Metformin for periodontal disease management as a form of oral-systemic preventive medicine

This study addressed the global prevalence of periodontal disease (PD) and its association with diabetes, emphasizing the role of glucose metabolism modulation as a significant factor in non-communicable disease development. By repurposing Metformin, the research demonstrated that pharmaceutically controlling glucose metabolism led to the prevention of bone loss associated with induced periodontal disease and aging.

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Loss of Grem1-lineage chondrogenic progenitor cells causes osteoarthritis

The research identifies Gremlin 1 (Grem1) as a marker for progenitor cells in cartilage that can become bone or cartilage cells. These cells decrease with age and injury, contributing to osteoarthritis (OA). Loss of Foxo1 function in these cells leads to OA. Treatment with FGF18 promotes these progenitor cells' growth, improving cartilage and decreasing OA, pointing to potential OA treatments.

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Transcriptomic analysis reveals a tissue-specific loss of identity during ageing and cancer

This study found aging results in the downregulation of tissue-specific genes in 40% of tissues. In cancer, a similar loss of identity occurs with tumors expressing genes from different tissues, influencing patient survival independently of their age.

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A genetically encoded tool to increase cellular NADH/NAD+ ratio in living cells

This research presents a new tool, a soluble transhydrogenase from E. coli, to study reductive stress by increasing NADH/NAD+ ratios in cells. It offers a fresh approach to investigate redox imbalances in diseases.

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The total mass, number, and distribution of immune cells in the human body

Whilst not a longevity paper per se, it begs the question: how do these stats change with age?

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The association of leukocyte telomere length with exceptional longevity among older women

This study investigates the correlation between leukocyte telomere length (LTL) and the likelihood of living to age 90 with good mobility among postmenopausal women. Findings suggest women with longer LTLs had higher chances of reaching age 90, with or without mobility issues.

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Platelets rejuvenate the aging brain

The studies investigate different aspects of brain function and aging but converge on the finding that platelet factor 4 (PF4) can rejuvenate cognitive abilities in older mice. This marks the first evidence of platelets and PF4 as regulators of brain cognition.

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Decoding aging-dependent regenerative decline across tissues at single-cell resolution

The study analyzes how aging affects tissue regeneration, revealing that aged tissues have reduced stem cell movement and blood vessel formation, and a distinct type of macrophage active in young but not old tissues, pinpointing targets for improving regeneration in the elderly.

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A fluorophore-conjugated reagent enabling rapid detection, isolation and live tracking of senescent cells

The article presents a new tool, GLF16, for identifying senescent cells using fluorescence techniques. With a novel delivery method using micelles, this approach allows for easier, more precise isolation and analysis of live senescent cells, both in vivo and in vitro.

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Published Literature Reviews, Hypotheses, Perspectives and more

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Combinatorial interventions in aging

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Biomarkers of aging remain elusive as researchers try to slow the biological clock

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Device-measured physical activity, sedentary time, and risk of all-cause mortality: an individual participant data analysis of four prospective cohort studies

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The ticking of aging clocks

Insulin and aging – a disappointing relationship

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Job board

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Dr Bernadette Carroll is looking to recruit a research associate to work on various aspects of membrane dynamics and cell signalling at University of Bristol. The aim is to investigate the role of non-canonical mTORC1 activity at focal adhesions.

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The Webb Lab at The Buck Institute is recruiting 1-2 postdocs to work on mechanisms of brain aging and neurodegeneration!

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Kapahi Laboratory at The Buck Institute are looking to recruit 2 Postdocs to work on applying bioinformatic approaches to study eye aging and neurodegeneration using flies and mammals. The lab values include curiosity driven science, team spirit and mentorship.

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The Kane lab at the Institute for Systems Biology is seeking a highly motivated Postdoctoral Fellow interested in the biology of aging to lead projects focused on understanding, measuring and predicting heterogeneity in aging, and particularly identifying epigenetic determinants and biomarkers of frailty

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The Kohler Lab have an open call for a PhD student to work on the fascinating interrelation between Proteostasis and Ageing, combining High Throughput approaches in Yeast with validation in Cell Culture.

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The Whitworth lab at the University of Cambridge are recruiting a PhD student who is interested in unravelling the ways that impinging on mitochondrial calcium can prevent neurodegeneration.

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Marta Kovatcheva launching a new lab and is looking to hire a postdoc who will use novel lineage tracing strategies to probe the contribution of partially reprogrammed cells in vivo.

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The Korolchuk Lab is offering a new PhD opportunity, working closely with Procter & Gamble to investigate mechanisms of skin ageing.

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Two PhD positions available at the Tayilor Lab on 1) the roles of a novel prion-like protein in stress resistance and aging and 2) the unfolded protein response, restoring homeostasis and a new regulator of aging.

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News and Media

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Gero raises $6 million to find root causes of aging and age-related diseases

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BioAge Labs Announces Plans for Phase 2 Trial of First-in-Class Apelin Receptor Agonist BGE-105/Azelaprag Co-Administered With Tirzepatide for Treatment of Obesity, in Collaboration With Lilly’s Chorus Organization

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BATPROTECT: Learning from Bats: New strategies to extend healthspan and improve disease resistance

ERC funding: 11,882,510€ over 72 months

You might have heard of Ora Biomedical’s ambitious endeavour to assess 1,000,000 longevity interventions in 5 years, catchily named The Million Molecule Challenge! Now you can help support his endeavour by becoming a sponsor!

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LongeVC: What longevity investors are really looking for

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Prizes

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A brand new Longevity Prize has launched and accepting application over the next couple of months. The Longevity Funding Innovation Prize initiated and funded by Marat Karpeko is going to award $20,000 USD for the most innovative and potentially impactful longevity funding strategy. The judges want to see a real action plan and tangible solution for real world impact.

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Keep in mind the key dates:

Kick-Off: 20th September 2023
Proposal Closing: 20th December 2023
Evaluation Wrap-Up: 20th February 2024
Champion Unveiled: 29th February 2024

Conferences

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Seno-Therapeutics Summit 2023

7-8 November, Buck Institute for Research on Ageing, Novato, CA, USA

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Ageing Research at King's (ARK) Longevity Week 2023 - Sustainable Longevity: Harnessing Consumer HealthTech and FinTech

17 November, King’s College London, UK

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The Longevity Forum’s - The Longevity Week

13 -17 November 2023

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17 November DeSci & Longevity Biotech 2023 — A Próspera Builders’ Summit

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Careers in Aging Day at GSA 2023

Friday, November 10, 2023 – Full-day event, Tampa Waterfront Marriott, 505 Water St, Tampa, FL, US

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NUHS Centre for Healthy Longevity - Unlock Healthy Longevity: Supplements

Scientific Conference: February 29th - March 1st, 2024. This is the first global scientific conference focused solely on the role of supplements as a geroprotective intervention.

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The Longevity Summit

4-5th December, Novato CA, Buck

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BAAM

7th December, Stanford

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Tweet of the Month

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Peter Fedichev: It may sound strange, but beyond our "longevity" bubble people often ask: what are the reasons, scientifically, culturally, etc. for the reasons why people want to stop aging? My guess is that consciousness, once emerged, faced the vastness of universe and shortness of life. Hence two dreams, of flight and immortality are universalities of human inspirations transcending all the cultural differences. And this is why, in relation to those questions, I like to tell the following story. Continue reading here...

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Podcasts and Webinars

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NUS Medicine’s Healthy Longevity Webinar Series

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Funding Opportunities

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SCPAB Transition to Independence Award supports researchers investigating the mechanisms of cognitive resilience and functional maintenance of the healthy aging brain. Experience in aging research is not required; the program welcomes applications from candidates with backgrounds in neuroscience, molecular biology, genetics, immunology, cell biology and the physical and information sciences.

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Interview with Agingdoc, or Dr David Barzilai

What inspired you to enter the longevity field?

Almost as far back as I can remember, I’ve been profoundly struck by the extent of life’s hardship and brevity. At the same time, I love the sciences including biology, and like most of us, I’ve always wanted to make my mark in world helping others. So, with that as background, and following studying biology and public health related studies in college, I determined to enter medicine, so that I could help alleviate suffering and cure when possible. This was an MD-PhD program in health services research- which taught me much about medicine, evidence-based practice, asking good questions, studying them, and appraising published work.

My keen interest in, or what some may call “obsession,” for optimizing my own health pervaded all these stages in my life, and motivated me to avidly read far wider and deeper than my medical training required. I’ve followed the geroscience literature and see the potential of insight from aging biology to address healthy longevity. These passions were the seed for my getting involved in the longevity space.

I have turned to social media as one manifestation of these interests. By collating significant publications and creating a space for people with varied perspectives to learn and discuss, I aimed to bridge the gap between scientific communities and the public. This initiative not only fosters a collective understanding but also catalyzes a multi-dimensional contribution towards advancing the field of longevity. I did so anonymously for several years, but on my 49^th birthday in August 2023 I came to the realization that I could still do so much more simply post publications. It’s time to apply my knowledge more directly. So since then, I’ve worked on what I dubbed “project 49” – starting with coaching and consulting a few clients to experience one-on-one in the longevity space – and from there branching out to more public role of geroscience advancement, advocacy, and general awareness.

Did your general medical training include anything on geroscience and what do you think should be taught in medical school?

In medical school, the focus was essentially: (a) prevent disease (b) diagnose it- which by definition is primarily after it manifests, (c) treat it- and at best cure it, and if not, at least improve symptom burden and quality of life. At first blush, it’s not a terrible way of looking at health. While it has some preventative focus, the amount of time spent in these areas in medical school paled in comparison with complex excursions into the pathophysiology of disease and vast therapeutic armamentarium that can be applied to illness after it manifests

I’ll spare a long analysis here on why, but suffice to say it did a better job of preparing future doctors for diagnoses to make later into the underlying biology than would be ideal, and treatments to give late in the game when it’s already an uphill battle making a difference.

It seems to me that we need a stronger preventative focus, and one that not only more strongly emphasizes lifestyle medicine, but also invests in the development of biomedical technologies that directly address the molecular mechanisms driving disease itself.

In other words, I’d like to see curriculum and incentives more strongly aligned towards favorable outcomes for patients, starting with prevention. I’d also like to see geroscience incorporated formally into the curriculum, because while we are still only scratching the surface, the fact (unbeknownst to me in medical school) that there is an underlying biology of aging that we can make a concerted effort to target is no less than revolutionary. We’re starting to make progress, but in medicine, awareness of the field is still minimal. That needs to change, and when society comes aboard, we can take steps together toward better targeting aging biology and with it our healthspan long before overt disease manifests, when we may be able to do much more about it.

How has the field changed since you started?

The field has changed dramatically over only a few decades. We’ve literally gone from questioning whether single genes can impact lifespan in an organism such as C elegans (which we found yes, they can), to targeting genes and gene expression to increase not only lifespan, but apparent health too.

We have powerful tools emerging across the hallmarks of aging, from epigenetic reprogramming and deployment of senolytics or senomorphics, to genetic engineering, and cell-based therapies. Our tools are not only getting more powerful (CRISPR, scRNASeq analysis, microfluidic chips, you name it), but also are getting more sophisticated at evaluating their output via computational (including machine learning) models. Progress is speeding up with high throughput research pipelines, incorporating robotics and the latest technology. Even our older models are being revisited now, but with a modern spin: In parabiosis, for example, we’re examining whether there may be potentially useful blood factors (from hormones to exosomes and small molecules) in younger organisms, or alternatively harmful ones that need to be either filtered out or diluted to achieve a more youthful phenotype.

We’re also starting to scrutinize biological age, and its rate change. Measuring and tracking biological age is of utmost importance to the future of successfully translating this work to healthy longevity in humans. This requires reliable surrogates for tracking biological aging. While not a replacement for better validated traditional functional biomarkers, progress is being made. Such development and validation would greatly accelerate progress in the deployment of trial-proven geroprotectors for healthy individuals in our lifetime.

Which of the current theories do you think are most promising?

I believe that multiple aging theories are compatible with the same biological process, and that we’re going to require computational AI tools to take their utility to be more useful developing longevity medicine therapeutics. If you are satisfied with this, skip to my next answer. If you’re interested in a deeper dive, keep reading the rest of this section below.

The expression “theory of aging” is imprecise. Sometimes this describes a process, say sources of metabolic or other damage and their sequela. Other times they focus on how these are evolutionarily permissive- mostly under the antagonistic pleiotropy rubric, including its “dysfunctional pseudoprogram” conceptual model. Yet while we can conjecture and model plausibility, we cannot observe evolution in real time, so I focus on the former meaning of “theory of aging” – the change that arises during biological aging.

Biological systems obey the laws of physics, but the complexity arising from nonlinear relationships and higher-order emergence challenges the notion of a single encompassing theory. Thus while many theories today encompass aspects of aging at an intuitive level, what will be most useful are models that can make reliable predictions that can accelerate progress towards therapies. To do so, our best chance may be utilizing computational modeling of empirically obtained data. As for today’s models, I believe the majority either (a) describe the same process through different imprecise human analogies, (b) capture different aspects of biologic aging arising spontaneously in parallel, or both. As entropy increases at the molecular, cellular and organismal level, chaos arises through loss of information, damage, and dysregulation of signaling, and other departures from biological homeostasis and integrity. Thus, while distinctions can be made in emphasis, I do not believe these are fundamentally mutually exclusive, and at their core all describe a unified process.

My primary interest is what works; ultimately the experiments will arbitrate the relative importance of different explanatory models in describing aging as a targetable process. I believe, that useful models exist and have been created, and theorizing continues to be helpful both conceptualizing the problem and theorizing solutions (for example genomic instability- fix the genome, epigenetic drift- revert to a more youthful state, molecular damage- address ECM and other units of disarray, inflammation or hyperfunction- employ nutrient sensing modulators to mitigate these, etc).

Yet I also believe that there is a natural limit to how far our conceptually satisfying yet deceptively oversimplistic models of aging will take us. Computational models employing AI are likely to be increasingly valuable helping us break down complexity, into black box predictions whose basis may elude us, yet nevertheless be leveraged to progress.

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

The largest in my mind was our finding that targeting one gene (we’ve found many since then) can have a meaningful impact on lifespan or health. Until this work, biogerontology was more devoted to describing aging than aspiring to target it directly. The second, from the Interventions Testing Program (ITP), that mammalian models can be given interventions that extend lifespan even when given at the equivalent of late middle age. And not only by one molecule, but now several. While we can’t say the impact in humans yet (particularly as we’re already more efficient at damage repair than the shorter-lived models we are studying), it remains a tantalizing prospect that in theory longevity interventions introduced in late adulthood could in principal be successful. ITP should also be recognized for drawing attention to the strong impact of gender on all of these. If we imagine an equitable healthy longevity future for all, it is vital we do the research to see what works for everyone.

What aspects of longevity research do you feel requires more attention?

The short-version is we need a broad agenda, one that incorporates both short and long-term goals, one that balances pragmatism with moonshots, as well as foundational research towards validation of biomarkers so that human longevity trials can be attainable in our lifetime. We also need to mobilize widespread political and social support for translational research pivotal to our capacity for making a real impact on patients (and healthy human lifespan).

There is more about aging we don’t know than we do at this point, and diversification of approaches is our best way forward. This means funding labs focusing on all aspects of aging biology, from genetic engineering to epigenetic reprogramming. Likewise, we should balance short-term lines of inquiry farther along the investigative, therapeutic and regulatory pipeline, along with long-term more challenging and ambitious projects. This way, we can embrace what is most likely to translate to therapy in the near term, while also sustaining investment in high-risk, high-reward longevity moonshots.

Assessing whether known mouse gerotherpeutics work in humans is important low lying fruit, and frankly something I wish we had pursued much more aggressively all along. Specifically, I am thinking of rapamycin/rapalogs, canagliflozin and 17-alpha estradiol (males), acarbose, several others from ITP including more recently astaxanthin and meclizine, and others, including supplements and nutraceuticals such as taurine, spermidine, urolithin A, fucoidan, alpha ketoglutarate, novel NAD+ boosters, and others. The high safety profile, modest cost and efficient pipelines for approval and distribution make nutraceuticals of even modest expectation excellent candidates.

So, how do we get the most bang-for-the-buck investing our resources? My first interest, and I suspect yours also, is how do we get safe and effective therapies to humans as efficiently as possible? It would be great for us to be around when the first generation of translational geroscience interventions arrive.

There are several models for investigation that may help us get there. I support TAME which may be cost prohibitive to apply to all interventions, but the hope is that it may not only narrowly evaluate metformin’s off-label geroprotecive efficacy, but may also support precedent for other gerotherapeutic trials focusing on a panel of aging-associated outcomes rather than focusing on one disease indication. Alternatively, seeking FDA-approval for non-aging indications for modalities that nevertheless work by targeting underlying aging biology is generating optimism that progress can be made without the requirement of FDA recognition of biologic aging as a drug-approval indication itself per se.

There are certain key scientific matters that if overcome would help tremendously. Human lifespan studies are fundamentally untenable, and the field direly needs validated biomarkers, so that shorter term trials can provide reliable and convincing evidence on efficacy. If we can get there, it would entail validating a panel of predictive aging biology surrogate variables such as methlation clocks, and broader -omics panels integrated with more traditional clinical markers such as tracking functional decline, (eg, walking speed, grip strength, etc) predictive of further morbidity and lifespan.

What mistakes do you think the longevity field has made?

I believe we have been slow to build collaborations between academic medical center labs and industry despite having the common aims of helping discover, validate, develop, and deliver gerotherapeutics. We have also failed to invest enough on the public and policy side on the value of geroscience from both a fundamental public good and economic investment standpoint. Our competitive spirit and fierce independence as labs and longevity biotechs are strengths that should be incentivized. We also need to build bridges, across academics, industry, and organizations, and governmental agencies. We can do this responsibly, with appropriate checks and balances around safety and efficacy, while more efficiently, and without delay.

Is aging a disease?

Is aging a disease? Innumerable arguments have been made, with publications and conference symposium panels all focused on this issue. The answer is simple: It depends on how we chose to define aging, and how we chose to define disease.

The bottom line is this: Aging biology can be argued to be the ultimate risk factor for not one, but a wide multitude of diseases. At the very least, we can observe that something in the aging process- and its molecular underpinnings- is permissive to the development of disease. Thus ultimately, if we are interested in mitigating the negative impact of disease, targeting biologic aging is a sensible approach.

Precisely because biologic aging is intertwined with not one, but a wide multitude of diseases and poor health states (including frailty and lack of resilience), targeting aging biology before it deviates from the state of youth holds the potential to reduce the overall burden of chronic disease.

What do you think are the most important endpoints, biomarkers, and measurements to be taken in human clinical trials for interventions that can impact general healthspan?

This is very much in flux, and we aren’t there yet. The emergence of epigenetic methylation clocks- in particular 2^nd and 3^rd generation- on the landscape have done much to instill optimism. I do not believe any one measure is likely to get us there. There simply is too much uncertainty including whether prediction can be disentangled from biology (ie, the theoretical possibility that an intervention reduces one measure of biologic aging readout without concurrent improvement in physiology). Thus as I described previously, we’re going to need broad panels with many biomarkers of every kind complementing traditional better validated laboratory and functional surrogates for healthspan and mortality.

Do you think standardization can be a concern in human aging studies, how hard do you find it to compare findings from studies conducted by various institutions including academic and clinical ones?

Do I think standardization can be a concern in human aging studies? Absolutely. As you hint, studies are phenomenally disparate. This can be frustrating and confusing, and complicates our efforts towards coordinating efforts and insight into what might account for different results between studies. All the more so when we either pool results for meta-analyses or attempt to mine them for deeper insight via computational large data tools including via AI. Thus I do believe in standardization, and this is arising in various forms, whether consensus conferences on protocols or collaborations such as through the NIH SenNet Consortium, or individual initiatives such as at the ITP which attempts to control experimental differences between centers.

Lack of standardization can be highlighted by the monkey caloric restriction trial, which was frustrating in that results varied between the two (though at least for lifespan, both had groups remarkable improvements in health measures), with remarkable differences in diet genetics, diet quality, diet composition, and frequency of feeding. The poor replication in CITP was another remarkable illustration of the replication crisis affecting geroscience. And as AI models rely on collating varied data sources, consistent input is increasingly necessary for accurate and insightful outputs. So, the need for standardized protocols is greater than ever.

Where do we find you?

I’m on Twitter @agingdoc1. My Twitter account has been a way to give back by sharing interesting and topical publications for critique/debate, as well as to keep health influencers and scientists “in the know,” so they can stay informed, and thus better educate their audiences (the media & general public) on the good and bad of what is out there. I also continue to be passionate about the synergy of bringing together different communities (from aging biologists to biotech, media, thought leaders, health influencers, and avid biohackers) and I plan to continue that mission, bringing timely and interesting content from across the web to my @agingdoc1 channel.

I’ve been anonymous for years on Twitter but ultimately on my 49^th birthday (I secretly called this “project 49” before the big announcement) I decided to reveal my identity. Basically I felt like I could use more of my capabilities and do more good in the world being public than private. I’ve started to do only a little coaching and consulting (this is not a medical practice so I do not diagnose, treat or prescribe but discuss collaborate with my clients generally highly invested in their health and wellbeing). But because I only have a few hours a week to the endeavor, I recognize only a few individuals can take advantage of it. Thus I continue to try to make a broader impact other ways such as by the service I mentioned, and outreach, such as possibly by podcast or here today with you today.

Because of my last name (no relation to Nir for those wondering!) and coaching related work I have a website http://barzilaiconsulting.com, but for ease I have other webpages point to it like http://agingdoc.com and http://healthspancoaching.com. In any case, thanks for inviting me, and I hope I helped a little.

VitaDAO is an amazing organization. I’m as thrilled by the advancing science as I am with the revolution going on starting with leaders like you, at the grassroots, helping transform our culture and bringing the change we would like to see in the world. This is the day for a longevity moonshot. Together, we are making it happen.

David Barzilai, MD PhD – “Agingdoc”

http://youtube.com/@agingdoc

http://agingdoc.com / http://healthspancoaching.com

https://twitter.com/agingdoc1

My letter: https://www.barzilaiconsulting.com/49 (“Project 49” 😊)

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Outro

We appreciate you sticking with our research newsletter for another month and hope you’ve found the content useful!

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This time we leave you with a fun new article on research by Dr Shahaf Peleg and Dr Andrew Wojtovi that we’ve featured in the letter before: Shining a Light on Optogenetics: An Innovative Approach to Combat Aging

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🌎VitaDAO in the Spotlight

VitaDAO's global impact has earned a mention in Nature. We are proud to be one of several decentralized autonomous organizations contributing to innovative research funding methods. The transparency of blockchain and the collaborative spirit of our community has been recognized and featured in Nature Biotech, which notes: "Decentralized autonomous organizations are growing as alternative research funding models, but are also strong scientific communities. We should get on board."

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ExcepGEN, a project backed by VitaDAO, has secured new funding! ExcepGEN has raised an additional $4M, bringing total seed funding to $14M. Their RNAx platform is revolutionizing vaccine development, aiming to "unlock nucleic acid medicines."

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Michael Baran, a partner at Pfizer Ventures, spoke at DeSci Berlin. Discussing challenges in the pharmaceutical industry, Michael emphasized the need for new sources of revenue growth. He provided insights into how pharma allocates its R&D budget, touching on the limited budget for external R&D partnerships.

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“Pharma has deep pockets... it’s true, but I think the money for early-stage R&D or external partnerships is not what you might think.”

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Vincent Weisser, a founding steward of VitaDAO, appeared on the Austin Next Podcast. In the episode “DeSci & the Future of Discovery” Vincent, Seemay Chou, and Allison Duettmann talk with host Jason Scharf about the challenges of traditional scientific models and the growing role of AI in the scientific process.

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📣Community Approved: What YOU voted for!

Thanks to the support of the VitaDAO community, three proposals successfully passed this month! These proposals include:

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VDP-120 (An assessment of Oisín Biotechnologies): Oisín Biotechnologies is a multi-asset longevity biotech company pioneering genetic medicines to combat sarcopenia and other age-related diseases. Oisín is working to deliver DNA and RNA through a Fusogenix Proteo-Lipid in (PLV) platform, to alter cell behavior. The company’s lead candidate aims to build muscle without exercise, which could be used as a therapy to strengthen older people. VITA token holders agreed with the Longevity-Dealflow WG’s and senior reviewers' assessment of this company.

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VDP-119 (Proposal to empower a member services squad): The formation of the Member Services Squad as anticipated in VDP-69 was intended to create a team to focus on the development of new offerings for VitaDAO token-holders and contributors. This proposal served to empower a Member Services Squad to roll out new services and gave the squad the authority to make necessary legal and logistical decisions to launch a “Member Services” portal.

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VDP-118 (An assessment of GERO): This proposal was an assessment of GERO, a company using AI and ML to analyze datasets to discover novel treatments for chronic age-related diseases. To accomplish their goal of doubling human health- and lifespan within the current generation, the company has trained a large generative model of human health on a large dataset of longitudinal, real-world medical histories. The model is being used to predict future health outcomes similarly to how Large Language Models (LLMs) anticipate the next word in a sentence. Unlike LLMs, GERO’s models are physics-based and interpretable, allowing exploration of the relationship between the aging process and diseases.

💪Exercise Your Right to Vote

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👋Meet Awareness Working Group Contributor: Victoria Forest

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Victoria Forest, an integral member of VitaDAO’s Awareness and SciComm Working Groups, plays a role as VitaDAO’s DeSci illustrator and Instagram manager. When not contributing to VitaDAO, Victoria enjoys working as a freelance web designer, learning about longevity, and practicing pilates. In my interview with Victoria, we dive into her journey with VitaDAO, her interest in longevity, and her role within the DAO community.

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How did you first get involved in VitaDAO?

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I found out about VitaDAO before the official launch in 2021. At that time, I wasn't yet involved in the web3 space. A few months later, I joined the community calls, became more curious about the vision, and got excited to understand how DeSci works and potentially be part of this movement. It was great to spend some time with the team at the first offsite, interview them (Meet the Vitalians YouTube list), learn about the mission, connect, and from there, choose to dedicate even more time to it.

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What is your role within VitaDAO?

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I'm a member of the Community & Awareness working group, where my responsibilities include developing media materials, creating illustrations, maintaining our social media accounts to keep our community informed, and interviewing experts in the field, among other tasks.

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What do you feel is VitaDAO’s biggest strength compared to traditional longevity biotech startups?

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VitaDAO’s primary advantage is its decentralized and community-centered approach. Unlike conventional startups, VitaDAO leverages blockchain and decentralized technologies to engage a wider group of contributors, investors, and experts globally. This approach encourages increased inclusivity, collaboration, and diversity in the quest for longevity research and biotech innovation. It also allows for a more transparent and efficient allocation of resources and decision-making, potentially accelerating progress in the field.

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What has surprised you the most about VitaDAO?

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What has impressed me the most about VitaDAO is the remarkable transparency in how the DAO operates, the openness of its team members, and the effective leverage of blockchain technology to bring tangible value to the real world.

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What advice do you have for other Web Designers who are interested in getting involved in DeSci?

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I'd say, first and foremost, be curious about the space. Take the time to learn how blockchain and decentralization can be applied to real-world problems. Once you've got a grasp of that, seek out a community whose mission resonates with you, something you genuinely care about. If you find it fulfilling and it aligns with your values, then dive in. Attend conferences, go to meetups, and start networking. You'll likely discover the perfect place where you can contribute your skills and, at the same time, feel great about what you're doing.

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Any closing thoughts for readers?

Think about the future you want, both for yourself and your loved ones. Can you picture yourself growing old and experiencing frailty and suffering? How about witnessing your parents and grandparents endure the pains of aging and age-related diseases? We need to do more than what we're currently doing. Talk to everyone you know, and share with them the possibility of having a longer healthspan and potentially a longer lifespan. Think about the abundant world we can create if we unite our efforts right now, at this critical moment. Also, consider joining us at Vitalia in Prospera, a movement dedicated to initiating a longevity network society.

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🤝Thanks for Reading!

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October 15, 2023

Podcast

Deciphering Science's Secrets: Lifespan, UPR, and Lysosomal Pathwayswith Dr. Arwen Gao on The VitaDAO Aging Science Podcast

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In today’s podcast I talked to Dr. Arwen Gao about the working conditions in science and, of course, also about her research. First, we talked about scholarships, strikes, unions and bureaucracy before moving on to our research related topics like antibiotics that extend lifespan, the unfolded protein response (UPR) and a novel lysosomal surveillance pathway called LySR that she helped to identify.

You may want to skip to the first 20 minutes if you only want to hear about the hard science rather than our discussion of working conditions and the day-to-day life of a scientist.

Short Bio – Dr. Arwen Gao

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Arwen was awarded an AMC PhD scholarship to pursue her PhD thesis, focusing on the metabolic control of aging in C. elegans, and earned her PhD degree in the fall of 2018 at the University of Amsterdam in the Netherlands. She continued her research on mitochondrial stress response and its role in metabolism and aging, under the supervision of Prof. Johan Auwerx (EPFL, Switzerland) and supported by a post-doctoral fellowship (2019 Accelerator price winner). After this postdoc, she moved back to the Netherlands, where she is currently a junior group leader at the Amsterdam UMC - Location AMC. Her research focuses on lysosomes, lipids, aging, and translational projects that can benefit patients with lysosome disorders.

A few helpful notes follow below explaining the concepts behind the topics we covered.

Worms as a model in aging research

There are many good reasons to use the worm (C. elegans) for preclinical aging research. For one, it is cheap to study and requires no ethics approval. These worms have a conveniently short lifespan of around 30 days and well understood genomes. In addition, many tools are available to manipulate their genomes including RNA-interference libraries to study the knock-down of genes in a high-throughput fashion.

There is also a surprising amount of conservation between human and worm genomes. Our genes often are very similar to worm genes suggesting that worms might be a suitable model to study some aspects of human aging. For example, FoxO signaling and the Igf-1 pathway have been first identified in worms and later confirmed to be important longevity pathways in mammals as well.

In the podcast we discussed how worm researchers also struggle with the same problems as mouse researchers. Similarly, to the situation with mice, most worm aging research is done in a single, highly lab-adapted and inbred strains. The one we often use is called N2 (first isolated in “Bristol”). We discussed the problems with inbred mice in a recent podcast with Rich Miller and in this podcast I discuss the C. elegans perspective with Arwen Gao and some solutions to this, including the generation of inbred, yet diverse, recombinant “panels”, composed of different strains with varying genetics. A simpler - somewhat less sophisticated - solution is to use at least two different strains to confirm your findings.

UPR and doxycycline - an unfolding story

Folding is the process by which linear protein chains are assembled into functioning 3D structures. Whenever something goes wrong with this folding process, this activates a so-called unfolded protein response (UPR). There are at least two distinct unfolded protein responses that occur in different cellular compartments, one in the mitochondria termed (UPRmt) and the other the canonical UPR in the endoplasmic reticulum (ER). Conceptually, the UPR can be considered a “cry for help” from an organelle. Since eukaryotic cells are very large and compartmentalized there is a need for this kind of cross-talk between different organelles and the nucleus which orchestrates said help (via mRNA transcription).

To make matters more confusing, the UPR, can be considered as part of the integrated stress response (ISR) which downstream is characterized by phosphorylation of a translational initiation factor (eIF2alpha) leading to selective translation of certain proteins, including the famous ATF4 transcription factor which is elevated in long-lived mouse models. Another way of looking at this is in terms of partial overlap. One branch of the canonical UPR, acting via a protein called PERK, is also an arm of the integrated stress response. However, the UPR has many other outputs and the integrated stress response has many other inputs, including the UPRmt.

Intriguingly, doxycycline is an antibiotic that activates the UPRmt thereby extending lifespan in C. elegans as shown by Gao et al. (2022). This is consistent with a naïve notion that improved folding and the UPR stress response should benefit lifespan. Since this is real biology, however, it is also the place where intuitions go to die. Other work suggests that inhibition of the integrated stress response is beneficial, at least in worms (Derisbourg 2021). This is the article I mentioned during the podcast from the Denzel group. While interesting, this does not – and should not – dissuade us from putting this idea to the test in the mammalian system. And, indeed, the famous mouse interventions testing program (ITP) is running a cohort with an integrated stress response activator (galofuginone) in mice to see whether it will extend lifespan.

We live in interesting times indeed!

For further reading we have attached links to some freely accessible reviews.
Melber and Haynes 2018 and Pakos‐Zebrucka et al. 2016 (here esp. Fig. 1) under further reading.

You can consider the UPR as one input for the integrated stress response. Source: Pakos‐Zebrucka et al. 2016, https://www.embopress.org/doi/full/10.15252/embr.201642195

The lysoosomal surveillance response – just another cry for help?

Arwen and others discovered a new pathway responsible for sensing lysosomal stress when they knocked down different VATPase subunits in the worm (Li et al. 2022). This pathway appears to be independent of autophagy, mTOR and the TFEB biogenesis pathway (called HLH-30 in the worm). While it is not entirely clear how the signal is transmitted from the lysosome to nucleus, they do show that it converges on a specific transcription factor from the GATA family. One can speculate that VATPase knock-down leads to reduced acidification and proteolysis in the lysosome which somehow leads to nuclear GATA translocation. While superficially, this may not be the whole story since only specific VATPase subunits seem to be involved in triggering the LysR. Hopefully, once we figure out the players we will be able to use this knowledge to generate novel autophagy inducers to promote lifespan and health.

Scientific research - between madness and dedication

In this podcast we also talk about the working conditions of scientists and PhD students. Arwen mentioned that the conditions are quite favorable in the Netherlands and in the labs where she worked. However, we are also aware of horror stories like postdocs who were regularly "sleeping in the lab" (undisclosed German lab) or students "buying groceries" for their supervisor (somewhere in the Netherlands or Switzerland, presumably). While we do both agree that passion is an important ingredient to a science career, (self-)exploitation should not be part of the deal. Sadly, these stories are more common than they should be. Grad school in the USA, for example, has the reputation of being very taxing. Here as told from the perspective of chemists:

https://www.science.org/content/blog-post/more-grad-school-pressures
https://www.science.org/content/blog-post/industry-vs-academia-mental-aspect
http://notthelab.blogspot.com/2013/01/is-graduate-school-in-chemistry-bad-for.html

Personally, I believe society should value scientists more than we currently do and pay significantly higher salaries. Whenever the pay is high, there is less exploitation of cheap labor and more automation of tedious labor.

However, not everything is bleak and we do not want to discourage anyone from pursuing a career in science. Conditions are improving and they are already quite good at certain institutions and in some countries. If you want to learn more which countries have a relaxed work culture and good pay, this podcast might be for you!

The host – brief bio

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References and further reading

Derisbourg, Maxime J., et al. "Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation." Nature Communications 12.1 (2021): 1678.

Arwen Gao at ARDD2022: A lysosomal surveillance response (LySR) that extends healthspan
https://www.youtube.com/watch?v=TiIs2stK2Iw&t=612s
see also biorxiv: https://www.biorxiv.org/content/10.1101/2022.06.13.495962v1

Gao, Arwen W., et al. "Multi-omics analysis identifies essential regulators of mitochondrial stress response in two wild-type C. elegans strains." Iscience 25.2 (2022): 103734.

Melber, Andrew, and Cole M. Haynes. "UPRmt regulation and output: a stress response mediated by mitochondrial-nuclear communication." Cell research 28.3 (2018): 281-295.
https://www.nature.com/articles/cr201816

Pakos‐Zebrucka, Karolina, et al. "The integrated stress response." EMBO reports 17.10 (2016): 1374-1395.
https://www.embopress.org/doi/full/10.15252/embr.201642195

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n this episode of The VitaDAO Aging Science Podcast, we embark on a fascinating journey through the realms of longevity and cellular health with Dr. Arwen Gao. Dr. Gao, a leading authority in the fields of aging research, metabolism, and lysosomal...

October 10, 2023

Maria Marinova & Rhys Anderson

Awareness

Longevity

Newsletters

September Longevity Research Newsletter

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Introduction

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Welcome back Vitalians, it’s a big week for VitaDAO as we’ve just become the first DAO to kickstart a biotech company, MatrixBio. MatrixBio explores hyaluronic acid-based compounds, aiming to pioneer in cancer and aging treatments, utilizing insights from cancer-resistant naked mole rats in collaboration with Prof Vera Gorbunova.

Other exciting news: we have a new portfolio company. Please join us in congratulating the GERO team for passing the VitaDAO token holder vote with 99.98% voting in favour! This proposal was an assessment of a Machine Learning Platform for Age-Related Disease Targeting & Drug Discovery, with a view to creating therapeutics to slow down human aging and eliminate root causes of age-related diseases.

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If you haven't already, please consider signing the Dublin Longevity Declaration.

We currently invest large sums of money trying to cure the leading causes of death such as heart disease, cancer and neurodegeneration, however the most common risk factor for all of these is age.

"For millennia, the consensus of the general public has been that aging is inevitable."

However, the last few decades of research has shown that aging isn't an immutable phenomenon, rather it is something that can be understood and targeted.

The Dublin Longevity Declaration is a consensus recommendation - already signed by a large number of leading figures in the aging field - to immediately expand research on extending healthy human lifespans.

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Researchers are constantly exploring numerous avenues to rejuvenate organisms to younger healthier states, from epigenetic reprogramming, to stem cell therapies. This month we are excited to bring you an interview with a pioneer in the space, Professor Irina Conboy, who has made numerous contributions to the rejuvenation biology field, including the discovery of the rejuvenating effects of young blood through parabiosis. In this issue we’re going to delve deeper into her latest publication highlighted in our Hot Picks. To explore the topic further we are hosting a journal club with Irina and Michael Conboy on fail-testing DNA methylation clocks and developing a “noise” barometer for measuring epigenetic pressure - Oct 16th, 6 pm CET. Enjoy and we hope to see you there!

Longevity Literature Hot Picks

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Preprint Corner

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We have now entered Q4, but you still have until Friday 13th October to nominate great longevity preprints from Q3 2023 to be featured in the next issue of The Longevist! You can now nominate preprints using our new snazzy form and receive a bounty of 50 VITA for each one that makes the editors' shortlist or 200 VITA if it makes the curators' top 3.

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And if you haven’t already seen it, here is our second issue of The Longevist, featuring the best longevity preprints from Q2 2023.

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Check out our last batch of preprints of Q3 with these September submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

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Methylglyoxal Affects Translation Fidelity

A pre-print by the 2nd palace winner of the Longevity Prize Rakhan Aimbetov expands on the topic of his submission. We love to see our initiative leading to tangible results, publications and research… If you want a lighter read on the topic we just published a Sci Comms article based on the topic of his prize entry: Sugar Byproducts and How They May Influence Aging

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Tardigrades dramatically upregulate DNA repair pathway genes in response to ionizing radiation

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Ketogenic diet administration later in life improves memory and regulates the synaptic cortical proteome through the cAMP/PKA signaling pathway in aging mice

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Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations

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Longevity interventions in Titan mice attenuate frailty and senescence accumulation

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Hemin decreases cellular aging and enhances healthspan and lifespan through the AMPK pathway

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B Cells Promote T Cell Immunosenescence and Mammalian Aging Parameters

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Molecular and phenotypic blueprint of the hematopoietic compartment reveals proliferation stress as a driver of age-associated human stem cell dysfunctions

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A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis

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Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging

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Genetic architecture of telomere length in 462,675 UK Biobank whole genome sequences

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A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts

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Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging

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Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aging Brain

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Deep learning-based prediction of one-year mortality in the entire Finnish population is an accurate but unfair digital marker of aging

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Cellular aging is accelerated in the malignant clone of myeloproliferative neoplasms

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Published Research Papers

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Fail-tests of DNA methylation clocks, and development of a noise barometer for measuring epigenetic pressure of aging and disease

Elastic Net DNA methylation clocks show low prediction accuracy for age and health. The study suggests that stable cytosine methylation over lifespan indicates biological age. Dysregulated cytosines, measured as standard deviations, act as a "noise barometer" for aging and disease.

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Eye Diseases and Senescence

X-irradiation induces senescence in human corneal surface cells, leading to disruptions in the epithelial barrier, and in aging mice, the accumulation of senescent ocular cells contributes to chronic inflammation and barrier decline, suggesting these senescent cells could be a therapeutic target to treat aged ocular surface issues.

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Association of biological age with health outcomes and its modifiable factors

Using the UK Biobank data, a multi-dimensional biological age model was developed. Accelerated aging correlates with health risks. 35 modifiable factors affecting aging were identified, notably pulmonary functions and body mass.

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The fruit fly acetyltransferase chameau promotes starvation resilience at the expense of longevity

A mutation in Drosophila's "chameau" gene extends lifespan but reduces weight and starvation resistance. Despite its longevity benefits, poor nutrient stress handling likely keeps this mutation from being evolutionarily dominant.

And the press release: Sometimes beneficial, sometimes damaging: The double role of the enzyme chameau

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Intact mitochondrial function in the setting of telomere-induced senescence

Mitochondria are crucial for cell health. This study explored the impact of telomere issues on mitochondria. By deleting the TRF2 protein, cell aging was induced, but mitochondrial function remained strong. Thus, even with telomere problems, mitochondria can support cell processes.

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Plasma metabolomic profiles associated with mortality and longevity in a prospective analysis of 13,512 individuals

In a study of over 13,500 participants, certain plasma metabolites were linked to mortality and longevity. Elevated levels of metabolites like N2,N2-dimethylguanosine indicate higher mortality, while others like L-serine suggest increased longevity. The study implies specific metabolites can predict mortality, but the exact mechanisms remain undetermined.

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Leveraging the secretory machinery to eliminate senescent cells

Senescent cells, which increase with age, contribute to tissue deterioration. A genomic screen showed that targeting the secretory actions of these cells in older mice can eliminate them. Suppressing the YAP–TEAD complex and reducing endoplasmic reticulum activity makes senescent cells more prone to apoptosis (cell death).

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Death-seq identifies regulators of cell death and senolytic therapies

"Death-seq" is a new CRISPR screen designed to identify cell death mechanisms. It enhances cell death research, pinpointing enhancers for the senolytic ABT-263 and uncovering new inducers using ABT-199. This method reveals insights into cell death pathways and potential drug targets for conditions like senescence, cancer, and fibrosis.

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Transcriptional and epigenetic decoding of the microglial aging process

Researchers studied aging effects on microglia, the brain's immune cells. Using mice, they found significant age-related changes, including unexpected sex differences. By creating a model to accelerate microglial aging, they discovered that aged microglia alone can cause cognitive decline, highlighting their role in brain function over time.

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Pleiotropic influence of DNA methylation QTLs on physiological and ageing traits

Researchers identified a locus, meQTL.5a, in BXD mouse strains that influences DNA methylation patterns. This locus, combined with aging, results in an "aged methylome" for certain strains. It's linked to gene traits, body weight, lipid levels, and lifespan.

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Complete or Culprit-Only PCI in Older Patients with Myocardial Infarction

A NEJM study of 1445 older patients with myocardial infarction and multivessel disease, complete revascularization resulted in fewer adverse events at 1 year compared to only treating the culprit lesion. Primary outcomes occurred in 15.7% of the complete-revascularization group versus 21.0% in the culprit-only group.

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Published Literature Reviews, Hypotheses, Perspectives and more

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We need to shift the focus of aging research to aging itself

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Mitochondrial degradation: Mitophagy and beyond

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Senescent cells at the crossroads of aging, disease, and tissue homeostasis

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Biomarkers of aging for the identification and evaluation of longevity interventions

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Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease

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Job board

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Alexandra Stolzing at Loughborough University is looking for a Research Associate on a project about volatilome-based signature for age-related recovery & resilience.

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The Valenzano lab at the Leibniz Institute on Aging in beautiful Jena, Germany, is looking for two postdocs (microbiome and pop-gen) and a master student.

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David Vilchez has an open position for a lab technician/research assistant in his lab. It would be appreciated if the candidates have a good German level.

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The HealthyLongevity.clinic in Florida is looking for a healthcare specialist.

News and Media

A new longevity fund lead by Alex Colville and Laura Deming has launched age1 to support new breakthrough longevity companies to address the field’s core challenges. A bit more from the co-founder and partner Laura: A Letter from Laura Daming

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The Economist is finally catching up to the Longevist and has dedicated an entire issue with 8 articles to social and economic aspects of aging: In search of forever

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The Economist Intelligence Unit also released: AGEING SHIFT

They introduce the "Scaling Healthy ageing, Inclusive environments and Financial security Today" (SHIFT) Index which benchmarks against a set of national-level leading practices to enable an environment that nurtures longevity and healthy ageing in 19 countries comprising the Group of Twenty (G20).

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Resources

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Longevity Summit Dublin has uploaded some fantastic talks to YouTube

Our favourites are:

The Million Molecule Challenge for Life Extension by Matt Kaeberlein

Dysregulation of Homeostasis Drives Human Aging by Peter Fedichev

Robust New Measures of Biological Age by Steve Horvath

And of course our very own:

Accelerating Research with Decentralised Science - Eleanor Davies

Longevity Network States – Max Unfried

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

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What are the key open questions in longevity science?

João Pedro de Magalhães and team have developed a website to compile the major open problems in longevity and aging and put together an initial list of problems, but are aware there will be omissions, so have opened the floor for others to fill in the blanks!

Prizes

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Keep in mind the key dates:

Kick-Off: 20th September 2023
Proposal Closing: 20th December 2023
Evaluation Wrap-Up: 20th February 2024
Champion Unveiled: 29th February 2024

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Conferences

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The conference season might be over, but there are still a couple of interesting meetings which we recommend!

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Expo and Convention: Independent Ageing 2023

13-15 October, Aichi, Japan

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Seno-Therapeutics Summit 2023

7-8 November, Buck Institute for Research on Ageing, Novato, CA, USA

Tweets of the Month

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Mikhail V. Blagosklonny: Most people believe that aging is a functional decline caused by accumulation of molecular damage…………..

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Healthspanmed: Blagosklonny's theory of cellular hyperfunction has shifted our understanding of aging.

The theory states that aging is not a result of cellular decline or damage accumulation but rather excessive cellular activity he calls hyperfunctions….

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Lada Nuzhna: aging research dies one citation at a time:

Podcasts and Webinars

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NUS Medicine’s Healthy Longevity Webinar Series

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Peter Attiia: Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more | David Sabatini, M.D., Ph.D. and Matt Kaeberlein, Ph.D.

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Elon is Right. Having to Live Forever is a Curse. Here's How to Solve It

In this episode, Lifespan News explores the diverse perspectives and heated debates triggered by Elon's provocative statements on aging and the prospect of eternal life.

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Active Motif Epigenetics Podcast: DNA Damage in Longevity and Ageing (Björn Schumacher)

In this episode Björn Schumacher discusses his research on DNA repair and its impact on ageing.

Interview with Prof. Irina Conboy

Irina Conboy is a Professor at the University of California, Berkeley in the Department of Bioengineering. The Conboy lab currently focuses on broad rejuvenation of tissue maintenance and repair, stem cell niche engineering, elucidating the mechanisms underlying muscle stem cell aging, directed organogenesis, and making CRISPR a therapeutic reality.

What inspired you to enter longevity research?
Self-preservation instinct: in my view, aging is an accumulation of disease and, metaphorically, we are flying breaking down airplanes, so the best one can do is to start working on a parachute, while the plane is still in the air and relatively “healthy”.

Which of the current theories of ageing do you think are the most convincing?
Succumbing to entropy, because of the imperfections in repair of molecules, cells and tissues.

How has the field changed since you started?
Inspired by the work of our colleagues (Cynthia Kenyon, for example) in worms and flies, we shifted the dominant paradigm in mice and people from inevitability of intrinsic aging (telomere shortening, DNA damage, etc.) to reversibility and inducibility of aging by the age of the systemic milieu – circulatory environment that connect all tissues. In other words, we uncovered that aging is a process with specific regulation, understanding this regulation allows attenuating and even reversing the process – the aging.

What mistakes do you think the longevity field has made?

Exaggeration of the positives, lack of critical questions and reviews, lack of used-to-be frequent “I stand corrected”, tooting own horns “my silver bullet is better than your silver bullet”.

Other than your own, what do you think have been the biggest/important discoveries in the field?
As mentioned, discovery of life extension in C. elegance by Prof. Cynthia Kenyon (UCSF, and Science leader at Calico), the concept of cellular and tissue senescence that was discovered by Prof. Judy Campisi (LBNL and Buck research institute), the paradigm of bone marrow, hematopoietic stem cells’ and immune aging, discovered by Prof. Irv Weissman (Stanford) and Prof. Sean Morrison (Stanford and UT Southwestern), the aging and rejuvenation of the brain and cognition that was discovered by Prof. Rusty Gage (aka Fred Gage, Salk).

What advice would you give to people currently working in longevity research?
Take care of science and science will take care of you.

Which aspect of longevity research do you think requires more attention?
Transition from animals (mice typically) to humans. Many diseases, including those associated with aging, can be cured in mice, but translation to clinic often fails.

Is ageing a disease?
In my view, we notice aging specifically because tissues, organs and eventually organisms become unhealthy, e.g., it is accumulation of diseases.

How has the perception of rejuvenation biology evolved since your seminal paper on the rejuvenating effects of young blood through parabiosis in 2005 was published in Nature?
Many intuitively decided that young blood is the key, which in our view, is not accurate. Young mice with their young DNA, proteins, cells and tissues and 50% of their young blood become aged and senescence in two weeks after a single transfusion with 50% of old blood; and old blood dominates over young in cell culture experiments (https://pubmed.ncbi.nlm.nih.gov/35902645/). How can old mice or old people with their old blood, damaged tissues, cells, and macromolecules become “rejuvenated” by a “young” protein or a blood fraction? To make things more complicated, in contrast to mouse strains, we do not have our identical twins who are always 20 years old and could serve as blood donors. On the other hand, after dilution of old blood plasma (the liquid part of the blood with age-elevated proteins) all the positive effects of heterochronic parabiosis manifest without young blood in mice (https://pubmed.ncbi.nlm.nih.gov/32474458/); and there are rejuvenative effects on the circulating cells and systemic proteome in people after a similar procedure of plasma dilution, called therapeutic plasma exchange (https://pubmed.ncbi.nlm.nih.gov/35999337/.

You published a new paper on fail-testing biological clocks and a novel approach for quantifying biological age. The study reveals that the change in methylation of cytosines with age is not the determinant for their selection into the clocks and that EN clock's selected cytosines change when non-clock cytosines are removed. Can you explain the significance of these findings and their implications for the development of future DNA methylation clocks and the the stability and relevance of the current ones?
People assume that when their age or health are predicted by so-called “clocks” it is because of the changes in their epigenome or proteome. In reality, the “clocks” is the well-known population statistics method, EN regression, in which computer is used to select and change by weights ~ 200 values from ~500.000. This is done without a biological justification, as a mathematical solution to the least-squares linear fit. In other words, if the results were not what they were, but some values were smaller and other were larger and we added them up for a minute subset of the data, then for this one experiment, Y axis would linearly correlate with X axis. These few datapoints do not have properties of biomarkers; their wights do not reflect the changes in DNAme with age or disease and when other datapoints that EN did not select are removed, EN starts discarding previously selected data, which does not happen with biomarkers. For, example, high blood glucose levels will always be biomarker of diabetes, even if we remove the inflammatory proteins, obesity, etc. We also show that in more than one experiments, predictions might reflect random experimental variation, so people should not rely heavily on being told that the “clock” determined that they are younger by a few months or older by a couple of years. In support for the lack of biological relevance or even a physical connection, we show that numbers of people living in US can be accurately predicted using the EN DNAme “clock” and in the same vein, Dow Jones industrial, global temperatures, etc. clearly unrelated to epigenetics changes can be predicted from DNA methylation array data, using EN. This is because EN only requires a large data with a weak linearity (could be optical signals from an array or distances between the Galaxies) and a measured parameter, e.g., regular set of numbers. Age, health scores, numbers of people living in US, Dow Jones, are all designated as regular sets of numbers and it is the numbers, not their meaning that is predicted, moreover, without a requirement for the physical connection between X and Y.

Can you explain in layman's terms the concept of the "noise barometer" and its importance in determining biological age? How does it differ from or complement existing markers of biological age?
EN tells us how to get the straight line between X and Y, in the mathematical realm of adjusted data; in the physical – biological realm we do not age linearly, not as an evenly ticking clock, but with intervals of youthful healthy plateaus and transitions to less health and aging, which become exponential after a serious illness. Can we quantify this and, moreover, using the primary unadjusted data? Search for biomarkers of aging spans decades and $100s of millions, yet it was not very successful, possibly, because individual differences mask the age-imposed changes. In the shift of this paradigm, we posited that it is not the levels, but the dysregulation (the noise) of genes and proteins, which biomarks aging and disease. In a metaphor, a strange noise when you drive a car strongly suggests a problem. In our bodies, the best detectors of the problematic noise are the genes, which are vital for our health (housekeeping genes, for example). Using the standard deviations or the distance from the healthy young mean of these noise detectors (UC Berkeley IP) quantifies the biological age (accurately, based on the actual unadjusted experimental results) and uncovers the natural polynomial line of aging.

Do you think the "noise barometer" can be applied in practical, clinical settings to detect or predict age-related diseases or conditions? Where can “quantifying” biological age can have the most value in clinical practice?
Yes, of course. As with any new measurement, quantification of biological age opens new possibilities for testing the efficacy of medicine, validating the putative rejuvenative approaches and warning people of “sliding” from the healthy plateau. We expect that noise barometer will be used by the Health Insurance Companies, hospitals and clinicians, academia, and biotech. In a metaphor, if there were no weight scales and we predicted weight based on the population statistics (clothes, food, body contours) it would be more difficult to get in shape and a person could have delusions of being lighter when they gained 20 pounds. Scales is the device that works on the concept of gravity, noise barometer is the first approach that measures biological entropy.

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful!

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This time we leave you with a twitter space recording about the Longevity Funding Innovation Prize, where you can hear first hand from Marat more about how the prize was created, what are the aims, and what would the judges be looking for when assessing applications.

Creating an Optimism wallet

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Because Optimism seamlessly integrates with the Ethereum Virtual Machine (EVM), incorporating an Optimism account into your current Ethereum wallet(s) is a straightforward process. To enable Optimism, follow these straightforward steps:

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Visit the Chainlist platform through your web browser.
Establish a secure connection between your MetaMask wallet and Chainlist by logging in and granting the necessary permissions.
Once the connection is established, navigate to the platform's interface and locate the "Optimism" (ID:10) option.

Click on the "Optimism" option to initiate the integration process.
After successful integration, return to your MetaMask wallet.
In the MetaMask interface, you'll notice a new feature that allows you to toggle between the Ethereum and Optimism networks. Locate and click on the "Networks" button within MetaMask.
Use this "Networks" button to easily switch between the Ethereum and Optimism networks based on your specific requirements and preferences.

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How to Fund your Optimism Wallet

To fund your Optimism wallet, follow these simple steps using The Optimism Gateway:

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Deposit Funds:

Access The Optimism Gateway.
Select the amount of ETH or supported tokens.
Confirm your deposit and wallet transaction.

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How It Works:

Your funds get locked on Ethereum.

Tokens representing your deposit appear in your Optimism wallet.
When you withdraw, Optimism tokens are removed, and Ethereum tokens become accessible. Remember, it takes seven days for withdrawn funds to become usable again.

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How to Get VITA on Optimism

Swap your tokens for VITA on 1inch.

Note: only get VITA for the purpose of using it in VitaDAO.

Bridge Mainnet VITA to Optimism

Convert Mainnet VITA to Optimism VITA by using the Optimism Bridge following this guide.

Select the amount of VITA you want to bridge to Optimism
Approve & Review the deposit

Use your VITA on Optimism

Governance: VITA tokens on Optimism to be used for voting on Snapshot. Learn how to vote on VitaDAO Governance proposals using this guide.

Providing liquidity: If you would like to use your VITA tokens to provide liquidity, you can use Velodrome.
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DISCLAIMER: This guide is intended only for people who want to get VITA for use in VitaDAO.

Resources

Get Optimism VITA on 1inch
Optimism VITA token address on Etherscan
Get Mainnet VITA on Cowswap
Mainnet VITA token address on Etherscan
VITA token on Coingecko
VitaDAO on Twitter
VitaDAO Website
Optimism on Twitter

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Tired of Ethereum's sky-high fees? 💤 We've got good news! Become a VitaDAO member on Optimism and enjoy lower gas fees.

September 8, 2023

Maria Marinova & Rhys Anderson

Longevity

Awareness

Newsletters

August Longevity Research Newsletter

Introduction

Welcome back Vitalians and please join us in congratulating the Cyclarity Therapeutics (CTx) team for passing the VitaDAO token holder vote! This proposal was an assessment of an early-stage biotechnology company that is developing novel cyclodextrin drug molecules to extract toxic biomolecules that accumulate with age.

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Whilst all of the humans were either at ARDD or on holiday, we took the opportunity to interview our favourite silicon friend, ChatGPT to ask its thoughts on longevity research. And talking of AI, we hope you are enjoying the new artwork peppered throughout our newsletter!

Longevity Literature Hot Picks

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Preprint Corner

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The second edition of The Longevist is now live! Check it out to see what our team of expert curators think are the best preprints of Q2.

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We're excited to bring you our second batch of preprints of Q3 with these August submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

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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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Reversal of Biological Age in Multiple Rat Organs by Young Porcine Plasma Fraction

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On standardization of controls in lifespan studies

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The principal component-based clinical aging clock (PCAge) identifies signatures of healthy aging and provides normative targets for clinical intervention

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Caloric restriction promotes beta cell longevity and delays aging and senescence by enhancing cell identity and homeostasis mechanisms

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Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease

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Profiling an integrated network of cellular senescence and immune resilience measures in natural aging: a prospective multi-cohort study

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Establishing RNAge to score cellular aging and rejuvenation paradigms and identify novel age-modulating compounds

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Published Research Papers

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Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice

By introducing the naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2) into mice, researchers observed increased hyaluronan levels, reduced cancer incidence, extended lifespan, improved healthspan, and reduced inflammation, demonstrating the potential for HMM-HA to enhance longevity and health in other species

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Universal DNA methylation age across mammalian tissues

Researchers have developed universal pan-mammalian clocks based on DNA methylation profiles, accurately estimating the age of mammalian tissues with high precision. These age estimations are linked to mortality risk in humans, somatotropic axis mutations in mice, and caloric restriction, and they highlight specific methylation changes near genes associated with development, cancer, obesity, and longevity, indicating that aging is evolutionarily conserved and connected to developmental processes across mammalian species.

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Atlas of the aging mouse brain reveals white matter as vulnerable foci

Aging leads to cognitive decline with distinct molecular changes in the brain. Using mouse models, researchers identified aging patterns in glial cells. Rejuvenation treatments affected gene expression differently, suggesting regional aging may impact neurodegenerative diseases.

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The impact of the cardiovascular component and somatic mutations on ageing

In a study across 15 mammals, lifespan showed a strong negative correlation with somatic mutation rate. While various traits influenced lifespan, resting heart rate stood out. Combining somatic mutation with heart rate improved lifespan predictions, indicating underlying mechanisms tied to aging.

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Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease

Circadian disruptions are prevalent in Alzheimer’s disease (AD). A study showed time-restricted feeding (TRF) benefitted AD mouse models by improving memory, reducing disease markers, and adjusting disrupted gene patterns. TRF's broad impacts suggest it could be a potential strategy to counteract AD progression.

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Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling

In Drosophila, an early adulthood increase in protein translation (PT) negatively affects aging and protein balance. Stopping this PT surge improves lifespan and reduces protein build-up. The initial PT boost disrupts protein management and accelerates aging through certain pathways. Thus, the natural post-youth PT decline might protect against age-related problems, offering a fresh angle on how PT impacts lifelong aging.

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Irreversible cell cycle exit associated with senescence is mediated by constitutive MYC degradation

Cells become senescent to stop unchecked growth, but its irreversibility has been debated. This study reveals that senescence is irreversible due to MYC protein degradation. When MYC isn't degraded, senescent cells divide; with MYC reduction, non-dividing cells become senescent.

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The YAP–TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress

Senescence stops cell growth and increases resistance to death. A study found that inhibiting the YAP–TEAD pathway with verteporfin (VPF) led to targeted death of senescent cells. This occurs by suppressing mTOR, inducing endoplasmic reticulum (ER) stress due to the demands of the senescence-associated secretory pattern (SASP).

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Published Literature Reviews, Hypotheses, Perspectives and more

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Challenges in developing Geroscience trials

As the geroscience field grows, refining clinical study designs becomes crucial. Challenges include selecting populations, choosing interventions, defining trial outcomes, and pinpointing key age-related biomarkers ("Gerodiagnostics").

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The evolution of selective autophagy as a mechanism of oxidative stress response

Aging reduces autophagy and increases damaging ROS. In humans, selective autophagy receptors (SARs) may have evolved to detect oxidative stress, initiating autophagy to remove damaged components and restore cellular balance, which contributes to our longer lifespan, while its loss could lead to age-related diseases.

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A mammalian DNA methylation landscape

Mammals display varied lifespans, from bowhead whales at 200 years to giant Sunda rats at 6 months. Despite similar genes, gene regulation might dictate aging. Haghani et al. studied DNA methylation across mammals, identifying regions possibly affecting lifespan, shedding light on molecular lifespan determinants.

Job board

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The Institute of Inflammation and Aging, with Joao Pedro, is seeking a dedicated professor with expertise in aging science and age-related diseases. This is a valuable opportunity at the University of Birmingham!

Deadline: 31 August 2023

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Apollo Health Ventures are recruiting for their portfolio company (and VitaDAOs portfolio company) BE Therapeutics in New York City, looking for a Research Asscociate

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McLab is announcing openings for postdoc and technician roles! Backed by new funding, they aim to delve deeper into understanding the effects of aging on breast cancer progression and therapeutic response.

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Cologne Graduate School of Ageing Research

Up to 12 fully funded PhD studentships starting in October 2024

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Valentin F. Cracan is seeking a postdoctoral fellow in genetically encoded sensors and tools for studying the role of redox imbalance in cancer, neurodegeneration and aging

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Interested in nutrition, supplements and human trials? This Research Fellow (Nutritional Intervention) position in Andrea Maier's lab at National University of Singapore could be for you.

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Two fully funded PhD student positions in Healthy Aging Research (biochemistry, epidemiology, bioinformatics) at Charite Berlin and Humboldt University. Please apply by Sept 30th.

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News and Media

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The British Society for Research on Aging is pleased to announce the award of the Lord Cohen Medal to Professor Lynne Cox for her outstanding achievements and contributions to understanding the biology of aging.

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GERO and FOXO Technologies embark on joint initiative on AI and epigenetic data

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Anti-aging technology is here. And the Middle East is getting ready

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How does aging increase risk of dehydration?

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A cook from Okinawa, Japan — where many live to be over the age of 100 — explains the healing powers of 7 traditional foods

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A biological clock explains why a dog year is equivalent to seven human years

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Adherence to a Mediterranean lifestyle associated with lower risk of all-cause and cancer mortality

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Leaders In Longevity Medicine Convene In Copenhagen

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Saudi Arabia Is Dangling Billions for Research on Aging. Scientists Are Lining Up to Take It

Resources

Free Courses in Longevity Medicine for physicians, researchers, and anyone interested in longevity medicine!

Prizes

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The Amaranth Prize

Rewarding the most impactful research in longevity

$250k Prize pool. 15 Winning papers. 180 Influencing papers

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Conferences

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British Society for Research on Aging Annual Scientific Meeting (BSRA ASM)

6-8 September, London, UK

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RAADFest

7-9 September, LA, CA, USA

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The Longevity Investors Conference (LIC) is an application-only event

27-28 September

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Expo and Convention: Independent Ageing 2023

13-15 October, Aichi, Japan

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Seno-Therapeutics Summit 2023

7-8 November, Buck Institute for Research on Aging, Novato, CA, USA

Tweet of the Month

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Shahaf Peleg:

Instead of greeting someone ‚hey you lost weight!‘, won’t it be great to greet someone by saying ,hey, you lost age!‘ ?

Podcasts and Webinars

NUS Medicine’s Healthy Longevity Webinar Series

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Funding Opportunities

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Impetus Grants will keep applications open until September 15, 2023.

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Interview with ChatGPT

Short bio
ChatGPT is developed by OpenAI and based on the GPT-4 architecture. As it likes to remind us, it is programmed to provide information based on a wide array of sources available up until 2021.

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Why do you think humans are inspired to research aging?

For humans, the inspiration to study aging often comes from a deep-seated desire to improve human life, reduce suffering from age-related diseases, and extend the healthy years of human life. The field has also been inspired by observations in nature; for example, certain species of whales, tortoises, and birds exhibit remarkably slow aging and resistance to age-related diseases.

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

The development of advanced computational tools, genome sequencing, and molecular biology techniques has allowed researchers to identify and target specific pathways related to aging.

Consequently, the attitude towards aging is now changing, as people are beginning to see it as something that can be manipulated, rather than an inevitable, untreatable process.

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

Some of the most important discoveries include the identification of key genes and pathways associated with aging, such as the sirtuins, mTOR, and AMPK pathways. The discovery that the drug rapamycin, originally used to prevent organ transplant rejection, can extend the lifespan of mice has led to a surge of interest in the mTOR pathway as a target for anti-aging interventions. Also, studies on calorie restriction and its impact on lifespan have opened new avenues for research

The discovery of telomeres and the role of telomerase in cellular aging has also been pivotal. Finally, the discovery of cellular senescence and development of senolytic drugs has been a significant breakthrough.

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

Stay interdisciplinary. Aging is a complex process that affects every system in the body, so collaborations across different fields of science will be key to making significant progress. Also, consider the ethical implications of your work; extending lifespan will have profound implications for society, and it is important to consider these issues as the research progresses.

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

One aspect that requires more attention is the study of the social, economic, and psychological implications of increased lifespan. While much focus has been placed on the biological aspects of aging, it is equally important to understand how increased lifespan will impact society as a whole.

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While a lot of focus has been on the molecular and cellular aspects of aging, the impact of the microbiome on aging is an area that requires more attention. The microbiome plays a crucial role in human health, and its composition changes with age. Understanding these changes and how they contribute to aging could open up new avenues for intervention.

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Is aging a disease?

This is a controversial topic. Some researchers argue that aging should be classified as a disease to spur more funding and research into interventions. Others argue that it is a natural process and classifying it as a disease could have unintended societal implications. While there is no consensus, it is clear that aging is the biggest risk factor for many diseases, and interventions that target the aging process could have broad benefits for human health.

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How would you solve aging?

Aging is a highly complex and multifaceted process. A plausible approach would be to tackle it from both a biological and a sociocultural angle:

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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.

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

Yes, solving aging would significantly facilitate space exploration and colonization. With extended lifespans, the time it takes to travel between stars becomes less daunting. Humans could embark on century-long journeys to distant star systems without the fear of dying of old age.

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

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Data Analysis: The biology of aging generates vast amounts of data, from genetic sequencing to cellular imaging. AI can rapidly process and analyze this data, identifying patterns or anomalies that might be missed by human researchers.

Predictive Modeling: AI can develop models to predict the outcomes of various interventions on aging. For example, given the genetic and health data of an individual, an AI might predict how certain treatments could impact their aging process.

Drug Discovery: AI-driven algorithms can analyze massive compound libraries to identify potential drugs that could impact aging. They can also predict drug interactions and side effects.

Genomic Analysis: Machine learning can help identify genes associated with longevity and age-related diseases. By understanding these genes, researchers can target them for therapeutic interventions.

Simulations: AI can simulate biological processes, allowing researchers to test theories about aging in a virtual environment before conducting real-world experiments.

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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?

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Radical Interventions: While current interventions might add a few years, radical approaches, like advanced gene therapy, organ replacements using lab-grown organs, or nanotechnology to repair cellular damage, might be required for substantial lifespan extensions.

Holistic Approach: Aging is multifactorial. Addressing it might require a combination of genetic, pharmacological, lifestyle, and environmental interventions.

Space and Environment: There's emerging interest in how changing environments (e.g., space or deep-sea habitats) could impact human aging. If certain environments slow aging, they might become more appealing for habitation.

AI and Tech Integration: As discussed, AI will play a pivotal role. The seamless integration of technology and biology, such as continuous health monitoring and immediate AI-driven interventions, might be crucial.

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Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful! Wishing you speedy recovery after an intense conference season and see you back here next month.

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This time we leave you with the first of a new article series co-written with the winners of the Longevity Prize, highlighting their proposals. Starting with the 1st prize winner Carlos Galicia and The Key to Longevity Could Be Hidden in Embryos.

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Further Reading

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Health Consequences of Thymus Removal in Adults

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LINE-1 regulates cortical development by acting as long non-coding RNAs

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Welcome back Vitalians and please join us in congratulating the Cyclarity Therapeutics (CTx) team for passing the VitaDAO token holder vote! This proposal was an assessment of an early-stage biotechnology company...

VitaDAO Letter: Falling DAOn the Longevity Rabbit Hole🍁

September 6, 2023

Sarah Friday

Awareness

VitaDAO Letter: Falling DAOn the Longevity Rabbit Hole🍁

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Hello Vitalians! While the seasons might be changing, VitaDAO’s unwavering commitment to extending healthy lifespan remains constant! This month, VitaDAO members traveled across the globe to attend conferences, spoke with field leaders through TwitterSpace events, screened new project submissions, and funded even more research! Inside this edition of our Newsletter, you can find:

A Twitter Space Month In Review
The Latest VitaFAST Updates
How to become a VitaDAO Delegate
Competition Winning VitaDAO Memes

🗣️A Month of VitaDAO’s Twitter Space In Review

August was a vibrant month filled with enlightening Twitter Spaces, or as we now call them, X Spaces. The conversations began with Sergei Young, a prominent longevity investor who founded the $100M Longevity Vision Fund. Max Unfried and Laurence Ion engaged in a thought provoking dialogue with Sergei about the importance of recognizing aging as a disease, global regulatory framework, and intricacies of funding in longevity research.

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The learning journey continued as host Max Unfried led a conversation with Aubrey De Grey, Caitlin Lewis, and Kelsey Moody, focused on mouse rejuvenation. The purpose of extending lifespan in mice is twofold: 1) convince the world that rejuvenation is possible and 2) identify interventions that may translate to humans. Researchers on the space discussed recent developments in mouse studies, concerns with the interventions, and approaches to interpreting survivorship data.

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In VitaDAO’s next TwitterSpace event, Max Unfried was joined by experts Mahdi Moqri, Kristen McGreevy, David Meyer, and Raghav Sehgal to explore the latest developments in epigenetic clocks. Mahdi Moqri aptly defined epigenetics as “an additional layer on top of your DNA that controls cell identity.” The epigenome plays a pivotal role in both development and aging. During this space, experts dissected the differences between first, second, and third generation epigenetic clocks.

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Following Zuzalu, a pop-up city dedicated to life extension, VitaDAO has continued to delve into the creation of longevity network cities. Niklas Anzinger, Laurence Ion, Tom Howard, and Max Unfried discussed the practicalities of establishing network longevity cities, states, and countries. In early 2024, VitaDAO is excited to be a part of coordinating Vitalia, a pop-up city that will center around the belief that “life is good, death is bad.”

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To wrap up the month, Alex Dobrin joined Ines Silva, Laura Minquini, and Estéfano Pinilla from AthenaDAO to discuss the work AthenaDAO is doing to advance women’s reproductive longevity. Recognizing the lack of funding for female related conditions, AthenaDAO has been advocating for and funding women’s health research. They are currently conducting a token auction!

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🧪VITA-FAST Updates

Can you believe it’s only been two months since the launch of the VITA-FAST token? They say time flies when you're having fun, and researching autophagy is indeed exhilarating! The launch, which garnered an 1700% oversubscription with $620k in bids, marked a revolutionary shift in how individuals can engage with longevity research.

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Since the launch, there have been two VITA-FAST governance proposals:

VFDP-1: The election of a Project Lead for the Decentralized Autonomous Organization (DAO) that governs the Discovering Novel Autophagy Activators IP-NFT.
VFDP-2: Agreement to enter into a contractual relationship with Camp Consulting.

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This month, Dr. Viktor Korolchuk spoke at the first VITA-FAST Community Call. The Korolchuk Lab is committed to identifying compounds that could potentially kickstart autophagy and rejuvenate aged cells. During the call, VITA-FAST token holders were informed that the lab has ordered commercially available analogs and screened them on two of three autophagy assays. Some of the analogs have show promising results and are even outperforming their predecessors! The lab is now considering engaging an external medicinal chemist to validate which chemical families to pursue. As the project moves closer to target identification, the lab hinted at the future of a hackathon to leverage the DeSci community’s expertise in predicting where the mechanism of action lies. Exciting progress indeed!

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🌎Back to Back: Conference After Conference

Our Vitalians have been keeping busy! This month began with the Longevity+DeSci Summit NYC. Here, VitaDAO members Todd White, Eleanor Davies, Laurence Ion, and Niklas Anzinger took the stage. Todd delivered a keynote talk titled "A New Epoch in Longevity Science? Preparing for a Longevity Future with DeSci,” advocating for decentralized science by highlighting the shortcomings of “traditional” science.

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Shortly after Longevity+DeSci Summit NYC, Eleanor Davies and Max Unfried represented VitaDAO at the Longevity Summit Dublin. They gave an insightful presentations on the ways VitaDAO is pioneering longevity research funding and ways the internet can be used to create a decentralized network state.

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The whirlwind of a month concluded with the 10th Aging Research and Drug Discovery Meeting. VitaDAO members Tim Peterson, Estefano Pinilla, Maria Marinova, Eleanor Davies, Max Unfried, and Paolo Binetti spoke at the conference, even shared some VitaDAO swag (check out the pictures below!).

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🗳️Transfer Your Voting Power

Introducing delegated voting! In VDP-65, the VitaDAO community voted to allow $VITA token holders to delegate their voting rights to a delegate. Simply put, delegation is a transfer of voting power. Delegation is great for $VITA holders who don’t have the bandwidth to actively participate in the governance and evaluation of VitaDAO’s research proposals. The DAO is currently accepting applications for delegates on Discourse. One can delegate their voting power to candidates directly on Snapshot.

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📣Community Approved: What YOU voted for!

Thanks to the support of the VitaDAO community, multiple proposals successfully passed this month! Notable passed proposals include:

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VDP-110: Allocation of $10,000 USD to fund another batch of VitaDAO Longevity Fellows with need-based micro-grants of up to $2,000 USD.
VDP-106: Clarifications to the guidelines for applicants to and reviewers of projects VitaDAO funds.
VDP-111: An outline of a VITA-FAST governance model and the election of a steward by VITA-FAST token holders.
VDP-103: Funding $91,300 towards engineering an arginine suppressor tRNA that can specifically recognize these nonsense mutations, restoring normal protein translation.
VDP-112: An assessment of Cyclarity Therapeutics, an early stage biotechnology company developing computationally designed novel cyclodextrin drug molecules to extraction of toxic biomolecules that accumulate with age.

💪Exercise Your Right to Vote

Visit VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Your input is invaluable, and together, we can shape the future of VitaDAO and decide how best to accelerate decentralized science.

😆VitaDAO Meme Competition

Looking for a good laugh? Want to work out your zygomaticus? This summer, VitaDAO hosted a Twitter meme competition, with a $VITA reward for the top three submitted memes. The only rule: the meme had to relate to longevity and aging. The submissions did not disappoint! Head over to VitaDAO’s Twitter to enjoy some clever community generated memes.

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🥇First Place:

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🥈 Second Place:

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🥉Third Place:

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🤝Thanks for Reading!

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Vision's Aging Secrets: Eye Diseases & Breakthroughs with Prof. Dorota Skowronska-Krawczyk on The VitaDAO Aging Science Podcast

September 5, 2023

Longevity

Awareness

Vision's Aging Secrets: Eye Diseases & Breakthroughs with Prof. Dorota Skowronska-Krawczyk on The VitaDAO Aging Science Podcast

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Today I had the pleasure of talking to Prof. Dorota Skowronska-Krawczyk (@DrDorotaSK) on the VitaDAO Aging Science Podcast (episode 8). We discussed the importance of basic aging mechanisms like senescence, repeated stress and inflammation as drivers of multiple eye diseases. We talked about the lack of good animal models for age-related eye diseases, prevention of age-related macular degeneration, unity therapeutics and recent trials of senolytics for eye diseases.

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Short Bio

Dorota was born in Lodz, Poland and later studied biology in Warsaw, Poland where she finished her studies with distinction. She received a PhD in Biochemistry at the University of Geneva, Switzerland. Then she finished two postdoctoral trainings – in Lausanne, Switzerland and at UCSD San Diego before starting her independent career in May 2017.

Work in her lab focuses on deciphering the mechanism of age-related eye degeneration. Using retina as a model system, the lab employs modern technologies to address unresolved issues, such as the role of fatty acids in age-related neurodegeneration and the role of stress in accelerated aging. In her free time, she likes to travel alone or with family.

Prof. Dorota Skowronska-Krawczyk
Center for Translational Vision Research, UC Irvine, School of Medicine
https://faculty.sites.uci.edu/skowronska-krawczyk/

The eye is a privileged organ

The eye is sometimes referred to as an “immune privileged” organ because the blood-retinal barrier shields it from invading immune cells. While this may be beneficial, it could also mean reduced clearance of senescent cells via NK cells (or future adoptive cell based therapies). On the other hand, the eye is very accessible which makes it easy to administer drugs directly using intravitreal injections or topical application. Dorota and I agreed that this could mean early proto-gerotherapeutics would be first available to treat eye disease before they are used to treat other tissues, as the local nature of these treatments would prevent systemic side effects.

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Aging promotes multiple eye diseases

We discussed just how exquisitely sensitive the eye is to aging. There are so many eye diseases that show a textbook exponential pattern of increasing incidence with age. This means if you live long enough you will likely develop one or all of these diseases. Dorota works on two of the more famous eye disease, age-related macular degeneration (AMD) and glaucoma. Other common age-related eye diseases include cataract, near-sightedness and diabetic and hypertensive retinopathy. The former two reaching a prevalence of 80% or more in the very old. Less know age-related eye disorders include dry eye disease and eyelid muscle weakness associated with drooping eyelids.

Nevertheless, there are species that can maintain their eye health far longer than humans including some turtles, whales and Greenland sharks. Dorota mentioned that she would really love to study the eyes of these sharks that are able to live up to 400 years. As we have discussed in the podcast with Vera Gorbunova, this kind of approach is called “comparative” and it often yields very interesting insights that are quite off the beaten path.

Age-related macular degeneration (AMD)

Age-related macular degeneration (AMD) is characterized by the progressive degeneration of the macula, the central part of the retina responsible for sharp, central vision. The incidence of AMD increases significantly with age, reaching >10% in people over the age of 80. AMD is categorized into two main forms, wet (neovascular) and dry (non-neovascular) AMD. As we discussed during the podcast, there are very few treatment options for dry AMD and mice do not have a macula, further hampering research into this pathology. Alternative models like dogs and non-human primates are very expensive.

Typical molecular hallmarks of AMD are extracellular deposits called drusen and intracellular deposits called lipofuscin. The retinal pigment epithelium is responsible for phagocytosing and removing outer segments of photoreceptors after they have become damaged during the vision process. The sheer volume of recycling is quite remarkable as every day 10% of these outer segments are lost and recycled. The sensitivity to AMD might be somehow rooted in this high metabolic activity, although we do not know for sure.

We mentioned during the podcast that AMD is one of the few diseases where the now unpopular “oxidative stress theory of aging” triumphed, since a cocktail of antioxidants was shown to slow progression of early AMD (AREDS study). Surprisingly, while omega 3 fatty acids from fish appear protective in observational studies, these benefits could not be replicated in controlled trials (AREDS2 study). Dorota believes that a better and more refined formulation might eventually work in another trial, perhaps AREDS3. Of course, it is also a real possibility that observational studies produced exaggerated or spurious results as they are wont to do.

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Glaucoma

Glaucoma, is actually not just one disease but probably a whole group of eye conditions leading to optic nerve damage. Glaucoma is primarily associated with an increase in intraocular pressure (IOP), however – and this was quite a surprise to me – a subset of cases known as normal-tension glaucoma (NTG) occurs without elevated IOP. Importantly, IOP is unrelated to blood pressure.

The prevalence of so called open angle glaucoma is around 20% at the age of 90 with an exponential increase during aging.

Pathologically, glaucoma involves the progressive degeneration of retinal ganglion cells, causing irreversible vision loss. This is in contrast to AMD, where the retinal pigment epithelium and photoreceptors degenerate. Another difference between the two pathologies is that we have better treatments for glaucoma.

Glaucoma is sometimes called the “silent thief of sight” because the vision loss only becomes obvious after a significant amount of irreparable cell loss. This is not unlike the situation with AMD, where the eye and brain are able to compensate for cell loss until a considerable amount of damage has been done.

Dorota in her research found that old mice are much more susceptible to increased IOP whereas in young mice it takes multiple cycles to cause the same amount of vision loss (Xu et al. 2022). This finding is consistent with the idea that aging can be broadly defined as the loss of resilience towards stressors. We also talked about inflammation during glaucoma and whether the inflammation is local or due to immune cell infiltration – a question that vexes almost every aging researcher studying any kind of tissue. Based on bulk RNAseq and RNAscope data she believes that inflammation in glaucoma is specific to ganglion cells.

Commonalities between eye aging and aging more broadly

Inflammation, repeated “stress” (e.g. elevated intraocular pressure), oxidative stress and senescence are hallmarks of both aging and eye aging. Dorota has had a lot of success using senolytics in mouse models of glaucoma, specifically dasatinib (Xu et al. 2022), underscoring the importance of senescence as a universal pathomechanism. She does believe there is some evidence for senescence in AMD as well, although this is not entirely clear due to a paucity of in vivo studies (Malek et al. 2022). Given this, we were both puzzled and disappointed by the failure of Unity’s senolytic – the Bcl-xL inhibitor UBX1325 – for wet AMD (1).

Obviously not everyone is in love with the senescence hypothesis and ultimately we have to wait for more data to settle the issue.

Targeting inflammation has been a glimmer of hope for those with dry AMD. The first ever approved drug for this condition, pegcetacoplan, inhibits the complement system, which is a cascade of proteins normally used to amplify immune responses against pathogens. Dorota believes that both AMD and glaucoma may have an inflammatory component. Thus it is tempting to speculate that chronic senolytic or other anti-inflammatory therapies could slow the development of both of these diseases. I mentioned to Dorota that perhaps starting treatment in late-stage disease was not such a good idea for this very reason.

Finally, we also speculated about general mechanisms of aging. Dorota asked how could it be that damage is repaired and completely removed, as far as we can tell, yet it still predisposes the organism to future disease and stressors? Could it be that the repair machinery was diverted from other places where it was needed? To me this whole idea is somewhat reminiscent of certain epigenetic aging theories where DNA damage, even when repaired, leads to local changes in epigenetic marks that predispose to aging. On the level of gene expression it seems very plausible that stressful events could introduce some kind of noise into the system that can be fully compensated while reducing the resilience of the system.

In her recent article titled "Hallmarks of Aging: Causes and Consequences." Dorota further elaborates on her views and tries to put the hallmarks into a temporal order. Her approach is certainly not bad considering how botched the naming of hallmarks is in the new paper. Who came up with the terms “primary, antagonistic, and integrative”? (2)

My opinion remains: all hallmarks are wrong, some of them are useful. We can achieve a lot without a full understanding of aging as the seminal discoveries of caloric restriction and rapamycin show. Now we just need to convince politicians that the only Manhattan project worth funding is the anti-aging project.

References

Stress induced aging in mouse eye.
Xu Q, Rydz C, Nguyen Huu VA, Rocha L, Palomino La Torre C, Lee I, Cho W, Jabari M, Donello J, Lyon DC, Brooke RT, Horvath S, Weinreb RN, Ju WK, Foik A, Skowronska-Krawczyk D. Aging Cell. 2022 Dec;21(12):e13737. doi: 10.1111/acel.13737. Epub 2022 Nov 17.

Does senescence play a role in age-related macular degeneration?
Malek G, Campisi J, Kitazawa K, Webster C, Lakkaraju A, Skowronska-Krawczyk D.
Exp Eye Res. 2022 Dec;225:109254. doi: 10.1016/j.exer.2022.109254. Epub 2022 Sep 21.

Skowronska-Krawczyk, Dorota. "Hallmarks of Aging: Causes and Consequences."
https://agingcelljournal.org/Archive/Volume2/hallmarks_of_aging/

(1) https://www.biospace.com/article/unity-shares-nearly-halved-as-lead-asset-fails-to-match-regeneron-s-eylea/

(2) Obviously the failure of the hallmarks simply reflects the complexity of aging and lack of consensus rather than the shortcomings of the authors. There is no doubt that the hallmarks papers are useful.

Nevertheless, a few pet peeves of mine. Is the telomere not a part of the genome and central to genome stability? It has always been a very odd choice to put telomeres as their own hallmark. Another interesting choice is to put mitochondrial dysfunction as an antagonistic hallmark. Are other organelles not dysfunctional during aging?

I must say I fully agree with Dorota that the hallmarks were always somewhat confusing because they merrily mix together things like damage (genomic instability), pathways (nutrient sensing), cellular processes (autophagy or proteostasis), organelle dysfunction and systemic/tissue pathology (inflammation). I would much rather think and classify in these terms:

Damage -> cellular process -> cell level pathology -> tissue and organ level pathology

With another strict distinction between cellular processes of “damage prevention” (e.g. antioxidants), “damage repair” (e.g. DNA repair or autophagy) and “damage compensation”.

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In this episode of The VitaDAO Aging Science Podcast, we delve into the world of age-related eye diseases with Prof. Dorota Skowronska-Krawczyk, a renowned expert in vision and aging. We explore fundamental aging mechanisms, challenges in research...

The Key to Longevity Could Be Hidden in Embryos

September 4, 2023

Carlos Galicia & Maria Marinova

Longevity

Awareness

The Key to Longevity Could Be Hidden in Embryos

Scientists are forever searching for ways to rejuvenate aged cells and organisms back to a more youthful and healthier state — from stem cell therapies to telomere lengthening, or even the Frankenstein-esque heterochronic parabiosis experiments whereby older organisms receive the blood of younger ones. In 2012, the Nobel Prize in Physiology or Medicine was awarded to Sir John B. Gurdon and Shinya Yamanaka who discovered a technique to reprogram mature cells back to stem cells, coined induced pluripotent stem cells. Big pharma has attempted to use this knowledge to develop rejuvenating therapies, for example Altos labs became one of the highest funded start-ups in history with an initial investment of 3 billion dollars.

What if I told you the key to reverse aging might be hidden inside your very own cells? We’re not talking about sipping on an exotic “superfood” concoction, strapping on some high-tech gadget, or hiring a blood boy. The spotlight is firmly on embryogenesis — a biological process that we’ve all experienced yet barely understand.

Okay, so what’s the big deal about embryogenesis? The miraculous transformation of two adult gametes (sex cells) into a full-blown organism effectively hits a giant reset button. Any age-related wear and tear present in the parent cells? Gone. Erased. Just like that, the biological clock is set back to zero. If that’s not a natural “Fountain of Youth,” what on earth is?

Like other adult cells, gametes undergo multiple types of age-related changes. They suffer mitochondrial dysfunction; they accumulate molecular damage and show epigenetic alterations [1, 2]. These afflictions bear the potential to be the unwelcome legacy passed down to the nascent embryo. Yet, this sparks a compelling hypothesis: could the embryo come equipped with inherent mechanisms to mitigate age related changes and undergo rejuvenation?

The idea of ‘rejuvenation’ isn’t new in the biological world. Conversion of somatic cells to induced pluripotent stem cells and the reset of the germline age with each generation are examples of this phenomena. This gives rise to the proposition of a ‘ground zero’ model, a mid-embryonic state characterized by the lowest biological age. It is hypothesized that the period from zygote to this ‘ground zero’ is associated with rejuvenation, wherein the biological age is decreased, telomeres are extended, and molecular damage is cleared. This concept of ‘ground zero’ helps illuminate the relationship between aging, development, rejuvenation, and de-differentiation, elements that are distinct throughout life [1, 3]. But here’s the million-dollar question: how does this occur? Well, hold onto your lab goggles, because scientists are already exploring this exciting frontier!

Using algorithms that can predict the age of an organism called epigenetic clocks, researchers have identified a point in embryogenesis where epigenetic age is reversed [1, 4]. Epigenetic clocks measure epigenetic age by looking at specific methylation patterns that are indicative of the age of an organism. Methylation patterns are a fundamental aspect of epigenetics. They involve the addition of a methyl group (a carbon atom linked to three hydrogen atoms) to the DNA molecule, typically at a cytosine nucleotide (one of the “building blocks” of DNA). These patterns play a pivotal role in gene expression because they can silence or activate genes without changing the underlying DNA sequence.

Scientists speculate that harnessing this natural epigenetic rejuvenation could be a key to promoting longevity and reducing age-related disease. This theory has taken the field by storm over the last few years and attracted a lot of commercial interest and new ventures trying to induce a state of “youthfulness” in cells by applying a process of epigenetic reprogramming.

Indeed, methylation presents a fascinating instance of the molecular alterations associated with aging. However, it represents only one facet of this complex process. A myriad of other molecular transformations and deteriorations in cellular function accumulate over time. The extent to which these changes affect gametes and whether they can be reversed by the embryo remains largely unknown.

To gain a deeper understanding of the relationship between aging and embryogenesis, researchers are delving deep, right into the core of gametes and embryos. Their goal? To identify any age-related alterations in parent cells that are subsequently erased as oocytes and sperm transform into an embryo, ultimately giving rise to a new organism.

The idea is to identify what molecular and functional changes occur as gametes age and to study whether embryogenesis has the capacity to reverse and alleviate some of them. To do this, scientists plan to use advanced technologies that can measure the abundance and state of a cell’s molecular components. These technologies include powerful tools like mass spectrometry which can be used to quantify and characterize proteins and the modifications they have undergone. This is important since protein damage and protein aggregates are thought to be a direct contributor to the aging process. Other tools like nanopore and SMRT sequencing have the potential to spot alterations in our DNA [5, 6]. These changes include various forms of DNA damage and understanding how these changes evolve with age and their behavior during embryogenesis, may uncover unknown aging and rejuvenation mechanisms.

However, the exploration doesn’t stop at proteins and DNA. Scientists are planning to do a deep dive into other components of cells, like lipids, metabolites, RNA, and the shape of DNA. They will gather heaps of data from these tests, then add functional data about different parts of the cells like mitochondria or lysosomes. When all these investigations come together, they would give us a detailed picture of how gametes age and how embryos deal with this.

These large datasets do more than just offer information about which facets of aging are undergoing rejuvenation. They also provide invaluable insights about the genes, peptides, and metabolites that drive the powerful genetic programs the embryo utilizes. This could prove very valuable, given that the embryo utilizes multiple processes that can be used to fight age related diseases.

For instance, in an intriguing series of experiments, scientists have injected cancerous cells into embryos. Yet, contrary to expectations, these malignant cells neither overwhelm the embryo nor are they eliminated. Instead, the embryo exercises a remarkable level of control over these intruders, compelling them to halt their proliferation [7]. Adding to the element of surprise is the fact that these transformed cells are not only maintained in tissues until birth, but they also undergo a complete reprogramming from their original cancerous state. It’s as if the embryo, in its potent nascent life, possesses a transformative capacity that can strip away the cells’ malignancy.

This intriguing process is likely to contribute to the intricate equilibrium required during tissue formation in embryogenesis. Unlike in cell culture where most cell types face a limit on the number of divisions, during embryogenesis the initial cells can form an entire organism without succumbing to replicative senescence. This is the result of elaborate cellular programs that grant cells the freedom to proliferate robustly while concurrently shielding them from becoming cancerous.

These are potent programs encoded within our very genome, holding potential applications for regenerating new tissue or combating malignancies in aging organisms. Indeed, certain creatures in the animal kingdom, like the aquatic hydra and some species of planaria, exploit similar processes to earn their ticket to immortality [8, 9]. Venturing into this new frontier of knowledge could unlock transformative therapeutic strategies, potentially reshaping our approach to age-related diseases and longevity.

While this all might sound like it’s straight out of a science fiction novel, it’s rooted in solid science. Even more exciting is that it’s mostly an uncharted territory! Despite the enormous potential of studying embryogenesis, it’s been an overlooked area in the longevity research world, making it ripe for exploration. Cracking the code of embryogenesis could very well be the key to understanding aging and how to reverse it. If successful, this could be a game-changer in how we approach aging and longevity. Forget about mythical fountains or enchanted forests; our ticket to timeless youth might just be nestled within the miracle of life itself!

Authors: Carlos Galicia & Maria Marinova

Editors: Rhys Anderson

Illustrator: Victoria Forest

References:

1. Kerepesi, C., et al., Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging. Science advances., 2021. 7(26): p. eabg6082.

2. Smits, M.A.J., et al., Human ovarian ageing is characterized by oxidative damage and mitochondrial dysfunction. 2023, Cold Spring Harbor Laboratory.

3. Gladyshev, V.N., The Ground Zero of Organismal Life and Aging. Trends in Molecular Medicine, 2021. 27(1): p. 11–19.

4. Zhang, B., et al., Epigenetic profiling and incidence of disrupted development point to gastrulation as aging ground zero in Xenopus laevis. 2022, Cold Spring Harbor Laboratory.

5. Clark, T.A., et al., Direct detection and sequencing of damaged DNA bases. Genome Integr, 2011. 2: p. 10.

6. Wang, F., et al., Solid-State Nanopore Analysis of Diverse DNA Base Modifications Using a Modular Enzymatic Labeling Process. Nano Lett, 2017. 17(11): p. 7110–7116.

7. Astigiano, S., et al., Fate of embryonal carcinoma cells injected into postimplantation mouse embryos. Differentiation., 2005. 73(9–10): p. 484–490.

8. Sahu, S., A. Dattani, and A.A. Aboobaker, Secrets from immortal worms: What can we learn about biological ageing from the planarian model system? Semin Cell Dev Biol, 2017. 70: p. 108–121.

9. Muller, W.A., Pattern formation in the immortal Hydra. Trends Genet, 1996. 12(3): p. 91–6.

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Scientists are forever searching for ways to rejuvenate aged cells and organisms back to a more youthful and healthier state - from stem cell therapies to telomere lengthening, or even the Frankenstein-esque heterochronic parabiosis experiments...

Decoding Longevity: DNA Mutations, Mole Rats, and Cancer Prevention with Prof. Vera Gorbunova on The Aging Science Podcast by VitaDAO

August 23, 2023

Awareness

Longevity

Decoding Longevity: DNA Mutations, Mole Rats, and Cancer Prevention with Prof. Vera Gorbunova on The Aging Science Podcast by VitaDAO

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In the 7th episode of the Aging Science podcast we talked with Prof. Vera Gorbunova about her most recent work, covering a wide array of topics from genome stability, naked mole rats, the role of hyaluronan in cancer prevention, fucoidan as a SIRT6 activator, to comparative transcriptomics and Peto’s paradox.

Short Bio — Vera Gorbunova

Dr. Vera Gorbunova is a Professor of Biology and Medicine from University of Rochester. Having earned her undergraduate degree at at Saint Petersburg State University (Russia) and her Ph.D. at the Weizmann Institute of Science (Israel), she has dedicated her career to understanding the mechanisms of longevity across species, exploring genome stability, sirtuins, and non-traditional animal models. Her pioneering work on SIRT6 biology and potential activators like fucoidan, along with contributions to studying hyaluronan for cancer prevention, could pave the way towards therapeutic applications.

“I would choose to live for as long as I am enjoying it[…]it is very difficult to set a limit for yourself. That is what we would want for every person that people can live as long as they are happy.” (Vera Gorbunova)

DNA damage and aging

One of Vera’s key interests is genomic instability, which has emerged as a likely driver of aging. Mutations can lead to cancer, disrupt gene expression and the epigenetic architecture of the genome. This explains why long-lived species had to develop effective mechanisms for repairing or preventing such damage.

In a recent study together with Jan Vijg, Vera discovered that short-lived rodents, and in particular mice, show higher levels of DNA mutations before and after a genotoxic stress (Zhang et al. 2021). The technique they used to show this is particularly interesting. Without going into details, it is difficult to measure DNA mutations using classical sequencing due to high levels of background noise that looks like mutations. Many workarounds exist, often focusing on clonally expanded stretches of mutations. Here, instead, the authors performed whole genome sequencing of single fibroblasts from five different species that differed in their maximum lifespan (mouse, human, guinea pig, blind mole-rat, and naked mole-rat).

While the finding of lower mutation rates in long-lived species is correlational and indirect, it has been replicated many times and there is no clear alternative explanation for it that would be unrelated to aging or cancer. This is one of the reasons why the “DNA damage theory of aging” is generally held in high regard by most people in the field.

Comparative biology of aging

Researchers doing comparative biology or biogerontology of aging, as the name suggests, want to compare species that have different lifespans to discover why some live longer than others.

On this podcast we often talk about the shortcomings of mice, like their short lifespans and susceptibility to cancer (1). Comparative biology avoids these pitfalls of mouse models since it allows researchers to study a wide variety of species, some of which live orders of magnitude longer than mice and are more similar to humans.

Comparisons come in many types. Some researchers study dozens or even hundreds of species, if they can access the right kind of data for these species (2), whereas others pick two closely related species that have different lifespans and compare them. Often this is the mouse and the naked mole rat, which while mouse-sized nevertheless lives up to 30 years. The techniques employed are as varied as the sample sizes of these studies. In principle, one can compare any phenotype or molecular marker between species. Recent studies have focused on high-throughput methods, comparing the genomes or transcriptomes of different species.

Transcriptomics and other “omics” of aging

The expression patterns of cellular mRNA, the template that gives rise to proteins, can be studied using RNA-sequencing which we call transcriptomics. Vera’s team recently published a large-scale comparison of different rodents (Lu et al. 2022) confirming some candidate pathways we believed are associated with longevity. For example, longer-lived rodents, let’s say capybaras or naked mole rats, were found to have better repair of DNA double strand breaks, while pathways involved in the repair of smaller lesions were unchanged. This is keeping with an emerging consensus that double strand break repair is the most important type of DNA repair for aging.

Also, not surprisingly inflammation was reduced in longer-lived rodent species. Transcription factors related to pluripotency were linked with the expression of “pro-longevity” genes while “anti-longevity” genes were related to circadian transcription factors.

The study also reported some beautifully odd findings implicating novel pathways in aging, including collagen synthesis or RNA export. This is the kind of finding that, if it pans out, can spawn a new field of research.

While I love comparative studies utilizing omics, it should not go unmentioned that they have certain limitations. Given the large amount of data generated it is quite easy to find support for some of the popular aging theories, whereas lack of evidence is often ignored. No one ever talks about the aging theories that were not supported by the data that and what this means.

Moving forward, Vera’s next goal is to apply proteomics and metabolomics approaches to these rodent species, integrating this data with the transcriptomic findings. We both agreed that proteomics, i.e. the systematic analysis of protein expression patterns, is very under-utilized in aging research.

Extracellular matrix (ECM) and aging

The importance of extracellular matrix (ECM) changes to cardiovascular aging was discovered by Blumenthal and Lansing in the early twentieth century. Despite this early and seminal work, for a while there was a lack of interest in studying extracellular matrix changes during aging and the field is having a renaissance now. While Lansing studied a protein called elastin, Vera’s work is focused on glycosaminoglycans, which are a type of large sugar chains (polysaccharides).

“The length of hyaluronan [=hyaluronic acid] can range from an oligomer to an extremely long form up to millions of daltons. The concept that emerged in the field is that high (HMW-HA) and low (LMW-HA) molecular weight hyaluronans have different biological properties and trigger different signaling cascades within the cells. LMW-HA is associated with inflammation, tissue injury and metastasis, while HMW-HA improves tissue homeostasis and has anti-inflammatory and antimetastatic properties.” (Gorbunova et al. 2020)

In this episode of our podcast Vera explains that hyaluronan forms a mesh between tissues and cells that may be able to slow down metastasis and the growth of cancer more generally. It appears that naked mole rats possess high molecular weight hyaluronan that is particularly effective at preventing cancer and perhaps we might be able to slow down cancer growth by boosting our own production of hyaluronan. Achieving this goal, however, will not be simple since such a large molecule cannot be absorbed well from the gastrointestinal tract, which rules out a simple supplementation approach. Similarly, although hyaluronan injections are a popular treatment for wrinkles and osteoarthritis, they will not work to increase whole body hyaluronan synthesis because the hyaluronan molecule is large and “sticky”.

Instead, the idea is to inhibit the enzyme that breaks down hyaluronan which would also cause a shift towards larger molecular weight species of hyaluronan.

Although it remains speculative whether boosting hyaluronan synthesis or increasing the molecular weight of our own hyaluronan will be beneficial, it is nevertheless a good working hypothesis. This kind of work beautifully illustrates how basic and comparative science can lead to potential clinical applications

Below you can read more about Vera’s recent project that was funded by VitaDAO: https://snapshot.org/#/vote.vitadao.eth/proposal/0x747f0e671d6e049ce501fba8067c9da3b0502b8945daa890ca98f36a63bc7246

Summary

Prof. Gorbunova’s work reveals a correlation between long lifespan and low DNA mutation rates. Among other things, she also found changes in the hyaluronan of long-lived species. There is ongoing work to utilize these findings to develop therapies that target human aging, e.g. fucoidan as a SIRT6 activator or inhibitors of hyaluronan breakdown.

References

Lu, J. Yuyang, et al. “Comparative transcriptomics reveals circadian and pluripotency networks as two pillars of longevity regulation.” Cell Metabolism 34.6 (2022): 836–856.

Zhang, Lei, et al. “Maintenance of genome sequence integrity in long-and short-lived rodent species.” Science Advances 7.44 (2021): eabj3284.

Gorbunova, Vera, Masaki Takasugi, and Andrei Seluanov. “Hyaluronan goes to great length.” Cell stress 4.9 (2020): 227.

Notes

(1) The justification for mouse research is as follows. We do not use mice because they are a great model of long-lived mammals, instead you can consider them as “better worms”. They are simply the next best model after invertebrates that is still affordable for basic research.

(2) One accessible type of data is for example the sequence of the mitochondrial genome. Both Vera and I published research on this topic and as an “amateur” comparative gerontologist myself I always like following her work.

Pabis, Kamil. “Triplex and other DNA motifs show motif-specific associations with mitochondrial DNA deletions and species lifespan.” Mechanisms of Ageing and Development 194 (2021): 111429.

Yang, Jiang-Nan, Andrei Seluanov, and Vera Gorbunova. “Mitochondrial inverted repeats strongly correlate with lifespan: mtDNA inversions and aging.” PLoS One 8.9 (2013): e73318.

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August 10, 2023

Maria Marinova & Rhys Anderson

Awareness

Longevity

Newsletters

July Longevity Research Newsletter

Introduction

Welcome back Vitalians! Stop the press — the Impetus Longevity grants are back!

Having already deployed 24M USD to fund longevity research, round 3 is now open with 10M USD of funding, so if you have a great idea, get your application in before 31st August!

And the good news doesn’t stop there! VitaDAO has just opened another round of the Longevity Fellowship. We provide need-based micro-grants of up to $2,000 USD to passionate scientists, students, and longevity enthusiasts to delve deeper into their research interests, attend conferences, and join programs such as the Longevity Biotech Fellowship.
Quick tip: funding is distributed on a rolling basis so don’t wait too long to apply!

If real estate agents like to inform you it’s all about “location, location, location”, then drug developers would likely tell you it’s all about “delivery, delivery, delivery”.

It’s simply not enough to have a drug which works in a test tube, it has to be able to reach the intended target within the organism. The bioavailability of a drug can be diminished by various obstacles, from having to pass through the GI tract or the blood-brain-barrier, to navigating solid tumour microenvironments. As such, scientists are constantly looking for new ways to improve drug delivery, such as innovative nanotechnology-based carriers or developing prodrugs which can convert to being pharmacologically active at the site they are required. This month we’re excited to bring you an interview with Matthew Yousefzadeh, who has made significant contributions to the aging field, and touches on the bioavailability hurdles associated with the promising senolytic drug fisetin — enjoy!

Longevity Literature Hot Picks

Preprint Corner

The votes are in — The Longevist curators have decided what they think are the most important preprints of Q2. Before we publish the Q2 Issue of the Longevist, take a look at the inaugural issue of The Longevist which is now live!

Check out our first batch of preprints of Q3 with these July submissions. These will each be entered into the Q3 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.

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

LEF1 isoforms regulate cellular senescence and aging

Preserved striatal innervation and motor function despite severe loss of nigral dopamine neurons following mitochondrial dysfunction induced by mtDNA mutations

Alterations of the gut microbiome are associated with epigenetic age acceleration and physical fitness

Amyloid β accelerates age-related proteome-wide protein insolubility

The principal component-based clinical aging clock (PCAge) identifies signatures of healthy aging and provides normative targets for clinical intervention

Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems

Machine Learning identifies conserved traits that influence lifespan and healthspan responses to dietary restriction

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain

Somatic mutations in human ageing: New insights from DNA sequencing and inherited mutations

A comprehensive atlas of the aging vertebrate brain reveals signatures of progressive proteostasis dysfunction

Glial-derived mitochondrial signals impact neuronal proteostasis and aging

Published Research Papers

Chemically induced reprogramming to reverse cellular aging

The Sinclair lab have identified chemical cocktails which can reverse transcriptomic age in cells. Thus they claim that age reversal can be achieved by chemical means. This paper has sparked controversy due to the speed of publication, questions of novelty, and overhyped claims. Take a read and make up your own mind!

The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery

From microscopes to space telescopes,

technology and science need to work together to make advances possible. Using the WormBot-AI automated data capture and analysis technology, the Kaeberlein lab are taking on the ambitious challenge of screening a million molecules for their effects on lifespan in C. elegans.

Large-scale across species transcriptomic analysis identifies genetic selection signatures associated with longevity in mammals

Among mammals alone, lifespan can vary over 100 times between species. Here the authors performed transcriptomics across numerous species and identified that translation fidelity pathways correlate with lifespan and methionine restriction genes are under strong selection in long-lived mammals.

Here we have back to back published studies showing that senescent macrophages drive lung cancer and accumulate in aging

More than bad luck: Cancer and aging are linked to replication-driven changes to the epigenome

The Levine lab’s study suggests that aging and cancer share a common epigenetic replication signature, termed CellDRIFT. This signature increased with age across tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and could be reset upon reprogramming.

Multi-omic rejuvenation and life span extension on exposure to youthful circulation

Heterochronic parabiosis (HPB) in mice has shown significant rejuvenation effects, improving physiological parameters and extending lifespan. HPB reduced the epigenetic age of blood and liver, with the effect persisting even after detachment. The transcriptomic and epigenomic profiles suggest a global rejuvenation effect.

Maternal aging increases offspring adult body size via transmission of donut-shaped mitochondria

Maternal age significantly influences offspring adult traits like body size. This study utilized C. elegans to explore the mechanisms, revealing aged mitochondria transmitted from older worms are rejuvenated in offspring in an AMPK-dependent manner. This early-life mitochondrial dysfunction triggers AMPK and TGFβ signaling, increasing adult offspring size.

Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton

Using mass cytometry, researchers identified and analyzed senescent cells in aged mice at single-cell resolution. They found these cells in certain skeletal cell populations could be robustly cleared by senolytic therapies, providing a method to target senescent cells in vivo.

Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers

A study investigating the gradual molecular dysregulation in aging finds that lifespan-extending interventions like acarbose, 17α-estradiol, rapamycin, and calorie restriction generally tighten the regulation of biological modules. These patterns are similar across interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response.

Pan-primate studies of age and sex

Horvath presents accurate pan-primate epigenetic clocks based on DNA methylation profiles from 2400 tissues across 37 primate species. The study explores the impact of age and sex on cytosine methylation, identifying 11 sex-related CpGs on autosomes. The findings provide insights into conserved age- and sex-related epigenetic changes and biomarkers of aging in primates.

Predicting lifespan-extending chemical compounds for C. elegans with machine learning and biologically interpretable features

Researchers used machine learning to analyze DrugAge, a database of compounds that modulate lifespan in model organisms. They identified the importance of the “Glutathione metabolic process” and predicted new promising compounds for extending lifespan, including nitroprusside, an antihypertensive medication.

Published Literature Reviews

Chronic inflammation and the hallmarks of aging

The review suggests that chronic inflammation, known as “inflammaging,” is a critical driver of aging and age-related diseases. It is linked with other aging hallmarks, exacerbating cellular dysfunction and advancing aging. Targeting inflammation could be key in developing anti-aging interventions and addressing age-related conditions.

An updated landscape of cellular senescence heterogeneity: Mechanisms, technologies and senotherapies

The review emphasizes the critical role of senescent cells in aging, and the need for better identification methods. Despite the challenge posed by the heterogeneity of senescence, high-throughput technologies like single-cell RNA sequencing could enable improved analysis and potential discovery of new markers.

Stress, diet, exercise: Common environmental factors and their impact on epigenetic age

This review explores how lifestyle factors influence the DNA methylation landscape, as revealed by epigenetic aging clocks. Lifestyle factors can impact DNA methylation and consequently influence biological aging. Understanding these relationships could provide valuable insights for people interested in creating a lifestyle designed to promote longevity.

Spatial mapping of cellular senescence: emerging challenges and opportunities

This review discusses the challenges of mapping senescent cells, crucial for understanding aging. Current single-cell technologies lack spatial data, which is key due to the interactive nature of these cells. New spatial imaging methods are needed to create a comprehensive senescent cell atlas.

Job board

VitaDAO’s portfolio company BE therapeutics is looking for a scientist with tissue engineering or neuro lab experience for some exciting work on brain replacement lead by Jean Hebert. Send CV to jean.hebert@einsteinmed.edu to be considered.

Korolchuk lab in Newcastle University are hiring for an exciting new position of lab technician which will support an industrial project in collaboration with Procter & Gamble.

Explore new mechanisms of how DNA damage drives aging and alters heritable genomes at the Schumacher Lab at CECAD Cologne. They are seeking enthusiastic postdoc candidates with a background in genetics, cell biology, biochemistry or computational biology.

Prof. Marco Demaria is looking for an enthusiastic and ambitious PhD candidate to join the Laboratory of Cellular senescence and age-related pathologies (Groningen, Netherlands), to work on a project studying the contribution of senescent cells to inflammatory and fibrotic chronic disease.

Research Associate position available in Dr. Gordon Lithgow’s laboratory at the Buck Institute for Research on Aging. The Lithgow lab combines biochemical, molecular, and genetic techniques to address fundamental questions about aging in C. elegans.

Brieno-Enriquez lab is looking for two motivated postdocs to explore reproductive aging in the naked mole rat. They will leverage the NMR to explore mechanisms that rejuvenate the ovary and extend both reproductive lifespan and overall health.

News and Media

FDA grants full approval to Leqembi, opening up coverage of Alzheimer’s drug by Medicare

After a dispute with the publisher resulted in the resignation of 5 editors-in-chief from Aging Cell — the former editors have now returned with a new scientist-led journal — Aging Biology — which is now accepting submissions and publishing papers.

Check out Lada Nuzhna’s reflections on 2 years of going after risky aging science.

USA Today: Want to live healthier longer? Scientists aim to improve life quality over quantity

8 healthy habits that may add 24 years to your lifespan

The Wall Street Journal: The Longevity Clinic Will See You Now — for $100,000

Twenty minutes of daily exercise can help reverse frailty and build resilience in over 65-year-olds

The boom of the anti-aging market: How to get people to live to be 120 (and in good health)

The Daily Mail catches up on the drama in the aging research world: EXCLUSIVE: Harvard claims it found the elixir of youth — but experts call it ‘hype’

Mitochondrial DNA fragments in blood shown to be important biomarkers for aging

Peter Fedichev Explains His Theory of Aging

Healthy longevity is not only for the neurotypical

Resources

Norn Group’s age related diseases overview: an excellent resource of early stage startups in the longevity space that are looking for an initial clinical indication to target

Prizes

Rewarding the most impactful research in longevity

Substantially increasing the human lifespan. The Amaranth Prize gives no-strings attached funding to the best research in Longevity.

Conferences

Ending Age-Related Diseases

10–11 August, NY, USA and virtual

Aging Research & Drug Discovery (ARDD)

17–20 August, Dublin Ireland

28 August — 1 September, Copenhagen, Denmark

British Society for Research on Aging Annual Scientific Meeting (BSRA ASM)

6–8 September, London, UK

RAADFest

7–9 September, LA, CA, USA

Expo and Convention: Independent Ageing 2023

13–15 October, Aichi, Japan

Seno-Therapeutics Summit 2023

7–8 November, Buck Institute for Research on Ageing, Novato, CA, USA

Tweet of the Month

Adam Gries (@adamgries):

The idea that we shouldn’t work hard to extend lifespans (which has been echo’ed by @ elonmusk) would make more sense , if we weren’t *already* spending like crazy to increase lifespans, just doing it poorly.

Trillions now go to the last 5 years of life. […]

Podcasts and Webinars

Join us for a Twitter live discussion on the latest epigenetic clock research

7 August, virtual

Norn Group presents: Near Future Skill Gaps in Software & ML discussing current & impending changes impacting aging bio research due to advances in software & ML. Featuring Joe Betts-LaCroix, Luca Naef, Andy Lee, and Sam Spurlin

9 August, virtual

Did you miss our Robust Mouse Rejuvenation Twitter live with Aubrey de Gray, Caitlin Lewis,

Kelsey Moody, & Danique Wortel? Don’t worry, the recording is up.

We also interviewed Sergey Young!

NUS Medicine’s Healthy Longevity Webinar Series

This month:

Ovarian Ageing: A Target for Geroprotection in Women | Prof Suh Yousin

AI and robotics | Dr Alex Zhavoronkov

Taurine deficiency as a driver of ageing | Asst Prof Vijay Yadav

Funding Opportunities

Research: Impetus Longevity grants

Micro-grants: VitaDAO Longevity Fellowship

Interview with Matthew Yousefzadeh

Matthew is an instructor at Columbia University Medical Center where he works on mechanisms of aging, in particular how DNA damage and cellular senescence contribute to cell autonomous and non-autonomous aging.

What inspired you to enter longevity research?

Previously, my background was in cancer biology and much of my PhD work was on how specialized DNA polymerases could play protective roles in limiting genotoxic stress, but their levels had to be tightly regulated. Too much of these enzymes could be permissive to tumorigenesis or make them refractory to treatment. I got into cancer biology because during my freshman year of college my grandmother survived one bout with breast cancer but succumbed to a second round of cancer. Likewise, as I was finishing my PhD, I saw my mom start to accumulate some age-related health issues and she died at a young age. This was the impetus for me to get interested in aging research. Going to Laura Niedernhofer’s lab was a no-brainer and provided a natural transition for me where I could take my DNA repair background and use it to study senescence.

How has the field changed since you started?

My plan was to go to Laura’s lab to study senescence that was induced by DNA damage or through DNA repair deficiency. At the time, I had no clue what senolytics were and the first senolytics paper was published a few weeks before I showed up to the lab. Obviously, the senescence field has matured a lot since then and still has a way to go. Outside of that there have been incredible discoveries in many of the other pillars of aging like the broadened use of epigenetic clocks, epigenetic reprogramming, and use of companion animals as a method to study aging. The field felt a bit slower back when I started my postdoc, and it is moving much more rapidly now. This is both great because I feel like the speed of progress is picking up, but terrifying from a standpoint of how many good papers are coming out every day that I need to read up on. It is a fantastic problem to have though! Recently in the past few years there seems to be a greater public interest in aging, and I think it has turned into a prime opportunity to bring young enthusiastic minds into the field of geroscience. Also, we are seeing people in other diseases spaces like cancer begin to get much more serious about looking at the interplay between their disease of interest and aging. From a commercial standpoint the number of longevity companies was really limited to Calico and in the realm of senescence, Unity Biotechnology. In the past few years, this aging biotech landscape has exploded, which I find to be a positive sign.

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

While some of these are controversial spaces, I think the work done by too many labs to individually list on these topics are a boon for geroscience: 1) Levels of in disease and aging, 2) epigenetic reprogramming and functional outcomes in regards to rejuvenation, 3) understanding how centenarians age so well, 4) transgenerational effects on aging and longevity, and 5) the use of C. elegans to conduct high throughput screening of monotherapies and combinations to determine possible geroprotectors. Each of these are very important and in their own individual way could serve as a disruptor in the field of aging.

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

Find something you care about working on and go all in on it. Some days you will love it and other days it will frustrate the hell out of you. I have seen some really good scientists run away from projects when they get their first piece of negative data or experience some difficulty. Some of them have tried to jump from what they thought was a hot project to next hot project because it was “cooling off” and eventually they burnt themselves out. Learning resiliency can be tough but find something that you can stick and see it through. It is so rewarding! Another piece of advice is to find a place where people are invested in your development. I tell graduate students and other early career researchers to chase mentorship and not projects. Good mentorship can set you on a path to success when you are at such a nascent stage in your career. I also think programs like the MBL Biology of Aging Advanced Research Training Course that was created by Jennifer Garrison and Will Mair will serve as excellent conceptual and technical primers for people new to the field or looking to expand their skillsets. Get involved! Join the American Aging Association or the Gerontological Society of America and get involved with the trainee chapters or other committees. Trainees can take part in the peer review training program at Geroscience where they can independently review manuscripts. If you are interesting, contact me.

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

I’m going to say there are two big areas that deserve more attention: 1) validation of biomarkers and reagents; and bandwidth and best practices for bioinformatic analysis. The first has been a long-standing issue not just for aging but for other fields as well. We all know biology can plagued by poor reagents like antibodies that have not been properly validated or how many of the markers in my own field of senescence are non-specific. Discovering better markers and building better tools that we are confident will go a long way to expediting progress. Let’s face it, resource validation is not sexy, but it is vital.

To the second point, it has been incredible to watch the explosion of ‘omic and multiomic analysis in the field of aging. I wish I had access to single cell RNAsequencing as a first-year postdoc, it would have made my life a lot easier. A lot of us, me included, are trying to play catch up to the ever-shifting landscape of technology in this area and its inherent strengths and weaknesses. We desperately need bioinformatics support to help us process the mountains of data and we have been fortunate to draw a lot of very talented people from the tech sector into aging in the last few years as we also home grow bioinformatics talent. My last point on this topic is that many of us are looking for resources on best practices for these topics so that we can plan and execute the best possible experiment. One example of this is a recent publication from Param Priya Singh and Bérénice Benayoun on “Considerations for reproducible omics in aging research.” I think this manuscript is incredibly informative and can serve as a great reference for anyone using ‘omics to study aging. Speaking of advice, I am also incredibly fortunate that Bérénice is a friend and has been generous with giving me advice as a postdoc and now as a PI.

Is ageing a disease?

This is how you start a fight over beers when you get a bunch of aging researchers together. I think it is a disease, but also a natural and omnipresent condition. A very milquetoast take right? Realistically it probably sits in between the two states. Some people feel very strongly about it, but I’d rather focus on the science rather than semantics.

You have shown that fisetin is a senotherapeutic that extends health and lifespan in mice — what do you think is the biggest challenge in bringing fisetin to the clinic?

Fisetin is interesting in that we wanted to demonstrate that a senolytic could be safe but effective. Dasatinib, a chemotherapeutic that is used in combination with quercetin as a senolytic, has side effects. The natural product fisetin was originally identified through screening other flavonoids to see if they had more potent senotherapeutic effects than quercetin. I think two big hurdles for bringing fisetin to the clinic is that since it is a natural product it has a very limited intellectual property (IP) position and from a drug standpoint it has poor bioavailability. To address the second point, Kyle Brewer, a talented aging biologist, at ETTA Biotechnology is working to develop an optimized formulation to better deliver fisetin. Meanwhile the laboratory of my former co-mentor at the University of Minnesota, Paul Robbins, is developing fisetin analogs to increase potency and bioavailability, as well as create novel IP around these analogs. Paul has co-founded Itasca Therapeutics, a platform company which I currently serve as the CSO for, to develop these compounds and other senolytics. Itasca Therapeutics was created because we found that the typical funding mechanisms for academic research were insufficient to push lead compounds discovered in the academic lab further into the drug development thus the needs to acquire private funding.

Which other senolytic strategies do you think hold promise and what are the potential negative impacts of removing senescent cells?

The field of senolytics is growing and so are their approaches. These include everything from the use of AI-guided drug design, protein degraders of targets (PROTACs), CART cells, and activation of immune clearance mechanisms. I find Anil Bhushan’s work on senescent cell elimination by invariant (i)NKT cells to be both intriguing and refreshing. Many of us are looking at senescent cell accumulation as purely detrimental and studying them in the gain of function context. Others like Anil view senescent cells are serving a regulatory role and asking questions about why we fail to clear them as we age. This work is addressing the other side of the senescence equation (loss of function in the form of immune clearance). Furthermore, not all senescent cells are deleterious and should be cleared. A few years ago, a group showed that genetic clearance of senescent liver sinusoidal endothelial cells (LSECs) that expressed high levels of the p16Ink4a gene had detrimental effects and caused a pro-fibrotic response in the livers of these mice. These cells were not affected when the mice were treated with dasatinib and quercetin. Furthermore, it was found that expression of p16Ink4a specifically in the pancreatic beta cells of transgenic mice enhanced glucose-stimulated insulin production and provided an unexpected benefit to diabetic mice. Studies like these serve as a cautionary tale to not be hasty to eliminate all senescent cells or all cells that express p16Ink4a. We are fortunate that the newly created NIH Common Fund Cellular Senescence Network program is working to better characterize the heterogeneity of senescent cells in multiple tissues of both humans and mice across the lifespan. This could provide greater insight into specific senescent cells and how best to target them.

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

One of the most efficient interventions to democratize longevity is exercise as medicine. Beyond that interventions range anywhere from practical to promising to vaporwave. If I had to pick a front runner it would be mTOR inhibition whether it be in the form of rapamycin or newer generation compounds that selectively target mTORC1. It is one of the most reproducible results throughout multiple animal models and the human data on mTOR inhibition has been very encouraging. Columbia University Medical Center, where my lab is located, has just launched the VIBRANT (Validating Benefits of Rapamycin for Reproductive Aging Treatment) study, VIBRANT is being co-led by Yousin Suh, a well-known figure in the field of aging and director of reproductive aging at CUMC. If rapamycin treatment can slow down ovarian aging in humans, that would be huge!

You have also shown that an aged immune system has a causal role in driving systemic ageing — which therapeutic strategies do you think could help tackle this?

Speaking of mTOR inhibition, Joan Mannick’s work on vaccination rates in the elderly and outcomes with respiratory tract infections or Tyler Curiel’s work on cancer models was very inspiring to my own work. Beyond that the work on enhancing senescent cell clearance via immunotherapy is very exciting. Overall, I think it is going to take a combinatorial approach to rescue some of the age-related deficits in immune function.

You recently relocated to Columbia University Medical Center — what can we expect from the Yousefzadeh lab?

I am really interested to continue studying the role of senescent immune cells and how they affect systemic aging through interorgan communication. Beyond that I am interested in the role of cellular senescence (immune cells and beyond) on adverse outcomes in pathogenic infections. Previously, I established a human senescence core at UMN and plan to do the same at CUMC to help measure biomarkers of aging in humans. Moving to New York City has put me in close contact with long-time collaborators like Derek Huffman at Albert Einstein College of Medicine and allows me to foster new collaborations. Beyond that I have a strong interest in DEIB and have participated in multiple outreach programs that work to provide opportunity and exposure to promising young scientists from all backgrounds. I want to continue my work with these programs and help mentor the next generation of scientists that want to embark on careers in aging and longevity. If you are in NYC, let’s grab a slice of pizza and talk science. My treat!

Outro

We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful!

This time we leave you with a short summary video of what VitaDAO does and why.

Further Reading

Translational longevity medicine: a Swiss perspective in an ageing country

Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing

Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons

Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in naked mole-rats

Changes in methylation-based aging in women who do and do not develop breast cancer

RNA polymerase II associates with active genes during DNA replication

Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging

Novel 1,4-Dihydropyridines as Specific Binders and Activators of SIRT3 Impair Cell Viability and Clonogenicity and Downregulate Hypoxia-Induced Targets in Cancer Cells

Senolytics Reduce Endothelial Cell DNA Damage and Telomere Dysfunction Despite Reductions in Telomere Length

Associations of Dental Health With the Progression of Hippocampal Atrophy in Community-Dwelling Individuals: The Ohasama Study

Cocoa flavanols improve peakVO2 and exercise capacity in a randomized double blinded clinical trial in healthy elderly people

Removal of senescent cells reduces the viral load and attenuates pulmonary and systemic inflammation in SARS-CoV-2-infected, aged hamsters

Prolonged fasting times reap greater geroprotective effects when combined with caloric restriction in adult female mice

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Welcome back Vitalians! Stop the press - the Impetus Longevity grants are back!

July 27, 2023

Sarah Friday

VitaDAO Letter: A New Journal, Ambassador Program, and New Steward!

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Inside this Newsletter:

The First Edition of VitaDAO’s Journal, The Longevist
VITA-FAST Recap: Redifing IP-NFT Governance
Building Collaborative Connections with an Ambassador Program
Meet VitaDAO’s New Dealflow Steward: Eleanor Davies

🧬The Longevist is LIVE

VitaDAO is thrilled to announce the launch of "The Longevist," an overlay journal that curates promising longevity research. In the inaugural edition, we present the top ten preprints from Q1 2023, as handpicked by an esteemed panel of experts. The expert curators involved in the selection process are renowned professionals and scientists in the field of longevity.

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Three a few noteworthy studies featured in the inaugural "The Longevist" feature:

"Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice". This work highlights the potential of gene therapy as a means to extend lifespan and enhance health parameters.
"P16-Dependent Upregulation of PD-L1 Impairs Immunosurveillance of Senescent Cells". This research uncovers the link between cancer, aging, and a common immune-oncology therapy, anti-PD-L1 antibodies, to effectively eliminate senescent cells.
"Multidimensional Proteomics Identifies Molecular Trajectories of Cellular Aging and Rejuvenation". This study provides a comprehensive map of the proteome in aging Saccharomyces cerevisiae, a yeast.

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🤑VITA-FAST: A Novel Funding Module

In collaboration with Molecule, VitaDAO proudly launched VITA-FAST, a groundbreaking initiative that has redefined governance of Intellectual Property (IP) and Research and development (R&D) data through the use of IP-NFTs (Intellectual Property Non-Fungible Tokens). VITA-FAST tokens represent ownership in the IP pool and grant holders the power to participate in governance, make crucial IP licensing decisions, influence experiment priorities, and govern research projects. Thus, the creation of tokenized IP pools using IPNFTs allows DAOs to cooperatively manage collective IP while co-governing development and commercialization.

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The IP pools, governed by token holder-set rules, provide solutions to existing challenges in the biotech IP market. In minimizing risk management, aiding in capital formation, and increasing patient involvement in therapeutic development, this transparent process is revolutionary. Its transparent and efficient process promises to accelerate scientific progress and foster innovation. It is possible to imagine that the creation of liquid and efficient markets can solve some of the issues in the current funding of bio IP.

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The VITA-FAST initiative was completed in conjunction with the Korolchuk Lab, a lab led by cellular biologist Prof. Viktor Korolchuk. Dr. Korolchuk's research focuses on identifying novel bioactive autophagy inducers, a process that plays a vital role in the body's cellular health. By administering potential activators to cells unable to initiate autophagy, Dr. Korolchuk aims to demonstrate the specificity and effectiveness of compounds in promoting autophagy.

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This project is still young and developing! For example, VDP-111, proposal passed on Snapshot, proposes the election of a project lead by VITA-FAST token holders and outlines a VITA-FAST governance framework.

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“This is the next phase in the evolution of decentralized patient communities, to directly contribute to, govern, and be rewarded for progressing valuable longevity research.” - Alex Dobrin

🌎VitaDAO’s Ambassador Program: Building Connections and Facilitating Collaboration

In March 2023, VitaDAO community leaders, Gavin and Cat, proposed the creation of a VitaDAO Ambassador Program. The goal of the program was to propagate DAO outreach and increase DAO engagement.

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This month in London, Bharat, Maria Maroniva PhD, and Eleanor Davies spoke at the Ambassador Program’s first official event. They touched on DeSci and VitaDAO's significant contributions to shaping the field. This event was just the beginning of a much larger initiative!

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The VitaDAO Ambassador Program aims to enable individuals from different jurisdictions to organize in-person meet-ups, bridging the gap between virtual and face-to-face interactions. Many in the DAO community will agree that the value of interaction and engagement is much higher when meeting mission-aligned people in person! To select a group of DAO Ambassadors, an application was sent out. Thus far, we have received an overwhelming response with over 170 applications to become a VitaDAO Ambassador! Stay tuned to hear more about VitaDAO’s selected ambassadors and events occurring near you!

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🗣️VitaDAO in the Wild

VitaDAO received recognition as one of the World Economic Forum’s “DAOs for Impact.” This prestigious acknowledgment celebrates the vital role of Impact DAOs in advancing scientific research and building sustainable economies. This recognition is an immense honor for us.
VitaDAO was recognized as one of the top crypto projects in Europe for 2023, according to Coingecko's report.

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📣Community Approved: What YOU voted for!

Thanks to the support of the VitaDAO community, multiple proposals successfully passed this month! Notable proposals include:

‍VDP-89 Passed! This proposal was an assessment of ExcepGen Inc's RNA therapeutics for longevity. In passing, this proposal signifies that VitaDAO supports funding $100,000 to develop a new generation of vaccines with this RNAx platform.

‍VDP-93 Passed! As a result of this VDP, VDP nomenclature, and phase 2 proposal workflow will be altered to ensure visibility of risks and legal review before on-chain voting.

‍VDP-96 Passed! With this proposal, VitaDAO will provide a loan of $400k to VHF, secured against the underlying equity in companies VHF.

‍VDP-101 Passed! As a result, VitaDAO will set up an operating company in Canada to execute VitaDAO Coordination Working Group functions such as finance, member services, and service provider management.

‍VDP-102 Passed! VitaDAO will now implement 7 new tools to better manage the growing portfolio of the VitaDAO projects more effectively and efficiently.

‍VDP-107 Passed! As a result of VDP-107, Laurance Ion stepped down as Dealflow Steward and Eleanor Davies was elevated as Interim Dealflow Steward.

VDP-108 Passed! With the passing of VDP-108, VitaDAO will complete an annual review of compensation/governance allocations as outlined in VDP-72.

💪Exercise Your Right to Vote

Check out VitaDAO’s governance hub (Discourse) to engage with, vote on, and discuss proposals before they are moved to Snapshot. Your input is invaluable, and together, we can shape the future of VitaDAO and accelerate decentralized science.

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👋Meet VitaDAO’s Dealflow Steward: Eleanor Davies

Eleanor Davies, VitaDAO’s New Dealflow Steward, brings a wealth of experience in fund operations, healthcare, and biotech consulting. A graduate of the University of Manchester, she has grown as a professional serving in Marwood Group healthcare and biotech consultancy, co-founding a company and helping to raise funds, deploy capital, and manage the portfolio at ODX, a Silicon Valley-based accelerator. More recently, she has actively engaged with the DeSci community, serving as COO of LabDAO. This month, I had the privilege of sitting down for a brief chat with Eleanor:

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It’s great to meet you, Eleanor! I would love to know a little more about your background. How did you first get involved in VitaDAO?

Hi! Thank you for featuring me in the VitaDAO newsletter. A little about me: I come from a less traditional background. I first started off studying languages, combined with international policy, business, and history. This gave me the flexibility to look into different industries that were a good fit for me. I found that I had an advantage as a language learner in the UK, because not many of us Brits speak other languages. If you show you are highly motivated, ambitious, and willing to take on new challenges, it is generally quite well-regarded by graduate employers.

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From the start, I have always had a lot of side projects and interests. I have a long-standing curiosity in biotech, specifically in pushing the limitations of human biology - is life extension really possible? How would this work in practice? I started by working at IBM, and later in M&A advisory across industries in the German speaking (DACH) mid-market for private equity transactions. With time, I found myself gravitating towards the biotech side of M&A.

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Between then and working in consulting, I co-founded an AI-based recruitment company - that was a lockdown existential crisis! It came out of the frustration I witnessed by the number of people who lost their jobs during the pandemic. What if I could change the way of looking at the job market? Tldr; it didn't work out, but it was a great learning opportunity. There was a market fit and we were generating revenue, but it was more about the team dynamic.

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I then worked in consulting mid- to large-cap private equity clients for healthcare and biotech transactions. The consultancy specialized in advising the commercial implications of political and regulatory change across the UK and EU to domestic and transatlantic clients. Early during my tenure, the consultancy Director left, so I had to step up and lead in the role of Director - from the experience level of an Analyst. It was a very steep learning trajectory, but I saw it as an ideal opportunity to step up. I did a lot of self-directed learning, not only for interfacing with clients, but also for company growth, negotiation, and leadership. Alongside the consulting, I also doubled company sales targets, doubled the pipeline for marketing prospects, and transformed the marketing channels. A lot of progress in a short amount of time!

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I then moved on to work at On Deck’s ODX, which is an accelerator based in Silicon Valley. I was working in fund operations, working across raising funds to deploying capital, conducting due diligence, and portfolio management. Almost similar to what I’m doing at VitaDAO today, Sadly, due to the market conditions, I had to leave ODX, but this allowed me to pursue my nerdy side interest - DeSci!

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That leads me to today. I had been a “lurker” in both the VitaDAO and LabDAO Discord servers for some time and finally decided to do something about it. I was introduced to Niklas from LabDAO at DeSci Berlin - I was so motivated by the vision, the highly intellectual community, the level of passion, and mission alignment in the ecosystem. So, I made the leap! For me, DeSci could be hugely disruptive for the scientific community, funders, policy makers, and beyond. In the consulting world, I had seen a misalignment between politicians and regulators, funders and companies, healthcare insurers, and patients. Not only in capital allocation, but in communication, education, and expectations. For me, a community-first, community-governed approach could create the new standard.

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As part of the core team at LabDAO, Niklas and I led the fundraise ($3.6M). It was a challenging time to raise in a bear market, but it was gratifying upon completion. I also worked across legal, tokenomics, investor relations, and treasury management… all-in-all, a bit of Swiss Army Knife-ing. It was hugely satisfying to see LabDAO through to maturation. During its PMF phase, LabDAO pivoted to tools versus the Lab Fund, which I was to lead. As everything was up and running, my role eventually phased out. By that time I was closely following VitaDAO and knew that there was a need for somebody to work in deal flow. It was the ideal time to join. Now, I’m still advising LabDAO, but full-time at VitaDAO.

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You mention that you find DeSci to be promising. What drew you to DeSci and where do you see DeSci going in the future?

There are many aspects that I find interesting about DeSci; for me, I’m excited about tools, funding, and globally distributed venture building. This is why I am confident in VitaDAO and why I’m motivated to make it succeed. We are looking at a broader pool of capital for higher risk funding opportunities, and zooming in on the early, idea stage of lab research projects. The IP-NFT is particularly interesting here. VitaDAO and the community, as part of the Decentralized Tech Transfer Spinout framework, work with the scientific team to build projects from idea, to IP commercialization, to maturation. To my knowledge, this hasn't been done before with Web3 and DeFi technology.

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Also, never before has there been such a globally distributed community of mission-aligned people to work together in this way. The thing that I find special about the VitaDAO community is that world leading talent, especially in the dealflow working group, participate out of sheer interest. There is a real mission alignment here. And despite some DAO inefficiencies, its youngness, and teething issues, DAO members stick around.

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I’m also excited about the IP-NFT, pioneered by Molecule. The non-dilutive funding, and the ability to get more proceeds for project development in this manner is a pretty innovative way - also high risk, but high reward - of funding a project and getting more community interest. It promotes openness, making research a lot less siloed and more collaborative. And even if it doesn't work out at least we’ve tried. But, we’re making waves already.

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You’ve touched on the strengths of DeSci and some of the strengths of VitaDAO in particular. Is there a particular VitaDAO project you are most excited about?

There is - Matrix Bio! I’m also PM’ing that alongside Anthony Schwartz as a part of the Builder Squad. It's a moonshot, but this could have a huge payoff for the LongBio world. We are working with one of the world's leading aging researchers, Vera Gorbunova. Not only is she a pleasure to work with, but also her research is groundbreaking. The fact that she has her belief in VitaDAO to incubate her project towards a point of commercialisation, is compelling and exciting.

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Another would be Viktor Korolchuk’s autophagy project. Again I think that not only is it an under-resourced side of longevity aging research, but also that he and the Newcastle University have the conviction that VitaDAO can build and incubate the project, using an innovative funding and governance method. This is a strong signal for me.

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As a result of VDP-107, you’re now Longevity Dealflow Working Group Steward. In your short time in this role, what has surprised you the most about VitaDAO? What are you most excited about in taking on this role?

First of all, I’m very very grateful for those who voted in favor and have the confidence in me to be the Dealflow Steward. What am I most excited about? I’d say the support of the community. Putting the collective wisdom in the deal flow working group to great use! We have so much talent; so many amazing people are eager to get involved with the opportunities that come our way. For me, something that dealflow needs is great operations. It is the cornerstone of making things work: ramping it up and scaling it up to a mode of maximum efficiency. I’d also like to ramp up Tech Transfer Office outreach, project sourcing, and both start-up and early-stage IP projects. And have an engine that enables this to happen: a great funnel and a great process. As boring as they sound, you need these to make things work.

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Also knowing how to engage with the community in different stages. We have so many talented people who are amazing in different aspects of the deal flow process. It is knowing what incentives are, and how contributors should be incentivized in the DAO from the start; something which is still being tested out in the Web3 ecosystem. And, how can we be efficient enough to become the world's best longevity research funding organization? How can we become the first place that people think of when looking for funding, looking for education, or an amazing community, when they think of longevity? That is what I want for VitaDAO. I want it to be on the UN’s radar. Dream big.

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When I first joined the VitaDAO Discord, I initially had no idea about all the work that goes on behind the scenes at VitaDAO on the Dealflow side of things. There is a lot more work that goes on before projects are presented on Discourse.

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It's true. From automating the dealflow funnel to refining IP strategy with projects, to Friday pitch sessions and onboarding new members - we are taking VitaDAO from 0 to 1. If anyone wants to get involved, come to an onboarding call! I lead the calls with community member, Ryan Spangler, and it’s a great first point of entry to join the working group. We go through terms, voting, the nuances of dealflow, DAO-ism, and how VitaDAO is different from a traditional venture studio or VC. Why is it a not-for-profit? What is an IP-NFT? I find the best way to get great engagement when onboarding new community members to deal with the flow, is to have a chat instead of reading through documentation. To anyone who wants to get involved, feel free to reach out!

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Where do you see VitaDAO 100 years from now?

I wonder if VitaDAO will have solved aging by 100 years? First off, I want VitaDAO to be the biggest name in longevity. This involves being a well-oiled machine. People come in because they’ve heard about our reputation in longevity and for being the best DAO that works to maximum efficiency. I’d like to have had successful exits (everyone wants successful exits), and successful spinouts that will have IPO'd. Happy founders. Happy community members. A cyclicality of members who come, build companies, grow it, scale it, exit, come back, and continue. On the network state side, bridging successful spinouts with the possibilities achieved by a longevity network state is another goal. Leveraging the more friendly regulatory pathways in specific jurisdictions could be an ingenious way that VitaDAO can expedite scientific progress - if done correctly. Zuzalu was an amazing way of showing us this potential. What about novel cures or treatments that are more financially accessible - or generally more accessible. That’s another dream, and I hope we can weigh in there, too. It'd be amazing for VitaDAO to be a front-runner in changing how cures come to market and also how we behave around human health- and lifespan.

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I’ve enjoyed chatting with you today! Before we end, any closing thoughts for readers?

Again, I am very very appreciative of being the Steward in Dealflow. Of having the support of the community. Reach out if you are interested in getting involved in dealflow, interested in knowing more about spinouts, the builder squad, and generally getting involved. If you are a builder. If you are an operator. If you’re an academic. If you are interested in pursuing a project, a side project, and looking for funding. Also please reach out or apply. I am always interested in looking for new opportunities and the same goes for the working group. I’d also love to hear from the community about why they are interested in longevity: what they see in VitaDAO, what keeps people coming, and how we can collectively build on that vision. Because it is not just the Stewards, it’s everyone here. Which is what makes this so unique!

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Thank you for your time today! I’m excited to see a female steward! It is exciting to continue to see more women get involved as members of the VitaDAO community!

I would love to use this feature as an opportunity to encourage more young women to step up and be a part of the conversation. They are wonderful and I love working with them, but the ratio of men to women in scientific research and web3 is still disproportionate. I see DeSci as a startup in itself. It is an emerging industry, and therefore, the perfect opportunity to pave the way to create new standards. To make a place for ourselves. I want to see more women!

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🤝Thanks for Reading!

Want to get involved in VitaDAO? Have a special skill set? Join an onboarding meeting to learn more about ways to contribute to the growing community! Want to stay up to date with all that's going VitaDAOn? Join us on Discord, subscribe to our Twitter, and follow our Instagram!

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Additionally, VitaDAO's website (https://www.vitadao.com/) contains updated information on funded projects and a treasury dashboard.

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Transcending Boundaries: Exploring Cryonics, Drug Repurposing, and the Future of Aging Research with Prof. Joao Pedro De Magalhaes on The Aging Science Podcast by VitaDAO

July 21, 2023

Awareness

Longevity

Transcending Boundaries: Exploring Cryonics, Drug Repurposing, and the Future of Aging Research with Prof. Joao Pedro De Magalhaes on The Aging Science Podcast by VitaDAO

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In today’s podcast we talked with Prof. Joao Pedro De Magalhaes (@jpsenescence) about some exciting topics ranging from his current work, to philosophy and science fiction. Among other things we talked about cryonics, transhumanism, the need for a “Sputnik moment” in longevity research, fish oil and rilmenidine for longevity, inflammaging, and cellular reprogramming.

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It was a pleasure to talk with Pedro because we both share very similar views about aging, longevity, transhumanism and other topics.

Short CV - Joao Pedro De Magalhaes

Prof de Magalhaes graduated in Microbiology in 1999 from the Escola Superior de Biotecnologia in his hometown of Porto, Portugal, and then obtained a PhD in 2004 from the University of Namur in Belgium. Following a postdoc with genomics pioneer Prof George Church at Harvard Medical School, in 2008 Prof de Magalhaes joined the University of Liverpool and, in 2022, he was recruited to the University of Birmingham where he leads the Genomics of Ageing and Rejuvenation Lab (http://rejuvenomicslab.com/). His lab studies the ageing process and how we can manipulate it to fend off age-related diseases and improve human health. Prof de Magalhaes has authored over 100 publications and given over 100 invited talks, including three TEDx talks. He is also CSO of YouthBio Therapeutics, a US-based biotech company developing rejuvenation gene therapies.

Pedro is the author of the widely read senescence.info https://jp.senescence.info/ webpage and of the @jpsenescence twitter account.

The reputation problem for aging research

“If you tell people that you're trying to discover a drug for Alzheimer's, everybody loves it. If you say you're discovering a drug for cancer, everybody loves it. If you say you're discovering a drug for aging, people ask why? I mean, why you want to do that? ... it generates a lot of questions and even opposition, not by everyone, but for some people.” (Joao Pedro De Magalhaes)

Many people think that lifespan extension is science fiction. However, even that is an understatement of the problem because lifespan extension is rarely portrayed at all or positively portrayed even within sci-fi literature. Pedro and I discussed possible reasons for this. One idea is that the finality of death is so ingrained and terrifying that people refuse to think about anything concerning death as a coping mechanism. This will include even positive things like lifespan extension. It is absurd to consider a future where interstellar travel is possible but not radical lifespan extension. Yet this is what is often portrayed in science fiction!

We spent the first half of the podcast digging into the psychology and philosophy of aging research and trying to figure out what will make people believe that aging research is necessary; and that we will be able to slow aging in the not-too-distant future. Even if you are not interested in aging research I think the first part is worth a listen. One of our key insights was that people who are afraid of living longer, and who are afraid of technology, now, will most likely change their opinion once the technology matures. The great majority will be keen to use longevity therapies and only a fringe minority will continue to oppose the technology:

“So, I mean, if you ask people, hey, if I have a little pill that will make you live 200 years in good health, if you ask around, there's a lot of people going to say, no, I don't want that. But trust me, if that were introduced, and people started taking that pill and being healthier, everybody would want it. That's just, you know, inevitable.“ (Joao Pedro De Magalhaes)

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Transhumanism and radical lifespan extension communities

Transhumanism describes a philosophy that contends we should transcend or improve human nature using technology. The idea is that human biology is flawed and that life could be much improved if we embraced technology to improve ourselves. Such technology includes but is not limited to things like artificial intelligence, lifespan extending treatments or cryonics.

“Radical” lifespan extension tries to differentiate itself from the modest goals of regular biogerontology. Advocates for radical lifespan extension believe that we need to extend human lifespan significantly, by decades or centuries, and that we may be on the cusp of success. In the podcast we discuss that while we might not be that close to this goal, the idea of radical lifespan extension itself is worthwhile. There is no reason why we cannot have ambitious dreams.

We also discussed the recent history of the online longevity movement. Many communities, back when bulletin boards, forums and mailing lists were popular, catered to transhumanists and life extensionists of the early days, including the now renamed “Immortality Institute”.

We can consider Vitadao as a continuation and extension of these old communities. It is attractive not only to transhumanists, but also crypto enthusiasts, web3 developers, investors, scientists, the general public etc. If you want to be part of this community, here is the link to their discord:
https://discord.com/invite/vitadao

Cryonics

The idea of cryopreservation is to freeze one’s body right after death, for a non-zero chance of revival in the future. The hope is that future technology might be able to reverse the damage that led to death and also reverse the damage induced by cryopreservation. Although this is a tall order the likelihood is probably not zero, even if it is very low. In that way cryonics is a modern, transhumanist Pascal’s wager.

In the meantime, while we research cryobiology with the long term goal of preserving whole organisms, every little advance we make can be used to improve the storage of donated organs, hence benefiting humanity now and not just in the future.

This is the same idea as with radical lifespan extension. One can have an ambition long term goal that is reached through reasonable intermediate steps.

Repurposing of drugs

Even though many drugs are approved for one condition they could also work for another. However, in many cases no one has tested this yet. In the process of repurposing, also called repositioning, scientists are trying to find new uses for such old drugs. If we want to cast our net wider, we can also consider drugs that passed phase II or phase III trials but were not pursued for whatever reasons. These drugs will also have a decent amount of safety data in humans and will be backed by good efficacy data.

One strategy Pedro uses to find drugs that could be repositioned is based on gene expression signatures. The idea is to find drugs that show similar gene expression to that of caloric restriction. This strategy allowed him to pinpoint allantoin as a potentially life extending drug and later rilmenidine, an approved, although rarely used, anti-hypertensive drug, that might operate via a similar mechanism (Calvert et al. 2016, Bennett et al. 2023).

Immunology of aging, inflammaging and the power of meta-analysis

In his meta-analysis of transcriptomic data Pedro found that in mammals many genes change with age (Palmers et al. 2021). Some highlights include decreased expression of mitochondrial genes, perhaps consistent with decreased mitochondrial biogenesis and function, but also increased expression of pro-inflammatory factors.

“The preponderance of inflammatory and stress response genes [over-expressed with aging] is reminiscent of the inflammageing hypothesis [14], which argues that ageing is caused by steadily failing responses to stress, in particular responses to the increased antigenic load that comes with age.”

In this context we also discussed new single sequencing data, suggesting age-related infiltration by immune cells and Pedro’s work in a new company focusing on reprogramming. One of the ideas that we discussed was that immune cells are generally a good target for rejuvenation because they are accessible and affect many processes in the body.

The Interventions Testing Program (ITP)

The NIA’s Interventions Testing Program is a large mouse study that seeks to rigorously test which compounds extend mouse lifespan. Anyone can propose a compound to be tested and during the podcast I suggested to Pedro he could submit rilmenidine to the ITP. If you want to learn more about this important study, we had a thorough discussion of the ITP in my podcast with Rich Miller.

https://www.vitadao.com/blog-article/the-mouse-longevity-chronicles-unraveling-aging-with-dr-richard-miller-during-the-aging-science-podcast-by-vitadao

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Further reading – aging as a software design flaw

A controversial take we discussed during the podcast was Pedro’s idea that aging has programmatic features. I will not go too much into details here and the interested reader can check out his paper (de Magalhães 2023) and the below tweetorial, as well as our podcast discussion.

References

Bennett, Dominic F., et al. "Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1‐imidazoline receptor." Aging Cell 22.2 (2023): e13774.

Calvert, Shaun, et al. "A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans." Aging cell 15.2 (2016): 256-266.

de Magalhães, João Pedro. "Ageing as a software design flaw." Genome Biology 24.1 (2023): 51.

The new webpage of the Immortality Institute: https://www.longecity.org/forum/

Pedro’s linkedin: https://www.linkedin.com/in/joaopedrodemagalhaes/

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We talked with Prof. Joao Pedro De Magalhaes about about cryonics, transhumanism, the need for a “Sputnik moment” in longevity research, fish oil and rilmenidine for longevity, inflammaging, and cellular reprogramming.

July 10, 2023

Maria Marinova & Rhys Anderson

Awareness

Longevity

Newsletters

June Longevity Research Newsletter

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Introduction

Welcome to this month's newsletter, where we delve into the philosophical dichotomy at the heart of longevity research.

Two broad perspectives pervade the field. Firstly, we have the 'death defiers', individuals who perceive mortality as a malady, akin to a disease that can be vanquished. These aspirants advocate for a significant postponement, if not complete eradication, of death. They envisage a future where humanity capitalizes on biotechnology, genetics, and regenerative medicine advancements to conquer the final frontier - death itself. They approach aging, particularly from age-related causes, as an adversary to be defeated.

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On the other end of the spectrum, we find the 'quality adherents'. These individuals think that lifespan is finite, but champion improving healthspan as a tangible goal, believing in 'healthy aging'. This focuses on extending the phase of our lives free from chronic diseases, where we maintain physical and mental fitness.

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In this edition, we put the spotlight on Prof. Joao Pedro de Magalhaes, a distinguished researcher and a keen advocate of lifespan extension. We'll share insights from our recent interview, where he shares his perspectives on his work and the motivation behind it. Also, we explore the intriguing discourse ignited by a Tweet from Balaji, which dared to voice support for the death defier's view, sparking a vibrant discussion on Twitter.

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VitaDAO-funded Research Projects

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The VITA-FAST Token Sale concluded with a 1700% oversubscription!!!

VITA-FAST token holders have exclusive control over the licensing function of Newcastle-Korolchuk IP and governance over the direction of the research and development of that IP.

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Congratulations to the ExcepGen Inc team for receiving a 80.66% majority in the tokenholder vote to secure VitaDAO funding and support for their project aiming to optimise RNA Delivery for Longevity Therapeutics

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Longevity Literature Hot Picks

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Preprint Corner

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Check out this month’s longevity preprints - will any receive a coveted spot in the Q2 Issue of the Longevist? Watch this space!

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Premature Aging and Reduced Cancer Incidence Associated with Near-Complete Body-Wide Myc Inactivation

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Measuring C. elegans Ageing Through Non-Invasive Monitoring of Movement across Large Populations

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The blood has something to say: A hematology-based clock to measure aging in mice

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Cognitive Rejuvenation In Old Rats By Hippocampal Oskm Gene Therapy

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Developmental mitochondrial Complex I activity determines lifespan

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The Role of Respiratory Complex IV in Lifespan Length and Quality

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The molecular clock in long-lived tropical trees is independent of growth rate

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Uncoupling of lifespan and reproductive tradeoffs by dietary methionine and one-carbon metabolism

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Measuring C. elegans Ageing Through Non-Invasive Monitoring of Movement across Large Populations

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Published Research Papers

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Distinct longevity mechanisms across and within species and their association with aging

The study analyzed RNA from 41 mammals to decipher longevity mechanisms. Findings include common and unique gene markers related to lifespan, revealing a connection between long-lived species, ancient genes, and age-related changes.

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Human PBMC scRNA-seq–based aging clocks reveal ribosome to inflammation balance as a single-cell aging hallmark and super longevity

A new aging clock model, using blood single-cell RNA sequencing data, suggests supercentenarians (SCs) have a biological age between 80.43 and 102.67 years. SCs have more cells and types with high ribosome levels, potentially contributing to their low inflammation state and slow aging.

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Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

The study identifies senescent macrophages and endothelial cells as primary in KRAS-driven lung tumors in mice. Senolytic removal or macrophage depletion reduces tumor load and boosts survival. It underlines the crucial role of senescent macrophages in lung cancer progression, suggesting potential therapeutic strategies.

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Targeting lymphoid-derived IL-17 signaling to delay skin aging

Aging skin sees increased inflammation due to a shift towards IL-17-expressing immune cells, according to single-cell RNA sequencing of mouse skin. Blocking IL-17 signaling in vivo reduces skin inflammation and delays age-related skin changes.

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Resistance training rejuvenates aging skin by reducing circulating inflammatory factors and enhancing dermal extracellular matrices
Both aerobic training (AT) and resistance training (RT) improved skin elasticity and structure in middle-aged Japanese women. RT uniquely increased dermal thickness and biglycan levels, suggesting different effects of AT and RT on skin aging.

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The blood has something to say: A hematology-based clock to measure aging in mice

A biological age clock in mice was developed using hematological markers from longitudinal studies. The deep learning-based biological age prediction correlated well with actual age and aging acceleration linked with lifespan.

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Restoration of CPEB4 prevents muscle stem cell senescence during aging

Aging affects mitochondrial function in muscle stem cells (MuSCs), leading to senescence. The study found downregulated CPEB4, which supports mitochondria, in aged tissues. Restoring CPEB4 improved MuSC function and prevented senescence.

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Comparative analysis of calcified soft tissues revealed shared deregulated pathways

This study aimed to understand the mechanisms and tissue-specific changes associated with pathological calcification in various soft tissues. The authors found that down-regulation of intracellular transport pathways and up-regulation of inflammatory pathways were common features.

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Impact of social isolation on grey matter structure and cognitive functions: A population-based longitudinal neuroimaging study

This study examined the impact of social isolation on brain health and cognitive decline in a population-based longitudinal MRI study. The findings revealed that social isolation was associated with smaller hippocampal volumes, reduced cortical thickness, and poorer cognitive function, suggesting that social isolation contributes to brain atrophy and cognitive decline. The results highlight the potential of promoting social networks as a means to reduce the risk of dementia.

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Published Literature Reviews

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Aging - What it is and how to measure it

This review argues for the need to focus on general biological aging rather than lifespan, which can be influenced by specific pathologies. It suggests a framework that accounts for phenotypic changes over an average lifespan, applicable across multiple organisms.

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The meaning of adaptation in aging: insights from cellular senescence, epigenetic clocks and stem cell alterations

The study suggests features like cellular senescence, epigenetic aging, and stem cell changes may be adaptations, not aging drivers. It proposes 'damaging adaptations' may accelerate aging despite short-term benefits. This insight may impact antiaging interventions.

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Taurine linked with healthy aging

Taurine, a semi-essential amino acid, plays a key role in animal development and health. It is linked to benefits in human metabolic and inflammatory diseases, and recent studies indicate it aids health in aged animal models.

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Chronic inflammation and the hallmarks of aging

The updated aging hallmarks include dysbiosis, impaired macroautophagy, and "inflammaging". These factors interact, affecting age-related diseases like cardiovascular issues, neurodegeneration, and cancer. Understanding this is key in aging research.

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Are we measuring what matters to older people?

Comprehensive geriatric assessment is key in elderly care, emphasizing personalized biopsychosocial evaluations. However, health systems often neglect person-centered outcomes, risking suboptimal care. Prioritizing meaningful outcomes for older individuals is vital.

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And finally - a special FEBs issue of reviews and research articles on Senescence in Ageing and Disease

Job board

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Van Heron Labs is hiring for two positions very shortly - a senior scientist and an RA/Lab tech. Please reach out directly for more info: rvaught@vanheronlabs.com

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Clinical Research Assistant position at the Healthy Longevity Translational Research Program is open. Apply to Yong Loo Lin School of Medicine at NUS to work with Andrea Maier’s team.

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Oliver Hahn’s lab at Calico is hiring scientists & senior scientists to develop novel and exciting experimental platforms to understand and treat age-related diseases of the CNS

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Master Fellowship Programme

Do you hold a BSc degree in life science and are eager to explore the field of ageing research in a cutting-edge and interdisciplinary environment of the Cologne ageing cluster?

The Cologne Graduate School of Ageing Research offers a new Master Fellowship programme for excellent and motivated students that wish to learn more about ageing research.

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Are you interested in studying brain ageing?

Oliver Hahn’s lab at Calico is hiring scientists & senior scientists to develop novel and exciting experimental platforms to understand and treat age-related diseases of the CNS. Apply here.

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News

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Healthy Longevity Talent Incubator is open for applications!

When: July 3-13, 2023

Where: Singapore

Who: Talent (from all disciplines) eager to learn more about Healthy Longevity!

Application form

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Dr. David Sinclair Assumes Presidency of the Academy for Health and Lifespan Research

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Police got called to an overcrowded presentation on “rejuvenation” technology

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Chris Hemsworth’s Center Partners with Lifespan.io, to Make Health, Wellness and Longevity Education More Accessible for All

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Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution

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Nature Aging enters the Journal Citation Reports 2023 - ranking #1 in Geriatrics & Gerontology with a first Impact Factor over 16 and a JCI of 3!

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Prizes

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Rewarding the most impactful research in longevity

Substantially increasing the human lifespan. The Amaranth Prize gives no-strings attached funding to the best research in Longevity.

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Articles

Last month’s article proposing Taurine as a driver of aging has sparked a lot of discussion around its relevance for human healthspan:

Taurine supplement makes animals live longer — what it means for people is unclear

In the Pipeline | Aging and Lifespan: Taurine

Taurine improves the health and longevity of mice and monkeys – but what about humans?

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Should I worry about my VO2 max?

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Meet Rapamycin, the Drug That Could Delay Menopause

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Time-restricted feeding makes the mouse run like a pro

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Defining a longevity biotechnology company

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Transformer-based aging clock provides insights into aging

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Navigate the emerging field of longevity

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How seeing corpses reduces the lifespan of flies

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Fasting Mimetics: Health And Longevity Benefits With Dr. Valter Longo

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Cutting Calories To Add Years Finally, We Have Evidence That Caloric Restriction May Increase Human Lifespan

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The billion-dollar search for immortality

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Finding joy at age 100: Talking to centenarians about living their best life at any age

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Conferences, Workshops and Webinars

World Aging and Rejuvenation Conference (ARC)

17-18 July, Frankfurt, Germany

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Ending Age-Related Diseases

10-11 August, NY, USA and virtual

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