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.

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.

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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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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:

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

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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! 

Want to stay up to date with all that's going VitaDAOn? Join us on Discord, subscribe to our Twitter, and follow our Instagram! You can also find updated information on VitaDAO's funded projects and a treasury dashboard on our website. 

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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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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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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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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

• Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
• Senescent alveolar macrophages promote early-stage lung tumorigenesis

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

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

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

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

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

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

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

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

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

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

Pan-primate studies of age and sex

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

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

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

Published Literature Reviews

Chronic inflammation and the hallmarks of aging

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

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

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

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

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

Spatial mapping of cellular senescence: emerging challenges and opportunities

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

Job board

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

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

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

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

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

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

News and Media

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

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

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

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

8 healthy habits that may add 24 years to your lifespan

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

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

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

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

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

Peter Fedichev Explains His Theory of Aging

Healthy longevity is not only for the neurotypical

Resources

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

Prizes

Rewarding the most impactful research in longevity

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

Conferences

Ending Age-Related Diseases

10–11 August, NY, USA and virtual

Longevity Summit Dublin

17–20 August, Dublin Ireland

Aging Research & Drug Discovery (ARDD)

28 August — 1 September, Copenhagen, Denmark

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

6–8 September, London, UK

RAADFest

7–9 September, LA, CA, USA

Expo and Convention: Independent Ageing 2023

13–15 October, Aichi, Japan

Seno-Therapeutics Summit 2023

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

Tweet of the Month

Adam Gries (@adamgries):

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

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

Podcasts and Webinars

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

7 August, virtual

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

9 August, virtual

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

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

We also interviewed Sergey Young!

NUS Medicine’s Healthy Longevity Webinar Series

This month:

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

AI and robotics | Dr Alex Zhavoronkov

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

Funding Opportunities

Research: Impetus Longevity grants

Micro-grants: VitaDAO Longevity Fellowship

Interview with Matthew Yousefzadeh

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

What inspired you to enter longevity research?

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

How has the field changed since you started?

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

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

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

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

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

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

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

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

Is ageing a disease?

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

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

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

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

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

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

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

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

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

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

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

Outro

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

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

Further Reading

Translational longevity medicine: a Swiss perspective in an ageing country

Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing

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

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

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

RNA polymerase II associates with active genes during DNA replication

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

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

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

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

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

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

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

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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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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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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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Longevity Summit Dublin

17-20 August, Dublin Ireland

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Aging Research & Drug Discovery (ARDD)

28 August - 1 September, Copenhagen, Denmark

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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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Zuzalu talks recordings are out!

https://zuzalu.streameth.org/archive

Tweet of the Month

This month we leave you with some food for thought from a leader in the crypto world, Balaji Srinivasan

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Balaji: CHEATING DEATH IS GOOD

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People often associate performance enhancing drugs with “cheating”. And of course it’s true that if you’re an athlete it’s cheating and against the rules. But there’s nothing wrong with cheating death.

[Full text]

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Also check out this interesting thread from Healthspan on Blagosklonny's theory of cellular hyperfunction

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Podcasts and Videos

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Wired: Have a Nice Future: Gideon Lichfield and Lauren Goode talk to Celine Halioua, the founder and CEO of Loyal—a company that researches drugs to extend the lifespan of dogs.

Brain Boosting Effects of Young Blood Revealed

Lifespan news talk about the most problematic yet perhaps one of the most promising cures for aging, young blood. Heterochronic parabiosis is a well-known aging intervention in mouse studies, but it happens to be one of the more, shall we say, unrealistic procedures for humans.

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Interview with Prof Joao Pedro de Magalhaes

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Joao Pedro de Magalhaes is a world renowned leader in aging research using computational and experimental approaches to untangle the secrets of human aging. He is the Chair of Molecular Biogerontology at  the University of Birmingham, and currently leads the Genomics of Aging and Rejuvenation Lab there.

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What inspired you to enter longevity research?

I have never made it a secret that I work on aging and longevity to cheat death. When I was a child and realised that my parents and everyone I love would age and die, I made it my mission to develop a cure for aging.

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

I’m very interested in the idea that programmatic features originating in development contribute to aging. I think it’s a very overlooked area, as most scientists assume that aging is caused by molecular and cellular damage. However, I think some genetic programs originating in development continue later in life and become detrimental. That said, it’s clear that some forms of damage contribute to certain aging phenotypes, like for example mutations contribute to cancer. I also think it’s important we keep an open mind and explore different avenues, because at the moment we don’t know what are the drivers of human aging.

How has the field changed since you started?

In some ways, the field has changed substantially in the past 20 years because there is a lot more focus on translational research, many more companies, more investors; there has been a big growth in the longevity field. This growth has been catalysed by the discovery of longevity manipulations in animal models, and the huge medical and commercial potential of applying those to humans. In that sense, there has been a huge growth in longevity pharmacology and in longevity biotech in general. That said, at the mechanistic level things have not progressed so much, we still have a very poor understanding of what causes human aging.

What mistakes do you think the longevity field has made?

I think a common mistake in science is being overly conservative. This issue is not limited to the longevity industry; you can observe it in other fields as well, like Alzheimer‘s. Scientists, investors and funding bodies are often conservative. What this means is that scientist and companies tend to focus on the same mechanisms, targets and pathways, as I pointed out in a recent article (https://www.sciencedirect.com/science/article/pii/S1359644621000982?via%3Dihub). I think we need to be more creative in the field, and in fact, I would argue that the creativity is there, it’s just not well supported because most people and institutions are risk-averse. We need to be bolder.

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

There have been some important discoveries in the past 10–20 years. One important discovery was that rapamycin extends mouse lifespan even in middle-aged animals. It showed we can significantly extend lifespan in animal models with pharmacological interventions. The discovery of epigenetic clocks by Horvath and others has also been an important breakthrough, even if we don’t understand the underlying biological mechanisms very well. In addition, the discovery of cell rejuvenation with partial reprogramming has been an important discovery, although we still need to establish whether it can be applied to retard aging in whole organisms.

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

Be bold, be creative, don’t be afraid to take risks and to create an environment that allows others to take risks. Aim high, don’t settle for the low-hanging fruit.

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

As I mentioned above, there has been a shift in the field from understanding ageing to developing interventions. I would argue that going back to basics and trying to understand the underlying drivers of human aging is still the big question, and if we could better understand the causes of human aging this would be a watershed moment and open the door to much better therapies. Of course, trying to understand the aging process is hard; it’s a lot easier to give drugs to worms or flies and see if they live longer than trying to figure out why human being age. Studying aging processes also requires a sustained long-term investment that most funders and companies are unwilling to provide.

Is ageing a disease?

That’s a good question, but I suppose it depends on the definitions of aging and of disease. As such, I think it’s more of a semantics question than a biological one. Regardless of the definitions, aging is a trigger for diseases, and it should be targeted therapeutically.

In your recent paper you compare aging to a software design flaw. Can you briefly summarise this theory and discuss how it has influenced your approach to studying aging and potential impact on the development of interventions to delay or reverse age-related decline?

The hypothesis is that ageing is not just driven by damage to the hardware, defined as cells and their components, but rather by design flaws in the software, defined as the DNA code that orchestrates how a single cell becomes an adult human being composed of billions of cells with many different identities. My view is that some processes set in motion by the genetic software during development continue in adulthood and become detrimental as a form of antagonistic pleiotropy. If aging is an unintended outcome of a program this explains the accuracy of epigenetic clocks, it explains species differences in aging as developmental rates correlate very strongly with aging rates in mammals, and fits the major genetic, dietary, and pharmacological manipulations of aging in animals. As a result, we should see aging is an information problem.

Seeing aging as the outcome of flaws in our software has important implications for studying and developing interventions for aging. Traditional anti-aging interventions targeting damage, like oxidative damage and telomere shortening, will – I predict – have limited success. By contrast, aging therapies will only be effective if targeting the software rather than the hardware. As such, interventions like a computer restart such as partial reprogramming could hold clues for future interventions.

Your research involves using computational biology and machine learning to better understand the molecular mechanisms of aging. Can you discuss the most promising applications of these techniques in the field of aging research and how they can accelerate academic research?

The problem we have in the field, and others, studying complex diseases and phenotypes, is that aging and longevity derive from the interactions of multiple genes with each other and the environment. In that regard, we need to take a systems biology approach to study how the components of the system interact with each other and ultimately understand the whole from its parts. So, in a way, we are trying to make sense, trying to tackle the complexity of biology. Using these computational methods, we can identify and prioritise new genes, drugs and pathways. For example, we have done some recent work on drug repositioning in the context of aging, revealing new existing drugs that, in animals, extend longevity and may ultimately have human applications (https://onlinelibrary.wiley.com/doi/10.1111/acel.13774). Also for a recent talk on computational approaches and aging please see:
https://www.youtube.com/watch?v=VhaAGwh012k

Your research has also covered comparative biology of aging, looking at how different species age and what factors contribute to differences in longevity. What have been some of the most surprising or interesting findings from this work?

I have always been fascinated by species differences in aging. I’ve always liked animals and used to have many different pets as a child. It is fascinating how no matter how well you care for a hamster, or a mouse or rat for that matter, they’ll still age 20 or 30 times faster than a human being. However, just like we don’t understand the mechanisms of aging, we have a very poor understanding of species differences in aging. In our work, we have tried to find genes and pathways associated with the evolution of longevity, for example studying the bowhead whale which is the longest-lived mammals. But of course we cannot do experiments in whales. My dream is to take some genes from the bowhead whale that we have found and put them in mice and see if they live longer or if they are cancer resistant, but we unfortunately don’t have the funding to do it. We have also done studies in the naked mole rat and in primates, and others have studied other species like bats. But we have really only scratched the surface as far as mechanisms of cancer resistance and longevity across species. My rationale is that different long-lived species use different molecular tricks and if we can figure out the longevity mechanisms of other taxa maybe we can apply them to human beings.

Your new pre-print paper proposes a conceptual model for explaining aging based on first principles, suggesting that epigenetic aging might be inevitable. Can you discuss how this model is different from existing models of aging, and what are the key implications of this conclusion for our understanding of the aging process?

This was a different approach for me as well, as you say, based on first principles, and credit to a brilliant PhD student, Thomas Duffield, for leading this work. Ultimately, this model assumes that epigenetic changes drive aging. This is based on the observation that epigenetic damage cannot be repaired in the same way as DNA damage, and we show that the epigenetic system has a built-in, unavoidable fidelity limitation. Based on this theoretical model, we looked into epigenetic data, namely methylation, and surprisingly found that there is an increase in noise with age and, strikingly, we can use neural networks to build accurate epigenetic clocks based on noise. I think this is very surprising, and I happily admit I’m still trying to get my head around what it means for understanding aging.

Outro

Thanks for reading and sticking with us for another month. We leave you with a short but insightful article on the potential of tokenizing IP-NFTs, where you can find more detail on the recent VITA-FAST launch!

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VITA-FAST — Revolutionizing Governance in Longevity Research

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Further Reading

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Association between infectious exposures in infancy and epigenetic age acceleration in young adulthood in metropolitan Cebu, Philippines

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Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing

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Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria

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Does omega-3 supplementation improve the inflammatory profile of patients with heart failure? a systematic review and meta-analysis

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Curcumin, Inflammation, and Neurological disorders: How are they linked?

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Epigenetic and Metabolomic Biomarkers for Biological Age: A Comparative Analysis of Mortality and Frailty Risk

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Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop

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To keep up-to-date with the latest breakthroughs in longevity research, exclusive insights, and exciting updates from our team, make sure to subscribe to our newsletter.

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In this podcast with Dr. Heidi Pak (@pak_heidi) we primarily talked about the difference between fasting and time-restricted feeding, how and why it works and also the efficacy of caloric restriction (CR) in different mouse strains and species. It was a great podcast, very fun as well.

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Other topics that we touched on included sleep, the postdoc shortage, hardships of being a grad student, the healthspan vs lifespan debate and some more. We also came up with some less-than-serious nutritional recommendations:

"I guess the diluted [fasting] diet [I studied] is the equivalent of eating celery" (Heidi Pak)

If you want to know why we were talking about celery and why Heidi wants to put pigs on a weight loss and fasting diet, then this podcast is for you.

Heidi Pak – short bio

Heidi did her PhD with Dudley Lamming at the University of Wisconsin–Madison where she studied fasting, time-restricted feeding and caloric restriction in relation to aging. She now works as a postdoc for Joseph Takahashi, continuing her work on fasting and moving into the relatively new field of circadian rhythms.

What is caloric restriction?

Also known as dietary restriction is the practice of restricting the caloric intake of mice, usually by 30%. This extends the lifespan of many, although not all, mouse strains considerably. CR is hailed as one of the biggest breakthroughs in biogerontology and for good reason. If it worked in humans; or if we could find a drug that mimics CR in humans it would be the biggest biomedical revolution since the invention of antibiotics!

The discovery of CR is often attributed to seminal work by Clive Mccay in the 1930s. However, what made CR big was not the work by McCay showing that food restriction from birth stunts growth and extends lifespan, rather it was protocol improvements. For example, Walford and Weindruch found in the 1980s that adult-onset CR can work reliably in many strains if it is introduced gradually.

This podcast episode is about another such protocol improvement. The disambiguation of fasting and caloric intake through modern feeding protocols and enabled by 24/7 monitoring of food intake, locomotion etc.

Using those new feeding protocols Heidi and others found that fasting contributes to the lifespan and health benefits of CR.

What is fasting and time restricted feeding?

The idea behind fasting to slow aging was that after the body has digested most of the food, when hunger starts setting in, an organism might be in something akin to a CR state. Therefore, imposing periods of fasting could reap some of the health benefits of CR without the drastic weight loss, constant hunger and other side-effects normally associated with CR. While plausible this theory had many problems, not least the fact that it seemed to contradict the work of Walford and Weindruch who suggested that gradual onset CR was more beneficial in adult mice than starting the protocol abruptly. It stands to reason that alternating periods of fasting and feasting could be stressful to the body, just like the abrupt CR protocols used in the past, and thereby shorten your life (or that of a mouse).

We needed evidence to settle this debate, or at least start addressing some of the major points. Before we can understand the evidence, let us take another look at what fasting exactly is.

Defining fasting is not easy since the cutoff when “fasting” starts is somewhat arbitrary and that can be a problem when reading papers and articles on this topic. When reading about fasting research it is important to keep in mind that a 16hr fast and a one-week water fast could be reported as the same thing by the media, even though the physiologic effects will be very different. Importantly, it could well turn out that certain eating windows are much more beneficial than others. Maybe the water fast is healthier, or maybe it is not. We do not know what will work in humans yet.

Intermittent fasting and time-restricted feeding mean similar things in mice. Although generally fasting refers to on-off feeding schedules and restricted feeding refers to shorter and variable eating windows within a day.

Little progress was made on this matter and some people, like me, remained convinced that fasting has no benefits or that we “simply do not know”. Early studies using intermittent fasting protocols were always biased by weight loss. Since the fasted mice lost weight, even if it was less than during CR proper, it was hard to attribute the health benefits to fasting rather than weight loss. There were also studies suggesting that fasting is not an important component of CR (Nelson and Halberg 1986).

However, one observation pointed out in the work by Heidi Pak always made a strong case for the importance of fasting. While, yes, intermittent fasting induces CR; CR actually induces a form of intermittent fasting! Apparently, the CR data itself was always potentially biased by the effects of fasting.

From Mitchell 2019, eating windows indicated for caloric restriction (CR), control (AL) and meal fed mice (MF).

As you can see from this image taken from a typical fasting study, mice tend to self-impose a fasting window when they are under CR. They are so hungry that they gorge on their food early during their waking hours and then fast for many hours afterwards.

Building on this finding Heidi Pak and many others designed protocols to test this further.

How do we test the effects of fasting?

Several protocols exist to induce fasting without weight loss. One is caloric dilution, the other is time-restricted dispensation of food using a machine, or training mice to eat during a specific time window. All of them have advantages and disadvantages.

Caloric dilution involves diluting the diet with cellulose that cannot be digested and is one of the approaches that Heidi used in her research. While a very smart idea, I am not the biggest fast of the caloric dilution approach as I have written on my blog when I was first reviewing Heidi’s paper.
See here for more information why I think this way: http://biogerontolgy.blogspot.com/2021/12/caloric-restriction-and-fasting-does-it.html

Be that as it may, I do not want to be overly critical of the research here. As scientists we tend to be overly skeptical of new research. Fact is, modern fasting research was a big breakthrough in the field of CR because it provided conclusive evidence that fasting contributes at least to some of the health and longevity benefits of CR as we discuss in the podcast. This is very exciting because fasting is much more tolerable than CR in humans, thus could see actual application in the real world.

Another strategy to study fasting is removing the fasting window that CR mice self-impose to isolate the effect of calories. This means forcing CR mice to eat multiple times throughout the day. Such studies generally find that fasting is one but not the sole contributor to the health benefits of CR.

This is where it gets complicated – circadian timing

Recent work has shown that not only is fasting one component of CR that contributes to the lifespan extension, there is also a component of circadian alignment. The recently published work by Acosta-Rodríguez et al. 2022 from the Joseph Takahashi lab demonstrated this nicely. This paper has some of the most beautiful figures I have ever seen so highly recommended to check it out.
Here is a very good video explanation of the paper: https://www.youtube.com/watch?v=q5ZN_mT-xbw&t=12s

During the podcast we briefly talked about this work and I mistakenly mentioned that mice in that paper were fasted during the night. In fact it is quite a bit more complicated than that. Night is the active period for mice and it is generally beneficial for them to eat during this period. The above paper actually tested two groups fed at night. One with a 12 hr feeding window and one with a 2 hr feeding window during the day or during the night period. The latter was the most beneficial for lifespan, meaning the mice will be fed at the beginning of the dark period, will quickly finish their food and then will fast for most of the night and the day.

Why humans are not two-legged mice

Even though mice are my favorite animal model and I consider myself a mouse researcher, I have to admit that mice have their limitations as a model of aging. Let us first talk about the benefits of mice, though. Running mouse studies is orders of magnitude cheaper than running human studies, it is more ethical, the mouse is well-understood as to its genetics and longevity, it is amenable to transgenic manipulation and so on. In contrast to nematode worms and fruit flies, the other two popular aging models, mice are closer relatives of humans; they are real, breathing mammals with many of the same traits as humans. They get cancer, they like to cuddle with other mice and sometimes fight with them as well.

The fact that mice are so similar to humans, by the way, is also a reason why we need to treat them well and keep them healthy. Only data from healthy mice will translate to healthy humans. In the podcast we briefly discussed how important it is to keep mice healthy, which is reflected by long lifespans of the control group.

What is the problem with mice then? Well, they are unusually “fragile”, as we have alluded to in our podcast with Peter Fedichev. Meaning, they are unusually short-lived for their size, and unusually prone to cancer, whereas humans are exceptionally long-lived given their body mass and size.

Another limitation is the small size and high metabolic rate of mice. This precludes many surgical interventions and has led to a lot of spurious findings. In this context I like to tell the story of hydrogen sulfide induced suspended animation, which would be also very interesting to aging researchers, if it worked. However, as it turned out this was an intervention that only worked due the physics of small body sizes (Asfar et al. 2014). This is where other animal models come in handy to validate the mouse data. We were talking about pigs as one option during the podcast.

It is difficult to overstate the differences in metabolic rate between mice and humans. A mouse heart contracts at an unbelievable rate of 500 to 700 beats per minute and their energy needs are commensurate with their fast metabolism. Although a mouse may not eat much in absolute terms, per gram of body weight it eats much more than a human, consuming a staggering 10% of bodyweight every day. Imagine eating 8kg of food every day! If you starve a mouse for a couple of days, it will die. Humans in contrast can go on for months without food.

Nevertheless, we can learn a lot from mice. We learned that fasting can work to extend health and lifespan, in principle. Nevertheless mice cannot tell us whether fasting will work in humans.

Perhaps there is an eating window in humans that can mimic mouse time restricted feeding? No one knows whether this will have to involve a week of severe fasting, maybe 2 weeks of moderate fasting or whether the currently used protocols in clinical practice employing moderate fasts are enough. 

Hopefully future research by Heidi and others will help us to understand this issue.

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References and notes

Acosta-Rodríguez, Victoria, et al. "Circadian alignment of early onset caloric restriction promotes longevity in male C57BL/6J mice." Science 376.6598 (2022): 1192-1202.

Nelson, W. & Halberg, F. Meal-timing, circadian rhythms and life span of mice. J. Nutr. 116, 2244–2253 (1986).

Asfar, Pierre, Enrico Calzia, and Peter Radermacher. "Is pharmacological, H2S-induced'suspended animation'feasible in the ICU?." Critical Care 18.2 (2014): 1-8.

Mitchell, Sarah J., et al. "Daily fasting improves health and survival in male mice independent of diet composition and calories." Cell Metabolism 29.1 (2019): 221-228.

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VitaDAO, the global community accelerating research and development in longevity science, is pleased to announce the launch of the VITA-FAST tokens. This marks the first-ever opportunity for token holders to directly influence longevity research, setting a new precedent in the field of decentralized science (DeSci).

The VITA-FAST tokens, which allow holders to make decisions on IP licensing, set experiment priorities, and govern research on autophagy, have been met with overwhelming interest.

The initial token sale was 1700% oversubscribed, with $620k in bids, demonstrating the public’s eagerness to participate in scientific research.

This groundbreaking initiative is spearheaded by the esteemed Korolchuk Lab, led by renowned cellular biologist Prof. Viktor Korolchuk. The lab’s work focuses on autophagy, a process vital to cellular health and implicated in ageing and various diseases. The launch of VITA- FAST tokens not only provides financial support for this cutting-edge research but also fosters a community-driven approach to biomedical research.

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

VitaDAO engaged its community in the token sale by using a newly launched crowdsales platform developed by Molecule AG, which developed the original IP-NFT platform for capturing IP in web3, and is a strategic contributor to VitaDAO.

“The success of the VITA-FAST token sale is a testament to VitaDAO’s innovative approach to integrating public participation into scientific research. It also underscores the potential of decentralized finance (DeFi) to fill in the gaps left by traditional funding agencies”, as noted by Paul Kohlhaas, CEO of Molecule.

Professor Matthew Grenby, Pro-Vice-Chancellor for Research and Innovation at Newcastle University added “It’s great to see this cutting-edge research going out into the world, and we are excited to be at the forefront of biomedical research funding. We look forward to supporting Molecule AG and VitaDAO with development of this novel platform and commercialisation of their IP”.

The VITA-FAST token offering marks a significant step forward for VitaDAO as it begins advancing its early research assets toward their next development milestones. The VITA-FAST tokens will provide ongoing options for funding for the Korolchuk Lab as it advances its research program.

For more information, visit https://www.vitadao.com/viktor-korolchuk-lab-vita-fast-token-sale-with-vitadao and talk to us in our Discord auction channel.

‍Discover the power of autophagy, a natural cell rejuvenation process, through the enlightening YouTube video, Autophagy as a Target for Rejuvenation | VitaDAO and Viktor Korolchuk Lab.

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Welcome back to the VitaDAO Newsletter, your monthly source of insights into the VitaDAO community. In just 20 months, we have successfully deployed over $4 million to fund 17 cutting-edge projects, pushing the boundaries of what is possible in the field.

From our upcoming token sale, which introduces the innovative VITA-FAST tokens, to the one-year anniversary of our renowned “Longevity Research Newsletter, we are pushing the boundaries of what is possible. Let’s dive in and explore the latest developments in VitaDAO’s mission to extend healthy lifespans. Inside this Newsletter:

• VITA-FAST Tokens: Steering Korolchuk Lab’s Research
• Celebrate One Year of the Longevity Research Newsletter
• Recent VitaDAO Votes
• Meet Rhys Anderson

VITA-FAST Token Crowd Sale

Hold up, I thought that $VITA was the community token of VitaDAO? It is! Then what is the talk of a VITA-FAST Token? 🤔

If you’re new here, welcome! Sit back, relax, and keep on reading as I introduce you to VDP-100,, and the utility of VITA-FAST tokens. This story dates back to 2021 when the VitaDAO community voted to fund Viktor Korolchuk Lab in the discovery of new autophagy inducers. Dysfunctional autophagy affects cellular functions including DNA repair, metabolism, and survival. Thus, activation of autophagy is considered a promising therapeutic approach to combat aging and age-related diseases.

“We see that activating this process makes old cells look young, which is quite striking from our point of view.” — Viktor Korolchuk

Flash forward to earlier this month, the community voted on VDP 100, the fractionalization of the IP-NFT minted pursuant to VDP-16. In layman’s terms, fractionalization is the concept of splitting up ownership of something. Here, the final model is a little different: not split ownership, but rather shared governance. In this case, VitaDAO is distributing governance over the Korolchuk project by allowing individuals to buy or earn governance rights in order to have a more active role.

This brings us to VITA-FAST tokens. $VITA-FAST will be Intellectual Property (IP) governance tokens that provide membership to an IP pool for the IP-NFT. Members of this pool will actively decide what happens with the IP and R&D data attached to the Korolchuk IP-NFT. Thus, VITA-FAST token holders have the right to participate in the governance of the IP-NFT and its development.

This necessitates token distribution! 1,000,000 VITA-FAST tokens will be minted, with 10% available for sale to VitaDAO members, and the rest divided among VitaDAO, researchers, Newcastle University, and a liquidity pool. The 10% will be sold to $VITA token holders in a fixed-price sale with pro rata distribution, overflow refunds, and 2-month vesting. VitaDAO members can bid as much as they’re willing to contribute to the sale, with the final allocation of tokens proportional to each participant’s contribution.

We invite you to join us as we make history! Before participating in the sale, familiarize yourself with the Korolchuk project page, the project white paper, and VitaDAO’s blog announcement.!

Sale duration: June 15 5pm CET — June 23 5pm CET

Participate in the sale here: https://mint.molecule.to/ipnft/2

🧪VitaDAO’s IP-NFT Funded Research Projects

In a newsletter discussing fractionalization, it feels wrong not to briefly cover IP-NFTs. IP-NFTs connect IP and research and development data rights to NFTs on the Ethereum network by attaching legal contracts to smart contracts. They represent a new paradigm in the evolution of legal contracts for scientific research. Benefits of IP-NFTs include: creating efficiencies in IP licensing, creating entirely new IP markets, and enabling decentralized IP ownership, governance, and commercialization.

VitaDAO has multiple IP-NFT-funded projects including (but not limited to):

• ApoptoSENS — Senolytic CAR-NK Cells
• Discovery of novel mitophagy activators for Alzheimer’s disease
• Scheibye-Knudsen Lab
• Reversing periodontal disease using Geroscience: Jonathan An
• Probing DNA Quadruplexes in Age-Related Proteostasis

🌎VitaDAO & Zuzalu

Last month, Zuzalu & VitaDAO took Montenegro by storm. VitaDAO’s “Longevity Zero to One” and “Longevity Biotech Conference” encouraged conversation about network states and the pursuit of extended life. Want to learn more? Check out the full article by MIT Technology Review for an immersive glimpse into this groundbreaking event:
https://www.technologyreview.com/2023/05/31/1073750/new-longevity-state-rhode-island/

🥳A Year of the Longevity Research Newsletter

Has it already been a year? Time flies when you’re having fun! Join us in commemorating the one-year anniversary of our renowned VitaDAO’s “Longevity Research Newsletter.” This fun initiative, led by Rhys Anderson and Maria Marinova, keeps VitaDAO members up-to-date with the most important longevity research activity happening across the globe. The newsletter offers updates about VitaDAO’s funded projects, highlights hot longevity research, and features top scientists in the field. Swing by VitaDAO’s Medium to read this month’s edition and stay informed about the latest breakthroughs.

🗣️VitaDAO in the Wild

Discover VitaDAO’s growing presence in the scientific and technological community:

• The Fitt Insider Newsletter highlighted VitaDAO’s funding of ImmuneAGE Bio, a drug discovery firm focused on immune system rejuvenation.
• This month, DeSci Japan hosted an event alongside VitaDAO.This gathering was featured by Longevity.Technology.
• Wish you were still in sunny Montenegro? Read Lifespan.io’s piece re-capping highlights from Zuzula, VitaDAO’s longevity pop-up city.
• Decrypt spoke to Pfizer Venture’s involvement in cryptocurrency and decentralized science through a VitaDAO investment.

📣Community Approved: What you voted for!

VDP-97 Passed! This vote distributed 700,000 VITA tokens to 6 of the top community & awareness contributors, with an additional allowance of up to 300,000 VITA for allocation to other core contributors.

VDP-99 Passed! As a result of this vote, VITA will launch on layer2s. Currently, VitaDAO is prioritizing launching on Optimism, Arbitrum, and Polygon with $250k of liquidity in each VITA + ETH.

VDP-100 Passed! In case you skimmed past the earlier part of this newsletter, VitaDAO’s Newcastle IP-NFT will be fractionalized! This vote confirmed the creation of IP-NFT tokens to govern the IP and control the R&D decision-making and capital allocation process.

💪Exercise Your Right to Vote (on VitaDAO’s Governance Forum)

Find all of VitaDAO’s pending proposals on Discourse, VitaDAO’s governance hub for proposals before they are moved on Snapshot. Proposals are open for engagement, voting, questions, and conversation!

Your voice matters, and together, we can shape the trajectory of VitaDAO and contribute to the advancement of decentralized science.

👋Meet Key VitaDAO Contributor: Rhys Anderson

Rhys Anderson is a research scientist and active VitaDAO contributor. In 2016, he received his PhD in Cell Biology from Newcastle University. Currently, his time as a postdoctoral research associate is spent researching senescence and aging at King’s College London. On the side, Rhys is a part of the Longevity Dealflow Working Group, and Community and Awareness Working Group, and has played an integral part in the initiation of the Longevist. Rhys’s dedication and expertise exemplify the collaborative spirit of our community.

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How did you first get involved in VitaDAO?
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I’m a cell biologist and in late 2021 I received a Longevity Impetus grant to support my research on targeting senescent cells. Shortly after, I received an email from VitaDAO saying they are reaching out to the Impetus awardees. I had a call with Dealflow Steward Laurence to discuss my research, and he also explained how the DAO works and that anyone can get involved — so I did, and the rest is history……

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What does your contribution look like?

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I started off contributing to deal flow by helping to evaluate funding applications before going on to “shepherd” some of my own. In mid-2022, Maria Marinova and I began co-authoring a monthly Longevity Newsletter, keeping people up-to-date with all the goings on in the longevity world from publications to conferences and interviews with prominent longevity scientists.

Recently I have also been busy working away on VitaDAO’s new initiative, an overlay journal — The Longevist — which will be ready for launch soon!

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How does it work for you?

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I work full-time doing research, but due to the remote and flexible nature of VitaDAO, I’m able to make contributions on weekends, evenings, and early mornings before my toddler awakes and summons his loyal servant.

You played an integral part in establishing The Longevist. What exactly is The Longevist?

The Longevist is a curation of the world’s most exciting longevity research each quarter. Our editorial team created a shortlist of preprints that we believe have the potential to have a big impact on the field and then our team of expert curators vote on-chain to determine which of these preprints they think are the best.

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Why preprints?

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Preprints have accelerated the rate at which scientific discoveries are shared with the world. However, so much research is published on a daily basis that it’s impossible to keep up with all the literature and it could be months to years before publication in a traditional journal. So we are using our platform to highlight research that deserves special attention.

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

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VitaDAO has an extensive network with a real breadth and depth of expertise. With the opt-in nature, no one is lumbered with unwanted assignments from the boss — instead, people can focus on contributing to the projects they are most passionate about. I’ve been extremely impressed by the rate at which ideas can go from inception to reality.

The community is also willing to take risks on projects which would be unlikely to receive conventional funding as well as being able to support the longevity ecosystem in numerous other ways from prizes to fellowships.

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Any closing thoughts for readers?

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There’s a real buzz around DAOs at the moment — I imagine it’s akin to what the early stages of the dot com boom would have felt like in the 90s.

Looking at the DeSci space alone there are new DAOs popping up all the time and they are proving to be instrumental in bringing both the tech and science worlds together.

The success of VitaDAO has been enabled by decades of longevity research showing that aging isn’t an immutable universal constant but rather a process that can be understood and targeted. The tech world has bought into this and has created the infrastructure and provided funding to support longevity research, which has the potential to lead to a healthier, more prosperous future for all of humanity.

🗓️Upcoming Event

June 15, 5 pm CET — June 23, 5 pm CET: VITA-FAST Token Crowd Sale

We’ve made it possible for you to govern and engage with Viktor Korolchuk Lab’s research as a VitaDAO Member. As you know, we’re all about putting the power in the hands of our community and we’re doing exactly that with the VITA-FAST tokens.
Participate in the Sale: https://mint.molecule.to/ipnft/2

🤝Get Involved

Have a special skill set? Contribute to VitaDAO and receive $VITA in return. Want to stay up to date with the VitaDAO community? Join us on Discord, subscribe to our Twitter, and follow our Instagram!

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

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Greetings, Vitalians!

Imagine having a direct hand in the future of longevity research. Today, we’re thrilled to introduce VitaDAO’s innovative approach to scientific research funding, giving you an exceptional chance to participate in the decision-making processes of longevity research. With our community fundraising effort for the “Discovering Novel Autophagy Activators” Intellectual Property Non-Fungible Token (IP-NFT) from the Korolchuk Lab at Newcastle University, you are invited to contribute to the democratization of one of the most cutting edge longevity research and development (R&D) projects funded by VitaDAO.

This fundraising effort will be a sale of VITA-FAST tokens, a.k.a. Molecules, representing governance rights over the pool of Intellectual Property (IP) and R&D generated by the esteemed Korolchuk Lab’s research centered on the discovery of novel autophagy activators–the research funded by VitaDAO’s Korolchuk IP-NFT. Autophagy is a cellular process whose decrease can contribute to our biological systems’ decline, particularly as we age. By stimulating autophagy, we’re exploring promising therapeutic approaches to combat aging and age-related diseases, with the goal of improving human healthspan.

By enabling community-led decision-making and governance, VitaDAO’s novel funding model redefines how research programs, including the Korolchuk Lab, are supported. Participating in this crowdsale means not just funding research, but driving scientific progress, shaping therapeutics’ future, and joining a devoted community of pioneers committed to extending human lifespan.

Your contribution to the VITA-FAST Molecules crowdsale provides you with more than just a chance to fund potential longevity therapeutics; it enables you to actively guide them. As a VITA-FAST tokenholder, your voice counts in making crucial decisions. You can influence how the program’s resources are allocated, ensuring they are put to the most effective use in our quest for groundbreaking research and discoveries. You’ll have the ability to dictate the priority of experiments, ensuring that we concentrate on the areas you believe hold the most promise. This unique capability lets you stay at the cutting edge of scientific exploration, directly impacting the path of life-extending advancements. You can decide who licenses the IP & R&D data and what the license terms are.
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Your role as a VITA-FAST tokenholder is not passive. It’s about engagement and contribution, and there’s no one-size-fits-all approach. We value and need your unique skills and perspectives, regardless of your background. Whether you bring scientific knowledge, business development expertise, or other abilities beneficial to early-stage drug development, we welcome your input. We believe in collective intelligence and decentralized science, and we’re eager to see how your involvement will generate value for patients.

The number of available tokens are limited. A total of 1,000,000 VITA-FAST tokens will be minted, with 10% available for sale to VitaDAO members, and the rest divided among VitaDAO, researchers, Newcastle University, and a liquidity pool.

Our innovative Genesis Sale Structure further democratizes the process. This fixed-price sale allows VitaDAO members to bid as much as they’re willing to contribute to the auction, with the final allocation of tokens proportional to each participant’s contribution. VitaDAO members must lock their VITA for two months to participate in the sale. If we meet or exceed our sales target (~32,000 USD), the surplus will be returned to bidders. Importantly, the VITA-FAST tokens will be vested (non-transferrable) over a 60 days to ensure equitable participation in governance during vesting. The vested VITA-FAST tokens and the locked VITA will vest and unlock at the same time, 60 days after the Genesis Sale. For a more detailed explanation, read VDP-100 on Snapshot.

The funds raised from the sale will be directed towards providing liquidity for the VITA-FAST liquidity pool until token holders govern where the resources should be allocated. This could include contracting computational biochemists, engagement of experienced medicinal chemists, or filing patents.

We, therefore, invite you to join us on this revolutionary journey. Engage in this unique opportunity to support the Korolchuk Lab and the wider field of longevity research. Make your mark in a cause aiming to enhance human health and longevity. Every contribution, every Molecule purchased, every decision made, brings us a step closer to deciphering the mysteries of longevity.

While we aim to democratize research funding, we acknowledge that all biomedical research is unpredictable, laden with twists, turns, and complexities. Therefore, we ask those considering purchasing VITA-FAST tokens to do so with a comprehensive understanding of these inherent uncertainties.

First and foremost, please recognize that purchasing VITA-FAST tokens should not be regarded as an investment but as a contribution towards advancing scientific research. The focus is on the technology of tokenization, the utility of tokens within the IP pool, and the mission of scientific research.

It’s important to stress that VITA-FAST tokens are IP governance tokens that provide membership in an IP pool where members actively decide what happens with the IP and R&D data attached to the Korolchuk IP-NFT. They do not automatically confer any economic benefits or returns. This is not an investment contract where you’re buying a share of future profits.It is important to understand that there may never be a distribution of proceeds.

In fact, it is crucial to bear in mind the expectation of loss. The landscape of biotech research is fraught with challenges and the vast majority of research projects do not yield patentable IP. It’s very likely that the research may not lead to patentable IP, that buyers will not receive any money back, and that the tokens might not acquire any financial value.

As a VITA-FAST tokenholder, you have the responsibility to actively participate and put in work to generate value for yourself. Participation involves more than just owning VITA-FAST tokens. It means actively governing the direction of research and decision-making processes, and ensuring the responsible usage of the IP and R&D data.

Owning VITA-FAST tokens may require you to sign NDAs and provide KYC in order to access sensitive IP or R&D data. This is for the protection of the data and the rights of all parties involved. The rules for data access and privacy are to be governed into place by VITA-FAST tokenholders.

Finally, to our US community members, please note that due to unclear regulations, we unfortunately cannot include US buyers in this endeavor. This is an evolving area of law and while we are exploring ways to include the US, we are erring on the side of caution to ensure compliance with existing regulations.

The potential and the mission of this project are vast and exciting. However, it is crucial to approach this opportunity with a thorough understanding of the intricacies and potential risks involved. We encourage all potential participants to conduct their own due diligence and make informed decisions.

With these understandings and acknowledgments, we warmly invite you to participate, contribute, and make a difference today in the world of longevity research. Every step we take together brings us closer to deciphering the mysteries of longevity.

For more information, visit https://www.vitadao.com/viktor-korolchuk-lab-vita-fast-token-sale-with-vitadao and talk to us in our Discord auction channel.

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Discover the power of autophagy, a natural cell rejuvenation process, through the enlightening YouTube video, Autophagy as a Target for Rejuvenation | VitaDAO and Viktor Korolchuk Lab.

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Introduction

Welcome to this month's edition of our newsletter, where we delve into the fascinating realm of gerontology - the scientific study of ageing - which has increasingly become a pivotal area of research, given the world's ageing population. This discipline, which explores the biological, psychological, and sociological aspects of ageing, has led to significant advances in understanding age-related diseases and interventions. Key to these advancements are human trials and interventions, turning laboratory findings into strategies that can enrich our lives as we age. This month, we are thrilled to feature an exclusive interview with renowned gerontologist, Professor Andrea Maier who brings an invaluable perspective and continues to break new ground in age-related diseases research.

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This issue emphasizes the need for standardization in research methodologies to optimize comparability, which in turn may accelerate potential breakthroughs. As always, we strive to bridge the gap between the scientific community and policy makers, underscoring the urgent necessity for gerontology insights to inform public health strategies, legislation, and societal views on aging. Stay tuned for a captivating exploration of gerontology with Professor Maier.

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VitaDAO Funded Research Projects

Viktor Korolchuk’s project, which aims to discover novel autophagy activators, will be the first VitaDAO project to undergo Synthesis of its IP-NFT after  receiving a 100% majority in the tokenholder vote.

Synthesis will create direct capital for the project and incentivise the VitaDAO community to contribute and move it into overdrive.

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Longevity Literature Hot Picks

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Preprint Corner

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VitaDAO’s very own longevity overlay journal - The Longevist - had its first on-chain vote to determine what our team of curators think are the most exciting preprints of Q1 2023. We are aiming to launch the website later this month.

Prizes will be awarded for nominating preprints which make it into future issues of The Longevist. If you would like to nominate a preprint for inclusion in Q2 2023, then please follow this link - deadline 30th June 2023. 

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This month we are featuring 6 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in previous issues of this newsletter.

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DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale

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

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Cellular Senescence is a Double-Edged Sword in Regulating Aged Immune Responses to Influenza

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DNA methylation rates scale with maximum lifespan across mammals

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Breast cancer risk based on a deep learning predictor of senescent cells in normal tissue

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Causal evidence that herpes zoster vaccination prevents a proportion of dementia cases

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Published Research Papers

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DNA methylation clocks for clawed frogs reveal evolutionary conservation of epigenetic aging

DNA methylation-based aging is conserved in frogs and mammals. The identified age-related CpGs are located in neural-developmental genes, implying a connection between epigenetic aging and age-associated diseases. The study opens avenues for using frogs as an aging model.

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Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models

Researchers identified a peptide called Pep 14 that can effectively reduce senescence burden in human skin cells without toxicity. By modulating the activity of a specific enzyme involved in DNA repair and senescence pathways, Pep 14 improved the skin phenotype and reduced the biological age of aged skin samples in a safe manner.

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

Study across 41 mammalian species reveals genetic signatures of lifespan control, including shared mechanisms like downregulated Igf1 and upregulated mitochondrial genes. Lifespan-extending interventions target genes related to energy metabolism.

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Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging

Exercise rejuvenates aging stem cells, improves tissue regeneration, and reduces inflammation. This study examines the molecular changes induced by exercise in various stem cell compartments, highlighting its positive effects on intercellular communication and immune cells.

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Effects of hunger on neuronal histone modifications slow aging in Drosophila

The sensation of hunger, by limiting BCAAs or directly activating hunger neurons, extends lifespan in Drosophila. Hunger-induced changes in neuronal histone acetylome seem to play a role.

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Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial

Participants taking multivitamins had better immediate recall memory compared to those taking a placebo. This effect was sustained over a three-year period, suggesting multivitamin supplementation could be a safe way to maintain cognitive health with age.

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Association between genetically determined telomere length and health-related outcomes: A systematic review and meta-analysis of Mendelian randomization studies

Leukocyte telomere length (LTL) is associated with various health outcomes. Longer LTL is linked to increased neoplasm risk, while shorter LTL is associated with conditions like coronary heart disease and rheumatoid arthritis.

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Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Activated autophagy in disease-associated microglia helps maintain amyloid plaque homeostasis and prevent senescence. Inhibiting microglial autophagy worsens neuropathology, while removing senescent microglia could be a therapeutic strategy for AD.

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Discovering small-molecule senolytics with deep neural networks

Deep learning was used to identify three drug-like compounds that selectively target senescent cells, similar to a known senolytic drug. These compounds reduced senescent cell burden in aged mice, highlighting the promise of deep learning in drug discovery.

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Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis

Lifelong exercise training in a rat model of prostate cancer led to increased γδ T cells and lymphocyte infiltration in the prostate tissue. Exercise also induced changes in the expression of Oestrogen Receptor and Mitogen-activated Protein Kinase 13.

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Region-based epigenetic clock design improves RRBS-based age prediction

Epigenetic clocks for mouse RRBS data have poor performance on external datasets. A study introduces regional blood clocks (RegBCs) that improve age prediction by using average methylation over large regions and outperform individual CpG-based techniques.

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Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing

Thrombomodulin (THBD) signaling identified as a key pathway in senescence. Inhibiting THBD signaling with vorapaxar eliminates senescent cells and restores tissue homeostasis in liver fibrosis models.

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Alpha‑ketoglutarate supplementation and BiologicaL agE in middle‑aged adults (ABLE)—intervention study protocol

The ABLE trial investigates the effects of Alpha-Ketoglutarate (AKG) on aging in humans. Participants will receive AKG or a placebo for 6 months, with follow-up for 3 months. The study aims to measure changes in DNA methylation age, inflammatory and metabolic parameters, strength, arterial stiffness, skin autofluorescence, and aerobic capacity.

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Published Literature Reviews

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Chronic kidney disease promotes ageing in a multiorgan disease network

Chronic kidney disease has been identified as a significant risk factor for accelerated aging in multiple organ systems. This highlights the interconnectedness of age-related chronic diseases and their impact on mortality.

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Senescent Cells: A Therapeutic Target in Cardiovascular Diseases

This review emphasizes the impact of senescent cells on different cardiovascular cell types and discusses the potential of senotherapeutics for treating cardiovascular diseases.

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Senescence: a double-edged sword in beta-cell health and failure?

In pancreatic beta-cells, senescence contributes to age-related decline and diabetes. Targeting senescence is a promising approach for diabetes treatment. This perspective discusses the importance of senescence in beta-cell homeostasis and pathology.

Job board

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Looking for a job in longevity research? Check out jobrxiv - we have saved you milliseconds by entering “aging” in the keyword search, but enjoy searching for whatever your research interests are!

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Wyss-Coray Lab looking for a research assistant/associate to work on microglia, HSCs, lipidome or aging clocks

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Hansen lab at the Buck are looking for new postdocs!

The focus of the research is to understand how the basic cellular recycling process called autophagy is regulated during aging, using the nematode C. elegans and mammalian cell culture systems, and a combination of biochemical, imaging, and genetic approaches.

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The Benayoun lab at the Leonard Davis School of Gerontology at the USC is seeking a Research Lab Technician. They aim to use mice to understand sex differences in the aging process!

News

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Hevolution Foundation Geroscience Research Opportunities (HF-GRO) Awards Unveiled, with a Budget of up to $115M Over Five Years

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Resources

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Longevity Biotech Landscape

Ada Nguyen provides us with an overview of the longevity biotech landscape, by sorting the different companies into 4 key therapeutic areas: reset & repair, replace, reprogram and discover.

Prizes

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The Maximon Longevity Prize for Translational Research

Awards outstanding breakthrough research in the field of longevity that can be translated for clinical or non-clinical applications and has the potential to substantially increase health span or life span of humans.

They are welcoming applications from all academic/non-profit researchers, inventors, scientists, students or startup founders who either published breakthrough research, hold the patent or are in very advanced stages of research.

Articles

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Biopharma Targets the Untapped Potential of the Human Healthspan

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The Longevity Skeptic

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The Secrets of Aging Are Hidden in Your Ovaries

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Can a Kidney Transplant Drug Keep You From Aging?

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Inside the Secretive Life-Extension Clinic

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Speaking of Illusions: Sirtuins and Longevity

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Combilytics: Taking a combined approach to senescence

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NPR-8: The Protein That Could Extend Human Lifespan in a Warming World

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The unexpected force that may make us get less sleep

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More geriatricians needed to meet the needs of the UK’s ageing population

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Why do some people live to be a 100? Intestinal bacteria may hold the answer

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Vitalik Buterin Exclusive Interview: Longevity, AI and More

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Speaking of Vitalik, he published a longevity pyramid short survey on his website. See where your health philosophy fits in!

Conferences, Workshops and Webinars

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Meet the most inspiring speakers and experts gathering to discuss their present research.

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Authophagy UK

19-20th June, University of Birmingham, UK

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DGfA (German Society for Research on Aging) Annual Meeting

29-30th June, Volkshaus Jena, Germany

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5th World Aging And Rejuvenation Conference

17-18 July, Frankfurt, Germany

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Longevity + DeSci Summit NYC: Ending Age-Related Diseases 2023

10-11th August, New York

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International Longevity Summit Africa

23-24th August, Johannesburg, South Africa

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10th Annual ARDD

28th August - 1st September, Copenhagen, Denmark

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BSRA Annual Scientific Meeting

6–8th September, University of Westminster, UK

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The Groningen-Jena Aging Meeting "G-JAM" 2023 

28-30th September, European Research Institute for the Biology of Ageing (ERIBA) in Groningen, the Netherlands

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Tweet of the Month

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By Matt Fuchs - an excerpt from a twitter thread on the article mentioned above “The Longevity Skeptic”:

Messiness is Good. You want to find and follow scientists who’ve published research over the years that does *not* tell a clean story. “Our goal is to disprove our models,” @mkaeberlein said. Their findings and views should zig and zag as their careers – and science – progress

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Follow scientists who write and talk publicly about new evidence that’s convinced them to reevaluate their own positions. Who embrace the inherent messiness of science – that’s the hallmark of an honest researcher

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Podcasts and Videos

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Pathways to Impact

A series of 12 virtual panels with longevity leaders

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Coming on June 21st: Oprah and Dr. Peter Attia Get Real About Living Better for Longer

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The Art of Aging: A Tail of Canines, Rapamycin, and Longevity with Dr. Matt Kaeberlein

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The Sheekey Science Show: Is aging adaptive?

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Interview with Prof. Andrea Maier

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Andrea Maier, a renowned professor of gerontology, serves as the Co-Director of the Centre for Healthy Longevity at the National University of Singapore. With over 350 published articles, her groundbreaking research in ageing and age-related diseases is globally recognized, influencing health policy discussions including at the WHO.

What inspired you to enter longevity research?

It was a long, long time ago when I first observed that people age differently. This observation was especially apparent in some older women who exuded an undeniable power and vitality. This led me to question, how does this happen?

At the time, I was already engaged in research within the field of pulmonology, focusing on diseases like cytomegalovirus and other viruses. However, my observations compelled me to switch my focus. First, I transitioned into geriatrics, but I was always drawn towards research into longevity.

I find it truly astonishing how some individuals possess such vitality, even at an advanced age. Admittedly, I was also drawn to this field because it was not overly crowded. For instance, many researchers are interested in diabetes, making it a highly competitive field. Aging and longevity research, on the other hand, is a bit different. I would argue that this is still one of the least explored fields, especially when you consider it through the lens of a physician.

How has the field changed since you started?

In my view, the field hasn't changed at all in terms of the key players. That's something we might need to reflect on. However, the field itself is undeniably evolving. There's been a shift from purely academic pursuits to a greater involvement of startups. Venture capitalists are now engaging in our field and there's also a different level of government inclusion.

In the past, societal discussions were often centered around issues in nursing homes and frailty in hospitals. But now, we're talking about prevention and biological age. We're now in dialogues with organizations like the WHO how to introduce healthy aging to all citizens and the FDA about approving new drugs targeting ageing. This represents a substantial shift from being a purely academic field to one with a much broader scope and a greater societal impact. There should also be ubiquitous presence of regulators to ensure a balanced evolution of the sector.

Speaking of regulators, Singapore is allocating resources and effort to several exciting initiatives aimed at promoting healthy aging and the longevity industry. Could you give us with the latest and most significant updates?

Absolutely, Singapore is at the forefront of implementing many innovative healthcare strategies, largely out of necessity. Singapore boasts one of the highest life expectancies on earth, a distinction it shares with Japan and Switzerland. The country also has a remarkably low fertility rate, and individuals there tend to develop their first diseases at a relatively young age. These factors create a pressing need to lower healthcare costs, increase productivity, and reduce absenteeism. We are focused on stimulating human potential, given the limited natural resources due to the country's small size.

 Our current projects, such as the Healthier SG initiative, emphasize preventative actions and cost-benefit analysis, pushing towards a preventative approach in healthcare. They've also established health districts in collaboration with universities, the Housing Board, and industry partners, aiming to study and implement ways to enhance health and longevity.

In addition, Singapore is attracting startups for diagnostic or intervention purposes, utilizing a strong network of researchers and a robust engineering department. At the Center for Healthy Longevity, which I lead, we're conducting clinical research to bridge the gap from preclinical findings to clinical practice, integrating these into the healthcare system through evidence-based longevity clinics. All these efforts are driven by the necessity to enhance human potential.

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

There are many theories regarding aging. One such theory I came across is the grandmother hypothesis. This theory posits a question: why do women live beyond their reproductive age? Some research, including studies conducted in Ghana, suggests that there's not much evolutionary need for women to live beyond their reproductive years.

However, I think aging is much more complex. We recently published a paper in Nature Medicine that I'm quite proud of. It demonstrates how different organs within our bodies age at varying rates, and that there's a chain of action. If one organ begins to deteriorate, it's likely that another will soon follow, and we can now predict this.

There's not a singular mechanism behind aging. Rather, I think we're still uncovering the intricate complexities of the aging process and the networks between all the various hallmarks or mechanisms that influence each other.

Certainly, the accumulation of damage over time is a part of aging. But the question is how this damage occurs and how it can be repaired. We are dedicated to developing diagnostics to identify the weakest links in our bodies - which organ needs attention, what the common mechanisms are, and what the organ-specific mechanisms might be.

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

There have been many significant findings in the field of aging, including the study of senescent cells. Therapies targeting these cells seemed to extend lifespan and improve health span in mice, creating significant excitement.

However, our field progresses through a series of small, yet important steps rather than a single breakthrough. One crucial development is our evolving understanding of the pathophysiology of aging, which has led us to develop diagnostics for biological age. This has the potential to be greatly impactful in our field.

The integration of our knowledge into practical applications that could impact everyday life is particularly exciting. Future interventions, backed by advancements in multi-organ treatments, could significantly increase health span, possibly more than lifestyle changes alone.

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

Currently, our focus is on human research, specifically on different organs' biological ages and how interventions can impact them. Over the last year and a half, we've developed a framework for diagnosing different physiological systems in the human body. If we want to tackle aging effectively, we should be able to measure the impact of interventions on every organ.

We use the eleven physiological systems defined by the Society of Physiology, such as the cardiovascular and endocrine systems. We've found that many trials only use a limited range of outcome parameters such as blood pressure, walking speed, and a few blood parameters. However, we often overlook critical aspects like lung function, women's health, cognitive function and oral health, which could be crucial in aging. Similarly, while many are focused on the microbiome, few are investigating the interaction of several organ systems.

In essence, we are trying to identify and fill the gaps in our understanding of aging across the various physiological systems. By systematically reviewing the literature, we're discovering blind spots and working to address them, to truly comprehend the complexity of aging across our body's many intricate systems.

What mistakes do you think the longevity field has made?

I wouldn't say mistakes. Instead, I'd liken our current stage to that of a toddler. Like a toddler, we are learning, experimenting, observing our environment, and trying different approaches. We're not yet in the stage of 'puberty'; we're still trying to grasp the basic concepts and parameters of our field.

However, one thing we could improve upon is leveraging insights from various specialties and fields. We should learn from others, review the literature, understand different trial designs and methodologies, and apply them in our field. This sort of cross-pollination is essential for growth and advancement.

While it's difficult to pinpoint any specific mistake with a significant negative impact, we must realize that, like a growing child, we will eventually need to mature and refine our approaches. The understanding and patience granted by governments and institutions due to our field's relative youth won't last forever. We need to keep learning and advancing to fulfill the potential of our field.

Is ageing a disease?

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.

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.

Your lab is mostly focused on longevity interventions in humans. What are the most important endpoints, biomarkers and measurements you look at?
In terms of endpoints and biomarkers, there is a both short-term and long-term answer. I have gained experience from various fields, including endocrinology and oncology, where trial designs have been well-established over several decades. We are now realizing the importance of implementing proper trial designs in the field of aging research as well. Simply relying on observational studies is no longer sufficient for determining outcomes.

Currently, we utilize surrogate markers or parameters, such as C-reactive protein (CRP), which is an inflammation marker. In some of my studies, I use CRP as a primary outcome, not necessarily as a longevity marker, but as an indicator of reduced inflammation. By demonstrating a decrease in CRP levels, we can refer to existing literature to understand the implications of such a change, such as the decreased likelihood of developing cardiovascular disease, for example. Additionally, we employ epigenetic clocks using methylation data in our trials. Instead of relying on a single clock, we use the median of multiple clocks since it is still uncertain which one is the most accurate. This approach allows for risk spreading, which is crucial since our trials have relatively short durations of two to three years. We need to consider outcomes that we would like to avoid in the long run, even if they might take a hundred years to manifest.

However, it is important to note that the long-term outcome parameters are more organ-specific and highly significant. In my research, the population I focus on for randomized control trials is much younger, typically between 30 and 60 years old. Therefore, using these specific endpoints would require significantly longer follow-up periods. It is also worth mentioning that I'm not primarily interested in dichotomous outcomes where individuals either develop a disease or not. Instead, I focus on continuous outcome parameters indicating the function of organs.

Ultimately, the decline of function in aging is a continuous process, and our goal is to determine how much decline we can prevent to make a clinically relevant impact. Currently, our field is in the process of understanding what is considered clinically relevant and within what timeframe such interventions need to take place.

As standardization can be a concern in human aging studies, can you elaborate on your ability to compare your findings with other similar studies conducted by various institutions, including academic and clinical ones?

This is a huge problem! It is a big mess at the moment and this brings me back to the toddler analogy. We haven't defined or standardized our approaches yet. I often find it challenging to conduct meta-analyses in systematic reviews due to the heterogeneity of studies. This serves as an alarm signal that standardization is necessary.

That's why I founded the Healthy Longevity Medicine Society (HLMS) to bring together healthcare professionals, scientists, and entrepreneurs. One of our major goals in HMS is to establish standards in research. This includes standardizing how we measure parameters like musculoskeletal or women’s health outcomes. Currently, there are numerous different ways to measure these parameters, leading to inconsistent outcomes.

We have learned from other fields, such as cardiology, that standardization is crucial. For example, we know how to measure blood pressure accurately by ensuring individuals rest for 3 to 5 minutes in a quiet room. We are now at the stage where we need to standardize our methods, what we measure, and when we measure it.

To address this issue, we established a consortium of publicly funded hospitals that are setting up longevity clinics. We are currently designing standardized protocols for measuring physiological systems in humans. By adhering to these protocols, we can ensure consistency. The next step will be certification, where practitioners receive a certificate for following the standardized protocols.

We need to accelerate the implementation and scalability of these standards to effectively reverse the aging process. Without standardization, we are just surrounded by noise caused by inconsistent methodologies.

When selecting interventions to test in humans, how much significance do you place on data derived from animal models, and what has been the level of translatability in your experience?

I always look at animal models as an initial step before starting a study. We conduct systematic reviews and analyse animal and human studies to inform our translational approach. Learning from past experiences, we have seen successful translation in the longevity field. For example, supplements that have shown positive effects in animal models often have a good success rate when translated to humans. The success depends on the mechanism being studied, as certain mechanisms are conserved across species.

However, it's important to note that we don't solely rely on animal data. If a therapeutic intervention shows safety in humans, and the animal data is not available or necessary for safety assessment, we may proceed directly to human trials. The primary consideration here is the safety aspect. Once we establish the safety, we can implement it in human studies to assess the effects.

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Outro

Thank you for staying with us until the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues. See you next month!

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Further Reading

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Unbiased evaluation of rapamycin's specificity as an mTOR inhibitor

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Mapping the trajectory of healthy aging: Insights from longitudinal cohort studies examining lifestyle factors

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Novel Strategy in Searching for Natural Compounds with Anti-Aging and Rejuvenating Potential

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In this episode of the Aging Science podcast I talked with Prof. Nir Eynon (@nir_eynon). We touched on many topics, including elite athletes, how COVID affected working culture (for the better), the benefits of tabatas, epigenetic and muscle clocks and how they are affected by exercise, biases in research and the role of meta-analysis. I hope you will enjoy this episode as much as I did.

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Short Bio – Nir Eynon

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Nir earned his PhD degree with high distinction in 2010 from Porto University, Portugal. Early during his career, he was studying the genetics of elite athletes before switching to aging research and epigenetics.

His work on aging brought him to Victoria University where he became a program leader, at the Institute of Health and Sport (iHeS). Among other things, at Victoria he now runs the Gene SMART study on exercise through which his team aims to uncover the genetic and epigenetic responses to exercise.
https://www.vu.edu.au/institute-for-health-sport-ihes/research-areas-in-ihes/mechanisms-interventions-in-health-disease/muscle-exercise-movement/human-gene-smart-study

Let’s keep in touch - the Australian Physiological Society Meeting and more

Before we talk about epigenetics and exercise a few housekeeping notes.

Nir asked me to promote this year's AuPS Annual Scientific Meeting (@AuPhysiolSoc) which will be held in Melbourne on 26-29 November 2023. This, I am sure, would be a great opportunity to meet Nir personally so please attend if you can. I will also keep an eye on this meeting and hopefully there will be other Australian aging researchers attending. In particular I would be keen to meet with Rene Koopman who has published excellent work on iron dyshomeostasis and age-related muscle loss (Alves et al. 2021).

Would be lovely to run into other aging researchers or longevity enthusiasts there. In the meantime I suggest you can follow us on these channels if you have questions or speaker suggestions:

VitaDAO twitter account: @vita_dao
VitaDAO discord channel: https://discord.gg/vitadao
My own twitter account: @Aging_Scientist
VitaDAO telegram: https://t.me/vitadao

What is epigenetics?

The term epigenetics describes a form of gene regulation that relies on modifications to the (chemical) structure and organization of DNA and chromatin. This is in contrast to genetics which deals with changes to the DNA sequence itself.

Epigenetic marks are a type of modification that is attached to DNA that help genes to be expressed at the proper time. There are two major types of epigenetic marks, those found on histones and those found directly on the DNA. Histone modifications are highly diverse, whereas regulatory DNA modification is largely limited to the methylation of cytosines.

The different epigenetic marks are recognized by reader proteins that affect gene expression. Although these marks can have complex effects, some broad patterns are evident, like for example repression of transcription through CpG methylation.

Although methylation serves an important regulatory role, it turns out not all species have methylation at CpG sites. Bacteria have a different type of DNA methylation whereas C. elegans seems to have lost this feature altogether during evolution (2). That is one of the things I learned in this podcast!

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The rise of epigenetic clocks

When we age so does our epigenome and one way to measure this epigenetic aging is through so called DNA methylation clocks. Many studies, initially pioneered by Steve Horvath, have shown that methylation at certain sites in the genome can be used to construct a clock that closely tracks the passage of time.

These clocks are exciting because they are much better at predicting chronologic and biologic age than the biomarkers we used to have. In fact, I still remember going to conferences and listening to talks that painted a rather disappointing picture of blood based aging biomarkers (e.g. based on the MARK-AGE project [2]).

These clocks are also exciting because they promise to become a surrogate endpoint for medium sized phase II-like studies. A surrogate endpoint is a cheap, easy-to-measure marker that substitutes for something else more expensive. The hope is that a slowing of epigenetic aging in small studies would be predictive of success in larger trials that focus on harder outcomes like health and survival. If true, this would push down the cost of trials by orders of magnitude because we could pre-select promising compounds before going into large studies. However, even the best surrogate endpoints like LDL or HDL cholesterol cannot substitute for large studies, as the countless failures and disappointments in the clinic show (e.g. CETP-inhibitors for atherosclerosis and the clinical failure of most non-statin drugs).

Another reason why clocks are important is their link with the biology of aging. Understanding why methylation at certain sites changes and what harmful effects these changes have, could improve our understanding of aging and allow us to find new therapies. To give an example of such advances, as mentioned in a prior podcast, the study of epigenetics has uncovered not only the importance of entropy in the process of aging, but also ways to reset some of these age-related changes (partial reprogramming). Nir is also interested in understanding sex differences in epigenetics as well as the effects of exercise on epigenetics. This could be very important since we still cannot fully explain why women live longer than men, much less on the epigenetic level.

However, there is a world of epigenetics beyond clocks, as Nir mentioned during the podcast. He is very interested in studying sites that are not commonly selected to build clocks because these could still have important functions that are being neglected.

Biases and problems in research

"Better take your chances when young" (Nir Eynon)

We discussed two large problems in research, one was the lack of diversity in the choice of our research subjects and the second one were the working conditions for scientists.

Historically, clinical trials have included predominantly Caucasian white males. This underrepresentation of minorities and women has obvious negative consequences because the therapies and clinical practices developed for white men may not translate to other groups (also known as lack of external validity). Interestingly, the same issues plague mouse research. Many studies use one strain of mice, therefore not representing the true genetic diversity of the species and in the past most studies used almost exclusively male mice of one common strain.

In his research Nir seeks to correct these biases by recruiting at least 50% female participants for his studies. This will allow him to better understand the epigenetic differences between men and women. 

As for the second point, poor working conditions, we specifically talked about the difficulties that parents and couples face. In fact, scientists are often expected to move across the globe in search of a lab that is a good fit for them and to further their career. Modern science is extremely specialized so only a couple of labs across the whole globe may be working in your niche. Therefore, it is almost impossible to be successful without moving from position to position and country to country.

Given this, it is almost surprising that people are still willing to work as scientists. Very few jobs in the world demand constant relocation, combined with low pay, long working hours, high pressure and mediocre job stability. In our conversation with Nir we explored ways in which this is improving and what career path might be most suited for those who cannot or do not want to relocate (I won’t spoil the answer). 

Exercise and Aging - facts, controversies and open questions

I think Nir is doing brilliant work trying to figure out how exercise affects the epigenetics of aging but I would like to provide an interesting perspective worth discussing.  Does exercise really slow aging? I think some of the data Nir mentioned himself is consistent with the idea that it does not.

However, whether we believe that exercise actually slows aging or that it “only” has tremendous benefits for age-related health, we all agree that exercise is very important.

From a public health perspective exercise is still the holy grail, but from gerontologic perspective I think exercise is a bit oversold (2).

The other issue with exercise is compliance. No matter how healthy it is, many people do not have the time or motivation to actually go out and exercise. We need exercise in a pill and this is where Nir's research comes in and that of other exercise researchers. Although drugs will never fully recapitulate the benefits of exercise, we will nonetheless be able to reap some of the benefits of regular exercise if we gain an understanding of the molecular changes underlying exercise adaptation.

“I think at the end of the day, scientists that are working in aging, the differences in opinions between everyone are not that large. We want to think that they are very large and very big. But it's all nuances. Because at the end of the day, we want people to be healthy for a long time. That's the goal.” (Nir Eynon)

References

Weinhouse, Caren, et al. "Caenorhabditis elegans as an emerging model system in environmental epigenetics." Environmental and molecular mutagenesis 59.7 (2018): 560-575.

Alves, Francesca M., et al. "Iron accumulation in skeletal muscles of old mice is associated with impaired regeneration after ischaemia–reperfusion damage." Journal of Cachexia, Sarcopenia and Muscle 12.2 (2021): 476-492.

Notes

1/ There appears to be some genuine controversy whether C. elegans shows no methylation or whether they do have adenine N6 methylation (6mA).

Greer, Eric Lieberman, et al. "DNA methylation on N6-adenine in C. elegans." Cell 161.4 (2015): 868-878.

Also: https://pubpeer.com/publications/B024A9B1AFF2ED7E69DB745662382B?utm_source=Chrome&utm_medium=BrowserExtension&utm_campaign=Chrome

2/ The idea that exercise does not affect aging rate is based on studies in mice that fail to show lifespan extension with exercise and a rather pessimistic reading of the outstanding rat literature by John Holloszy. While in his studies he did usually find that exercise led to a modest extension of median lifespan in rats, this increase was lower than for caloric restriction. Furthermore, there was no improvement in maximal lifespan with exercise which led him to argue that exercise does not slow the aging rate. However, this might be over-interpretating the absence of a signal since maximal lifespan is notoriously difficult to measure due to dwindling sample sizes at old ages; and its use as a marker of aging rate remains somewhat controversial.

Garcia-Valles, Rebeca, et al. "Life-long spontaneous exercise does not prolong lifespan but improves health span in mice." Longevity & healthspan 2 (2013): 1-12.

Holloszy, John O. "Mortality rate and longevity of food-restricted exercising male rats: a reevaluation." Journal of Applied Physiology (1997).

3/ My intuition is that you can construct a clock using any type of dataset, be it epigenetic, transcriptomic, proteomic or using plasma proteins as was tried in the MARK-AGE study. However, the missing link was the combined use of multiple markers. No epigenetic clock uses a single site and it was a mistake to look for a single best blood biomarker of aging. The idea of using composite clocks is one of the big breakthroughs.

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Introduction

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Welcome back Vitalians! We are thrilled to celebrate our one-year anniversary of bringing you the latest research, insights, and developments in our field. Over the past year, we have covered a wide range of topics, from artificial intelligence and sustainability to genetics and aging research.

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As we reflect on the past year, we are grateful for the support and engagement of our subscribers. Looking ahead, we are excited to continue bringing you the latest news and trends in our field, while also exploring new areas and expanding our coverage. Thank you for your support over the past year, and we look forward to continuing this journey with you for many more years to come. 

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In this edition, we are excited to feature an interview with Dr. Shahaf Peleg, a renowned expert in the field of longevity research. His insights inspired us to consider some limitations the field might be facing. Despite the increasing interest and investment in the field of aging research, it has become progressively narrower in recent times. Many scientists concentrate their efforts on traditional aspects of aging research such as diet control, physical activity, and well known longevity interventions (e.g. Rapamycin), thereby disregarding less conventional areas that have greater risk. This tendency towards conventional approaches limits funding, publication, and progress in the field, and dominant concepts are unlikely to surpass the longevity ceiling, consequently decreasing the potential impact on healthy lifespan.

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To overcome this barrier, it is essential to allot more funds and attention to novel, high-risk projects that have the potential for more significant impacts on health lifespan. These undertakings may be less orthodox, but they could be the means to unlocking new discoveries that could revolutionize the field of aging research. By promoting more daring and innovative thinking, we can identify new avenues of research and discover new treatments that could help us increase healthy lifespan beyond the current limit. This requires a shift in the mindset of the research community, and greater support from funders and policymakers who understand the significance of investing in unconventional, innovative, and even risky projects that can progress the field.

VitaDAO Funded Research Projects

Congratulations to the ImmuneAge team for receiving a 99.83% majority in the tokenholder vote to secure VitaDAO funding and support. 

ImmuneAge aims to rejuvenate aged hematopoietic stem cells to tackle age-related decline in the immune system, which is associated with numerous diseases due to pathological effects including chronic inflammation and loss of tumour surveillance.

Longevity Literature Hot Picks

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Preprint Corner

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VitaDAO’s very own longevity overlay journal - The Longevist - had its first on-chain vote to determine which preprints will receive a coveted place in the inaugural issue! Announcement of the preprints and journal launch coming in mid-May!

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This month we are featuring 6 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in previous issues of this newsletter.

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Five years later, with double the demographic data, naked mole-rat mortality rates continue to defy Gompertzian laws by not increasing with age

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Development of a novel epigenetic clock resistant to changes in immune cell composition

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Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction

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OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular 

senescence

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Evidence of a pan-tissue decline in stemness during human aging

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Epigenetic fidelity in complex biological systems and implications for ageing

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Published Research Papers

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Ageing-associated changes in transcriptional elongation influence longevity

This Nature study found acceleration of RNA polymerase II (Pol II) is linked to aging and shorter lifespan as it becomes less precise and more error-prone with age. Mutations in insulin-signaling genes and low-calorie diets can slow down Pol II speed and increase lifespan. The study establishes a causal connection between Pol II speed and lifespan.

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Dedifferentiation maintains melanocyte stem cells in a dynamic niche

Why does our hair turn grey with age? We know that it’s due to failure of the melanocyte stem cell (McSC) system, however the Ito lab has provided a mechanistic explanation as to why this happens. Unlike other stem cell populations, McSCs can switch between two different states (stem and transit amplifying) and have motility to travel between different compartments. However, some cells lose this motility, fail to dedifferentiate and melanocytes numbers diminish leading to a loss of pigment. 

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A population of stem cells with strong regenerative potential discovered in deer antlers

Numerous animals such as lizards and lobsters have significant regenerative capability whereby whole limbs can be regrown, whereas regenerative capability in mammals is rare and less extreme, for example mice can only regenerate digit tips. However, deer have an amazing capability to regenerate their antlers each year, which the Qiu lab show is due to a population of cells called antler blastema progenitor cells (ABPCs). Interestingly, mice have a similar cell type in their regenerative tip.

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Biological age is increased by stress and restored upon recovery

A study showing biological age - as quantified by transcriptomic, metabolic and epigenetic readouts - can increase as result of stresses such as heterochronic parabiosis in mice, or severe COVID-19 infection, which can then revert back following cessation of the stress and recovery. 

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Lung adenocarcinoma promotion by air pollutants

Research showing that air pollutants contribute to lung cancer by eliciting an inflammatory response resulting in macrophages releasing the cytokine interleukin-1β, which in EGFR mutant lung alveolar type II epithelial cells can induce a progenitor-like state that drives tumourigenesis.

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Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes

It has been shown that lowering body temperature can extend lifespan in numerous organisms such as nematode worms and fruit flies. The Vilchez lab now show that this effect is dependent on a protein involved in proteasome activation, which can allay age-associated protein aggregation. Interestingly, we recently featured research from John Speakman showing that body temperature impacts lifespan more than metabolic rate in 2 small mammals. Could these two findings be connected?

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CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging

We experience an age-related decline in immune function which can lead to chronic systemic inflammation, which is associated with numerous diseases. Here the Goronzy lab provide a mechanism whereby the proton pump V-ATPase is targeted for degradation, leading to faulty lysosomes and subsequent accumulation of amphisomes which undergo extracellular release of their mitochondrial DNA-containing cargos, which then elicit an immune response.

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Reversal of liver failure using a bioartificial liver device implanted with clinical-grade human-induced hepatocytes

A bioartificial liver device employing human-induced hepatocytes has shown promise in treating post-hepatectomy liver failure in both animal and human studies. The treatment was well-tolerated and improved liver function, suggesting it could expand the population of eligible patients for liver resection.

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Engineering longevity—design of a synthetic gene oscillator to slow cellular aging

By rewiring an endogenous toggle switch, sustained oscillations were created that increased the cells' lifespan by delaying the commitment to aging. This study provides a foundation for designing gene circuits that slow aging.

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CRISPR-activated expression of collagen col-120 increases lifespan and heat tolerance

sgRNAs fed to C. elegans to CRISPR-activate the expression of collagen col-120 and col-10 in adulthood increase lifespan and heat tolerance. Results suggest collagen enhancement may promote longevity and stress resistance.

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Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan

New evidence that cellular aging is fundamentally controlled by mitochondrial function.
This study identified a common mechanism that regulates lifespan by controlling cytosolic ribosomal protein abundance, actin dynamics, and proteasome function through mitochondrial genes. 

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Body composition and mortality from middle to old age: a prospective cohort study from the UK Biobank

300,000 participants study found that being overweight didn't increase mortality risk, but obesity did, though the risk decreased with age. Additionally, lean mass didn't reduce mortality risk.

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Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging

Aberrant transcription occurs during cellular senescence and mouse aging, impacting cellular health and signal transduction pathways. This suggest that age-related spurious transcription promotes a noisy transcriptome and degradation of coherent transcriptional networks.

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Published Literature Reviews

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No rest for the wicked: Tumor cell senescence reshapes the immune microenvironment

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Mitigating age-related somatic mutation burden

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Recent clinical trials with stem cells to slow or reverse normal aging processes

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Targeting the biology of aging with mTOR inhibitors

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Job board

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Retro biosciences are hiring across the board from fellows and research associates to project managers 

Retro are focusing on Cellular reprogramming, autophagy, & plasma-inspired therapeutics.

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Rubedo are looking for Director of Program Management and Portfolio Strategy

Rubedo works on innovative therapies engineered to target cells which drive chronic age-related diseases and their drug discovery platform has engineered novel first-in-class small molecules designed to selectively target senescent cells.

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Calico is now accepting applications for postdoctoral fellowships

They have openings across Protein Biochemistry and Structure Biology, Lung Homeostasis and Aging, Immuno-Oncology, and Mechanisms of Yeast Aging

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The Hansen lab is inviting highly qualified, inquisitive scientists to apply for positions as a Postdoctoral Researcher

Buck Institute for Research on Aging, Novato, California

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The Lapierre Lab is looking for motivated Ph.D. students and postdoctoral researchers!

To study how nucleo-cytoplasmic protein partitioning affects proteostasis, autophagy and aging using C. elegans.

News

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People are taking a cheap drug to try reverse-age their ovaries — and cheat their 'biological clock'

Human trial - rapamycin for reproductive aging

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King’s College and the LSF partner to advance human longevity education and research

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

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Introducing the Time Initiative with AFAR are empowering undergraduate leaders in aging research

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Unity biotechnology announces positive 48-week results from phase 2 BEHOLD study of UBX1325 in patients with diabetic macular edema

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FDA approves Biogen’s ALS drug tofersen, paving new road for accelerated pathway in neuro diseases

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Drs. Sinclair, Huberman, and Brenner on the Future of NMN After the FDA Ban

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Experimental Alzheimer’s drug slows cognitive declines in large trial, drugmaker Eli Lilly says

The antibody therapy in stage III clinical trial improved cognitive and functional decline by 35%

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Longevity Investors Conference to showcase promising startups to high-net-worth investors

Resources

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Computational Biology of Aging coursebook

The course covers computational biology methods for studying aging and offers hands-on experience in analyzing gene expression, constructing aging clocks, and using dynamical systems modeling to study the biology of aging.

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Karl Pfleger: Announcing a categorization of 18 categories of aging/longevity companies & mappings between this, the SENS areas, Hallmarks & Pillars

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Articles

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Humans Can Stop—But Not Fully Reverse—Aging, Study Suggests

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Why don’t whales get cancer? Cracking one of medicine’s greatest mysteries

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Longevity for companion animals: why should we care

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Possible ‘Steps’ to Revealing Super-Agers

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The “stepping stone” approach to getting longevity drugs to market

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Longevity is a dish best served cold

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Ageing studies in five animals suggest how to reverse decline

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Boosting body’s antiviral immune response may eliminate senescent cells

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Benefits of 'zombie' cells: Senescent cells aid regeneration in salamanders

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The science of reversing aging

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Moderate Drinking Doesn’t Lower Mortality

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Longevity Seekers Embraced This Drug. But Does It Actually Fight Aging?

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Improving longevity literacy – and why digital health is the answer

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“We Have 30 Extra Years”: A New Way of Thinking About Aging

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Rapamycin's Role as a Molecular Brake for Cellular Hyperfunction and Runaway Cells

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Women In Longevity And The Renaissance Of The SENS Research Foundation

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The tech entrepreneur betting he can get younger

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Conferences, Workshops and Webinars

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Meet the most inspiring speakers and experts gathering to discuss their present research.

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Pop-up city - Zuzalu

Longevity Events in May

May 6-9th: Longevity 0-1

May 13-14th: Longevity Industry Talks

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The 2023 Harvard/Glenn Symposium on Aging

22nd of May, virtual

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Authophagy UK

19-20th June, University of Birmingham

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5th World Aging And Rejuvenation Conference

July 17-18, 2023 in Frankfurt, Germany.

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BSRA Annual Scientific Meeting

British Society for Research on Ageing is pleased to hold its 2023 annual meeting at the University of Westminster

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DGfA (German Society for Research on Aging) Annual Meeting

June 29-30th, 2023 at the Volkshaus Jena.

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The Groningen-Jena Aging Meeting "G-JAM" 2023 

28-30th September 2023 at the European Research Institute for the Biology of Ageing (ERIBA) in Groningen, the Netherlands. 

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Awards and Competitions

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Maximon Longevity Prize

50 000 CHF for the winner

Deadline for applications: 30th of June

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The Longevity Prize announces the winners of the Hypothesis Prize!

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Tweets

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Thought-provoking:

Anil Bushnan: Senescent cells are sentinel cells that coordinate an immune response. Immune surveillance with senescent cells is a mechanism for tissue homeostasis. There are no “good” and “bad” senescent cells-just the detrimental effects of failed immune surveillance leading to accumulation.

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Controversial:

Elon Musk: Our lifespan is programmed into our genes, just like it is for fruit flies or pets. Fruit are already vegan & even if they do yoga every day & take every supplement, they still only live 50 days.

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Elon Musk: The precision of our biological clock across trillions of cells is incredible. One never sees someone with an old left arm, but a young right arm. Aging can obviously be fixed. The real question is whether it should be.

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Books

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The Age of Scientific Wellness: Why the Future of Medicine Is Personalized, Predictive, Data-Rich, and in Your Hands

Taking us to the cutting edge of the new frontier of medicine, a visionary biotechnologist and a pathbreaking researcher show how we can optimize our health in ways that were previously unimaginable.

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Outlive: The Science and Art of Longevity

“A groundbreaking manifesto on living better and longer that challenges the conventional medical thinking on aging and reveals a new approach to preventing chronic disease and extending long-term health, from a visionary physician and leading longevity expert.”

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Podcasts and Videos

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What they thought of aging in 1931 - The Sheekey Science 

What did scientists think about aging in 1931? That’s right. 1931, because that is the year the first biological textbook was published “The Science of Life”.

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NewLimit are aiming to extend human lifespan, here is a progress update

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Interview with Dr. Shahaf Peleg

Dr. Shahaf Peleg is a group leader at the FBN Institute at Dummerstorf, Germany, where he focuses on studying the role of metabolism-epigenetics connectivity during early aging, response to stress, and cognitive impairment. Through his research, Dr. Peleg aims to identify new and innovative therapeutic avenues that can help increase healthy human lifespan.

What inspired you to enter longevity research?

When I was in high school, I was thinking about what I should do later in life. Should I become a lawyer? Politician? Businessman? But the more I thought about it, the more vain it seemed. I wanted to tackle an interesting challenge in life that would make a difference. Studying aging immediately popped up in my mind as such an (impossible) challenge. Also, I noticed with sadness that people age and die and I knew from a young age that I would go on one day to study aging.

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

To be honest, I believe that a truly convincing theory of aging has yet to emerge.

How has the field changed since you started?

To put it in perspective, When I started my Masters in 2006, there was already an increasing interest in researching aging, leading to more investment, funding, and conferences in the field.

Advancements in technology, such as CRISPR, advanced omics, AI, and novel drugs, have also enabled more efficient aging research. Also, the rapid development of the internet and applications such as Twitter have facilitated collaborations among scientists and enable them to interact more efficiently than before.

We also observed that many scientists have started to question previous assumptions, results, and theories on aging, which were previously published, and this is followed by heated debates. As the field of aging grows and we collect more observations, it is likely we will disprove more previous theories on aging.

Unfortunately, the field has surprisingly become narrower. A handful of concepts such as diet, exercise, rapamycin, mtUPR, and a few others have become dominant – so dominant that they are over-studied, over-published, and importantly, over-funded. This poses dual disadvantages by inhibiting other promising ideas to be studied/funded/published and by the fact that it is likely that the current dominant ideas will not break the glass ceiling of longevity.

What mistakes do you think the longevity field has made?

I have alluded to it in the previous point. The field is too narrow and it’s easier to get funded and publish if the scientist chooses a ‘safe’ canonical aspect of aging research such as caloric restriction. But this is not the way to go. We need to encourage risky projects, out-of-the-box ideas and younger researchers (not always the big names). If we really wish to have a fair chance to increase life span beyond 120, the field needs to also pursue such novel ideas – the current canonical ideas may increase healthy lifespan, but unlikely to bring us beyond the 120 mark.

It is also concerning that some of the so-called-established results (leading to theories of aging) were based on data that is not reproducible. Considerable time, effort, and money were invested in follow-up studies, which resulted in failures and even discredited the field of aging to some extent. This may have been due to researchers taking other labs' results for granted without sufficiently questioning and thoroughly reproducing the published data.

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

Naturally, the study by Cynthia Kenyon in 1993 showing that aging can be genetically modulated really pushed the field forward. I think many discoveries are important and big in the field, and it’s hard to pick just a few. However, I do find Darren Baker's work on targeting senescent cells interesting, and I believe the research on drugs such as Rapamycin and Metformin is crucial as they show potential in increasing healthy lifespan. Additionally, Alex Zhavoronkov's work on using AI to intervene with aging is novel and may be critical for the future of the field, as it's possible that AI could better assess the enormous amount of factors that contribute to aging. Nevertheless, there are many important discoveries in the field, and only time will tell which ones are promising.

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

To stay open-minded, respect the opinions of other colleagues (even when they differ from yours), be bold, think outside the box, and don't give up when things don't work. Longevity research is challenging, but that's precisely why we do it.

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

More attention should be given to data reproducibility and increasing funding, particularly for risky projects.

Is ageing a disease?

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.

Your research covers a broad range of topics, including epigenetics, metabolism, and various dietary interventions. What is the biggest impact of consuming certain foods and drinks on epigenetic age?

While I am not certain about the impact of epigenetic age (and in fact, what epigenetic age tells us in terms of aging really), maintaining a healthy diet and exercising regularly can significantly improve your healthy lifespan and delay the onset of certain diseases. However, it is important to note that these practices alone may not extend lifespan beyond the 120 mark.

Your latest study used optogenetics to increase mitochondrial membrane potential in C. elegans. Can you explain the basics of optogenetics and how you were able to use this technique to modulate mitochondrial function? Do think your finding might have translational potential in the context of human aging and longevity?

I'll start with the second question - yes, I think it has potential for translation to human aging, otherwise, I wouldn't be interested in it. Our goal is never to make yeast/worms/flies/fish/mice live longer - we always aim for human aging!

I'll leave the explanation of basic optogenetics to more qualified researchers. What we're doing is not really modulating mitochondrial function or even classical optogenetics in that sense. The idea, at least from my current view, is that we use an engineered light-activated proton pump and place it inside the mitochondria. This tool was developed by Brandon Barry at Andrew Wojtovich's lab. By taking this approach, we enable animal cells to harness the energy of light into chemical energy. We theorize that this can lead to several benefits in terms of aging. For example, it's currently assumed that mitochondrial function declines with aging, and as such, our approach may compensate for impaired metabolic function and increase cellular energy levels simply by exposure to light. Please read our Nature Aging paper that we published earlier this year. We're just at the beginning, and time will tell if this risky idea will work for us.

Looking ahead, what are your upcoming research projects or collaborations that you are particularly excited about? Can you give us a sneak peek into the direction of your future work?

I would like to continue the optogenetics project as I am very excited about its potential. As for a sneak peek… I would like to start a company!

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Outro

Thank you for staying with us till the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues. See you next month!

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Further Reading

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Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

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A hyper-quiescent chromatin state formed during aging is reversed by regeneration

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Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair

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Defining regorafenib as a senomorphic drug: therapeutic potential in the age-related lung disease emphysema

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Rhythms in barriers and fluids: Circadian clock regulation in the aging neurovascular unit

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Effects of intermittent fasting on cognitive health and Alzheimer’s disease

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Brain insulin responsiveness is linked to age and peripheral insulin sensitivity

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Contextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress

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Flow Cytometry-based Method for Efficient Sorting of Senescent Cells

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The multi-tissue landscape of somatic mtDNA mutations indicates tissue-specific accumulation and removal in aging

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A p21-GFP zebrafish model of senescence for rapid testing of senolytics in vivo

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The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

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Reviews

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Exploring the Causal Relationship Between Telomere Biology and Alzheimer’s Disease

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Aged brain and neuroimmune responses to COVID-19: post-acute sequelae and modulatory effects of behavioral and nutritional interventions

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Gene Therapy Strategies Targeting Aging-Related Diseases

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Fungi as a source of bioactive molecules for the development of longevity medicines

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Obesity: an evolutionary context

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Cellular senescence in skin-related research: Targeted signaling pathways and naturally occurring therapeutic agents

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To keep up-to-date with the latest breakthroughs in longevity research, exclusive insights, and exciting updates from our team, make sure to subscribe to our newsletter.

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VitaDAO Letter: Prizes and Research!

Welcome back to the VitaDAO Newsletter, your monthly source of insights into the VitaDAO community. Inside this Newsletter, find:

• Zuzalu: pop-up city community
• A recap of VitaDAO’s 3rd DeSci & Longevity Symposium
• Info on VitaDAO’s job openings
• Summary of VitaDAO’s recent proposals
• Meet DAO member: Laurence Ion

🚨Anotha One: A 3rd Research Symposium

An event so good, we did it a third time! On April 5th, Max Unfried and Eleanor Sheekey hosted a third VitaDAO research symposium. Garnering over 700 viewers, the event was a day packed with education and learning about the future of rejuvenation therapies and longevity. Speakers from around the world provided valuable insights into the fascinating world of aging, including talks on reproductive aging, AI and aging, and longevity drug discovery. Notable speakers included Jackie Han, Zhongwei Huang, Kamil Pabis, Dr. Arturo Bujarrabal, Prof. Karsten-Henrich Weylandt, Vadim Gladyshev, and Aubrey de Grey.

🏆Hypothesis Prize Winners

The Longevity Prize is a DeSci initiative aiming to accelerate research efforts. Coordinated by VitaDAO, Foresight Institute, Methuselah Foundation, and Lifespan.io, the Longevity Prize aims to highlight and accelerate progress in longevity. The first prize, the Hypothesis Prize, was awarded to individuals who formulated a hypothesis in an undervalued area of longevity. First-place winner, Carlos Galicia, proposed the study of rejuvenation during embryogenesis as a solution to age-related decline. Second-place winner, Rakhan Aimbetov, proposed the study of proteostasis disruption in age-related diseases. Third-place winner, Shahaf Peleg, proposed the exploration of mitochondrial dysfunction in aging through the use of a novel approach of external energy replacement using mtON technology. You can watch a recording of the Award Ceremony, here.

The Longevity Prize is a crowdsourced prize funded through the Gitcoin community and matched by Vitalik Buterin to fund longevity research projects. Want to learn more? Listen to Allison Deuttman, president of Foresign Institute, and Eleanor Sheeky discuss this ecosystem generator.

🌎Zuzalu & Creating A Longevity Network State

Zuzalu is a first-of-its-kind pop-up city community initiated by Vitalik Buterin & frens in Montenegro, from March 25 to May 25, 2023. Taking place in Montenegro, Zuzalu has brought 200 core residents brought together through a shared desire to learn, create, live longer and healthier lives, and build self-sustaining communities.

VitaDAO is supporting every aspect of longevity at Zuzalu, including various events on biotech innovation and jurisdictions for longevity, as we’re exploring evolving VitaDAO towards a Longevity Network State, and building a special jurisdiction for medical innovation with a better regulatory framework.

We will dive into how biotech innovation can bring aging under medical control, and how new cities and states can enable better regulatory pathways for innovating in longevity therapeutics.

During the first week of Zuzalu, we introduced residents to longevity, starting with the lifestyle aspects, then an overview of how we can really bring aging under medical control, with biotech innovation and special jurisdictions with better regulations We then delved deeper into why Zuzalu is exciting to our mission — building new cities, jurisdictions, and states for longevity and medical innovation, exploring how people congregating physically can unite & foster groundbreaking advancements in healthcare and human lifespan.

And then we got to learn from many founders of new cities and network states — while exploring the intersection of longevity and network states on a panel with Adam Gries, Balaji, Laurence Ion and Niklas Anzinger

Sad you’re unable to join Vitalik and many others in person? Watch sessions live through the Zuzalu Livestream.

• May 7–10th: Longevity 0 to 1 Crash Course Come learn about the biology of aging and the longevity industry! This free 18 hour course will dive into scientific models of aging, the research behind aging interventions, and ways YOU can help advance longevity.
• May 12–14th: Longevity Biotech Conference
• May 24th: Final Demo Day

🧪The Longevist: A Curation of Longevity Research

Drum roll please🥁…. introducing The Longevist, an overlay journal curating the most impactful longevity research every quarter. You might be wondering to yourself, how exactly does this journal work? Each quarter, a mix of industry and academic experts in the longevity space vote on preprints to feature. With a focus on quality, The Longevist aims to select 10–20 articles a year, showcasing top articles from servers like BioRxiv, MedRxiv, and Arxiv.

This month, The Longevity launched 2023 Q1 voting. With over 20 voters, the top three selections were more than clear:

1. Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice
2. p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells
3. Multidimensional proteomics identifies molecular trajectories of cellular aging and rejuvenation

Want to join in on the action? Help fund the dissemination of longevity research. Connect with tim@vitadao.com or rhys@vitadao.com to vote, build, or contribute.

🗣️VitaDAO in the Wild

- Laurence Ion and Vincent Weisser joined the Epicenter Podcast to speak about the purpose of DeSci, the advantages of DeSci, and ways VitaDAO is accelerating the space.

- Coindesk wrote about VitaDAO’s new initiative, VitaTech, a for-profit company that will be created to secure and distribute funding for longevity research.

-VitaDAO Governance Lead, Gavin Singh, spoke at DeSci Tokyo about governance in the DeSci space.

🏛️VitaDAO Governance: Season 0 of Governance Recap

Earlier this year, the VitaDAO community voted to improve the governance process by “batching” governance into seasons. Expanding from February 20th to April 3, the VitaDAO community had its first round of seasonal governance: what a learning experience! It was exciting to see community engagement when discussing governance goals and during the creation of proposals.

Season 1 aimed to pass proposals that focused on increasing community size, increasing the number of token holders, accelerating research assets, and increasing researcher engagement. It is with excitement to share four proposals passed as part of VitaDAO’s first season of governance:

• SG 0.3a: This proposal will establish the Commercialization Squad, a group of individuals whose goals are to increase the $VITA token utility value and commercialize VitaDAO’s assets.
• SG 0.3c: This proposal will establish VitaTech, a US-based for-profit company to license longevity technologies from US universities and research institutions and raise non-dilutive funding to commercialize assets.
• SG 0.3b: This proposal approved Molecule’s offer to pay for IP services in sweat equity as opposed to cash.
• SG 0.1a: This proposal defined the creation of an Ambassador Program, a collection of people appointed to be Ambassadors and perform outreach on behalf of the DAO.

📣Community Approved: What you voted for!

VDP-63 Passed! VitaDAO and the Gorbunova Lab are launching Matrix Bio, a cutting-edge research venture leveraging the anti-cancer and pro-longevity effects of high molecular weight hyaluronic acid from naked mole rats to humans. VitaDAO will fund up to 300k to support the screening and development of small molecule inhibitors of hyaluronidases.

VDP-74 Passed! This vote was an assessment of Etheros Pharma, a preclinical biotech that is pioneering a new small-molecule drug class to extend mammalian lifespan and neural healthspan.

VDP-80 Passed! This vote was an assessment of ImmuneAGE, the first drug discovery platform for immune system rejuvenation. ImmuneAGE is developing compounds that target the hematopoietic stem cells (HSCs) of the bone marrow.

VDP-85 Passed! This vote was an assessment of HDAX, a preclinical-stage drug discovery company targeting a class of proteins implicated in neuropathies and inflammation.

VDP-86 Passed! This vote was an assessment of Humanity, an app that uses wearable technology and quantified-self methods to measure one’s rate of aging.

VDP-94 Passed! This vote re-allocates the remaining tokens already minted under VDP-11 and deploys them in partial satisfaction of VDP-72 obligations; to defer minting more tokens in the near-term.

💪Exercise Your Right to Vote on VitaDAO’s Governance Forum:

Find all of VitaDAO’s pending live proposals on Discourse, VitaDAO’s governance hub for proposals before they are moved on Snapshot. These proposals are open for engagement, voting, questions, and conversation!

💸We’re Hiring!

VitaDAO has six job openings! If you are a well-organized and dynamic person, curious about the world of longevity, crypto, and open-source communities, then we’re looking for you! Open roles include Legal Lead, Onboarding Lead, Governance Lead, Community Moderator, Company Builder, and Operations Champion. Come get rewarded with competitive compensation while simultaneously helping shape the future of VitaDAO!

🧑‍💻Ch-ch-ch-changes

Haven’t noticed? VitaDAO has made new changes to its website: https://www.vitadao.com/. Find updated descriptions of projected funded by VitaDAO and even explore VitaDAO’s new treasury dashboard.

👋Meet Longevity Dealflow Steward: Laurence Ion

Laurence Ion is an entrepreneur and investor working to “rejuvenate” the biotech industry. With a tech background and a keen passion for the scientific method, he’s helping translate science into startups, accelerating progress in medical innovation, on a mission to bring aging under medical control. He now serves as Steward of the Longevity Dealflow Working Group and as Director of Vitality Healthspan Foundation, a nonprofit organization that supports healthspan research.

Why longevity?

I am working in service of life (vita, in Latin), helping end aging.

Because I love life, it makes sense to tackle aging, the biggest hindrance to life (and the root cause of all age-related, chronic diseases).

Unlike most young people, I know what it’s like to lose my health and VITAlity (ok I’ll stop with the Vita puns). I know what it’s like to feel frail, to feel old — I’ve spent a lot of time in hospitals, I’ve had many surgeries.

How did you first get involved in the longevity space?

While I’ve had a big passion for biology and biomedical innovation, I was disillusioned with the current medical approach, so I was in tech entrepreneurship and investing, but about 5 years ago I decided to switch to the longevity biotech industry because progress was slower than expected.

I started as an angel investor, syndicating and working on a longevity VC fund. I realized that the bottleneck in the field is the lack of diversity of startups. Capital was needed earlier, to create more startups.

You were involved in VitaDAO from the earliest stages. How did you meet the team and what drew you to VitaDAO?

I had been growing my involvement in the crypto space since 2013 and was inspired by Griff Green to use the power of decentralized communities and cryptoeconomic incentives to fund longevity labs, especially given the alignment between the crypto and longevity fields.

When I came across the IPNFT framework, enabling DAOs to hold real-world IP assets, I reached out to Tyler and decided to drop everything and help in any way I can, because I wanted to fund early-stage research and accelerate it to commercialization, creating startups that wouldn’t otherwise exist, bringing that much-needed diversity, as well as scalable democratic participation.

What is the greatest challenge of being VitaDAO’s Longevity Dealflow Steward?

Keeping up with all the amazing things going on and all the requests from members, while also finding time to focus and innovate, myself.

So far, we, the VitaDAO community, have demonstrated we can act at a world-class level, with impressive, scalable, collaborative, deal flow, deploying $4M+ into 17+ projects, and bringing on the most fitting Strategic Members, including big pharma, crypto VCs, angels. This, while keeping things decentralized, requires tremendous coordination, but it’s worth it! I think that being a Steward in VitaDAO is the best way to achieve my mission of serving life… and it’s fun! Otherwise, I wouldn’t have dedicated my life to this, doing what was needed, as well as flying & living wherever needed.

While I don’t care about the title, people need to refer to me somehow, and I’m usually doing whatever is most important for VitaDAO at any point, but making sure deal flow runs smoothly while also empowering members and keeping it non-hierarchical, is definitely a challenge.

What does the future of VitaDAO look like?

Growing this highly-aligned community, a lot, with improving our capacity for action, such that we are scaling enough that the community has significant force. And with scale, as well as physical presence (special economic zones/jurisdictions/new cities, states, etc) the will of the people can be much more effective.

We can become as big and resourceful as a country. We can remove any barrier and achieve progress much faster than people think.

Any closing thoughts for readers?

Don’t hesitate to reach out, join us on Discord, hang out, and you’ll figure out how you can add value and potentially have the most significant role in VitaDAO. Think outside the box, be resourceful!

🗓️Upcoming Event

VitaDAO @ Longevity Med Summit — May 4–5, 2023- Come join VitaDAO in sunny Lisbon, Portugal at the 2023 Longevity Med Summit. Here, join other longevity enthusiasts, in learning about the development of anti-aging science, the exploration of new regenerative and longevity therapeutics, and the limiting R&D challenges faced in therapy development.

Longevity Zero to One @Zuzalu May 7–10 — Dive into the science, get career guidance from experts, and create your impact roadmap.

Longevity Biotech Conference @Zuzalu — May 12–14 — Discover breakthroughs in rejuvenation & anti-aging biotech.

🤝Get Involved

Have a special skill set? Contribute to VitaDAO and receive $VITA in return. Join the VitaDAO community on Discord and stay up to date on Twitter! As of February, VitaDAO’s Discord is now token-gated, requiring a minimum of 10 $VITA to gain access to basic contributor channels.

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Holding VITA tokens is an important step if you are looking to become an active contributor to VitaDAO's governance. VITA is the governance token our contributors use to vote on longevity research proposals, and direct the overall course of the DAO. 

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VITA holders have voting rights and are active stakeholders that determine how the DAO advances its longevity mission. We'll be walking you through all you need to know about the VITA token, how you can get some, and how you can begin contributing to our governance processes today!

Understanding the VITA Token and Its Purpose

VITA is an ERC-20 token. If you're not familiar with blockchain lingo, ERC-20 is simply a standard for tokens built on top of the Ethereum blockchain. The token is available both on the Ethereum network and the Gnosis chain (which is a sidechain built on the Ethereum blockchain). 

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As a governance token, VITA is used for voting purposes within the DAO. This includes decisions around what projects are funded, how they are funded, treasury management decisions, and other governance activities that help improve the DAO's processes. VITA holders vote based on the number of tokens held in their wallets. In other words, the more tokens held in a wallet, the weightier the vote from that wallet.

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The supply of VITA is currently capped at 64,298,880 VITA. This represents the number of minutes lived by Jeanne Louis Calment (the longest-lived person in history). The supply cap may only increase if someone lives longer than that. At Genesis, 70% of this supply was left unminted in the DAO's treasury while the remaining 30% was allocated to the community.

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While ownership of VITA grants access to governance processes, it does not give holders ownership rights to any of the IPs held by VitaDAO. However, VITA holders can determine how the IP is monetized and other decisions around its usage and application.

How to Get VITA Token

If you are new to cryptocurrency and you'd like to purchase VITA, here's a quick run-down with a brief explanation on how you can get started:

Create a Wallet

We recommend you use MetaMask, which is a popular wallet option for Ethereum and Gnosis networks. You can add the extension to your web browser on your personal computer. If you're more likely to interact on your mobile device, consider downloading the app on your play store or app store.

Buy Ether

Since the VITA token runs on the Ethereum network, you'll need to buy some ETH to be able to pay transaction fees on the network and swap for VITA. Note, VITA can only be purchased (swapped) with other cryptocurrencies. If you are on the mobile app, you can buy ETH directly on MetaMask using your credit card or other payment options available. On the browser extension for PC, you'll be directed to MetaMask's supported providers like Coinbase to buy cryptocurrencies. 

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Alternatively, you can buy ETH on a centralized exchange and send it to your wallet address on MetaMask. If you don't want to go through the route of a centralized exchange, Ramp provides the option of buying ETH directly to your wallet address by paying with your fiat currency using available payment methods.

Go Ahead to Buy VITA

Now that you've got some ETH, you can go ahead and buy VITA on supported decentralized exchanges. Here's how it works: you have to swap one token for the other in order to buy VITA on these decentralized exchanges (DEXs). The most popular would be to swap ETH for VITA. A step-by-step process to do this is as follows:

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• Buy the ETH equivalent of VITA using any of the methods earlier described
• If you are using the mobile app, open the dApp browser on the app, go to any of the DEXs listed below, and connect your wallet
• If you are on your PC, simply go to any of the DEXs below on your internet browser and connect your wallet 
• After connecting your wallet, swap ETH for VITA on the decentralized exchange.

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You can use any other supported cryptocurrency on the DEX to swap for VITA instead of ETH. Here is a list of several decentralized exchanges where you can easily buy VITA: 

• UniSwap
• CowSwap
• Matcha
• Balancer
• Bancor

Alternative Ways to Get VITA

Besides the option of buying, another way to get VITA is to earn the token through your contributions to the DAO. Contributors at the different working groups are compensated with VITA tokens. If you are looking to earn some, hop into the Discord channel and try to get plugged in to see how you can use your skills to help drive progress at the DAO. 

VITA Token in VitaDAO Governance

Governance at VitaDAO happens in two forms: Soft Governance, which involves governance decisions made without an on-chain vote; and on-chain governance, where on-chain voting is required to make decisions. Either of these governance mechanisms is used depending on the type and impact of decisions to be made. 

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Governance processes are based on three phases. Here's an outlook of how decisions are made and how we decide which of the governance forms are used in decision-making:

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Phase 1: Idea

This is where we receive proposal ideas for consideration. Anyone is invited to propose an idea. If an idea receives positive support from five or more people, it moves to phase 2.

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Phase 2: Proposal Development and Approval

Here, the idea is shaped into a proposal using a defined template. Based on the funds requested, the proposal is either passed via a soft governance approach or on-chain voting. Here's how we decide that:

• A proposal requesting up to 2,500 USD only requires approval from two working group representatives.
• If the proposal requests up to 10,000 USD, it will require approval from a majority of all the working group stewards.
• For proposals that ask for up to 50,000 USD, a public Discourse poll is set up and a majority vote is required for approval.
• Proposals with required funds greater than 50,000 USD require a majority vote on a public Discourse poll and it is moved to phase 3.

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Phase 3: On-chain Voting

The following are the kinds of decisions that require an on-chain vote for approval:

• Upon having a majority vote on a public Discourse poll, proposals with a ask greater than 50,000 USD are moved to Snapshot for on-chain voting. Here, VITA holders carry out gasless (without transaction fees) voting. Proposals must achieve a quorum and a majority vote before they are approved.
• Proposals that involve the operating rules of the DAO, changes to such rules, membership, and enforcement of norms all require on-chain voting before they can be passed. This is done regardless of the proposal's budgetary threshold.

How to Vote on Snapshot Using Your VITA Token

When proposals are posted on Snapshot, VITA holders are required to vote on those proposals to determine whether they will be approved or not. To vote on Snapshot, click the voting link and connect your wallet.

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Having connected your wallet, you can go ahead to vote on the current proposal. VitaDAO uses shielded voting on Snapshot so everyone can make their choice without being influenced by current voting results. 

Conclusion

We are democratizing longevity research through decentralized and community-governed processes. VITA token holders are an essential part of these governance processes as they help steer the course of progress at the DAO. Be a part of the voices that determine how VitaDAO is run by becoming a token holder today.

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Check out the podcast here. 

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I (@aging_scientist) had a marvelous conversation with Assoc. Prof. Viktor Korolchuk (@VIKorolchuk) about autophagy, mitochondria, senescence, the importance of modelling and human desire for radical lifespan extension. Originally from Ukraine where he received his PhD, Viktor worked in Cambridge as a postdoctoral fellow and later moved to Newcastle upon Tyne in the beautiful north of the UK to pursue his work on aging.

He has received a grant from VitaDAO to identify novel autophagy activators against aging and lysosomal storage disorders.
https://www.vitadao.com/projects/korolchuk-lab

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Lab page: https://www.ncl.ac.uk/medical-sciences/people/profile/viktorkorolchuk.html

Below we will review some of the concepts we discussed in the podcast.

Mitochondria – multifaceted players in aging

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

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

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

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

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

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

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

Rapamycin, mTOR and its effects on aging

Rapamycin is an approved immunosuppressant drug that is produced by a type of bacteria from the Streptomyces genus. The drug was first isolated from a soil sample found at the island of Rapa Nui hence the name.

Most of its effects are mediated via inhibition of the mTOR pathway. Generally speaking, this pathway is turned on during cellular growth when nutrients are abundant and need to be utilized for growth, and it is turned off during starvation when the cell needs to focus on survival, efficiency and recycling.

This relatively obscure drug has become the superstar and a major workhorse in biogerontology because it extends mouse lifespan and also leads to many physiologic changes that appear beneficial. 

These include increased autophagy, reduction of the senescence associated secretory phenotype (SASP), reduced cell growth and protein synthesis etc. Interestingly, rapamycin is not primarily senolytic, i.e. it does not kill senescent cells, rather it reprograms them to be less harmful. It remains a matter of debate which downstream effects of rapamycin are responsible for the lifespan benefits. Nonetheless, the efficacy of rapamycin does provide some evidence for the importance of autophagy during aging.

Senescence

Senescence is an irreversible non-proliferative state. This means senescent cells exit the cell cycle and stop growing, instead they secrete cytokines and growth factors, many of which are harmful. Senescence is considered anti-tumorigenic and senescent cells are involved in wound healing and possibly other physiologic processes like insulin secretion or structural integrity of tissues. Perhaps some of these secreted growth factors serve a purpose and therefore the removal of senescent cells poses a health risk.

However, given that ablation of senescent cells improves healthspan and extends lifespan in mice this suggests that, on balance, these cells are harmful. This alone does not explain the hype around senescence and senolytics (therapies that remove senescent cells).

The topic of senescence has received a lot of attention in the field, specifically because a single ablation treatment in mid-life can have lasting health benefits in mice. This is basically a dream therapy come true if it translates to humans. One time treatments are cheap and safer than chronic treatments, making them perfect for clinical use.

Senescence can be triggered by DNA damage, oxidative stress, telomere erosion, viral infection and many other stressors. This links senescence as a kind of downstream “damage” with many modern aging theories, like the stress resistance theory of aging, for example.

Autophagy and aging

"some of the data with these [autophagy-inducing] molecules looks almost magical" (Viktor Korolchuk)

The word autophagy describes a process of self-eating and self-recycling that almost every cell in the body utilizes. This process is necessary for a cell in order to adapt to changing environmental conditions. Organelles and proteins that are not needed in a given situation are broken down into their components, amino acids or lipids, for example, which are used to assemble whatever the cell needs at that moment. Another key function of autophagy is quality control and maintenance through the removal of damaged and dysfunctional organelles or proteins. 

Especially during starvation autophagy is needed to fuel essential cellular processes and to use cellular proteins for the production of energy (ATP).

We can distinguish several types of autophagy based on their molecular characteristics. The three key types are macroautophagy, microautophagy and chaperone mediated autophagy (CMA). As the name suggests macroautophagy degrades large, bulky structures whereas the other two do not. Chaperone mediate autophagy uses so called chaperones to help unfold proteins and import them into the lysosome, where they will be degraded. There is also crosstalk between the different types which makes it hard to study them individually due to compensatory mechanisms.

Macroautophagy has attracted a lot of attention because it is easy to measure and may remove damaged organelles and proteins believed to accumulate with aging. Macroautophagy itself is also subdivided into bulk and selective autophagy, the latter includes the autophagic degradation of organelles like mitochondria (mitophagy), peroxisomes (pexophagy), etc.

We have a lot of evidence which suggests that increased autophagy can delay aging. For example, there are comparative studies showing that cells from genetically longer-lived mice show more prolific autophagy. There is also a hint of increased autophagy in long-lived species more broadly.

The most specific and direct evidence comes from invertebrates, however, where it is possible to show that autophagy genes are necessary for the effects of caloric restriction. These things are always harder to show in mammals. However, we do have several genetic gain-of-function studies in mice suggesting that increased autophagy does indeed extend lifespan (e.g. Fernández et al. 2018), although they have their own limitations.

Other than that, there is a lot of indirect evidence. We know that many lifespan extending strategies in mice have autophagy in common, e.g. rapamycin and caloric restriction both induce autophagy.

Interestingly, autophagy deficient mice die early during life, whereas autophagy deficient cells appear fine at first glance. However, Viktor mentions that they have problems when they are forced to respire and utilize their mitochondria, which is when they start dying. This is why, in his VitaDAO project, he can use a viability assay in autophagy deficient cells to find novel autophagy inducers.

The philosophy of lifespan extension

Towards the end of the podcast, we had an interesting foray into the important question of “how long would you want to live?” and both Viktor and I agreed that: "an average person...would choose to live indefinitely if they were in good health, mental and physical".

However, this question is very sensitive to the phrasing and there are certainly people who would like to choose differently. If you are interested in understanding the psychology and philosophy behind this question, I have written extensively on this topic before and one of my recent blog posts might be a good primer for this kind of debate.
How long do you want to live? (June 22, 2022)
http://biogerontolgy.blogspot.com/2022/06/how-long-do-you-want-to-live.html

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Important Reading (selected references)

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

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

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

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

Gonzalez-Freire, Marta, et al. "Reconsidering the role of mitochondria in aging." Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 70.11 (2015): 1334-1342.

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

Fernández, Álvaro F., et al. "Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice." Nature 558.7708 (2018): 136-140.

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

(1) Regarding reduced mitochondrial biogenesis and mitochondrial mass during aging: I remain somewhat unconvinced by this aging theory, although I have not looked at this in much detail. If decreased biogenesis was a main driver of aging it should occur in both sedentary and exercised individuals, since both of them do show muscle aging, but this is not the case:

“However, it has become increasingly clear that most of the declines in mitochondrial biogenesis, turnover, and function are a consequence of physical inactivity. Indeed, when physical activity levels are matched between young and elderly people, or physical activity is otherwise taken into account, most investigations do not find any age-related changes in mitochondrial enzyme activities, mitochondrial respiration, or ATP flux” (Barbieri et al. 2017)

On the other hand, given this evidence, it appears that aging increases the susceptibility to muscle loss, including reductions in mitochondrial mass and biogenesis. This by itself does appear to be a proper aging phenotype -- consistent with the concept of reduced resilience during aging. 

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March Longevity Research Newsletter

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Introduction

Welcome back Vitalians!

In recent years, autophagy has emerged as an important topic in the field of aging biology and is now considered a major Hallmark of Aging.

Autophagy is a fundamental process that plays a critical role in the maintenance of cellular homeostasis. This process is involved in the degradation and recycling of cellular components, including damaged organelles, misfolded proteins, and intracellular pathogens.

Autophagy has been shown to become dysregulated with age, contributing to the aging process by impairing cellular homeostasis and increasing cellular damage. This is thought to play a role in the pathogenesis of several diseases, including cancer, neurodegeneration, and metabolic disorders. 

Understanding the role of autophagy in aging biology has important implications for the development of interventions to promote healthy aging. By enhancing autophagy, it may be possible to improve cellular function and delay the onset of age-related diseases. This has led to growing interest in the development of drugs and other interventions that target autophagy as a means of promoting healthy aging. 

VitaDAO are supporting autophagy research in several ways, including funding Dr. Viktor Korolchuk's lab to pursue the discovery of novel autophagy activating drugs. We had the pleasure of interviewing Dr. Korolchuk for this month’s newsletter - so don’t miss this insightful interview which touches on autophagy drug development potential, new theories of aging and the state of the longevity field.

Longevity Literature Hot Picks

‍Preprint Corner

This month we are featuring 7 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in our January and February research newsletters.

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Multidimensional proteomics identifies molecular trajectories of cellular aging and rejuvenation

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Modelling the dynamics of senescence spread

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The intensities of canonical senescence biomarkers integrate the duration of cell-cycle withdrawal

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Stochasticity explains non-genetic inheritance of lifespan and apparent trade-offs between reproduction and ageing

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Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection through aging

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Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality

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Mitochondrial H2O2 release does not directly cause genomic DNA damage

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Published Research Papers 

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The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities

Björn Schumacher’s team have discovered the first master regulator of somatic DNA repair capacities - The DREAM complex. This complex transcriptionally represses essentially all DNA-repair systems and inhibiting this can lead to improved DNA damage repair and resistance to various types of genotoxic insults.

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Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity

Horvath’s team develops a centenarian epigenetic clock to validate claims around exceptionally old age based on samples from centenarians, semi-supercentenarians (aged 105 +), and supercentenarians (+110, the oldest person being 115).

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TFEB-ependent lysosome biogenesis is required for senescence

Cellular senescence is associated with dysfunctional lysosomes which the cell compensates for by undergoing lysosomal biogenesis. Here the Carroll lab show that upon senescence induction TFEB accumulates in the nucleus and regulates lysosomal biogenesis. Furthermore, inhibiting this process results in the premature death of senescent cells due to diminished degradative ability as a result of impaired lysosomes and inability to produce more to compensate. 

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Long-term intensive endurance exercise training is associated to reduced markers of cellular senescence in the colon mucosa of older adults

Senescence markers are high in middle aged and older overweight adults than young sedentary people, but this was significantly reduced in aged matched runners suggesting that high volume high intensity endurance exercise prevents senescent cell accumulation. The resulting decrease in senescence associated inflammation is especially important in cancer prone tissues such as the colon mucosa.

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Aging disrupts MANF-mediated immune modulation during skeletal muscle regeneration

Skeletal muscle regeneration is disrupted with age. An immune modulator MANF is responsible for muscle injury repair in young animals but is not induced in old ones, thus impairing regeneration. Restoring MANF levels could be a viable strategy to preserve skeletal muscle regenerative function with age.

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Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice

The Miller lab previously published that genetic mouse models of slow ageing show similar changes in a number of pathways. They now observe similar changes with 4 lifespan-extending drugs and calorie restriction. Changes include an increase in anti-inflammatory macrophages and decrease in inflammatory macrophages, and differential expression of numerous proteins involved in age-related diseases such neurodegenerative, metabolic and inflammatory diseases. 

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Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

Single cell transcriptomic profiling was employed to measure changes in young and old mice brains after parabiosis. Analysis showed that multiple hallmarks of aging in the brain were regulated by heterochronic parabiosis in a cell type specific manner.

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Habitual daily intake of a sweet and fatty snack modulates reward processing in humans

Continued consumption of high fat, high sugar snacks in normal weight individuals resulted in decreased desire for low fat, low sugar food. The changes were independent of body weight and metabolic alterations.

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Sex differences in adult lifespan and aging rate across mammals: a test of the ‘Mother Curse hypothesis’

The Mother's Curse hypothesis suggests that as mitochondria are maternally inherited, there is no selective pressure to remove mitochondrial genome mutations which are exclusively deleterious to males. Here the authors study over a hundred mammal population across 104 species and concludes that Mother's Curse hypothesis doesn't affect mammalian ageing rated between male and females

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Published Literature Reviews

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The autophagy–NAD axis in longevity and disease

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‍Ageing as a software design flaw

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‍Impact of Cellular Senescence on Cellular Clocks

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‍BCL-2 proteins in senescence: beyond a simple target for senolysis?

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‍Cholesterol drives inflammatory senescence

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‍Cellular Senescence: beneficial, harmful and highly complex

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‍An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease

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‍Putting aging on ICE

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‍AI Technology for Anti-Aging: an Overview

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Job board

Joe Nassour is joining the University of Colorado as an Assistant Professor in summer 2023! His lab will study how telomeres interact with autophagy and innate immunity to prevent cancer initiation. Reach out to him to explore opportunities to join his team!

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Fabrizio d'Adda di Fagagna is looking for a new lab member to join his group working on telomere biology studies in cancer

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Research Lab Technician II (Mouse) - Benayoun lab/USC

The Benayoun Lab is seeking a mouse research lab tech II to join the team to help them understand sex differences in aging at USC in southern CA!

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Marco Demaria’s lab, working on aging and cellular senescence, has an available postdoc position. ERIBA - European Research Institute for the Biology of Ageing UMCG research

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BioAge is hiring a talented Senior Data Scientist and a Research Associated! BioAge’s mission is to deeply analyse human longevity data to discover drug targets for diseases of aging

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News

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First longevity clinical study design fetches FDA approval

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Rubedo Life Sciences Presents In Vivo Efficacy Data Targeting Senescence Cells to Treat Dermatological Diseases

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Sam Altman invested $180 million into a company trying to delay death

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Regenerative cell biotech Thymmune launches with backing from George Church, John Maraganore

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NVIDIA Unveils Large Language Models And Generative AI Service To Advance Life Sciences R&D

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Resources

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Spannr 2022 Longevity Funding Report

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Open Problems in Longevity Science

An online comprehensive compilation of open problems in longevity science for creating a coordinated scientific effort for finding cures for aging. Created by João Pedro de Magalhães, Hamid Hossein Alfatemi and Angelo Talay.

Articles

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A ridiculously fluffy rodent may hold the secret to longevity

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Who wants to live for ever? Quite a lot of people

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Ants Live 10 Times Longer by Altering Their Insulin Responses

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Want to live to 150? The world needs more humans.

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If they could turn back time: how tech billionaires are trying to reverse the ageing process

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Retro: A longevity biotech triple-threat?

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Fetal exposure to Great Depression economic hardship linked to accelerated aging

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Ageing is a disease, and Christian Angermayer is here to cure it

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Are you a rapid ager? Biological age is a better health indicator than the number of years you’ve lived, but it’s tricky to measure

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Loyal’s latest milestone: the first longevity clinical study design supported by the FDA

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Removing Senescent Cells May Slow, Halt, or Reverse Diseases of Aging

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People are desperately trying to live forever. Here are the biggest anti-aging trends sweeping the nation

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Four 80-year-old men finished a 100-mile race. Here’s how they did it

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Everything Wrong with Mouse Studies (Kinda)

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Conferences, Workshops and Webinars

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Longevity Med Summit - Lisbon

4-5th May, 2023 in Lisbon, Portugal.

The main goal of Longevity Med Summit is to provide and share knowledge to the medical community aimed at helping patients live longer and delay age-related health issues.

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5th World Aging And Rejuvenation Conference

July 17-18, 2023 in Frankfurt, Germany.

Meet the most inspiring speakers and experts gathering to discuss their present research.

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Pop-up city - Zuzalu

Longevity Events in May

May 6-9th: Longevity 0-1

May 13-14th: Longevity Industry Talks

Podcasts and Videos

Life Blood: Live Better and Longer with Dr. Charles Brenner

LifeBlood: We talked about how to live better and longer, what NAD is and how it impacts metabolism, how to become more physically resilient, and how to restore damaged cells, with Dr. Charles Brenner, Chief Scientific Advisor at ChromaDex, researcher and healthy aging advocate.   

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The Tim Ferriss Show

Interviewing Dr. Peter Attia — The Science and Art of Longevity, Optimizing Protein, Alcohol Rules, Lessons from Glucose Monitoring with CGMs, Boosting Your VO2 Max, Preventing Alzheimer’s Disease, Early Cancer Detection, How to Use DEXA Scans, Nature’s Longevity Drug, and More (#661)

Interview with Prof Viktor Korolchuk

An Associate Professor at Newcastle University, UK, Dr. Viktor Korolchuk received his PhD from the Institute of Biochemistry, National Academy of Sciences, Ukraine, and conducted postdoctoral research at the University of Cambridge, UK. Dr. Korolchuk's laboratory is presently dedicated to investigating the molecular mechanisms of ageing with the aim of discovering interventions that could potentially promote cellular rejuvenation and extend the healthy human lifespan. VitaDAO is proud to support his project on autophagy activators.

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What inspired you to enter longevity research?

When choosing the directions for my independent research over ten years ago I considered the biggest remaining questions and challenges in the field of life sciences. Upon extensive reflection I decided that philosophically there is no other problem as important as ageing.  Being able to contribute to our understanding of this process, to delay or prevent it all together, would have the greatest impact on human life, society, and the world as we know it. This was the reason for applying for an academic position at the first and most established Ageing research centre in the UK based at Newcastle University.

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

There are a lot of interesting developments in this area. Some are based on the idea of ageing as a programmatic process, e.g. a software design flaw by Joao Pedro de Magalhães (doi: 10.1186/s13059-023-02888-y) or a selective destruction concept by my colleague and friend James Wordsworth (e.g. doi: 10.1016/j.mad.2022.111709). Both could also potentially explain metabolic slowdown with ageing. We see experimental evidence of this age-associated sluggishness at every level of biological complexity, from individual cells isolated from aged human donors to whole organisms. Trying to explain the reasons and significance of these changes is very important but we also should consider that cellular metabolism could in turn affect the gene expression and the ageing clocks. This is where autophagy could also play the role and our working hypothesis that activating autophagy could restart metabolism and may even slow down the ticking of the clock.

However I think that neither programmatic or damage accumulation-based theories alone would be completely sufficient to explain why we become old and die. The obvious truth is that this is a very complex process and will probably require a theory that would integrate multiple mechanisms rather than attempting to use a reductionist approach. Developing a convincing theory is extremely important as it would lay the ground for probably equally complex anti-ageing interventions.

How has the field changed since you started?

Biogerontology is no longer a fringe science. With the increased awareness of the socioeconomic and healthcare problems associated with ageing it became a mainstream field. Ageing research centres sprung around the world and a lot of funding has been channelled into this area. There is excitement for the future at the moment and one can only hope that this trend will continue for the years to come.

What mistakes do you think the longevity field has made?

Working in silos, using the same reductionist approaches that work so well for simpler biological problems, forming and maintaining tribes which protect own ideas/theories. These are common problems in any area of biomedical sciences but particularly damaging for biogerontology which should ultimately explain and cure ageing, the most complex biological process of all.

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

The first example that comes to mind is cellular senescence, which was previously seen as no more than a curious artefact in a petri dish. Now senescence is recognised as an important driver of ageing and a target for rejuvenation therapies. The idea of rejuvenation by reprogramming has also taken off, although a lot of practical hurdles remain to be solved before we would be able to capitalise on its potential. However, the most dramatic development for me was the rise of longevity biotech, which was brought by the realisation (or a mere hope, time will tell) that ageing is a malleable process and that even the smallest advances in this area could bring a huge benefit for humankind.

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

Learn everything that we know about human biology, think outside the box, keep an open mind and challenge any established preconceptions.

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

Fundamental studies of biological processes underlying ageing, particularly using human-centric models. Only when we understand why we become old will be able to do something about it.

Is ageing a disease?

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

How do caloric restriction and intermittent fasting affect cellular autophagy in vivo? Do we have evidence of this process in humans and are benefits evident?

Most of our evidence is based on experiments using animal models. We are still far away from being able to monitor autophagy and its benefits in a living human, particularly in tissues that are not easily accessible for testing. Detrimental effect of impaired autophagy on human health is very clear (e.g. caused by mutations in autophagy-related genes), but the benefit of autophagy upregulation is largely an assumption. This being said, autophagy is probably one of the most promising target for interventions considering its homeostatic and metabolic functions.

What disease indications would autophagy enhancers impact the most? For example if your VitaDAO funded project for discovering novel autophagy activators was successful, what disease model would you use to validate it first?

The choice of initial disease indication is purely practical, based on the cost and the time required to demonstrate safety and efficacy. Rare monogenic diseases such as lysosomal storage disorders could be one potential application as these are associated with an accumulation of damaged cellular components. Activation of autophagy could be beneficial in this situation, and we see evidence of this in neuronal models of these diseases. A range of other age-related diseases could also be targeted depending on the type of pathology and drug pharmacokinetics.

Do you see autophagy activation as a longevity treatment? Is there evidence it helps healthy aging adults (i.e. in the absence of disease), reduces disease risk or lowers any biological age clocks/biomarkers?

It is certainly our hope that autophagy activators will be a part of anti-ageing strategies. As mentioned above, this is largely based on laboratory models where genetic or pharmacological (e.g. spermidine) interventions activating autophagy increase lifespan. There is also ample evidence for anti-ageing (as for example estimated using epigenetic clocks) effects of rapamycin which among other things activates autophagy. It is still early days for human trials of autophagy activators, for example rilmenidine has recently been found to be safe to use in patients with age-related neurodegenerative disease but larger scale randomised controlled trials are now needed. Before we could go into healthy people, we need specific and safe small molecules, which is what we and others are working on.

Tell us about your latest paper on the relationship between NAD+ metabolism and autophagy. What is the key take-away?

The paper is based on over seven years of our effort trying to understand the connection between autophagy and NAD. The key message is that when autophagy (or mitophagy) fails NAD levels also plummet down, which is not a good thing if you want to stay alive. The implications are not only for those specific pathological states where autophagy is impaired, but also for ageing in general. Autophagy is believed to go down with age and according to our model it would also bring down NAD levels thus resulting in a metabolic decline. 

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Outro

Thank you for staying with us till the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues. See you next month!

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Further Reading

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Acute Effects of Coffee Consumption on Health among Ambulatory Adults

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The Timing Sequence and Mechanism of Aging in Endocrine Organs

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VitaDAO Letter: ’Tis the Season (Of Governance)

Inside this Newsletter:

• VitaDAO’s Transition to Seasonal Governance
• Should VitaDAO Form A Longevity Network State?
• Steward Election Results!
• Meet DAO Member: Gavin Singh

A Lot Has Happened Since the Last Newsletter!

Early this year, VitaDAO announced a $4.1 million fundraising round, that included strategic members and longevity enthusiasts such as Pfizer Ventures, Shine Capital, L1 Digital, Beaker DAO, Balaji Srinivasan, and Joe Betts-LaCroix. Since this announcement, VitaDAO has been busy! Inside this Newsletter, find a recap on some of the things that have been going DAOn.

DAO News

The Results are In!

Earlier this year, several changes were made to VitaDAO’s governance structure. Most notable was the condensation of VitaDAO’s prior working group structure into three working groups: Longevity Dealflow, Community and Awareness, and Coordination. Following this structural change, VitaDAO voted to elect stewards for each of the three working groups (VDP-78.1, VDP-78.2, VDP-78.3). Elections are held every six months, with future elections to be held in September 2023. Congratulations to VitaDAO’s newest facilitators:

• Longevity Dealflow Working Group Steward: Laurence Ion
• Community and Awareness Working Group Steward: Alex Dobrin
• Coordination Working Group Steward: Todd White

Creating A Longevity Network State?

From March 25th- May 25th, VitaDAO is partaking in a pop-up mini-city experiment in Montenegro. This experimental mini-city, taking place at a resort, will offer mini-conferences, co-working spaces, tracking of biological age, and group exercise- all with a longevity focus! There are inefficiencies within VitaDAO’s current jurisdiction. This experiment is VitaDAO’s first step in exploring the possibilities of a highly aligned community with the capacity for collective action. Interested in learning more? Dig into some of the interesting conversations about the future of network states and the importance of sovereignty taking place on VitaDAO’s #Vita-State Discord Channel. Explore Balaji’s Twitter insight into VitaDAO’s evolution towards a network state. TLDR, he says network states should:

1. Start with 1–2 month experiments around the world
2. Recruit curious people
3. Make sure participant costs are reasonable
4. Scale if effective

A New Initiative: The Aging Podcast

VitaDAO started a podcast, more specifically, “The Aging Science Podcast”! In the first episode, host Kamil Pabis talks with expert Alaattin Kaya about challenges in research funding and the replication crisis in aging research. Alaattin Kaya, a research investigator who recently started a lab at Virginia Commonwealth University, uses yeast as a model to study the basic mechanisms of aging. When asked about yeast as a model organism: “Of course, yeah, everybody loves yeast.” Listen to the first episode of The Aging Science Podcast to hear about recent breakthroughs in the field, the difficulties of funding risky research, and the importance of overexpression genetic screens in aging research. Read highlights from the podcast on VitaDAO’s blog!

Vita Governance

Approved: Brain Tissue Replacement Therapy

VDP-10 Passed! This proposal was an assessment of BE Corp, a spinout company out of Jean Hebert’s lab at Einstein College of Medicine. Jean Hebert is a leading expert on the subject of brain aging. He is working on engineering transplanted stem cells that can replace damaged brain tissue, of particular use in stroke patients. Senior reviews voiced that this proposal has robust experimental data, a strong founding team, and a reasonable timeline!

Tis the Season(al Governance)

The VitaDAO community voted to improve the governance process by “batching” governance into seasons, each season consisting of a Governance Phase and an Execution Phase. As a result, VitaDAO has now divided operations into seasons, with each season being 4 months long. We are excited to say that from February 20th to April 3, the VitaDAO community is starting its first round of seasonal governance. We are currently voting on goals, creating budgets, and forming project teams. The goals and objectives of Season 1 include increasing community size, increasing the number of token holders, accelerating research assets, and increasing researcher engagement.

To get started in VitaDAO’s Seasonal Governance, visit our discourse for an overview of the process, sign up for an account, and join the conversation! Want to learn more? Watch a recording of a Live Twitter Space hosted by Catthu, Todd White, and Gavin Singh.

Other initiatives within Season 1 include:

• Creation of an Ambassador Program: A proposal to create a collection of individuals to perform outreach on behalf of VitaDAO. This proposal outlines general criteria for ambassadors, ambassador reimbursement, and goals for ambassador events.
• Creation of a Commercialization Squad: A proposal to establish a Commercialization Squad within VitaDAO to directly increase token utility value and commercialize VitaDAO’s assets.

Live on VitaDAO’s Governance Forum — discuss and vote!

Find all of VitaDAO’s pending live proposals on Discourse, VitaDAO’s governance hub for proposals before they are moved on-chain. These proposals are open for engagement, voting, questions, and conversation! Below, read through summaries of two proposals currently on VitaDAO’s Discourse:

• VDP-87 [Assessment] Zoe Biosciences: This is an assessment of an early-stage therapeutic biotech that has two programs centered on targets that are well-validated both for longevity and aging-related diseases. The first program is PAI-1 biologic inhibitors with high target selectivity and affinity, relevant for diseases including elevated FGF23 syndromes and metabolic disorders. The second program is APJ small-molecule agonists for similar age-related indications.
• VDP-88 Creating VitaTech: This proposes the creation of VitaTech, a US-based for-profit company to license longevity technologies from US universities and research Institutions and, raise non-dilutive funding to develop commercialized assets.

Zuzalu — The first pop-up mini-city experiment 25March — 25May

We’re exploring evolving VitaDAO towards a Longevity Network State, and building a special jurisdiction for medical innovation with a better regulatory framework.

Advances in aging research are being translated into medicine, in clinical trials. We will dive into biotech to bring aging under medical control, and into medical innovation jurisdictions to enable better regulatory pathways for innovating in longevity therapeutics.

Join us to embark on a journey of meaningful dialogue and build lasting connections
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If you would like to join the longevity events at Zuzalu, you can expect:
• workshops and initiatives to improve personal longevity
• engage in insightful discussion around biotech and medical innovation through the use of technology
• ideate around creating a new jurisdiction and regulatory environment to foster innovation

Apply to visit: https://vitadao.com/zuzalu

Meet Coordination Working Group Contributor: Gavin Singh

Gavin Singh is an active contributor to VitaDAO’s Coordination Working Group and Governance Squad. Since joining the DAO in August, he has worked to organize VitaDAO’s Discourse and is currently assisting in VitaDAO’s transition to seasonal governance. Outside of VitaDAO, Gavin graduated from McGill University in 2021 and has since worked in private equity as part of an impact-focused family office fund to build communities at several start-ups.

How did you first get involved in web3?

Surprisingly enough, it was my first venture in preventative healthcare right out of university. I was looking for ways to revolutionize the traditional healthcare system. This led me to web3 as it was the values behind the tech that made me realize the possibilities to empower people, not just patients, are endless. That sparked me to delve into DeSci, contribute to the Governance WG in VitaDAO, co-host events and spaces with VitaDAO, DeveloperDAO, and Gitcoin — and before you knew it, I was halfway across the world in Devcon Bogota assimilating with my tribe.

What attracted you to the VitaDAO community?

I was introduced to longevity at a young age. I remember watching a 90s Spider-Man TV series episode called “Neogenic Nightmare”. The villains were fighting over the ancient “tablet of time,” which promised a younger, stronger, and healthier life. To think that there was a community out there within the marriage of existing ideas around longevity and emerging tech with web3, just being a part of it was attractive enough and a dream come true alone.

Can you walk me through what role you have taken on in VitaDAO?

What got me to start to contribute was finding the rare Schelling point of all my passions combined — longevity, public goods, and meta-governance. The rest is history. I started by doing starter tasks like developing the VitaDAO constitution on our discourse forum and my continued involvement for more than half a year now eventually led me to take on the role of governance lead for the DAO.

Have you found that there are gaps in infrastructure and tooling that could enable the DeSci community?

The constant gap has always been onboarding the next billion. With DeSci, the battle against the disrupting the ancient structure of centralized science itself is hard to make researchers understand, as it seems almost alien to the pathways they’ve been led to know and experience. let alone, innovations in human coordination with meta-governance and DAOs. My goal is to bridge the gap with the rest of the community but more so in meta-governance tooling curated for academics as much as DeSci tooling as a whole. That is where my passion lies.

What has surprised you the most about VitaDAO?

The sheer passion within the contributors to empower everyone in our community regardless of their knowledge, background, and skills. I think that alone aside from our numbers went a long way in our recent fundraising round.

What excites you most about VitaDAO’s future?

I’m most excited about how long VitaDAO will be here. Not to take it for granted, but being in the midst of people that share my passions till the unforeseeable future feels like I’ve found my tribe. On the notion of longevity, VitaDAO’s future is an ever-extending one as we improve the lifespan of humans, our community, and the world.

Any closing thoughts for readers?

As a servant leader, my driven purpose of existence is to immortalize my ideas for the betterment of public goods. I’m a longevity and anti-aging enthusiast on a mission to attain optimal coordination with new paradigms in meta-governance and to revolutionize the world with unworldly regenerative innovations. I’d love to connect with anyone and everyone willing to see these goals flourish as much as I do. I’m most active on Twitter/Discord/Telegram: @consigli3re

Upcoming Events

The first pop-up mini-city experiment with longevity at heart — 25 March — 25 May — We’re exploring evolving VitaDAO towards a Longevity Network State, and building a special jurisdiction for medical innovation with a better regulatory framework. Apply to visit.

3rd VitaDAO DeSci & Longevity Symposium — April 5th — Sign up and learn to learn more about the science behind slowing down aging and the development of rejuvenation therapies.

VitaDAO @ Longevity Med Summit — May 4–5, 2023- Come join VitaDAO in sunny Lisbon, Portugal at the 2023 Longevity Med Summit. Here, join other longevity enthusiasts, in learning about the development of anti-aging science, the exploration of new regenerative and longevity therapeutics, and the limiting R&D challenges faced in therapy development.

Join Us!

Have a special skill set? Contribute to VitaDAO and receive $VITA in return. Join the VitaDAO community on Discord and stay up to date on Twitter! As of February, VitaDAO’s Discord is now token-gated, requiring a minimum of 10 $VITA to gain access to basic contributor channels.

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The Mouse Longevity Chronicles: Unraveling Aging with Dr. Richard Miller during The Aging Science podcast by VitaDAO

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Check out the podcast here.

In this podcast, I (@aging_scientist) spoke with Dr. Rich Miller about the ins and outs of mouse aging.

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The specific topics we discussed, roughly in this order, included the Interventions Testing Program, rapamycin, mecilizine and other lifespan-extending drugs. We talked about the importance of genetically heterogenous mouse stocks and the issues with fast-aging progeroid mouse models. We also covered his more recent work on aging rate indicators, and the difference between classic biomarkers and aging rate indicators. Finally, we talked about the importance of lifespan research, misuses of the word healthspan and the emerging use of frailty indices in mice.

I did not make it easy for Rich asking some difficult questions, most of which he answered quite well, even if I may disagree here or there. All in all, it was great to interview one of my favorite aging researchers!

About Rich Miller – short biography

Rich Miller got his BA degree at Haverford College, and then an MD and PhD at Yale.  He received postdoctoral training at Harvard and Sloan-Kettering and was a faculty member at Boston University before moving to Michigan in 1990.

Now he is a principal investigator at the University of Michigan where his lab studies long lived mice and tries to understand why mice and other animals live as long as they do. He has been instrumental in facilitating the birth of the interventions testing program (ITP) which was the program that first discovered that rapamycin extends the lifespan of mice. 

If you want to know one cool piece of trivia about Rich. I once checked and it appears that he has coauthored more mouse longevity studies than a small European country like the Netherlands. This attests to both his experience but also to the lack of mouse research in Europe.

http://www.richmillerlab.com/

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Scientific background

Let us briefly talk about the importance of mouse lifespan studies and why healthy mice are an irreplaceable scientific tool. I will also explain some of the concepts that we discussed in the podcast. 

"It's not simple" (Rich Miller)

About the Interventions Testing Program (ITP)

“The Interventions Testing Program (ITP) is a peer-reviewed program designed to identify agents that extend lifespan and healthspan in mice. Investigators at any university, institute, company, or other organization are invited to recommend interventions for testing by submitting an application before the February deadline each year. Testing is carried out in the genetically heterogeneous UM-HET3 mouse stock at three sites — the Jackson Laboratory, the University of Michigan, and the University of Texas Health Science Center at San Antonio.”

Several features of the ITP make it stand out as a very unique project. One is that almost anyone can propose a compound through a simple, short application. Scientists have been calling for simpler grant applications for a while so it is refreshing to see this implemented in practice. Hopefully other institutions will follow suit.

Another feature is the sheer success of the ITP in finding new interventions.

“the ITP has identified nine agents that significantly increase median lifespan — acarbose (Harrison 2014, Strong 2016, Harrison 2019), aspirin (Strong 2008), canagliflozin (Miller 2020), captopril (Strong, 2022), glycine (Miller 2019), nordihydroguaiaretic acid (NDGA) (Strong 2008, Strong 2016), Protandim® (Strong 2016), rapamycin (Harrison 2009, Miller 2011, Wilkinson 2012, Miller 2014) and 17α-estradiol (Harrison 2014, Strong 2016, Harrison 2021).”

Although, all these worked in a subset of mice, I think this list is slightly overstating the success of the ITP. Some of these drugs are much more effective than others. Some of these are in a league of their own. It is hard to compare rapamycin, perhaps the biggest breakthrough of the 21st century (so far), with compounds that produce minor benefits in one gender like e.g. protandim. However, even if the ITP had only discovered rapamycin, it would have been a success in my eyes.

Almost as important as the successes are the failures. The ITP has refuted or weakened the idea that several putative longevity compounds actually slow aging, e.g. metformin and resveratrol. While these could still benefit humans and improve health, the ITP provided strong evidence that they fail to slow aging in mice.

On the importance of good mouse husbandry and healthy mouse strains

"Inbred mice are an inappropriate model for most kinds of aging research" (Rich Miller)

Although in this case Rich was quoting other researchers, I think this does sum up the message he wanted to convey. While I would not go quite that far, I think he is totally right when he says that we need to use healthy, genetically heterogenous mouse models for aging research. As much as possible, whenever feasible.

Humans are diverse and we need diverse models to better represent our biology. Even more importantly, inbred mice often used in research have limited heterogeneity in what they die of. Thus, preventing this one idiosyncratic disease that is killing all mice of an inbred strain could appear to slow aging and extend lifespan when it was just mitigating this one condition. However, in defense of our traditional model the inbred “Black 6” (B6) mouse – and it is indeed a mouse with black fur, hence the name – I would like to note that genetically heterogenous mice still predominantly die from cancer (Lipman et al. 2004) not much different than B6 mice. On top of that, B6 mice are actually quite long-lived for a mouse.

The ITP uses UM-HET3 mice, which are a heterogenous four-way cross, to mitigate the issue of limited genetic diversity. I would like to champion the UM-HET3 mouse as a replacement of B6 and other strains whenever possible. It is a really amazing mouse strain. Please use it in your resarch and when you read a paper featuring UM-HET3 consider this a “bonus point” in favor of that work.

Aging Rate Indicators

The lab of Rich Miller is developing so called aging rate indicators, which could be used to predict how quickly a mouse or a cohort of mice will age. The idea is to find such indicators and to screen a battery of novel compounds against these, before testing them in large, expensive lifespan studies like the ITP. 

In the analogy he used the aging rate indicators are a kind of “speedometer”, whereas conventional biomarkers measure the damage that mice accumulated during aging akin to an “odometer”. A mouse that ages at a slower speed will accumulate less damage and hence live longer.

The controversial bits and pieces – progeroid models, frailty and healthspan

Rich is not the biggest fan of senolytics, progeroid models and frailty indices used in mice. We talked about the latter two in the podcast. I think he does a better job explaining this than I could so I will instead just explain the science necessary to understand our podcast.

So called progeroid mouse models show something akin to accelerated aging. They are employed by aging researchers because they die quickly allowing them to test more interventions in a shorter period of time. Whether these models faithfully mimic aging remains a matter of debate in the literature and both sides have good arguments. On the one hand, many of these models develop similar changes to aged mice due to mutations in pathways we think are involved in aging (e.g. DNA repair). On the other hand, most progeroid mouse models develop extreme phenotypic changes that are never seen in aging mice to the same extent.

Frailty indices were developed in order to measure something resembling health, healthspan or frailty in mice – whatever your preferred term is. Basically, functional decline during aging. Indeed, such functional decline almost always precedes mortality and the two are closely linked. However, measuring lifespanis very expensive as it requires many animals. So one of the reasons why mouse frailty indices are gaining popularity is the hope that they could serve as a replacement for expensive lifespan studies. While commonly employed frailty indices do seem to capture functional decline with aging, many parameters included in these indices are not very sensitive to aging (Schultz et al. 2020) and they have not been thoroughly validated across different mouse strains yet. Furthermore, it is also very difficult to observe frailty in mice non-invasively. Old mice often die spontaneously while still looking healthy.

My (minor) disagreements with Rich Miller – ITP compound selection

Asking hard questions is the job of a good journalist and being critical of conventional wisdom is the job of a good scientist. I am trying to be both here.

My major criticism, which Ì tried to explain, was that the ITP is somewhat biased towards approved drugs that target age related diseases, or diseases of affluence, instead of more experimental bona fide anti-aging drugs. As biogerontologists, we always say that we must target the root causes of aging. I do not think that approved most drugs are doing that. Certainly not statins and most blood pressure lowering medications, several of which were tested in the ITP.

As far as I can tell, Rich’ counterargument is that every suggested drug was evaluated on its own merits. Only if the proposal was persuasive then it was accepted. Maybe for some of these traditional drugs arguments can be made why they might slow aging. Indeed, rapamycin itself is an approved drug “traditionally” used for immunosuppression and the proposal certainly included a rationale why it could be repurposed to fight aging based on genetic data from yeast (Kaeberlein et al. 2005).

Furthermore, the proposed rationale and why a drug works do not need to be the same. For example, in the case of acarbose the mechanism of action in mice is subtly different from the one that was proposed, as we discuss in the podcast.

Nevertheless, in my opinion, there remains a bias towards “playing it safe” in the ITP. Just to give an example, I have a really hard time finding a rationale why simvastatin might have slowed aging in mice – because it so specifically targets atherosclerosis, an age-related disease that mice fail to develop. Statins do not work particularly well if you have low blood cholesterol levels and do not reduce all-cause mortality in these populations (Singh et al. 2020), hence the failure in mice was perhaps also predictable.

My (minor) disagreements with Rich Miller – does rapamycin slow or postpone aging?

My second disagreement concerns rapamycin. I think Rich and others are too hastily discounting the idea that rapamycin postpones aging rather than slowing aging, or that something else strange is going on with rapamycin. However, that is not to say that rapamycin would fail to extend lifespan in humans. It may, but the mechanism could be different than we think.

In fact, I believe that rapamycin is the best drug we have right now and I am on the record saying that it should be in the TAME study instead of metformin. No one can claim I am not an optimist about this drug.

I used to think the same way as Rich does: if a drug extends median and maximum lifespan in healthy mice and slows age-related decline then it slows aging per definition.

However, we need to be a bit more precise and distinguish between slowing and postponing aging. In the long term this will be very important.

Different papers studying mortality patterns using Gompertz and other mathematical approaches find that rapamycin behaves differently than caloric restriction and provide evidence for postponing rather than slowing aging (Garratt et al. 2016): “Reduced mTOR signalling extends lifespan in nematodes by strongly reducing the degree to which mortality rates increase with age (aging rate). By contrast, life extension in mice and yeast occurs largely by pushing back the onset of aging, but not altering the shape of the mortality curve once aging starts. Importantly, in mice, the altered pattern of mortality induced by reduced mTOR signalling is different to that induced by dietary restriction, which reduces the rate of aging”

The benefits of rapamycin in the ITP do not scale very well with age of onset. When treatment is started at 600 days of age (20 months), then, expressed as increase in mean lifespan, the effect sizes were +9% for males and +13% for females in the pooled data set (Harrison et al. 2009). For comparison, when treatment was started at 270 days of age or (9 months) then median survival was extended by an average of +10% in males and +18% in females (Miller et al. 2011).

Importantly, one recent paper found that an mTOR hypomorphic allele leads to immediate improvements in multiple age related parameters even in young mice (Xie et al. 2022). This suggests we are measuring age related decline incorrectly without including a young control group. Xie et al. concludes that: “Many [interventions] influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these [these interventions] have limited effects on aging.”

Hopefully we can revisit this debate some day

Rich Miller in other media

If you still cannot get enough aging science content after having finished our podcast, you can check out the below interviews with Rich.

On Peter Attia’s famous Drive podcast:
https://peterattiamd.com/richardmiller/

On the Live Longer World podcast, which is one of my favorite aging podcasts:
https://www.youtube.com/watch?v=42PzfNs9egA

On the The Sheekey Science Show, which is one my favorite aging channels on youtube:
https://www.youtube.com/watch?v=hHlDTiFWbbg
(you can follow Sheekey on twitter @EleanorSheekey)

On the amazing NUS Healthy Longevity webinar, as published on youtube:
https://www.youtube.com/watch?v=UPqstwgr7x0
(you can register for the webinar here so as not to miss any live sessions: https://medicine.nus.edu.sg/continuing-education/knowledge-hub/healthy-longevity/)

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References

Xie, Kan, et al. "Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice." Nature Communications 13.1 (2022): 1-29.

Harrison, David E., et al. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice." nature 460.7253 (2009): 392-395.

Miller, Richard A., et al. "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice." The Journals of Gerontology: Series A 66.2 (2011): 191-201.

Garratt, Michael, Shinichi Nakagawa, and Mirre JP Simons. "Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction." Aging Cell 15.4 (2016): 737-743.

Singh, Bishnu M., et al. "Role of statins in the primary prevention of atherosclerotic cardiovascular disease and mortality in the population with mean cholesterol in the near-optimal to borderline high range: a systematic review and meta-analysis." Advances in preventive medicine 2020 (2020).

Yourman, Lindsey C., et al. "Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: a meta-analysis." JAMA internal medicine 181.2 (2021): 179-185.

Schultz, Michael B., et al. "Age and life expectancy clocks based on machine learning analysis of mouse frailty." Nature communications 11.1 (2020): 1-12.

Kaeberlein, Matt, et al. "Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients." Science 310.5751 (2005): 1193-1196.

Lipman, Ruth, et al. "Genetic loci that influence cause of death in a heterogeneous mouse stock." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59.10 (2004): B977-B983.

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Introduction

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Welcome back Vitalians!

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Following our successful fundraise of $4.1 million (check out the Forbes article), a new wave of projects are in the pipeline to be funded. First up in 2023 is Brain Tissue Replacement Therapy with Jean Hebert - see his latest paper on rebuilding neocortical tissue in our hot picks below.

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The VitaDAO community also voted to develop a brand new overlay journal - The Longevist - a curation of the most impactful longevity research every quarter, as voted on by a large body of key opinion leaders. Stay tuned as we aim to launch our 1st issue in April!

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There are a plethora of different theories as to why we age, often with overlapping ideas that make it hard to separate the relative contributions of each factor. This month, we are excited to bring you an interview with Prof. John Speakman - a world leader on energy expenditure - who recently published his “Live cold, die old” paper, with some elegant experiments providing evidence that body temperature is a greater driver of ageing than metabolic rate in two species of small mammals. Check out the interview as Prof. Speakman discusses this and how it affects our understanding of calorie restriction interventions, free radical damage, and how temperature and entropy could be key to understanding biological ageing (recall our previously featured preprint from Dr. Peter Fedichev: Aging clocks, entropy, and the limits of age-reversal). Enjoy!

Longevity Literature Hot Picks

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Preprint Corner

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This month we are featuring 7 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in January's longevity research newsletter.

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p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells

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NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

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Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging

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Insulin-mTOR hyperfunction drives C. elegans aging opposed by the megaprotein LPD-3

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The human pathome shows sex specific aging patterns post-development

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Aging Atlas Reveals Cell-Type-Specific Regulation of Pro-longevity Strategies

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Biological Age Estimation Using Circulating Blood Biomarkers

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Published Research Papers 

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Photoactivatable senolysis with single-cell resolution delays aging +

A senolytic strategy integrating multiple technologies delays aging (research briefing)

Senolytics have been shown to promote longevity but precise and trackable senolysis is still a challenge. An interesting approach to tackle this is described here - a photosensitive senolytic drug targeting the enzyme substrate of SA-β-gal with fluorescence tag for the precise tracking.

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An In Vivo Platform for Rebuilding Functional Neocortical Tissue

While advances in stem cell transplantation have been made, the functionality of transplants remains a challenge. This in vivo transplant platform resulted in functional graft with differentiated layers of neurons, vascularization within a week, electrophysiological activity in a month and it responded to visual stimuli.

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Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice

The study provides evidence for transgenerational epigenetic inheritance, a long debated subject. They show the CpG island reprogramming in the parental generation was maintained and transmitted across multiple generation alongside the phenotypic traits.

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Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

The DNA methylation of 220 subjects with obesity randomized to 25% CR or ad libitum for 2 years were assessed but resulted in inconclusive results. There was a striking difference between DNAm tests with DunedinPACE showing slowed pace of aging, while PhenoAge and GrimAge showed no change in biological age.

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Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome (HGPS) phenotype by rescuing BUBR1

HGPS is a premature aging disease and there has been a growing body of evidence that mitotic defects play a role. A core spindle assembly protein BUBR1 had decreased levels and the remaining protein was anchored. A unique peptide prevented binding and increased expression, showing potential for progeria therapeutics. 

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Correlated evolution of social organization and lifespan in mammals

Phylogenetic comparative analysis of over 1000 species compares solitary vs group-living species and concludes that group-living species generally live longer than solitary-living, suggesting correlated evolution of social organisation and longevity.

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Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis

Dysfunctional telomeres were shown to activate immune responses as a mechanism for telomere mediated tumour suppression. The process is dependent on mitochondrial telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres forming oligomers with ZBP1 (Z-DNA binding protein).

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The multi-tissue landscape of somatic mtdna mutations indicates tissue specific accumulation and removal in aging

Mitochondrial DNA mutation rate and accumulation significantly differed across aged tissues. This was not correlated to tissue function and mitochondrial content. An unexpected lack of mutations linked to oxidative damage were found, suggesting dynamic clearance.

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Job board

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XPRIZE Healthspan Lead

A two-part role including being the Executive Director of XPRIZE’s Health Domain and Director of the upcoming “Healthspan XPRIZE”

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Lab Assistant for Killifish Husbandry and Research at The Department of Genetics at Stanford University, US

To help with research on aging and age-related diseases.

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SenNet Consortium Underrepresented Student Program Summer 2023 Application

Summer undergrad research internships at the NIH cellular senescence research consortium! Deadline 15th March 2023.

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A Postdoc (Research Fellow, RF) and Ph.D. position in Biology of aging are available in the Sorrentino laboratory at NUS in Singapore. The projects explore the interconnectivity and possible therapeutic targeting of the cellular hallmarks of the aging process, with a particular focus on mitochondrial dysfunction, protein aggregation and alterations of NAD⁺ metabolism. 

Are you interested in cardiovascular research and aging? Apply for a PhD position and join a research team part of the VASC-HEALTH Flagship Project at the Medical University of Graz

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News

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A4LI is proud to announce the founding of the Congressional Caucus for Longevity Science. 

The formation of the “Longevity Science Caucus” is a transformational moment for the longevity biotechnology industry and the movement to increase healthy human lifespans.

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Targeted degradation: putting autophagy to work

Autophagy inducing biotech company Casma Therapeutics closed a $46 million round with the aim to develop novel treatments for cancer, inflammation, neurodegeneration, and metabolic disorders

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Articles

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Antiaging talk: Is red wine good for the skin?

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Global longevity investment hit $5.2 billion in 2022

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The puzzling gap between how old you are and how old you think you are

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Mapping out the longevity investment landscape

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Anti-ageing scientists extend lifespan of oldest living lab rat

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Restrict calories to live longer, study says, but critics say more proof is needed

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Young female mice exposed to scents from older females live longer

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Just Getting Started at 75

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Study reveals how exercise turns back the clock in aging muscles

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Conferences, Workshops and Webinars

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Young ICSA Cambridge, UK 2023

Two-day cellular senescence symposium at Cancer Research UK - Cambridge Institute! A great opportunity for PhD students and postdocs.

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Workshop: Midlife Stress and the Hallmarks of Aging

Researchers at all career stages from academia, industry, and government with an interest in the impacts of stress on aging in human populations and animal models of stress and/or aging.

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Podcasts and Videos

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Bryan Johnson's Blueprint, Spotify Enters Health and VitaDAO Raises $4M

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Increased Lifespan from Beans

The intake of legumes—beans, chickpeas, split peas, and lentils—may be the single most important dietary predictor of a long lifespan. But what about concerns about intestinal gas?

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Interview with Prof. John Speakman

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Professor John Speakman is a leading expert on metabolic activity and energy expenditure and was instrumental in the development of doubly-labelled water (DLW) technique. He has made numerous significant contributions to our understanding of factors that govern variation in food intake and energy expenditure, and the consequences for fat storage (obesity) and ageing. He currently runs 2 research laboratories and is Head of Integrative Physiology at the University of Aberdeen, and a professor at the Chinese Academy of Sciences in Shenzhen. 

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What inspired you to enter longevity research?

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My PhD in the 1980s was to study energy balance and metabolic rates in wild animals. At the time there was a lot of interest in among species scaling relationships for all sorts of things – one of which was lifespan. Bigger animals live longer, and one idea why that was the case was because they have lower metabolic rate: the ‘rate of living theory’. This was also a potential reason why calorie restriction exerts its effects – by lowering metabolic rate. It was a pretty old idea from the 1920s and in the 1950s it got a boost by the idea that higher metabolism leads to greater production of free-radicals and therefore the reason we age is because of free-radical damage that stems from our metabolism. By the 1990s this idea had enormous traction among biologists studying ageing. Many of them were taking large amounts of vitamin C and E daily to quench their free-radical damage. Since I knew something about metabolism, I got interested in this idea that lifespan depends on metabolism and free-radicals, and that we have a fixed amount of lifetime expenditure of energy. I also started taking antioxidant vitamins daily. At the time in the 1990s however almost all the work on the idea was correlational and inter-specific. I figured that we could probably do intra-specific experiments to test the ‘rate of living/free-radical damage’ idea, by making animals expend more or less energy, and giving them anti-oxidants, and then looking at how long they live. I applied for money to the UK BBSRC to do such experiments as part of their first special topic on ageing and was successful. I recruited an amazing post doc (Colin Selman) who eventually became a great gerontology professor, and we did some interesting work together. The general outcome of our work was that the rate of living/free-radical damage model was not sustainable. Voles given antioxidants for example lived shorter lives. It had at least one direct human consequence, in that I personally stopped taking antioxidant vitamins. These studies eventually led to my groups work on calorie restriction which has dominated my work on ageing ever since.

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

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I quite like the idea from the Nobel prize winning physicist Erwin Schrodinger in the 1930s that he presented in a short book called ‘what is life?’. In it he posited that organisms are incredibly complex low entropy systems that naturally have a tendency to increase in entropy because it needs a constant and large flow of energy to sustain their low entropy state. For a while it is advantageous in terms of reproduction for us to invest in holding back the increase in entropy in our soma, and we do so, but then eventually it starts to accumulate (ageing). This becomes self-reinforcing because the cost to repair the system starts to get larger and larger. Eventually entropy accumulates to the point where the system is overwhelmed, and that overwhelmed state is what we call death. Many other theories of ageing are potentially just restatements of the entropy principle – eg mutation accumulation, free-radical damage, senescent cell accumulation. What I like about the entropy idea is that it is very non-specific, so the reasons people die are probably all slightly different and depend on the stochastic nature of the system falling to bits. This not just explains why living things age and die but why any complex system fails. If you go around a scrap yard and look at the cars in there they are all in there for slightly different reasons but fundamentally for many of them they are there because investing more money in stopping them falling to bits was too expensive. I think what this tells us is that chasing down a single problem (like accumulation of senescent cells for example) is unlikely to be very effective as an overall anti-aging strategy because there will always be another problem that arises reflective of the increasing entropy. In other words as we all know there are multiple hallmarks of ageing. Ultimately, then, I think the solution will be to increase the activity of the systems that keep entropy low when we are young. This will really mean intervening when that system starts to decline which is probably in our twenties or thirties, not our sixties and seventies. By then its probably already too late.

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How has the field changed since you started?

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I guess the major recent change in the field is the fact that the boomer generation has finally realised that they are all going to die and they are not happy about it. So now there are very large sums of money being poured into ageing research by very wealthy people in their late 50’s early 60’s and that has given ageing research a tremendous boost. The money invested in Calico by Google, the Hevolution project and into Altos labs by Bezos and colleagues is enormous. Whether they will see a practical return on this investment in their lifetimes is an interesting question. Most of them in my view have left it too late already.

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A second big practical difference is the interventions testing program in the USA. I think that was a real landmark achievement to set up an integrated multi-lab platform to test compounds that might have lifespan impacts in rodents. This program has saved a lot of time and effort chasing down false leads that would have been based on underpowered small studies.

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What mistakes do you think the longevity field has made?

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For cost purposes medical science in general has placed enormous efforts into understanding model organisms like yeast, C. elegans, Drosophila and mice. I think this has generally led to some important insights in many fields, but the benefit to cost ratio of understanding what causes ageing in C. elegans or yeast is very low. The translational benefits of working on ageing in mice are already not great because mice are not little people. Once you get into ectothermic animals, and single cell organisms that reproduce a-sexually, with fundamentally different physiology (eg ability to go into Dauer states in C. elegans or generate ethanol in yeast) the translational potential of such work is effectively zero. A recent review by Bene and Salmon in Geroscience showed that there was virtually no translation from C. elegans to mouse for life extending therapeutics. Studies of ageing in these organisms have led us down several expensive blind alleys, perhaps most notably the sirtuin story which is now starting to completely unravel.

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The key issue though is that as you get closer to humans and the translational potential increases there are increasing ethical issues. Moreover, as the lifespan of the organisms under study get longer, the required experiments get longer as well, until we get to a point where nobody can do the required experiments within a single career of one scientist and progress is phenomenally slow. It is a hard nut to crack in a world where people want answers yesterday. I think this impatience for answers is basically what continues to fuel C.elegans work on ageing irrespective of its likely utility.

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

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I have found it really intriguing the very simple observation that if you transfuse blood from a young mammal to an older one you can slow down its ageing. I think this will turn out to be an incredibly important and practically significant observation. Is it because the young blood contains life promoting compounds, as some recent work suggests, or does it just dilute life shortening compounds in the old blood. Either way I think this has the most exciting potential for an immediate practical intervention.

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

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Apart from finding out what is going on with young blood, if someone was just starting out a career then I think my advice would be to focus on ageing of the brain. You can envisage that for pretty much all our bodily functions it will eventually be possible to replace them with mechanical substitutes. In fact this is already true for many of our organs and musculo-skeletal systems. Recently exoskeletons were developed to augment declining muscle strength, thereby allowing elderly people to retain mobility and avoid falls. These days as people age we routinely swap out parts of their failing bodies and replace them with man-made mechanical alternatives – like heart valves and hip replacements. Although hip arthroplasty has a history dating back to the 1800s it only became a widely used and available procedure with minimal complications in the 1970s. Prior to that if your hips wore out you were basically crippled or bed-ridden and had a very low quality of life until you prematurely died. Nowadays, understanding the processes that lead to our hip joints failing as we get older is pretty much pointless because that problem has already been solved as far as practical aspects of hip ageing is concerned – although may give us insights into bone degeneration more generally. That will become increasingly the case as more and more mechanical replacements are developed. The one system, however, that I don’t see us ever being able to replace mechanically is the brain. That is the fundamental thing in your body that harbours what we identify as you. If it was possible to combine the head of a person grafted onto the body of a different person, we would identify the resultant being from the head (brain), not the body. Therefore, preserving the brain and preventing brain ageing is really the whole key to preventing ageing in the very long term. That, and inventing mechanical substitutes for all the other systems.

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

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Brain ageing – see above.

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Is ageing a disease?

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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.

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You recently published your “live cold - die old” paper - would you be able to summarise your findings?

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In general when endothermic animals like humans reduce their metabolic rate they reduce their heat production and this can lead to them having a lower body temperature. During calorie restriction for example it is pretty widely agreed that metabolic rate goes down (whether on a whole animal or normalised for body size basis) and that body temperature is also lower. Formally then because these two things go in tandem its not possible to separate which (if any) is a causal factor in the observed life extension. To separate the effects of metabolic rate and body temperature you need a situation where they change in opposite directions. One such situation in small rodents is when you change the housing temperature from below thermoneutral (around 20 oC) to the top of the thermoneutral zone (32.5 oC). When you do that metabolic rate goes down at the same time that body temperature goes up. Looking at that effect on lifespan in mice and hamsters at these temperatures allowed us to separate the effect of body temperature from that of metabolic rate. If lower metabolic rate was important then they should live longer when hotter, if body temperature drives the effect they should live shorter. The answer was that when you made the animals hotter their lifespan declined. We then showed that if you blow air over the animals in hot conditions you can prevent the rise in body temperature without altering metabolic rate, and when you do that you can rescue the lifespan effect. It seems that body temperature is more important than metabolic rate. In the press release we used the bumper sticker ‘live cold, die old’ to promote the work. Interestingly this may be a much more general principle than just organismal ageing. For example, the duration that transistors ‘live’ until failure is related negatively to their operating temperature. I suspect temperature is related to entropy change. When complex things are hotter entropy accumulates faster and they fail more quickly.

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Do you envisage that cooler environments / increased convection would benefit humans? / Do you have any plans to test this?

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Living in a colder environment will generally not reduce your body temperature much compared with the environments we currently seek out just below thermoneutral so that isn’t probably going to work. Similarly increased convection probably won’t be very effective either. It worked in the mice and hamsters to cool them down from a much higher temperature. We have recently completed some preliminary tests getting people to drink cold water and monitoring the impact on their body temperature as a pilot study to get the necessary data to perform power analysis for a randomised clinical trial. I like the idea but I didn’t start drinking cold water everyday myself yet.

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

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Although fraught with some ethical issues I think blood transfusion from young to older people holds a lot of promise based on the mouse work.

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Outro

Thank you for staying with us till the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues. See you next month!

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Further Reading

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The association between body height and longevity: evidence from a national population sample

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High Investment in Reproduction Is Associated with Reduced Life Span in Dogs

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Exploring the Frontiers of Science: Breakthroughs, Funding Challenges, and Replication Crisis with Alaattin Kaya during The Aging Science podcast by VitaDAO

 
Check out the podcast here.
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In this podcast, I (@aging_scientist) had the pleasure of interviewing Asst. Prof Alaattin Kaya (@akaya_lab).

We talked about recent breakthroughs in the field, the difficulties of getting funding for risky and novel research, funding agencies, “fishing expeditions”, the importance of overexpression genetic screens in aging research, novel mechanisms of action, and the replication crisis.

We also talked about yeast as a model organism and had a clear consensus:

“Of course, yeah, [it’s] everybody loves yeast.” (Alaattin Kaya)

It was a fun podcast! Since we really liked Alaattin’s overexpression screens (see below for more) we want to help him fund his amazing research. So if you know of any philanthropists or funding agencies that are willing to fund moonshots in aging research, please do reach out to us or directly to him.
link: https://vimm.vcu.edu/laboratory-groups/alaattin-kaya-phd/

Scientific background

Let me give a bit of scientific background on our main topics before we start. If you are quite familiar with this topic you can also just jump right into the podcast. Even if the below explanations are a little handwavy, I do hope they will be useful.

Overexpression of essential genes in yeast screens

The idea of genetic screening in model organism is quite simple. Models like yeast, worms or flies are less complex than humans, have a short lifespan and reproduce quickly making them facile models to study aging. Researchers can test thousands of compounds or change the expression of thousands of genes in a matter of weeks, in order to see whether these extend lifespan. Often they will find genes or pathways that are conserved between species, meaning they could also work in humans. One famous example of a conserved pathway is the Insulin/IGF-1 signalling pathway. Cynthia Kenyon and others discovered and validated this pathway in worms, showing that loss of daf-2 — which is related to human insulin and IGF-1 — leads to drastic lifespan extension in the worm. The importance of this pathway was later confirmed in mice.

Essential genes are those that are necessary for the survival of an organism. It stands to reason that these are important and often involved in tissues maintenance or repair. Given that “damage theories” of aging are well supported this makes essential genes attractive targets to study. What is more, essential genes will be often conserved between species. So if we found an essential longevity gene in yeast, for example, it would be more likely to do the same in humans than a non-essential gene.

Intriguingly, during evolution the duplication of (essential) genes often yields genes with novel functions, some of which are important for aging. Indeed, I worked myself on one such gene family. We suggested that cytoprotective metallothioneins might have undergone duplications that allowed for higher expression in longer-lived species (Pabis et al. 2021). While the evidence is not perfect, it is quite striking that humans have a dozen metallothioneins while short-lived mice have only three and worms have two metallothioneins. Alaattin mentions another example of an important gene duplication during the podcast.

Longevity probably evolves via gain of function (and change of function) rather than loss of function, which we usually study in the lab.

In contrast, essential genes are hard to study, because knocking them out, as is often done in genetic screens, would be lethal to the organism. Therefore most genetic screens focus on the knock-out of non-essential genes and in pharmaceutical screens inhibitors are easier to find than activators. Here is where Alaattin’s idea comes in. He decided to study the over-expression of essential genes to test whether these promote longevity in yeast, which are the perfect model for this since you can overexpress genes using so called plasmids.

If you want to know more about the project, Matt Kaeberlein explored this topic in his ARDD talk titled “The dark matter of bio-aging” (5). For those who are keen to read the paper itself, Alaattin’s preliminary work funded by Impetus grants, among others, has been published (Oz et al. 2022).

We scientists often call such screening experiments jokingly “fishing expeditions” because you never know what you will dig up. While a valid criticism of this approach, it is not a convincing one. During the podcast we discussed how reviewers take this criticism too seriously, favouring work with a clear mechanistic rationale instead and how this affected Alaattin’s research.

Lack of novel mechanisms?

“I think in aging everything is controversial at this point to be honest” (Alaattin Kaya)

Without getting into too much detail, reviewers who decry fishing expeditions could not be more wrong. While, yes, we do have some very outlandish ideas in the pipeline (reprogramming, parabiosis), by and large the field is almost exclusively dominated by quasi caloric restriction(CR)-mimetics. Treatments that target anabolic pathways and slow growth in one way or another are currently the only interventions that lead to robust mouse lifespan extension. Even worse, we still do not understand aging well enough and hence we need to feed the translational pipeline from the bottom up with the most novel and outlandish things we can find during our fishing expeditions — if we want to make any progress against aging in the longterm. Overexpression screens in model organisms would be great for that.

Bio and research focus — Alaattin Kaya

Alaattin is a young investigator who recently started his own lab at the Virginia Commonwealth University. He worked as a PhD and postdoc under the great Vadim Gladyshev and is a close collaborator of Matt Kaeberlein. His focus is on using yeast as a model to study basic mechanisms of aging. On his lab webpage Alaattin makes a good argument for using yeast in aging research:

“Current evidence suggests that many of the aging mechanisms and related genes are conserved among eukaryotes, from yeast to mammals. Each model system provides key advantages and challenges. Due to a variety of factors — notably including ease of genetic manipulation and a physiology similar to that of humans — the mouse has become the pre-eminent mammalian model organism in aging biology. However, in light of the high housing costs and relatively long lifespan of mice, large-scale unbiased screening to identify anti-aging medicines is not feasible in this organism. With the realization that many aging-related pathways are evolutionarily conserved, even among widely divergent species, short-lived invertebrate models have instead been employed for such screening.”

You can find more information under kayalab.org or on twitter @akay_lab.

References

1. Evidence that conserved essential genes are enriched for pro-longevity factors.
Oz N, Vayndorf EM, Tsuchiya M, McLean S, Turcios-Hernandez L, Pitt JN, Blue BW, Muir M, Kiflezhgi MG, Tyshovskiy A, Mendenhall A, Kaebverlein M, Kaya A. (2022) GeroScience https://doi.org/10.1007/s11357-022-00604-5

2. Kenyon, Cynthia, et al. “A C. elegans mutant that lives twice as long as wild type.” Nature 366.6454 (1993): 461–464.

3. Malavolta, Marco, and Kamil Pabis. “Elevated metallothionein expression in long-lived species.” Aging (Albany NY) 14.1 (2022): 1.

4. Pabis, Kamil, et al. “Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging.” GeroScience 43.4 (2021): 1975–1993.

5. Matt Kaberlein at ARDD2022: The dark matter of bio-aging
https://www.youtube.com/watch?v=kkozY2QlNZs&t=176s

Further reading

Kaya, Alaattin, Alexei V. Lobanov, and Vadim N. Gladyshev. “Evidence that mutation accumulation does not cause aging in Saccharomyces cerevisiae.” Aging cell 14.3 (2015): 366–371.

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Introduction

Happy new year Vitalians and welcome back!

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The Longevity field is starting the year strongly with new updated Hallmarks of aging, exactly 10 years after the original paper was published. So time to update your introduction slides with the figure we will see in every presentation for the next 10 years!

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For the first month of the year we want to focus on one of the original and major hallmarks of aging - genome instability. DNA damage is a well-known driver of aging. It comes in many flavours - including single and double strand breaks, base modifications and crosslinking. DNA lesions are very common, occurring by the tens of thousands every day in every cell of our body. Luckily, we have evolved extremely efficient DNA damage repair machinery to cope with this. These mechanisms, while effective, succumb to age-associated decline, allowing DNA damage to accumulate in later life. Many environmental factors can contribute to DNA damage, from UV to toxins and radiation. Genome stability and epigenetics are tightly intertwined as we’ll see in a few of our hot pick papers this month. To demystify this and other DNA damage queries you may have, we have interviewed Prof Björn Schumacher, an internationally recognised expert in the area.

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Longevity Literature Hot Picks

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Preprint Corner

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The rise of preprints has reduced the time it takes for new scientific discoveries to be disseminated to the world prior to publication in a peer-reviewed journal. For this reason we are introducing Preprint Corner to keep you even more up-to-date with the Longevity literature. This month we are featuring 6 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! We will also be awarding a 500 $VITA prize to the review which receives the most upvotes out of the 6 preprints listed! 

Reviewing bounty for these preprints available until 28th February, with upvotes counted and the prize winner announced 2 weeks later!

We are also excited to announce that voting is now open on Snapshot for our proposed overlay journal - The Longevist - aiming to be a curated collection of the most impactful longevity research every quarter, as voted on by a large body of Key Opinion Leaders.

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Accurate aging clocks based on accumulating stochastic variation

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A dual MTOR/NAD+ acting gerotherapy

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Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice

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All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ

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Learning accelerates the evolution of slow aging but obstructs negligible senescence

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Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites and pathways that regulate lifespan

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Published Research Papers 

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Inheritance of paternal DNA damage by histone-mediated repair restriction

Paternal, but not maternal, exposure to ionising radiation leads to embryonic lethality and the mechanisms are still unclear. Depletion of histone and heterochromatin proteins could reverse embryonic lethality by reducing histone methylation and enabling repair, ultimately improving offspring viability. 

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Loss of epigenetic information as a cause of mammalian aging

In the works for over 13 years, this massive study by Sinclair’s team presents an aging model - ICE (inducible changes to the epigenome) mice. DSB repair was reported to induce epigenetic deterioration earlier in life, which translated to physiological changes associated with aging. OSK reprogramming of ICE mice resulted in a lower epigenetic age.

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Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan

Metabolism is highly associated with ageing, with many longevity interventions targeting key metabolic pathways. Here the authors show that yeast cells can exchange metabolites across generations with the nature of these interactions capable of determining cellular lifespan. 

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OxPhos defects cause hypermetabolism and reduce lifespan in cells and in patients with mitochondrial diseases

Patients with mitochondrial disease have increased resting energy expenditure, or hypermetabolism, which is thought to accelerate biological aging. Disrupting OxPhos (oxidative phosphorylation) either genetically or pharmacologically doubles the energy expenditure in the cell. More studies are needed to understand how these processes interact and link.

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Intravascularly infused extracellular matrix as a biomaterial for targeting and treating inflamed tissues

Decellularized and enzymatically digested extracellular matrix with pro healing properties was infused intravascularly in rats and pigs post injury. Substantial improvements were seen in ventricle volumes and wall-motion scores as well as molecular level changes indicating tissue repair processes suggesting translational potential for this technology to heal the heart “from the inside out”.

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Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia

Sarcopenia is a major issue with the quality of life of older adults that does not have current treatment options. Inhibition of sphingolipid synthesis showed promise in the alleviation of age-related decline and improved functional parameters like exercise capacity and strength.

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Lithium treatment extends human lifespan: findings from the UK Biobank

Lithium has been used in the clinic for many years as a management strategy for bipolar and similar psychiatric disorders. A number of recent studies have shown it can increase lifespan in multiple animal models but now a correlation with human longevity is found. An observational study with over half a million people reveals that lithium was linked to decreased mortality and 3.6 times lower chance of dying when compared to users on other antipsychotic drugs.

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Genome-wide RNA polymerase stalling shapes the transcriptome during aging

Whilst gene expression analysis has identified that many genes are differentially regulated with ageing, little has been known about the mechanisms driving these changes. This research shows that endogenous DNA damage can lead to RNA polymerase stalling which lowers transcriptional output and acts in a gene-length dependent manner. 

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Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan

It’s been around half a century since Denham Harman updated his Free Radical Theory of Ageing to implicate mitochondrial ROS production in driving age-associated decline. Here the authors show that increasing mitochondrial membrane potential can decelerate ageing and extend lifespan in nematodes. This is achieved with an optogenetic approach with a light-activated proton pump!

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Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration

The study reveals how the lifetimes of proteins change in the aging brain. The altered rates of synthesis and degradation point to a metabolic adaptation prior to neurodegeneration.

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Published Literature Reviews

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Hallmarks of aging: An expanding universe

Here we have the above mentioned updated hallmarks of ageing publication!

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Insights into Alzheimer’s disease from single-cell genomic approaches

A complex interplay of numerous brain cell types is behind the Alzheimer’s dementia pathology. Cell type specific alterations and five main pathways were uncovered using single-cell profiling across five cell types. The highlighted pathways could be a important targets for therapeutic development.

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Unraveling female reproductive senescence to enhance healthy longevity

Reproductive longevity is still largely understudied. The review summarises potential intervention that can prolong fertility in females and delay the onset of menopause which comes along with increased risk of a plethora of age-related diseases.

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Testing the evidence that lifespan-extending compound interventions are conserved across laboratory animal model species

Concern about the predictive value of testing therapeutics in lower life forms is raised after surprisingly little predictive value for identifying drugs in worms that extend lifespan in mice. While not conclusive in making C. elegans obsolete as a model, the study raises the question of model accuracy and relevance to translation to humans. 

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Clinical Trial Updates

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Geron Announces Positive Top-Line Results from IMerge Phase 3 Trial of Imetelstat in Lower Risk MDS

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FDA approves Alzheimer’s drug lecanemab amid safety concerns

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Job board

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VitaDAO company builder

VitaDAO is looking for a relentless, resourceful, well-organized, and dynamic person to advance the projects in our portfolio and spin them out as a co-founder or EIR.

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PhD and Postdoc positions in the newly minted Correia-Melo Lab - Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)!

The new “Microbiome and Metabolism” research group studies the metabolic crosstalk between cells in health and disease, with particular focus on aging. 

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PhD positions available at the Computational Biology group at the FLI - a multi-disciplinary group composed of bioinformaticians, statisticians, biochemists, and biologists. Projects focus of using machine learning to uncover more about epigenetic changes during cancer and aging. Applications accepted until January 31.

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Postdoctoral positions are open at the McAlpine lab, Icahn School of Medicine at Mount Sinai. If you want to explore the role of immune cells in cardiovascular and neurodegenerative diseases, please reach out to the group.

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Gero is looking for a data scientist to help them in their mission to develop new therapeutics and biomarkers against aging and complex diseases.

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Retro is now offering a Graduate Research Fellowship, which is a great opportunity for undergraduates who do not want to do a PhD, but want to become scientists. Retro works on partial reprogramming, blood factors and autophagy for cellular rejuvenation.

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News

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Eisai’s approach to US pricing for Leqembi (Lecanemab), a treatment for early Alzeimer’s disease, sets forth our concept of “societal value of medicine”in relation to “price of medicine”

The study with more than 800 patients (early Alzheimer’s) showed Leqembi slowed physical and mental decline by 27% over an 18-month period. The average cost of the drug will be $26,500 per year. Eisai defended the price based on the drug’s value to society, but it is likely to cause concern and draw scrutiny because of its potential wide use.

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Hevolution Foundation Appoints William Greene, MD as Chief Investment Officer

Dr. Greene Draws on a Deep Reservoir of Experience as a Venture Capitalist, Impact Investor and Biotech Entrepreneur

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Former Aging Cell editors establish new journal - Aging Biology

After a dispute resulting in the resignation of editors-in-chief from the journal Aging Cell, the former editors have now founded a new journal - Aging Biology - publishing research in the field of aging. 

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Pfizer Takes First Small Step Into Longevity Field With Gero Collaboration

Big pharma dipping its toes in longevity with Peter Fedichev’s Gero collaboration

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Articles

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The start-ups seeking a cure for old age

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As a Doctor, I See Aging Differently

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A Drug to Treat Aging May Not Be a Pipe Dream

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Two research teams reverse signs of aging in mice

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DAOs Might Be Cure for Biotech Startups and New Drug Development

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Dietary Restriction Works in Lab Animals, but It Might Not Work in the Wild

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U.S. life expectancy continued to fall in 2021 as covid, drug deaths surged

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Robust Mouse Rejuvenation project details announced

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Urine test hope for early liver cancer diagnosis

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Inside the $3bn mission to reverse signs of ageing

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Can ageing be cured? Scientists are giving it a try

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This biotech startup says mice live longer after genetic reprogramming

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The Rich’s Search for the Key to Immortality Is Harmful to the Rest of Us

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I left my CTO job to work on longevity

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The Buck Institute, where the promise of aging research isn’t longevity

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How to Be 18 Years Old Again for Only $2 Million a Year

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Conferences and Webinars

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The first ever DeSci London Conference was a resounding success! Hosted over 2 days in January at the esteemed Francis Crick institute in London, it featured talks from the who's who of the DeSci world, with Ethereum founder Vitalik Buterin even dialling in to share his thoughts on DeSci. Live recordings from the conference coming soon….

Podcasts and Videos

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Why Aging is a Disease With David Sinclair | EP #18 Moonshots and Mindsets

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Repairing Cells and Longevity Myths with Dr. Charles Brenner

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Remarkable Science: Understanding lifespan and why aging might be reversible with Dr. David Sinclair

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Lessons From The World's Longest Happiness Study - Dr Robert Waldinger | Modern Wisdom Podcast 578

Longevity Tweet of the Month

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Sebastian J. Hofer:

“I asked #ChatGPT how to achieve #healthy #aging. Can't argue with its reasoning. Next, I asked which interventions should be combined to achieve maximal #lifespan extension in mice (see comment). So, who will try this? And who will fund it? 

@impetusgrants @agingdoc1”

Follow the link to see ChatGPT’s response!

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Longevity Resources

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João Pedro de Magalhães hosts an educational and information resource on the science of aging: https://www.senescence.info/

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A great resource showing Longevity biotech companies and their investors: https://agingbiotech.info/investorsXcompanies/

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Interview with Prof Björn Schumacher

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Prof Schumacher is a director of the Institute for Genome Stability in Ageing and Diseases (IGSAD) at CECAD Research Centre of the University of Cologne, a president of the German Society for Ageing Research (DGfA), a Vice President of the German Society for DNA Repair (DGDR) and serves on several editorial boards.

What inspired you to enter longevity research?

That happened during a biology class at high school, when I realised how little we knew about our own biology. We are all subject to the invariable fate of ageing but we don’t understand that process at all. I knew I had to study the biology of ageing even though that wasn’t even a research field back then. So I decided to study biology and over time I would find out what would be the most important aspects of biology to study in order to illuminate ageing.

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

The theory of ageing is pretty much settled. It is really clear that ageing is a consequence of the lack of natural selection to indefinitely maintain the soma after the genes have been passed on to the subsequent generation. This is reflected in Tom Kirkwood’s disposable soma theory but also in the mutation accumulation and the antagonistic pleiotropy theories. The soma is only the vehicle for the indefinite maintenance of the germline throughout the generations.

How has the field changed since you started?

The field has really expanded phenomenally in the past two decades. When I started there was some telomere research that was super exciting and the genetic work in C. elegans that was really driven into the spotlight by Cynthia Kenyon. The most important development in the field over the past two decades was that it attracted scientists from diverse fields. This has made the field much stronger because ageing is affecting about every biological process.

What mistakes do you think the longevity field has made?

Some of those big claims and great expectations have had an inflationary effect on expectations. “Ageing reversal”, “rejuvenation” are big words with very little factual biology to back it up as true physiological reversal of ageing. While it is great to inspire with exciting concepts, it is also important to realise that ageing is complex and we have only grasped the tip of the iceberg.

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

There were some real breakthrough discoveries. Conceptually, Tom Johnston’s and Cynthia Kenyon’s discovery of genetic mechanisms of ageing in the early 1990s, and Jan Hoeijmaker’s demonstration that DNA repair defects promote pretty much the entire set of ageing phenotypes in the early 2000s were really ground-breaking. The transformative discoveries of stem cell reprogramming by Shinya Yamanaka’s and Steve Horvath’s pioneering work on ageing clocks probably have the most practical consequences when it comes to interventions.

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

It is very important to study ageing with open eyes and receptive minds. The biological processes that impact ageing are intimately interconnected. We must further thrive to understand the physiology of ageing, which is why organisms are so important as study models. Often people stay within their own silos and are ignorant of other aspects of biology.

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

I think the integration of model organism and human data need to be much more proactively pursued. Cancer research has shown us how difficult it is to transfer interventions that work in mice to humans. Transferring geroprotective interventions will be hugely more difficult because ageing is an integration of long-lasting trajectories that are impacted by all those distinct genetic variants and epigenetic effects that each individual human is subjected to but are unaccounted for in laboratory animals.

Is ageing a disease?

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!

Can you discuss the relative importance and potential causative relationship between DNA damage and epigenetic alterations in aging with examples from your own work?

DNA damage is occurring all the time. Our genome is inherently unstable and requires constant repair. The DNA in our cells not only encodes all information but in contrast to all other molecules, the genome cannot be replaced. The response to DNA damage affects about every process in the cell. We found that the longevity assurance mechanisms that regulate lifespan respond to DNA damage and increase the tolerance of DNA damage accumulation. Epigenetic mechanisms are also a very important regulatory response to DNA damage. We recently found that epigenetic regulators mediate the recovery of protein homeostasis following the repair of DNA damage that interferes with transcription. This finding links three causal hallmark processes of ageing: Genome instability, epigenetics, and protein homeostasis.

Although there has been a lot of interest in epigenetic aging in recent years, there has been less excitement and success stories around DNA damage and repair. Why do you think this is the case? What are the biggest challenges in the field?

There are two important factors here: One is the complexity of the DNA repair machineries and the second one is technology. Epigenetic modifications are very easy to detect and quantify. DNA damage is much harder to detect because of the sheer number of distinct lesion types. There has been tremendous progress just in the past year to detect mutations, which are consequences of DNA damage and it has become clear that the rate of somatic mutations is highly correlated with the lifespan of a species. Despite the complexity, targeting ageing at the most fundamental level involves developing strategies for augmenting genome stability.

What do you think are the most viable therapeutic avenues for targeting DNA damage?

For human ageing DNA repair is absolutely fundamental as the pathologies of congenital disorders caused by mutations in DNA repair genes clearly demonstrate. DNA repair mechanisms are as complex as the plethora of lesion types in the genome. We are working on mechanisms that can augment the entire set of DNA repair machineries. The key lies in the germ cells, because they repair far more effectively than somatic cells as their genomes are maintained indefinitely. Our concept is to confer germline-like repair efficiency to somatic cells.

And how likely are they to increase healthspan and lifespan from what we know in animals?

The realization that both healthspan and lifespan could be increased in organisms is one of the defining concepts of ageing biology. The plasticity of lifespan is quite distinct in species. The nematode C. elegans is the gift that keeps on giving because of its vast plasticity of lifespan, which is an adaptation to the boom and bust economy in the ecological niche of this species. Amid ample food they reproduce exponentially and upon starvation they can outlive a normal developmental cycle at least ten times. Such a degree of plasticity doesn’t exist in more complex animals. Nonetheless, some of the centenarians are healthy until the last year before their death at very old age. So also in humans, it is perfectly possible to extend healthspan to the 120 years that are currently thought to be the upper limit of human lifespan. This would be truly transformative for human health and prerequisite for a demographically changed society that is inclusive and harmonious.

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Outro

Thank you for staying with us till the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues.

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Further Reading

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SIRT6 is a key regulator of mitochondrial function in the brain

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Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration

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Gut microbiota as an antioxidant system in centenarians associated with high antioxidant activities of gut-resident Lactobacillus

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Alcohol consumption and epigenetic age acceleration in young adults

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Biochemistry and Cell Biology of Ageing: Part III Biomedical Science

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Convergent genomics of longevity in rockfishes highlights the genetics of human life span variation

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Midnight snacks might shorten your life - lifespan and healthspan advantages of eating less and at the right time

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The importance of reaction norms in dietary restriction and ageing research

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Unravelling Effects of Anti-aging Drugs on C. elegans using Liposomes

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Is Aging a Disease? The Theoretical Definition of Aging in the Light of the Philosophy of Medicine

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Mechanisms of spermidine-induced autophagy and geroprotection

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Meta-hallmarks of aging and cancer

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Age Discrimination in the Context of Motivation and Healthy Aging

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ERCC1 mice, unlike other premature aging models, display accelerated epigenetic age

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

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2023 kicks off with strong support for longevity research and a huge step for decentralized science(DeSci) 

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We are excited to announce that we have closed a $4.1m fundraising round from strategic members including Pfizer Ventures, Shine Capital, L1 Digital; decentralised science and web3 organisations Beaker DAO and Spaceship DAO; and longevity enthusiasts including Balaji Srinivasan (former CTO of Coinbase and General Partner at a16z) and Joe Betts-LaCroix (Retro Biosciences) and many others.

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The proceeds from the fundraise will be used to fund further longevity research projects and precede the spinout of VitaDAO's first biotech startups, scheduled in the first quarter of 2023, as well as further investment in commercialization and licensing of its IP-NFT assets through its partnership with Molecule DAO.

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“2022 was a highly successful year for VitaDAO, and the quality of research we have seen has been impressive,” says Laurence Ion, Steward of the Dealflow Working Group. “We’ve also seen some of our projects move rapidly to the next stage in development -- such as entering into clinical trials with Mantis Photonics and new data from the Morten Scheibye-Knudsen Lab at the University of Copenhagen and the Victor Korolchuk Lab at the University of Newcastle. This has further proven that a highly aligned community can contribute to advancing the science and clinical innovation in longevity research.”

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The fundraising is an important milestone for VitaDAO and will allow the organisation to accelerate its mission of extending human life and healthspan. With these new funds, VitaDAO will be able to fund cutting-edge longevity research, commercialise new technologies that target human aging, and build out its global community of experts and enthusiasts.

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Pfizer is the first pharma to vote on DAO proposal (within VitaDAO), and also participates in VitaDAO in many other ways, including dealflow, scientific evaluation, incubation, and commercialization.

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In 2022, we grew our community to include over 9000 enthusiasts, researchers, and contributors, as well as deployed over $3.5m in more than 15 projects researching the diseases of ageing, and the repair of damage associated with the hallmarks of ageing. 

All researchers are welcome to apply for funding, including professors, post-docs, research scientists, and even students. 

VitaDAO wishes to thank its contributors for their support.  

How to get involved

VitaDAO is defined as an active and diverse community of contributors.  Everyone can contribute to VitaDAO. We’re looking for researchers to identify and assess longevity projects and non-researchers to help with tech, legal, awareness, and operations If you’d like to get involved, a great first step is to join our Discord.

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Do you want to stay up to date with VitaDAO? Subscribe to our newsletter, add the vitadao calendar, and visit our twitter. 

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For any media requests, reach out to dao@vitadao.com and check out our press kit.

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VitaDAO Letter: Year in Review + Interview with VitaDAO Co-initiator, Tyler Golato 

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What a year it has been! 2022 was a year full of growth, science, and a whole lot of funded longevity research. In the 1.5 years since VitaDAO’s historic Genesis auction, VitaDAO has funded 15+ longevity projects, gathered 9000+ community members, and continued to lead the decentralized science movement. Here at VitaDAO, as a new year begins, we’re filled with gratitude. Travel with us as we highlight some of the craziness that was 2022!

New Here?

VitaDAO is a decentralized organization made up of individuals from across the globe working to fund early-stage aging research and spin out longevity biotech startups. VitaDAO is focused on maximizing healthy human lifespan. 

In the coming year, we hope you’ll join our mission. Want to get involved in the longevity field? Contribute to VitaDAO and receive $VITA tokens in return. Join the VitaDAO community on Discord and stay up to date on Twitter! Want monthly updates on what’s happening at VitaDAO? Subscribe to this Newsletter to stay up-to-date. 

2022 in Review

Below, read about what went DAOn in 2022. Buckle up! Even though this is not an extensive list, it’s still a lot!

January

• VitaDAO launched a monthly Newsletter! You’re reading the 13^th issue of this newsletter now. We’ve come so far!
• Phase 3 voting moved to Snapshot. The benefit: gasless voting!
• Max Unfried hosted a VitaDAO Panel, “On the Quest to Quantify Biological Age.” 
• A new steward onboarding and offboarding process was approved.
• VitaDAO members approved minting an additional 10% of tokens for aligned partners.  

 February

• VitaDAO purchased a third IP-NFT, funding a longevity research project by Evandro Fang’s lab at the University of Oslo to discover novel mitophagy activators! The project aims to identify and characterize new drug candidates for the activation of mitophagy with a positive impact on Alzheimer's disease.
• The Legal WG released a framework for fractionalizing IP-NFTs, via sublicenses: “Say hello to our FRENS: Fair, Reasonable, Ethical, Nondiscriminatory Sublicense.”
• The SciComm squad released an article on “The Science Behind NAD-Boosting & Anti-Aging.”
• New Longevity Journal Club Episodes: “Can blood from youngsters make you young?” & “Doggos, doggerinos & their lifespan”
• In an UltraRareBio X VitaDAO collab, Jocelynn Pearl and Vincent Weisser had a conversation on: “Scientific Publishing is broken. Can web3 fix it?” 
• DAO members decided to bridge $VITA to the Gnosis Chain!  Ethereum mainnet fees are high, and to make participation in VitaDAO easier, we bridged $VITA to Gnosis Chain.
• A VitaDAO panel with Professor Jan Gruber, Processor Eugene Berezikov, and Professor Bjorn Schumacher, “Long Live the Worm: Studying Aging with Nematodes.” was hosted by Max Unfried
• We grew to 10,000 Vitalians on Twitter!
• The first round of VitaDAO Fellows was selected. The VitaDAO Fellowship was formed to enable and assist DAO members with learning about longevity.
• VitaDAO approved the creation of an IP Holding Company.  The IP holding company is intended to hold only that which cannot yet be held in IP NFTs.

March

• VitaDAO Working Groups released a 2021 VitaDAO Community and Treasury Report.
• New VitaDAO Partnerships!

• A VitaDAO X Peter Diamandis Partnership 
• A PrimeDAO X VitaDAO Partnership 

• VitaDAO approved the funding of Dr. Brad Stanfield’s clinical trial. The trial is looking at the effect of regular exercise and intermittent rapamycin dosing on muscle performance in older adults compared to exercise alone.
• The SciComm squad released an article on“Epigenetic Clocks: A Simple Lab Test Measuring Biological Age.”
• VitaDAO co-created and curated a quadratic Gitcoin round raising money for the Longevity Prize, Longevity Hackathon, and VitaDAO Fellowship. 
• VitaDAO allocated $100k for funding the Longevity Hackers Film, a feature-length documentary highlighting longevity and radical life extension.
• Episode 10 of the Longevity Journal Club explored if gut bacteria have aging implications.
• VitaDAO allocated 30,000 EUR to fund Mantis Photonics' hyperspectral camera technology for early screening of Alzheimer's Disease through the detection of the Amyloid beta peptide.

April

• VitaDAO hosted its first Crypto meets Longevity Symposium. This was the first-ever conference held with the intent to explore the integration of longevity and web3 and consisted of over eighteen scientists, blockchain experts, and longevity professionals. 
• VitaDAO hosted three panel discussions:

• On Female Reproductive Longevity
• Novel Mechanisms to Fund Longevity Science
• The Science of Biostasis and Cryopreservation

• VitaDAO was represented at ETH Amsterdam’s DeSci Day. Check out Laurence Ion‘s presentation on VitaDAO.
• We published “How Crypto Can Help Science & Medicine.” by Tim Peterson.

May

• VitaDAO sponsored DeSci Berlin! Laurence Ion presented VitaDAO and held a workshop. Many other VitaDAO working group members were in attendance.

• VitaDAO funded a 4-year doctoral research program probing DNA quadruplexes in age-related proteostasis with 50,000 USD.
• VitaDAO approved the funding of Tim Peterson’s research project looking to identify chemistry that acts as a cellular ‘soap’ to concomitantly thwart pathogens and senescent cells.
• VitaDAO hosted a Panel Discussion, “On Applied Longevity Medicine.”
• A new VitaDAO Partnership was established! As a result, a token swap was initiated with BanklessDAO for its governance token $BANK
• Podcast by @BioAgePodcast with Tyler Golato and Laurence Ion about the essence of VitaDAO, changing the incentive structures around drug development, and the intersection of biotech, blockchain, and longevity.
• DeFi Talks with DeFi Dad - An Intro to Decentralized Science (DeSci) with VitaDAO

June

• VitaDAO celebrated 1 year since its Genesis fair token auction!
• VitaDAO approved bounty payments in VITA tokens to create a decentralized tech transfer network that connects VitaDAO directly to researchers. Decentralized Tech Transfer (DTT) identifies researchers with a project, pays the researchers as consultants, uses CROs to execute research, and allows funders + researchers to own IP.
• We funded with 50,000 USD Repair Biotechnologies, a preclinical-stage biotech company developing a first-in-class universal cell therapy for atherosclerosis.

July

• Multichain voting went live! As a result, DAO members can vote on both the Ethereum and Gnosis chains.
• VitaDAO launched the Longevity Prize - a crowdsourced longevity prize to unlock progress in longevity research and recruited 3 top organizations as partners: Foresight Institute, Methuselah Foundation, and Lifespan.IO.  We raised over $250k in prizes through the Gitcoin Longevity Round we initiated, with support from thousands of community members, whose donations were matched by VitaDAO, Vitalik Buterin, and Stefan D. George.
• Laura Minquini and Ines Silva hosted a VitaDAO panel about Gender Biases in Research.

August

• VitaDAO member Tim Peterson started The Longevity Decentralized Review (TLDR), an on-demand peer review service.
• VitaDAO was highlighted in a Nature Biotechnology piece!

 September

• The funding of two more research projects via IP-NFT. Jonathan An’s lab is attempting to reverse periodontal disease using Geroscience. An’s project was the 1st IP-NFT for longevity research in the USA. The SENS Research Foundation's ApoptoSENS project is developing CAR-NK cells to precisely and safely eliminate senescent cells.
• We released a new article, expanding on “Decentralized Technology Transfer (DTT) - A Modern Framework to Empower Scientific Innovation.”

October

• Together with ResearchHub, VitaDAO announced a bounty for individuals to build a community-driven Review Paper.
• We released an article on  “Rapamycin is the most promising aging intervention we currently have”, by Adrian Moliere and Tomas Schmauck-Medina 
• Max Unfried and Eleanor Sheeky hosted the 2nd VitaDAO Crypto Meets Longevity Symposium, consisting of twenty-two scientists, blockchain experts, and longevity professionals from internationally recognized institutions who spoke on the intersection of longevity and the blockchain. 
• VitaDAO launched a JellyfishDAO x VitaDAO interview series.
• VitaDAO was represented at ARDD2022 VC PANEL: Investing in Longevity Biotechnology by Laurence Ion. 

 November

• VitaDAO’s Institutional Genesis Raise was a huge success. VitaDAO gained amazing strategic contributors committed to building a public good and participating in the governance of VitaDAO using $VITA tokens. Below, find a list of the contributors and their contributions: 

• Pfizer Ventures - $500k + dealflow, commercialization & pharma awareness
• L1 Digital - $500k + tokenomics & governance support
• ShineCapital - $1M + positioning, fundraising, partnerships & tokenomics support
• BeakerDAO - $75k + dealflow, incubation of spinouts, awareness & connections
• and more (including Balaji Srinivasan, SpaceshipDAO, and Retro Biosciences)

• VitaDAO voted to fund Longevity Research with a Nouns-style NFT project.
• VitaDAO realigned Working Group Structures around the concept of an execution layer and a consensus layer. 
• VitaDAO published a new article, “Synthetic Vitality-Therapies that act synergistically are needed to significantly promote longevity” by Tim Peterson.

December

• We implemented shielded voting. Now, votes can be private during the voting period and revealed with each proposal closure.
• The VitaDAO community approved delegated voting. VitaDAO members can delegate their voting rights to a delegate and wallet of their choice.
• Top contributors in the Longevity-Dealflow Working Group were allocated 900,000 VITA tokens over 4 years.

VitaDAO Numbers: The Low Down

$3.5M+ Research Funded

250+ Projects Sourced

1300+ Token Holders

9000+ Community Members

15,000+ Twitter followers 

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Meet: VitaDAO Co-initiator, Tyler Golato

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Tyler Golato graduated from Stockton University before completing research fellowships at Columbia University and the National Institute on Aging. As a researcher, he has a background in experimental therapeutics and biogerontology. As an entrepreneur, in February 2021, Tyler Golato co-initiated VitaDAO. Today, Tyler also serves as Chief Scientific Officer at Molecule AG, a platform created to facilitate decentralized, modular, and collaborative drug development. 

Can you speak to your interest and journey in biogerontology?

I started out my career aiming to be a physician. As I progressed in that, I became aware of how primitive medicine is as an applied practice. Beyond communicable disease, there is not much that we can cure. Most conditions are simply managed, at best. 

I had an interest in oncology, and in particular, intractable cancers such as glioblastoma and pancreatic cancer. As an oncologist, you mostly apply a standard of care and the outcomes fall along a predictable statistical distribution. Most prognoses are poor, and we have not advanced much regarding cancer therapy, across all cancers, over the last 50 years. Thus, I became more interested in research and trying to understand how I could advance the field.

I joined an experimental therapeutics laboratory at Columbia University where I worked with Dr. Robert Fine. I found the work very interesting and rewarding, but most of the developments and wins in pancreatic and brain cancer were focused on stabilizing or shrinking tumors and extending overall survival by months. I was really much more interested in how we might prevent cancer, or even mutation, altogether. 

With this in mind, I became more interested in biogerontology. When you realize how primitive medicine is and how poorly our reactive, treatment-focused health care system treats conditions (sick care, not health care), it becomes more attractive to consider how we might prevent disease. In my mind, biogerontology was the closest thing that existed to preventative medicine as a research domain. Most chronic disease and mortality is age-related. If we could understand the driving causes of aging, perhaps we could affect them and therefore also age-related diseases. Further, I was interested in the metaphysical aspects of fighting aging as a conquest. This always inspired a sense of awe in me, as I imagine it does for most people, and certainly has for humanity throughout millennia. 

When I finished at Colombia, I joined the National Institute on Aging in the Laboratory of Molecular Gerontology under David M Wilson and Vilhelm Bohr. My focus was on DNA damage and repair, and segmental progerias, which recapitulate some segments of the aging process. I really enjoyed my time at the NIA, but ultimately decided I wanted to focus on something that could improve the overall system of science funding and healthcare at the incentive level, as opposed to being a researcher. 

Before founding Molecule and later, VitaDAO, were you involved in Web3/decentralized technologies?

I interacted with Bitcoin as early as 2013, and found the technology curious. I was also interested in Ethereum from 2015 or so, but primarily around innovations in governance the ideas that were brewing around The DAO. After that failed, I remained skeptical about the general maturity of the technology. While I found it intriguing, I didn’t see many near-term relevant use cases. It was only in 2017/2018, when I met Paul Kohlhaas, my co-founder at Molecule, and the technology started to mature, that I became seriously interested. I was mostly interested in novel approaches to mechanism and incentive design in science and drug development, specifically. Web3 provided a clear architectural framework where one could create a sandbox environment to play with incentive and governance designs. This excited me a lot. 

How did you first come up with the idea of VitaDAO? 

VitaDAO is really an amalgamation of ideas. Before VitaDAO, Molecule had been working on the premise of creating a decentralized drug development protocol. We always thought about this through the lens of using IP ownership as a distributed incentive. What if, instead of a company owning a patent, a group of disparate collaborators - patients, researchers, VCs, pharmas, academic labs, biotechs - all worked together and contributed to the development of a drug in exchange for partial ownership in IP? This idea of turning IP ownership into a fractional incentive was really exciting to me, given how modular drug development had become, but also given the fact that there was often a missing incentive for collaboration. 

With this idea in mind, we began working on an IP-NFT framework for funding research projects. This is at the core of Molecule’s and VitaDAO’s technology stack today. 

VitaDAO was really the first working proof of concept to bring those principles together in a unified structure, focused on biogerontology, which is my passion. We believed that by bringing together a community of diverse stakeholders from all aspects of biogerontology, we could build a more robust organization than a biotech company, a nonprofit, a university, or a fund. While it is still a work in progress, I believe we are beginning to see the validation of that thesis. 

What do you think is VitaDAO's greatest strength? 

VitaDAO’s biggest strength is its community, and the fact that anyone capable of adding value can easily become a core part of that community. VitaDAO has a lower barrier of entry than a startup or a traditional org - you can show up in the Discord and if you have something the organization needs, you can become productive quickly. This is incredibly unique and enables a constant influx of talent and dealflow. Additionally, I think VitaDAO’s unique structure - one focused on creating a sustainable organization that is not distinctly for or non-profit - gives the organization the ability to succeed and rise up in a field currently bogged down by poorly designed incentives and a lagging status quo. 

What has surprised you the most about VitaDAO?

The thing that has surprised me most about VitaDAO is the extent to which it has been responsible for catalyzing the broader DeSci movement. There has been an explosion of new bioDAOs and DeSci orgs seeking to do something similar to VitaDAO, but in different therapeutic areas or with slightly different design parameters. This has been hugely exciting and rewarding to watch (and participate in), as it creates a real sense of legacy for one’s work. I take a lot of joy and comfort knowing that independent of the success of any of these organizations, the spirit of DeSci and making science more open, accessible, collaborative, and democratic is virtually unstoppable at this point. 

How do you see VitaDAO evolving in the future? - What is something you believe today that you didn't believe ten years ago?

VitaDAO is going to become laser-focused on translating its assets to market. Our first year was really focused on funding projects. Now, we will become more focused on incubating these projects, spinning them out, and really proving our thesis end-to-end. My hope is that the organization will continue to grow and thrive, and that we will be able to fund total moon shots - things that traditional organizations wouldn’t touch, where the risk is too high (but the reward also asymmetric). I believe VitaDAO will become one of the top 5 go-to sources for funding in biogerontology, and that we are at the beginning of a journey towards DAOs becoming the default organizational structure for funding and incubating assets. 

There are many things that I believe today that I did not believe 10 years ago. Technology is advancing so quickly that anyone who believes they can see 10 years into the future is likely wrong. 10 years ago, I couldn’t see the extent to which technology - things like web3, AI, etc - would completely transform how science is conducted. 

I’ve recently written about my vision for the future of science and drug development here: https://www.molecule.to/blog/the-scientific-singularity-our-vision-for-the-future-of-research-with-ip-nfts. This is a future I could not have fully imagined even 5 years ago, but I now have a high degree of confidence we will see this reality soon. We are already beginning to, and VitaDAO is playing a major role. 

Upcoming Events

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Hackathon: Jan 20th - 22nd - Join VitaDAO’s Hackathon - a remote, cross-disciplinary hackathon focusing on the future of longevity. Registration is now open! 

VitaDAO @ Longevity Med Summit: May 4-5, 2023 - Come join VitaDAO in sunny Lisbon, Portugal at the 2023 Longevity Med Summit. Here, join other longevity enthusiasts in learning about the development of anti-aging science, the exploration of new regenerative and longevity therapeutics, and the limiting R&D challenges faced in therapy development.

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Check out VitaDAO’s calendar and view all our upcoming events: https://vitadao.com/calendar 

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Introduction

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

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

Longevity Literature Hot Picks

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Aging is associated with a systemic length-associated transcriptome imbalance

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Could aging evolve as a pathogen control strategy?

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

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

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Biological Age Predictors: The Status Quo and Future Trends

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

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

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

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

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

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

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

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

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2022 Papers from the VitaDAO Community

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

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

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

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

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New hallmarks of ageing : a 2022 Copenhagen ageing meeting summary

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

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

Mitophagy and neuroinflammation: a compelling interplay

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

WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP

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

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

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

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

Nuclear morphology is a deep learning biomarker of cellular senescence

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

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

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

https://elifesciences.org/articles/75492

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

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

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

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

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

Clinical Trial Updates

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

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

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

Funding Opportunities

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British Society for Research on Ageing

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

1. Small Research Grant (equipment & publication costs)

2. Travel Grant (attending biology of ageing conference)

3. Summer Studentship (for undergraduates)

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Scholarship for the Longevity Biotech Fellowship

https://www.longbiofellowship.org/scholarships

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

Job board

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

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

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

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Deciduous Therapeutics are looking to hire a research scientists and associates

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

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

News

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

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

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The Longevity Biotech Fellowship

https://www.longbiofellowship.org/

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

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

https://peterattiamd.com/outlive/

Available to pre-order now wherever books are sold.

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

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

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Articles

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Why is progress in biology so slow?

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

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

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Funding science through blockchain technology and cryptocurrencies

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

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

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

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

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

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Sarcopenia: What a Waste

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

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

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Conferences and Webinars

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

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

You can see all recorded taks here:

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

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

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

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DeSci London

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

https://www.desci.london/

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

Travel grants available: 

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

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

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

Podcasts and Videos

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Evelyne Bischof: 100 Questions with Longevity Legends

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

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Infinite Monkey Cage Podcast: Can we cure ageing?

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

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

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

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

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

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Longevity Tweet of the Month

Prof. Charles Brenner:

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“animals have homeostatic functions that allow them to repair themselves

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their capacity to do so declines after they reach reproductive prime

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if you want to quantify aging, quantify repair capacity

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

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

Longevity Resources

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

https://norn.group/talent-bench

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Longevity Apprenticeship Journal Club

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

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

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

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

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Interview with Tim Peterson

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

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What inspired you to enter longevity research?

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

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

That there are multiple causes.

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How has the field changed since you started?

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

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What mistakes do you think the longevity field has made?

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

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

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

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

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

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

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

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Is ageing a disease?

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

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

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

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

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

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

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

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

Epigenetic reprogramming. Anything that would have synergistic effects.

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

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

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

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

Outro

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

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

Further Reading

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

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

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The Significance of NAD+ Biosynthesis Alterations in Acute Kidney Injury

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

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mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters

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

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

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

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

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Molecular mechanisms of exercise contributing to tissue regeneration

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

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

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

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Interaction of aging and Immunosenescence: New therapeutic targets of aging

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

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

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

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

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

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

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Therapies that act synergistically are needed to significantly promote longevity

The math behind the expression “aging is inevitable” is the Gompertz-Makeham law. This law describes the probability of death as a function of age. It reaches 99.9+% by the time we are 100. One doesn’t need to know math to realize this, but because you’re here the underlying formula is an exponential function.

“Aging is a math problem — multiplicative therapies is the answer.”

Exponents involve multiplication. Another way this can be understood is that multiple factors synergize to make us die. Factors like smoking, drinking, poor sleep, bad diets have multiplicative effects. They don’t add together. Like an evil 401K, they compound to kill us. Aging is a math problem — multiplicative therapies is the answer.

“Understanding that it is factors that synergize to cause us to die will be key to fixing how we make therapies.”

Understanding that it is factors that synergize to cause us to die will be key to fixing how we make therapies. For many decades now, since the rise to prominence of rational drug design, there has been a fixation on identifying silver bullet therapies. That is, if we can just find the right target and then drug it strongly and selectively enough, we can cure disease. The invention of Gleevac, which targeted the gene mutation BCR-ABL for the cancer type CML, added fuel to this fire. (You too can cure disease if you can just make your drug as good — potent, selective — as Gleevac!).

From the joke above, you can tell the CML example created a false expectation. CML is a monogenic disease. Targeting the single mutant gene with a single agent worked there, but it has nothing to do with polygenic diseases that are most diseases we care about (Alzheimer’s, most other common cancers, heart disease, etc.). The case is similar with two of the blockbuster drugs of the past decades — statins and ACE inhibitors. Those drugs have one job — to move a number down (cholesterol or blood pressure, respectively). That is not what’s being asked of most other drugs.

“Rapamycin is a start, but it is unlikely to promote the transformative longevity gains we are aiming for.”

For longevity, the current best case drug is rapamycin. Rapamycin has a 10–20% effect on lifespan in animals. Do the exercise and review the literature for other small molecules for any disease model. You’ll see that 20% improvements are a best case scenario in general. 20% is not good enough, especially because animal experiments are done in highly controlled conditions that are optimized to find an effect if there is one to be detected. This won’t be the case in people. All this is to say — Rapamycin is a start, but it is unlikely to promote the transformative longevity gains we are aiming for.

The longevity community needs to learn from the cancer community. More recently, the cancer community is focusing on synthetic lethality. “Synthetic” is a terminology geneticists use to describe what I’m referring to as synergistic or multiplicative.

What is a multiplicative therapy? I mean agents that have profound effects on physiology when combined. Their effects are not additive. They are multiplicative. 20 X 20, not 20 + 20. The former is 10X the effect of the latter. The Yamanaka four factors are perhaps the first bona fide example of a multiplicative longevity therapy. Combining four genes that can convert any cell to an embryo! Fortunately, people are already starting to leverage this technology to turn back the clock of old cells. Other strategies involving combinations of small molecules are emerging too.

“The radical view through the Overton window is that the FDA should require that a therapy hits multiple targets in order to be approved.”

The recently approved ALS drug, which is the only disease modifying drug for this fatal condition, is a combination of two agents. It’s not even known molecularly how they work! Considering one of the most valuable drugs ever Aspirin has 23 putative targets, I’m not sure why we haven’t done more to normalize ‘irrational’ drug design. The radical view through the Overton window is that the FDA should require that a therapy hits multiple targets in order to be approved. Otherwise I think if one soberly surveys what gets approved these days the cost/benefit analysis won’t be good. Even the aforementioned ALS drug, despite how promising it might be, is not sustainably priced at $158,000 per year.

Statins and blood pressure meds are what I call ‘counting’ medications. All we care about is the number going down. We’re rarely doing addition. We need to stop counting and start doing multiplication. Just as cancer needs synthetic lethality, aging needs synthetic vitality.

“Just as cancer needs synthetic lethality, aging needs synthetic vitality.”

At VitaDAO we are looking for multiplicative therapies. Rejuvenome is too. Here’s a starting list of projects doing multiplicative therapies. We’d love for you to add to the list.

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Introduction

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A multitude of discoveries and inventions throughout history have been made by people who were initially trained in one domain, but were able to make a significant contribution to a different field due to their ability to look at a problem with a unique perspective. Would Charles Darwin still have conceived the Theory of Evolution if it were not for his background in Geology and appreciation that for geological processes to have occurred, Earth must have been around for a vast amount of time!

The contributions of physicists in particular to our understanding of biology have been immensely valuable over the past century. Great thinkers such as Szilard, Schrödinger and Crick, compelled to find out what life is and how it works, were able to provide humanity with novel ideas and trailblazing discoveries in molecular biology. 

Take this month’s issue as a tribute to the novel insights provided from physics with a few newly published papers, pre-prints and an interview with Dr. Peter Fedichev - highlighting the power of cross-disciplinary thinking to help advance longevity research! 

Longevity Literature Hot Picks

After another month of overwhelming amounts of great longevity research being published,  we hope to make it easier for you to keep up with it all by presenting some of our favourite papers from the field (and remember our Further Reading section at the bottom of this page for even more new longevity papers).

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While we normally pick peer-reviewed published papers, there were a few interesting pre-prints this month which sparked a lot of debate that we couldn’t ignore!

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Unsupervised learning of aging principles from longitudinal data

https://www.nature.com/articles/s41467-022-34051-9?fbclid=IwAR0nILUom4ulJUGm3RY_uKcmCFTAaJuqX9NuSLsSYSUUYZTbZoKJdfC8q4Q

What is the relationship between physiological changes with age and lifespan? To answer this question analytical and machine learning tools were employed to design deep artificial neural networks with auto-regression model, identifying a relationship between physiological state during aging and a variable named “dynamic frailty index” or dFI. dFI increased exponentially with age and predicted lifespan from mouse blood samples. It also responded accordingly to know life-shortening and life-extending interventions.

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Aging clocks, entropy, and the limits of age-reversal

https://www.biorxiv.org/content/10.1101/2022.02.06.479300v2

A single variable called thermodynamic biological age (tBA) tracks entropy produced, and hence information lost, with age. As tBA increases with age it reduces resilience, and drives the exponential acceleration of chronic disease incidence and death risks, which is a linear and irreversible drift, setting severe constraints on age reversal possibilities. But wait, not all hope is lost. We might be able to figure out how to “cool down” the organism, control entropy and reduce the rate of aging in humans.

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F1F0 ATP Hydrolysis is a Determinant of Metabolic Rate, a Correlate of Lifespan, and a Weakness of Cancer

https://www.biorxiv.org/content/10.1101/2021.10.28.466310v3

F1F0 ATP hydrolysis generates metabolic heat in an organism. A drug that can selectively inhibit ATP hydrolysis, but not synthesis, is explored here, and hypothesised that it could extend lifespan by slightly lowering body temperature. In 12 different species, decreased F1F0 ATP hydrolysis correlates with greater maximal lifespan. Anti-cancer properties were also observed in vitro.

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Dietary restriction fails to extend life in stressful environments

https://www.biorxiv.org/content/10.1101/2022.10.17.512576v1

Dietary restriction has been shown to extend lifespan in numerous model organisms, however here the authors show that this effect is lost in fruit flies which are also under stress due to cold or hot living environments. This raises the question of whether laboratory-tested interventions will translate to animals living in more natural environments. 

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Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice

https://www.nature.com/articles/s43587-022-00304-x

Aging leads to the accumulation of hematopoietic stem cells with reduced regenerative potential. The mechanisms behind this are unclear but this study shows that inactivation of the plant homeodomain factor 6 (PHF6), a single epigenetic regulator, rejuvenates mouse aged hematopoietic stem cells.

The commentary on the article:

Is the philosopher’s stone to rejuvenate blood stem cells an epigenetic regulator?

https://www.nature.com/articles/s43587-022-00305-w

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Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms

https://www.mdpi.com/1422-0067/23/20/12325/htm

A new take on CR mimetics with Sodium-glucose cotransporter 2 inhibitors (SGLT2-i), which lower glucose by elimination through urine, and actually induce a net loss of calories, fostering ketones and fatty acids utilization as glucose-alternative substrates. This process modulates major nutrient-sensing pathways held to drive aging, such as mTOR and resembles CR. Preliminary data also shows that it can inhibit cellular senescence and inflammaging.

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Circadian transcriptional pathway atlas highlights a proteasome switch in intermittent fasting

https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01403-6

Intermittent fasting has gained traction among the longevity community as a safe lifestyle intervention hoping to improve healthspan and increase lifespan. The authors set out to discover if there was an internal "timer" to respond to fasting duration. They found that in mice, the hepatic proteasome switches leading to transcriptional resonance which is reversed upon re-feeding. It will be interesting to investigate if a similar mechanism is conserved in humans and what fasting duration is required to induce the switch. 

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The role of gut microbiota in liver regeneration

https://www.frontiersin.org/articles/10.3389/fimmu.2022.1003376/full

Unlike other human organs, the liver has an amazing ability to regenerate itself. 

Check out this review exploring how gut microbiota play a role in liver regeneration through regulating the liver immune microenvironment thus modulating inflammatory signalling at different stages of the regenerative process.

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Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan

https://www.aging-us.com/article/204347/text

The 2012 Nobel Prize for Physiology or Medicine was awarded for showing that differentiated cells could be reverted back to stem cells by activation of 4 transcriptional factors, now eponymously known as Yamanaka factors. This led to huge interest in the field including the founding of the multi-billion start-up Altos Labs. Another longevity target are senescent cells, the removal of which by either genetic or pharmacological means can increase lifespan in mouse models. Here the authors show that combining Yamanka activation with senescence removal has a synergistic effect on lifespan, with the largest effect resulting from transient treatment of both interventions.

Clinical Trial Updates

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A Randomized Clinical Trial showing that a sustained low-carbohydrate diet might be a useful dietary approach for preventing and treating type 2 diabetes.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797714

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Meta analysis of aerobic exercise improving intelligence and cognitive function in patients with Alzheimer’s disease

https://journals.lww.com/md-journal/fulltext/2022/10210/meta_analysis_of_aerobic_exercise_improving.15.aspx

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UNITY Biotechnology Announces Positive 24-Week Data from Phase 2 BEHOLD Study of UBX1325 in Patients with Diabetic Macular Edema

https://www.globenewswire.com/news-release/2022/11/01/2545288/0/en/UNITY-Biotechnology-Announces-Positive-24-Week-Data-from-Phase-2-BEHOLD-Study-of-UBX1325-in-Patients-with-Diabetic-Macular-Edema.html

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News

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JPMorgan Launches Life-Sciences Venture Group

https://www-wsj-com.cdn.ampproject.org/c/s/www.wsj.com/amp/articles/jpmorgan-launches-life-sciences-venture-group-11667300402

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Crypto entrepreneur Justin Sun, founder of Tron, donate’s 51k USD to the Longevity Prize 

https://www.longevityprize.com/

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Journal eLife eliminates reject/accept decisions from their review process

https://elifesciences.org/articles/83889

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Articles

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MIT Technology Review - The Mortality Issue

https://www.technologyreview.com/magazines/the-mortality-issue/#features

Featuring:

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The debate over whether aging is a disease rages on

https://www.technologyreview.com/2022/10/19/1061070/is-old-age-a-disease/

Why the sci-fi dream of cryonics never died

https://www.technologyreview.com/2022/10/14/1060951/cryonics-sci-fi-freezing-bodies/

How scientists want to make you young again

https://www.technologyreview.com/2022/10/25/1061644/how-to-be-young-again/

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Modern Vampirism: “Young Blood” Transfusions

https://peterattiamd.com/young-blood-transfusions/?utm_source=twitter&utm_medium=social&utm_campaign=221030-newsletter-blood-transfusion&utm_content=221030-newsletter-blood-transfusions-tw

Blood from young mice has rejuvenating effects on old mice, but it’s too early to translate these results into treatments for humans.

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Upcoming conferences

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A lot of us are conferenced-out for this year but there is one more meeting with an impressive line up we’d recommend:
The Longevity Summit

December 6-7 | Buck Institute for Aging | Novato, CA

https://longevitysummit.io/

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While we’re waiting for more exciting conferences, make sure you’re caught up with the recordings from ARDD and VitaDAO’s own crypto-longevity symposium.

https://www.youtube.com/channel/UClOnplI2mzpJlwdX3vlOMJA

https://www.youtube.com/watch?v=-70SgGJPzTo

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Evotec Webinar series focusing on 3 key areas:

• Therapeutic approaches for aging and age-related disease
• Aging and precision medicine
• Why older adults should not be underrepresented in clinical trials. 

https://news.evotec.com/a-spotlight-on-aging-webinar-series

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Funding Opportunities

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Hevolution Foundation Announces Pilot Grants Program for Top Healthspan-Related Research in the United States

https://hevolution.com/en/w/hevolution-foundation-announces-pilot-grants-program-for-top-healthspan-related-research-in-the-united-states

Job board

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The Schumacher lab is looking for a postdoc to join them at the Institute for Genome Stability in Ageing and Disease, CECAD-Cluster of Excellence in Aging Research, University of Cologne

https://schumacher.cecad-labs.uni-koeln.de/open-positions

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Vita therapeutics, a cell engineering company using iPSCs, have two open positions - research associate and a quality assurance director:

https://www.vitatx.com/careers#openpositions

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Head of Ops for Longevity Fund - $150K+ salary, higher if you’re significantly experienced. Looking for someone smart and capable with 3+ years of operating at a fast-paced startup or VC firm

email laura@longevity.vc if a fit! $10K referral bonus if you find someone great :)

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Longevity Tweet of the Month

Even if you don’t use Twitter, it must have been near impossible to escape the news and debate surrounding Twitter’s new owner Elon Musk and his plans to charge for verification. The author Stephen King took umbrage to this and threatened to leave the platform. Alex Zhavoronkov had an amazing response, leading to the inauguration of our new ‘Longevity Tweet of the Month’:

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Alex Zhavoronkov: “I will pay @StephenKing's $20/month twitter for the rest of his life if he writes his scariest book titled "The Biology of Aging" (the concept is so horrifying that after 40, you do not need a costume for Halloween anymore). With @davidasinclair as the savior protagonist  🎃👻💀”

https://twitter.com/biogerontology/status/1587477303671816192

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Interview with Dr. Peter Fedichev

Dr. Peter Fedichev describes himself as a "physicist in drug discovery land". With a background in condensed matter physics, biophysics and bioinformatics he has been able to provide a unique perspective to longevity research, for example the 2 papers highlighted in this month's issue. He is currently the CEO and co-founder of the longevity biotech company GERO.

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What inspired you to enter longevity research?

I am a physicist by training and did my studies in the field of strongly interacting and correlated systems. I am fascinated with phase transitions and emergence - the ability of complex systems to develop properties that do not exist on the level of their constituent parts. “More is different,” in P. Anderson's words, and we find novel interesting phenomena whenever it applies. Living systems and their gene regulatory networks fall into this category. Somebody brought my attention to negligible senescence (slow or no-aging in some species). I immediately recognized that such aging-resistance might also be an example of emerging property. 

Since then, we followed this lead and developed a set of ideas casting the “normal” Gompertzian aging and negligible senescence as two distinct phases of gene regulatory networks differentiated by dynamic stability properties. I am increasingly convinced that negligible senescence is the most important discovery in the field of aging studies. I also see that physics lends great tools for understanding this phenomenon and that achieving negligible senescence is a great scientific, humanitarian, and technological goal. 

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

Let me answer this question by bringing up the following analogy. In physics, there is the Standard Model. This is by far the best theory ever made. Until very recently (2018), there’s been no single experiment contradicting the theory. Even now, with only a few experiments in neutrino physics falling from the scheme, the discrepancy between the theory and the experiment is abysmal. Nevertheless, the Standard Model is a model, not a theory. This is because everyone knows it is inconsistent and thus can not be a complete theory. 

Compare this to the situation in aging sciences. We have a dozen of “theories” of aging. Such an impressive number of “theories” tells us that we do not have a theory of aging. It may look bad, but it is exciting too. Other fields of science lived through the times of such a  “zoo” of theories. The physics literature was full of unrelated forces and particles not long ago. We need the grand unified theory of aging, and it will come in due course. 

How has the field changed since you started?

The field matures. People do clinical trials. More people in science and the general public believe that lifespan is modifiable. We have more and increasingly better-trained people with diverse scientific and entrepreneurial backgrounds coming into the field (think, for example, of physicists, AI engineers, and crypto-activists joining biologists and medics). 

What mistakes do you think the longevity field has made?

There’s been tremendous progress both in understanding aging and translating the growing fundamental knowledge into preclinical and clinical trials. However, most currently developed solutions will produce small effects on par with the effects of lifestyles. For many, this strategy seems to reduce risks. But any working solution in biotech takes 10 years at least to develop fully. Working on weak interventions is a waste of resources and years of life. I would also think of hopes and expectations here. The public and policymakers have high hopes and may end up frustrated if the longevity biotech ends up with “statistically significant”  and, at the same time, miserable results. 

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

To my taste, the discovery of negligible senescence - the discovery of advanced animals, such as mammals, that defy Gompertz mortality law is the biggest discovery in the field of aging. This is a very important demonstrator proving that aging is not evitable. Reducing mortality acceleration to almost zero may increase human lifespan a few fold. 

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

Think big - avoid solving unimportant problems even if those lend you a paper in a good journal.

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

Negligible senescence

Is ageing a disease?

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.

Can you explain what you’ve found in your research to be the major difference in the ways different species age (e.g. mice, naked mole-rat (NMR), humans)?

This is a great question. We published two Nature Comms works (a week ago, Unsupervised learning of aging principles from longitudinal data | Nature Communications,  and a year ago, Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit | Nature Communications) suggesting that humans and mice belong to two distinct classes of regulatory networks function. Mice are dynamically unstable; their organisms amplify damage, the damage does more damage, and this vicious loop leads to the exponential accumulation of damage. We found that the damage accumulation rate is the same as the mortality rate doubling time, and therefore the inability of the regulatory systems to control damage is the cause of exponential mortality acceleration. On the positive side, aging in mice appears to be mostly reversible.

On the other hand, humans control the damage very well for the most time up until late in life. The transition from the stable to the unstable phase occurs stochastically at some age around 60 due to the gradual loss of resilience, the ability of the organism to regain its homeostatic equilibrium after a shock. 

If this is true, aging in mice is the model of late-life morbidity and mortality in humans. Drugs acting in mice and extending their lifespan will improve lifespan beyond healthspan. Since resilience is lost late in life, the effects of such drugs on the human lifespan will be limited. 

To develop drugs that could let people live in good health for 150–200 years, we must confront the loss of resilience. This is especially challenging since the resilience is already lost in mice by the age of 25 weeks, if not earlier. This forms what we would call a “preclinical trap”: to convince investors and peer scientists, you have to select drugs that work best in mice. Such interventions, however, could only help people late in life. Unfortunately, the same drugs will provide small effects in healthy people and likely would not affect resilience. 

What are the fundamental principles and mechanisms behind negligible senescence in some animals (like NMR) and what causes them to die if there is no increased risk of mortality or frailty over time?

This is an open question. Our models suggest that NMRs and other negligibly senescent animals die of the same diseases. Just the incidence of those diseases (and hence death) does not grow exponentially as we age. Our last publications hint that humans are already almost negligibly senescent. In contrast to mice, humans control the hallmarks of aging for dozens of years until resilience is lost, and all hallmarks of aging and chronic diseases start appearing simultaneously. I believe that humans and NMR belong to the same class of aging systems. NMRs lose their resilience way slower than us, and I want to learn how they do it. Or, better, how to make humans stop losing their resilience.

Could human biology be modified in a way that it utilises those underlying principles of negligible senescence?

The short answer is yes. People are working to find out how. This is what Gero does, and answering this question is my personal scientific goal.

What do you consider “true aging”? And in order to extend healthy life, should we intervene before cellular and organismal loss of resilience? 

As I said, we observe that humans are very resilient. More is different, we are not talking at the level of cells. We are describing and measuring the resilience on the level of the organism as a whole. We work with very large datasets of human data and find that it’s very hard to die before resilience is lost. Curiously, according to our measurements, the number of people demonstrating the loss of resilience increases in the population exponentially and doubles every eight years, exactly as fast as the mortality rate doubles. Once the resilience is lost, like in mice, you have just a few years of life left.

Therefore, the loss of resilience is the most fundamental aging phenotype in humans. We call it “true aging” and it is different from the classic  hallmarks of aging driving late-life mortality and morbidity. Our worst nightmare came true: this year, we put up a preprint, Aging clocks, entropy, and the limits of age-reversal | bioRxiv, suggesting that the loss of resilience is driven by a thermodynamically irreversible process. If this is true, true aging in humans can not be fully reversed but only stopped. This is the least fortunate outcome of our research, and we had to be very careful trying for a few years to disprove this conclusion.  

Our approach is human-centric. We are applying modern AI/ML tools for identifying markers and genetic determinants of true aging in human data. In this way, we aim at the disentanglement of aging and diseases.  This helps in two ways. First, it helps people who look for cures for specific diseases. We work with pharma companies to identify novel targets, targeting reversible processes leading to transformative medicines. 

Most importantly, we track true aging in real-world medical and genetic data to find genetic factors modifying the rate of true aging. We are making good progress and hope to initiate experiments to test the theories in practice. 

Our goal is to make humans negligibly senescent species.

Outro

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Thanks for reading our November issue of VitaDAO's Monthly Longevity Newsletter!

Once again, if there is anything you would like us to feature in future issues, please get in contact. 

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This time we leave you with a thought provoking article in Science from 1972 by Nobel prize winner in physics Philip Anderson - More is Different because even though it’s 50 years old it’s still relevant today. There Prof. Anderson challenges the hierarchical structure of sciences - from physics to biology - and argues that “at each level of complexity entirely new properties appear”:

https://cse-robotics.engr.tamu.edu/dshell/cs689/papers/anderson72more_is_different.pdf

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Further Reading

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Healthy Aging: Strategies to Slow the Process

https://www.sciencedirect.com/science/article/abs/pii/S0030666522000809

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Association of sleep duration at age 50, 60, and 70 years with risk of multimorbidity in the UK: 25-year follow-up of the Whitehall II cohort study

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004109

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Does Abdominal Obesity Increase All-Cause, Cardiovascular Disease, and Cancer Mortality Risks in Older Adults? A 10-Year Follow-Up Analysis

https://www.mdpi.com/2072-6643/14/20/4315/htm

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A long-term obesogenic high-fat diet in mice partially dampens the anti-frailty benefits of late-life intermittent fasting

https://link.springer.com/article/10.1007/s11357-022-00678-1

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Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy

https://www.sciencedirect.com/science/article/pii/S2213231722002907?via%3Dihub

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The time is now: Regular exercise maintains vascular health in aging women

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP282896

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One-year aerobic exercise increases cerebral blood flow in cognitively normal older adults

https://journals.sagepub.com/doi/abs/10.1177/0271678X221133861?journalCode=jcba&

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Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells

https://www.sciencedirect.com/science/article/pii/S1567724922000861?via%3Dihu

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The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside

https://www.frontiersin.org/articles/10.3389/fragi.2022.1005322/full#.Y1SIjLKuaWo.twitter

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Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis

https://www.hindawi.com/journals/omcl/2022/8063897/

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Inside:

• A Recap of VitaDAO’s 2nd “Crypto meets Longevity Symposium” 
• VitaDAO Fellowship Update
• New VitaSpotlight Series: Rapamycin as a Promising Aging Intervention 
• How to contribute to VitaDAO and ResearchHub’s Community Driven Paper
• Meet DAO Member Paolo Binetti

Upcoming Events

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Community Call: November 24th at 9 AM EST-  Swing by VitaDAO’s monthly community call and learn more about what is going on in VitaDAO behind the scenes! 

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The Longevity Summit December 6-7 | Buck Institute for Aging | Novato, CA -  THE FUTURE OF MEDICINE: ELIMINATING DISEASES OF AGING. Use the code "VitaDAO" for 15% off admission to the conference on the Eventbrite.

Hackathon: 13-15th Jan and 20-22- Join VitaDAO’s Hackathon, an online hackathon focusing on longevity. Registration is now open! 

DAO News

Symposium Recap: Exploring the Intersection of Longevity and Web3

On October 20th, 2022, Max Unfried and Eleanor Sheekey hosted the 2nd VitaDAO Crypto meets Longevity Symposium. The symposium consisted of twenty-two scientists, blockchain experts, and longevity professionals from internationally recognized institutions who spoke on the intersection of longevity and the blockchain.

Their talks highlighted updates in longevity medicine, strategies in drug development, discussions surrounding DAO economic ecosystems, and more!

Missed the conference? Catch up on VitaDAO’s Youtube. 

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The VitaDAO Fellowship: Funding the next generation of Longevity Enthusiasts

VitaDAO received over 200 applications for a 3rd VitaDAO Fellow Cohort. These funds were made possible by generous donors on Gitcoin, in addition to the funding provided by VitaDAO (VDP-57). 

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By providing grants up to 3,000 USD, the fellowship financially supports upcomers in the field to attend longevity conferences, fund research, and afford tuition to longevity programs.

Two cohorts, totaling 48 VitaDAO fellows, have been funded with over $45,000 USDC! Current VitaDAO Fellows have taken active roles in VitaDAO and are part of the exclusive VitaDAO Fellows network. 

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Learn more: http://vitadao.com/fellowship 

New VitaSpotlight Series: Exploring Rapamycin - a Promising Aging Intervention?

Vita Fellow Adrian Moliere and Tomas Schmauck-Medina explore Rapamycin’s mechanism of action and its potential. Additionally, Professor Mikhail Blagosklonny weighs in on the idea that inhibiting pathways responsible for growth also slows aging: 

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“Exploring Rapamycin: Most Promising Anti-aging Compound?”

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Find out more about how genetic knockouts or interventions showing the greatest increase in lifespan are targeting growth-, and not damage repair signaling pathways.

Exciting collab with Research Hub:
Contribute to a Community Driven Review Paper 

What are the most reliable longevity biomarkers, and how can they be evaluated? Alongside ResearchHub, VitaDAO is offering a bounty of 3,000 $VITA + 50,000 $RSC to be split among individuals who contribute to a community-driven review paper exploring current biomarkers for longevity.

Are you interested in exploring the pros and cons of different longevity biomarkers? Join the discussion on VitaDAO’s Discourse.

Governance: Funding Vita Fellows and Governance Updates

October’s Passed Proposals

VDP-57: $10k for the next VitaDAO Longevity Fellowship Batch 

As a result of this passed proposal, VitaDAO will donate $10,000 USDC to fund VitaDAO Longevity Fellows. VitaDAO Fellows can apply to receive micro-grants of up to $2,000 USDC.

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VDP-59: VitaDAO Governance Amendment #3

As a result of this passed proposal, seven changes will be made to VitaDAO’s governance framework. These changes include a time limit of three months for phase 2 proposals, a mandatory seven-day waiting period for phase 2 proposals after the last significant change to the proposal, a formal on- and offboarding process for managers and authors on VitaDAO’s Snapshot space, changes to the on- and offboarding process of becoming a signer on VitaDAO’s multi-signature wallets, introduction of “Stakeholders” as a new user type, and amendments to the Code of Conduct.

Live on the Vita Governance Forum - discuss and vote!

Find all of VitaDAO’s pending live proposals on Discourse, VitaDAO’s governance hub for proposals before they are moved on-chain. These proposals are open for engagement, voting, and questions! This month, several new proposals were added to Discourse:

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• VDP-60: Seasonal Governance 

This proposal suggests governance improvement by “batching” VitaDAO’s governance into seasons, with each four-month season consisting of a Governance Phase and an Execution Phase. Within the season, the Governance Phase lasts 6 weeks and the rest is the Execution Phase where ideas proposed during the Governance Phase are executed.

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• VDP-61: Funding Boston Matrix

This proposal requests $300k USDC to fund the discovery and development of a novel antiglycation and anticross-linking agent aimed at decreasing ECM stiffness.

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• VDP-62: Budget Allocation to Sponsor Longevity and Aging Conferences 

This proposal requests 20,000 USDC to sponsor eight months of Longevity and Aging Conferences and Events and requests that the SciComm and Awareness WG be given the power to decide which events to sponsor. 

Meet Key Longevity WG Contributor: Paolo Binetti

Paolo Binetti is one of our top VitaDAO Longevity/ Deal flow Working Group contributors. Outside of VitaDAO, he is a venture fellow for Healthspan Capital, a bio-expert for Capital Cell, an On Deck Longevity Biotech fellow, and an investor. Paolo holds a PhD in Controls, Robotics, and Bioengineering as well as a Bioinformatics specialization and has industry experience in R&D project management and business development.

How did you first get involved with the VitaDAO community?

Adding healthy years to our life will be beneficial for everyone. So everyone should be able to contribute to longevity biotech, either by funding it or working on it, but this is not happening, at least not as massively as it should. I want to solve this problem, VitaDAO could be one way to do it, so I decided to join.

What does your role as a Longevity/DealFlow Working Group Member entail?

Sourcing and reviewing research proposals and helping to mature them before they get to senior reviewers and community vote. I love it because every day I work with amazing researchers and founders on new cutting-edge ideas that could one day extend our healthspan and lifespan. I also help improve our infrastructure to make it even more effective.

What has surprised you the most about VitaDAO?

First, the amount of incredibly talented and competent people that I have come across, all committed to the same goal. Second, a rich infrastructure to collaborate in a decentralized way. Third, the flexibility to evolve toward ever more efficient ways of working. And the community’s welcome was phenomenal!

What are you most excited about in VitaDAO’s future?

Building a portfolio of solid projects with therapeutic potential, in collaboration with our new institutional partners in venture capital and pharma, and with an increasing contribution from the public. Everyone should have VITA tokens in their pockets, shaping the future of healthcare and reaping the benefits of the longevity biotech boom.

Any closing thoughts for readers?

I am always looking for new ideas for our deal flow, so if you have a great one that could generate valuable intellectual property and eventually translate to the clinic, please reach out!

Join Us! 

Have a special skill set? Contribute to VitaDAO and receive $VITA in return. Join the VitaDAO community on Discord and stay up to date on Twitter!  

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It was in 1975 when scientists from Ayerst (now Pfizer) discovered a novel compound called rapamycin (also known as Sirolimus) in bacteria on Rapa Nui(Easter Island) in Chile. In 1999 rapamycin obtained FDA approval for the prevention of acute rejection of renal transplant. Unknown at the time, rapamycin would become the most potent anti-aging drug that humans currently hold.

This is the first article of a two-part series on rapamycin.

Rapamycin extends lifespan in all model organisms tested

The profound effect rapamycin has on lifespan was first observed in yeast cells, and later confirmed in every model organism tested, including the nematode C. elegans, fruit flies, and mice.

The results in mice were carried out by the Interventions Testing Program (ITP), the gold standard for lifespan experiments in mice.

The first rapamycin experiment of the ITP was particularly interesting. Originally, the plan was to test the compound from young adulthood onwards. However, due to bioavailability problems, the mice were treated with rapamycin when they were already 600 days old, roughly corresponding to a 60-year-old human. Many thought that there was no way a drug can have an effect on aging when treatment starts at such a high age, but to everyone’s surprise, rapamycin still extended lifespan by up to 14%.

The effect of rapamycin on extending lifespan in mice has subsequently been replicated numerous times, and to this day rapamycin is the most effective drug at extending the lifespan of healthy mice, with increases of up to 26% when started earlier in life.

And since the dose and regimen for mice are not yet optimized, the maximum possible lifespan increase is probably even greater.

Another promising feature of rapamycin is that it works in both sexes, while many other interventions have beneficial effects either solely or predominantly in males, with little effect in female mice.

So, what is rapamycin doing to confer this longevity-promoting effect?

Rapamycin inhibits mTORC1 in a highly specific manner

Rapamycin works by inhibiting the function of an enzyme called mTOR (mechanistic target of rapamycin). mTOR is a master regulator of cell growth and metabolism.

mTOR is so critical to these essential processes that it can be found in all eukaryotic organisms. Furthermore, there is relatively little difference between mTOR in yeast and in humans, explaining the effectiveness of rapamycin at inhibiting mTOR in all animals tested. mTOR is an enzyme belonging to the class of kinases. Kinases work by adding phosphate groups to their substrates, which can cause conformational changes to the protein structure to regulate their function.

Rapamycin does not inhibit mTOR directly, but rather by forming a complex with a protein from the class of immunophilins called FKBP12. The resulting complex in turn binds mTOR and inhibits it allosterically. Allosteric inhibition means that the inhibitor slows down the enzyme, mTOR, without blocking its active site. The advantage of this mechanism is that rapamycin is highly specific to mTOR, compared to inhibitors that block the kinase function at the active site of mTOR directly, which tend to inhibit other kinases as well.

mTOR is part of two functionally distinct complexes, mTORC1, and mTORC2. Rapamycin only inhibits the mTORC1 complex directly, however, after chronic treatment with rapamycin mTORC2 levels decline as well. mTORC2 and mTORC1 functions are different. While the role of mTORC1 is well understood, many aspects of mTORC2 signaling remain elusive. We will focus on mTORC1 in this article, as it is the main target of rapamycin. We will cover the differences between mTORC1 and mTORC2 inhibition and its consequences in more detail in part two of this series.

mTOR is a master regulator of nutrient sensing and growth signaling

The mTOR complexes are the main signaling nodes integrating environmental signals into cellular responses. If the conditions are favorable for anabolic processes, the mTOR pathway will initiate growth and proliferation.

To facilitate this, mTORC1 responds to nutrient availability, energy, oxygen status, and growth signals. If, for example, there is an abundance of amino acids, then mTORC1 will get activated and anabolic processes will get initiated.

As a result, active mTORC1 increases protein, lipid, and nucleotide synthesis, promotes mitochondrial biogenesis and energy production, and inhibits autophagy, among other processes. Basically, active mTORC1 is telling the cell to go full throttle. By inhibiting mTORC1, rapamycin tricks the body into reacting as though nutritional resources are scarce, thus activating protective pathways and mechanisms, like autophagy.

For that reason, rapamycin was initially seen as a mimetic of caloric restriction, one of the most potent lifespan-extending interventions. However, even though mTOR inhibition is crucial for the lifespan extension of caloric restriction, rapamycin and caloric restriction are still distinct in their effect.

Rapamycin positively influences all hallmarks of aging

One of the most influential papers in the field of aging is a 2013 review titled “The Hallmarks of Aging”. Here 9 hallmarks are attributed to aging, such as telomere attrition, epigenetic alterations, genomic instability, and others. Rapamycin influences all of them.

The hallmarks of aging do not necessarily reflect a causal explanation for aging. Still, they touch on most aspects of molecular changes seen with age and if a compound manages to influence all of them, then there is a good chance that itwill have an effect on healthspan/lifespan.

mTOR regulates mitochondrial processes, such as ATP production and translation of mitochondrial proteins. And indeed, rapamycin treatment has been shown to increase mitochondrial efficiency.

That rapamycin improves the hallmark of nutrient sensing is unsurprising, given that mTOR is the central nutrient sensor in the cell. Similarly, improved proteostasis is a logical conclusion due to the upregulation of autophagy by rapamycin.

Regarding epigenetic alterations, rapamycin has been shown in vitro to rejuvenate epigenetic markers of age. In animals, this connection is less clear. While rapamycin treatment reduces epigenetic age in mice, this was not observed in marmosets, a type of primate.

Rapamycin has also been characterized as a senomorphic, meaning it blocks the conversion of cells into senescent cells and reduces inflammatory phenotypes in senescent cells.

Beyond that, rapamycin rejuvenates hematopoietic stem cells, reduces DNA damage, and counteracts telomere attrition. It furthermore remodels the microbiome, which is proposed to be a novel hallmark of aging.

The improvements of many facets of aging upon rapamycin treatment thus support the idea that it targets aging itself. But why is mTOR inhibition seemingly more effective than many other interventions that also target age-related cellular changes?

Development might hold the answer to the anti-aging effects of rapamycin

An interesting observation is that the most potent anti-aging interventions are targeting pathways that are highly relevant to growth and development, like mTOR, Insulin-IGF, and AKT signaling. There seems to be a general trend that inhibiting pathways responsible for growth also slows aging. This suggests that the same pathways that promote growth actually cause aging in some way. We are joined by Professor Blagosklonny, one of the main proponents of this idea.

Interview with Prof. Mikhail Blagosklonny

AM: Why is it important to develop theories that try to explain the cause of aging?

MB: Well, it’s important because a correct theory can allude to the correct treatment of aging. Many theories of aging have been proposed over the years and a lot of them state that aging is solely caused by an accumulation of molecular damage, for example by free radicals. Therefore, antioxidants are widely used in the general population to slow down aging despite animal studies contradicting that free radicals cause aging and clinical trials showing no benefit. In 2006 I predicted based on the hyperfunction theory that rapamycin will extend the lifespan of animals, which was later confirmed.

So this is why it’s important: the theory can be translated into clinical practice.

AM: So does the accumulation of molecular damage play no role in aging?

MB: Molecular damage accumulates with age and after a long time it would kill the organism, but the organism generally dies from normal (mTOR-driven) aging before that happens. Molecular damage is not life-limiting. Accumulation of molecular damage could be artificially accelerated in animals. For example, by damage in enzymes that repair molecular damage. But in these cases, symptoms are different from symptoms of normal aging.

AM: If an accumulation of molecular damage is not the cause of aging, then what is, and how is it connected to mTOR (Target of Rapamycin)?

MB: The basis of the hyperfunction theory is that aging is a continuation of growth and development. Genes are highly regulated during development but fall into an evolutionary selection shadow post development and reproduction. Thus many genes show antagonistic pleiotropy.

Antagonistic pleiotropy describes the idea, that the same gene can have multiple effects (pleiotropic) that can be both beneficial and detrimental to the organism. Genes are selected for their beneficial traits at the beginning of life, even though they might be detrimental later in life. Evolutionarily, this detrimental effect later in life is not selected against as it only occurs after reproduction, thus lying in a selection shadow.

This means that the program responsible for growth and development, mainly the mTOR pathway, doesn’t get properly switched off after development, the pathway becomes hyperfunctional. This unwanted continuation becomes harmful and leads to the development of age-related diseases and aging. This explains why the genetic knockouts or interventions showing the greatest increase in lifespan are targeting growth-, and not damage repair signaling pathways. That hyperfunctional growth pathways drive age-related diseases is not just speculation. Involvement of mTOR was described in all human age-related diseases.

But while the hyperfunction theory is in complete agreement with evolutionary concepts like antagonistic pleiotropy, it is not an evolutionary but a mechanistic theory, since it can also give a mechanistic explanation of aging on the cellular level.

When cells cannot divide anymore they can enter a state of cellular senescence, which is characterized by hypertrophy (the cells become enlarged) and a hypersecretory phenotype. When I was working on cell growth and cellular senescence we found that cellular senescence is a continuation of cellular growth, when the cell cycle is arrested. Hyperfunctional growth signaling leads to a geroconversion from reversible cell cycle arrest into a senescent state. One of the main growth-signaling pathways is mTOR, and we showed that rapamycin can stop cells from becoming senescent. This cellular geroconversion is one of the mechanistic explanations for aging on an organismal level as well.

AM: How is mTOR regulated at different life stages and why does it become hyperfunctional?

MB: This is related, as mentioned, to antagonistic pleiotropy. Evolutionarily, it only matters what is beneficial early in life, for reproduction, so natural selection doesn’t regulate mTOR activity in later life. So, natural selection keeps mTOR activity optimal for fitness early in life, but too high for longevity late in life.

When the mTOR pathway is inhibited early in life, during development, it results in slow growth and decreased reproduction. These observations are made in laboratory animals, such animals will die in the wild of course, due to decreased fitness. But in laboratory conditions, they survive and live longer. Just recently it was published that inhibition of mTOR with rapamycin in young animals also extends lifespan.

But of course, this is not translatable to humans, we cannot treat infants or children with rapamycin. To slow their growth so they live longer, that would be completely absurd.

But fortunately, we don’t need to do this. You don’t need to inhibit development. But you can turn mTOR down pharmacologically in adults after development, when it becomes hyperfunctional, which I think holds great promise.

Disclaimer & Disclosure

DISCLAIMER: THIS ARTICLE DOES NOT PROVIDE MEDICAL ADVICE. No material in this article is intended to be a substitute for professional medical advice, diagnosis, or treatment. The text, images, and other material contained in this article are for informational purposes only.

VitaDAO has funded a clinical trial by Dr. Brad Stanfield on exercise and Rapamycin dosing. Pfizer has recently joined VitaDAO as a strategic contributor.

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Introduction

Welcome back to VitaDAO’s monthly longevity research newsletter!

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Some species in the animal kingdom live extraordinarily long lives. They seem to be somehow protected from all the damage that we would expect to accumulate in aged tissues. Many are very large, like bowhead whales, and there is an established correlation between mass and lifespan, often attributed to slower metabolism. There are also animals like the naked mole rat, which live many times the life of a rodent of the same size with no increased risk of disease or decline of physiological function. We have a lot to learn from such species and Prof. Vera Gorbunova is doing just that - her lab focuses on understanding the underlying mechanisms of aging and how they differ between long-lived mammals and humans. We interviewed her for this month’s issue, so make sure you don’t miss this! (and if you just can’t wait, it can be found towards the bottom of this page!)

Longevity Literature Hot Picks

As so many great longevity papers are being published every month, we’ve decided to keep our newly introduced Further Reading section at the end of the newsletter! But first, here are our hotpicks of the month:

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Sex- and age-dependent genetics of longevity in a heterogeneous mouse population

https://www.science.org/doi/10.1126/science.abo3191

This substantial body of work, done on the largest-ever mouse longevity study unravels the distinct genetic determinants of male vs female longevity. The group has compiled their data with other sources to produce an interactive research tool, which is quite fun to play around with: https://lisp-lms.shinyapps.io/itp-longevity-app/

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Brown-fat-mediated tumour suppression by cold-altered global metabolism

https://www.nature.com/articles/s41586-022-05030-3

Cancer cells are known to utilise glycolysis to provide cellular energy - a process reliant upon glucose uptake. Non-shivering thermogenesis of adipose tissues also requires glucose uptake. Interestingly, Seki et al., show that cold exposure can lead to a non-shivering thermogenesis-induced decrease in blood glucose levels which can attenuate tumour growth!

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Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions

https://www.cell.com/cell/fulltext/S0092-8674(22)01127-8

A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors

https://www.cell.com/cell/fulltext/S0092-8674(22)01173-4

For years research has implicated a role for bacteria in cancer - now two papers published in Cell provide extensive evidence that fungi are also found in numerous cancers and can even be associated with different prognoses. Certain fungi and bacteria were even found to often co-exist in some cancer types. This adds an additional level of complexity to our understanding of cancer, and could provide new markers for diagnostic and prognostic testing.

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Insulin signaling in the long-lived reproductive caste of ants

https://www.science.org/doi/10.1126/science.abm8767

There is a trade-off between reproduction and lifespan in most organisms, but the queen ant is an exception. When a caste ant switches to a reproductive status of a pseudo-queen, her lifespan is extended 5x. During this switch, genes expression patters of insulin, MAPK, AKT is altered, consistent with the observed longer life.

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SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

https://onlinelibrary.wiley.com/doi/10.1111/acel.13721

Contrary to previous hypotheses that the mitochondrial SIRT3 is responsible for caloric restriction (CR) mediated lifespan extension, this study shows that deletion of SIRT3 actually extends the life of mice under CR conditions. This points to SIRT3 being dispensable for CR induced lifespan extension but it is required for aerobic capacity and oxidative metabolism.

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Ketogenic diet prevents chronic sleep deprivation-induced Alzheimer’s disease by inhibiting iron dyshomeostasis and promoting repair via Sirt1/Nrf2 pathway

https://www.frontiersin.org/articles/10.3389/fnagi.2022.998292/full

An interesting interplay between sleep diet and Alzheimer’s has been described. Ketogenic diet seemed to be preventative of cognitive deficiency, amyloid deposition and hyperphosphorylated tau induced by chronic sleep deprivation by inhibiting ferroptosis and alleviating oxidative stress. 

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Is “cellular senescence” a misnomer?

https://link.springer.com/article/10.1007/s11357-022-00652-x

David Gems and Carina Kern argue that considering cellular senescence has been shown to play roles in healthy physiological processes such as acute wound healing and embryogenesis, perhaps the word ‘senescent’ is a misnomer as the dictionary definition implies that something is old. Instead they propose the term should be replaced with one more descriptive of the phenotype - “remodelling activation” - which would consequently replace SASP with RASP. Whilst it’s unlikely that the word will change any time soon (historically used terms have sticking power) it’s an important idea to keep in mind when thinking about what exactly a senescent cell is.

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Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna

https://www.science.org/doi/10.1126/sciadv.abo5482

Another study convincingly shows how tightly connected development and aging are. Only 45 days of rapamycin treatment during early development (right after birth) were sufficient to increase lifespan by 10% in male mice. The cost of this was smaller size and slowed down development. 

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Drugs, clocks and exercise in ageing: hype and hope, fact and fiction

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP282887

This review takes a broad look at the field and compares the effects of pharmacological vs non-pharmacological interventions and the accuracy and predictive power of functional measurements vs aging clocks. Roadblocks in the advancement of the field and potential future strategies are also discussed.

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Aging and cancer epigenetics: Where do the paths fork?

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13709?campaign=wolearlyview

There is a clear association between aging and cancer on molecular and eidemiological level but can this also be explained via epigenetic mechanisms? While there are considerable differences between the two processes, epigenetic clocks could be key to unravel the intricacies of this relationship, especially if integrated with genetic evidence of DNA damage.

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News

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Celebrity Strategy Consultant Predicts What Will Be The Most Impactful Area In The Pharmaceutical Industry

https://www.forbes.com/sites/alexzhavoronkov/2022/09/19/celebrity-strategy-consultant-predicts-what-will-be-the-most-impactful-area-in-the-pharmaceutical-industry/?sh=7c19492316b4

Read Dr. Alex Zhavoronkov’s article on Dr. Michael Ringel’s ARDD lecture titled “The Emerging Commercial Landscape for Aging Biology-Based Therapeutics”.

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The US House of Representatives held a hearing on geroscience and how it drives age-related disease and disability

https://science.house.gov/hearings/the-fountain-of-youth-the-quest-for-aging-therapies

Speakers include: Dr. Jay Olshansky, Dr. Laura Niedernhofer and Dr. Steve Horvath.

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The Healthy Longevity Medicine Society Official Launch

https://hlms.co/

Led by President Prof. Andrea Maier and Vice President Dr. Evelyne Bischof,  the HLMS vision is “to develop longevity medicine as a respected and independent medical speciality that extends the healthspan of ageing individuals, tackles ageing mechanisms and optimizes an individual’s performance.”

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Methuselah Foundation Launch the ELONgevity Protection Project 

https://www.mfoundation.org/news/2022/9/29/life-insurance-only-pays-out-after-you-die-we-want-you-to-live

To promote human anti-aging efforts and provide members diagnosed with terminal diseases access to experimental therapies.

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1st NIH SenNet Consortium meeting in Rockville

https://sennetconsortium.org/

“The purpose for the Cellular Senescence Network (SenNet) is to catalyze the development of a framework for mapping cellular senescence and its associated secretory phenotype at high resolution, to provide atlases of cellular senescence in multiple tissues and under diverse conditions, including early development, and across the lifespan.”

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Launch of Biotech DAO Accelerator Bio.xyz 

https://www.bio.xyz/

Biotech DAO accelerator and meta-governance layer for the DeSci ecosystem! Expect resources, courses, frameworks and $100k USDC grants to enable a new generation of talented builders in DeSci to build and launch.

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Hevolution Foundation Matches Funding for Impetus Grants to Accelerate Research in Neglected Areas of Healthspan Science

https://hevolution.com/en/w/hevolution-foundation-matches-funding-for-impetus-grants-to-accelerate-research-in-neglected-areas-of-healthspan-science

Upcoming conferences

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2nd VitaDAO Crypto meets Longevity Symposium

October 20th, Online

Check out our 1st symposium here: https://www.youtube.com/watch?v=GJ-rJAfjhBE

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VitaDAO Hackathon 2022

Ideation weekend: 28th-30th October

Hackathon weekend: 4th-6th November

Register here: https://vitadao.com/hackathon

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The Longevity Summit 2022

December 7th-8th, Buck Institute for Aging, US

https://longevitysummit.io/

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Funding Opportunities

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The Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research

https://www.afar.org/imported/AFAR-Press-Release_HevolutionAFARNewInvestigatorsAwardandConferencesFund_08.31.22.pdf

Providing up to 18, three-year awards of US $375,000 each and will support research projects in basic biology of aging or geroscience.

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Job board

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Joao Pedro de Magalhaes’ lab is looking for a researcher/developer to work on online resources for research on ageing. https://www.linkedin.com/jobs/view/3311250129/?refId=TBaRILN%2FQN6S%2FH88SMOZaA%3D%3D

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Postdoc position is available at Antebi lab (molecular genetics) at the Max Planck Institute for Biology of Aging. Apply through the portal:

https://www.age.mpg.de/career-education/open-positions

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Cambrian Biopharma is looking for a product manager for their biomarker development program - Project Ordo. The position could be project based, part-time or full-time.

Please contact prashant@cambrianbio.com if interested.

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Gordian Bio is hiring PhDs, postdocs and technicians for two positions in San Francisco:

Molecular biologist: https://jobs.lever.co/gordian-bio/174715cc-62c5-4408-9053-51331b3f39b1

Single cell scientist: https://jobs.lever.co/gordian-bio/814a6528-4f4c-446b-9ea1-3711f1210b34

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Vincere Bio is looking for 1-2 mitochondrial biologists to test mitophagy enhancers on myocardial senescence or Parkinson’s and visualise mitophagy in vivo using mouse models. Boston, MA

Contact: recruiting@vincerebio.com

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DataBETA (Database for Epigenetic Evaluation for Treatment of Aging) is a non-profit, looking for a project director to hire as a contractor. More info at dataBETA.io
Reach out to Josh Mitteldorf, including why is this job best next step for your career and how will you launch the project with simultaneous fundraising: aging.advice@gmail.com

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Articles/Blogs

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Inside Saudi Arabia’s $20 Billion Bet On Longevity Biotechnology

https://www.forbes.com/sites/alexzhavoronkov/2022/09/28/inside-saudi-arabias-20-billion-bet-on-longevity-biotechnology/?sh=357610364aec

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Can You Increase Longevity? The Science Behind Living Longer

https://blog.insidetracker.com/increase-longevity-science-behind-living-longer?utm_campaign=september%202022&utm_content=220638130&utm_medium=social&utm_source=twitter&hss_channel=tw-425907208

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Hide and seek - Cancer cells hide inside each other when the immune system attacks

https://elifesciences.org/digests/80315/hide-and-seek

Original research: Transient cell-in-cell formation underlies tumor relapse and resistance to immunotherapy: https://elifesciences.org/articles/80315

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DNA clocks suggest ageing is pre-programmed in our cells

https://www.newscientist.com/article/2338033-dna-clocks-suggest-ageing-is-pre-programmed-in-our-cells/

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Book Review

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A science-based review of the world's best-selling book on aging

https://www.sciencedirect.com/science/article/pii/S0167494322002126?via%3Dihub

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Podcasts

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Investing in Longbio True Believers - Sebastian Brunemeier, Healthspan Capital & ImmuneAge Pharma

https://player.captivate.fm/episode/2fb68713-bea4-4706-ac3d-b19b8b53a811

Check out Sebastian Brunemeier discussing how the science of human longevity is transforming the way we treat disease.

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Should Aging Be Called A Disease?

https://www.youtube.com/watch?v=9kd5mQCfIfg

Listen to longevity heavyweights Prof. Nir Barzilai and Prof. David Sinclair discussing whether aging should be classified as a disease and the associated pros and cons. 

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The Sheekey Science show with Prof. Charles Brenner

https://www.youtube.com/watch?v=opMijdJ6z9Q

Catch up on this interesting discussion on NAD+, aging and fertility.

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Michael Levin on the Lex Fridman Podcast

https://www.youtube.com/watch?v=p3lsYlod5OU

Biology, Life, Aliens, Evolution, Embryogenesis & Xenobots.

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TV Series

Limitless with Chris Hemsworth | Disney+

https://www.disneyplus.com/en-gb/movies/limitless-with-chris-hemsworth/4MIMDuD9nF2s

Trailer: https://www.youtube.com/watch?v=SJPnK_NgHVI

“Chris Hemsworth explores the different ways humans can live better for longer by taking on physical challenges such as diving in ice or climbing skyscrapers.”

Just for fun

Wordle for Genes!

https://andrewholding.github.io/gene-wordle/

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Get Involved

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The Norn Group: http://norn.group (responsible for the Impetus Longevity Grants) will soon be launching a program to empower people across the globe to impact the Longevity field.

https://docs.google.com/forms/d/e/1FAIpQLSdrigugaS0W5sgtbQ9l15XeOsr7OkDaNHBIKt8614ksPtxPBQ/viewform

If you train and/or employ people to work on aging, the Norn group would love to hear your ideas for what a CompBio aging course should cover.

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Interview with Professor Vera Gorbunova

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Prof. Vera Gorbunova is a Professor of Biology at the University of Rochester and a director of the Rochester Aging Research Center. Her research is centred around aging, cancer and genome stability. Her lab aims to understand the basic mechanisms underlying these processes by studying multiple model organisms, especially long-lived mammals. 

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What inspired you to enter longevity research?

This is the most fascinating problem in biology and medicine… How could I work on anything else?
Longevity research addresses a fundamental problem of biology and has relevance to every living human.

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

I find the damage accumulation theory the most convincing. However, the nature of this “damage” is a subject of debate. Most likely, this is a combination of DNA damage, mutations and epigenetic dysregulation.

How has the field changed since you started?

I witnessed tremendous progress. We now have the tools we did not have before. Genomes of various species, various other omics tools became widely available and used in everyday research. Conserved pathways of aging had been identified in model organisms.

What mistakes do you think the longevity field has made?

Too much focus on short-lived model organisms. These organisms are helpful to identify conserved aging pathways, but they are not suitable to find longevity adaptations that evolved in long-lived species.

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

Do more bold and out of the box things. We need novel approaches and new research models. When studying long-lived organisms, do not just compare young to old. Obviously, the long-lived organisms age slower. What is most important is to find the mechanisms that make them age slower.

Is ageing a disease?

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

You have done research across the animal kingdom. How do long-lived animals benefit longevity research? What are the most promising organisms to study that are currently underexplored?

Long-lived animals are essential for longevity research as they hold the clues for long lifespan. I am particularly interested in long-lived mammals because they are phylogenetically closer to people and the discoveries would be more translatable. There are many long-lived mammals and each may have evolved unique longevity mechanisms. That is why it is important to study all of them. My group works on naked mole rats, bats, bowhead whales and many other mammalian species. 

What are the most interesting insights from naked mole rat studies and what are potential ways to translate them?

There were many interesting discoveries made on naked mole rats. The most interesting ones come when researchers look at novel mechanisms not merely testing the same pathways that were shown to be important in short-lived species. Here I can name our discovery of abundant hyaluronic acid and unique ribosomal structure with split 28S rRNA that results in highly accurate protein synthesis.

Could you explain hyaluronic acid anti-tumour and pro-longevity effects you have observed, and do you see this as a potential intervention in humans?

Naked mole rat tissues are saturated with hyaluronic acid of very high molecular weight (HMW-HA). Such hyaluronic acid has antiproliferative properties and arrests proliferation of premalignant cells leading to lower cancer incidence. HMW-HA is also a potent anti-inflammatory molecule reducing inflammation in the body and through this having an anti-aging effect.

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Outro

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Thanks for your interest in VitaDAO's Monthly Longevity Newsletter!

We hope to keep you up to date in this rapidly expanding field. Once again, if there is anything you would like us to feature in future issues, please get in contact. 

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If you have been wondering what has been going on in the VitaDAO community, here are some links below to some of our highlights from the past month. We look forward to seeing you again next month!

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The Longevity Decentralized Review (TLDR) by VitaDAO | With Tim Peterson

https://www.youtube.com/watch?v=MDH7ZmMgp4I

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VitaDAO IP-NFT Transfer Ceremony with Molecule & ApoptoSENS

https://www.youtube.com/watch?v=nUOhVGtb3zw

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Enjoyed this newsletter? Subscribing is the best way to guarantee you stay up to date with Longevity Research.

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Further reading

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Is early-onset cancer an emerging global epidemic? Current evidence and future implications

https://www.nature.com/articles/s41571-022-00672-8

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The emerging neuroprotective roles of exerkines in Alzheimer’s disease

https://www.frontiersin.org/articles/10.3389/fnagi.2022.965190/full

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Monocyte subsets display age-dependent alterations at fasting and undergo non-age-dependent changes following consumption of a meal

https://immunityageing.biomedcentral.com/articles/10.1186/s12979-022-00297-6

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Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion

https://onlinelibrary.wiley.com/doi/10.1111/acel.13713?utm_campaign=R3MR425&utm_content=LifeSciences&utm_medium=paidsearch&utm_source=google

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The lysosomal proteome of senescent cells contributes to the senescence secretome

https://onlinelibrary.wiley.com/doi/10.1111/acel.13707

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Psychological factors substantially contribute to biological aging: 

evidence from the aging rate in Chinese older adults

https://www.aging-us.com/article/204264/text

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An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory

https://www.nature.com/articles/s41556-022-00991-z

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Metabolic changes in aging humans: current evidence and therapeutic strategies

https://www.jci.org/articles/view/158451

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Transcriptional Heterogeneity of Cellular Senescence in Cancer

https://www.jci.org/articles/view/158451

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Relationship Between 5 Epigenetic Clocks, Telomere Length, and Functional Capacity Assessed in Older Adults: Cross-Sectional and Longitudinal Analyses 

https://academic.oup.com/biomedgerontology/article/77/9/1724/6473288?login=false

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Dermal Tattoo Biosensors for Colorimetric Metabolite Detection

https://onlinelibrary.wiley.com/doi/10.1002/anie.201904416

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Sirtuins are Not Conserved Longevity Genes

https://academic.oup.com/lifemeta/advance-article/doi/10.1093/lifemeta/loac025/6711379?login=false

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Umbilical cord plasma concentrate has beneficial effects on DNA methylation GrimAge and human clinical biomarkers

https://onlinelibrary.wiley.com/doi/10.1111/acel.13696

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Sexual activity and successful aging

https://link.springer.com/article/10.1007/s41999-022-00694-6

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Happy DeSci Fall! Inside this month’s newsletter:

• VitaDAO's first cell therapy funding: ApoptoSENS
• A New Publication on Decentralized Technology Transfer
• The Longevity Decentralized Review Explainer
• Meet DAO Member: Estèfano Pinilla 

DAO News

1/4 Million Research Funding for ApoptoSENS

On September 13th, VitaDAO celebrated the funding of its fifth longevity research project funded via IP-NFT! VitaDAO is supporting ApoptoSENS’s research with $253,000 as they develop CAR-NK cells to target senescent cells in vivo. ApoptoSENS will explore ways to make the elimination of senescent cells more precise and safe. You can watch a recording of the live-streamed IP-NFT Transfer Ceremony with Molecule and ApoptoSENS on VitaDAO’s Youtube. 

Publication: A New Scientific Incentive Structure

In “Decentralized Technology Transfer: A Modern Framework to Empower Scientific Innovation,” Zack West writes about a modern incentive structure for individual researchers, labs, and publishers that diverts from the traditional Technology Transfer Office (TTO) process. TTOs actively block the progression of IP getting to market. Ideally, the introduction of decentralized tech transfer can enable researchers to operate outside of their institutions and leverage other institutions’ resources.

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New VitaDAO Initiative: The Longevity Decentralized Review (TLDR) 

The Longevity Decentralized Review (TLDR) is an on-demand peer review service, founded by VitaDAO’s Tim Peterson. TLDR enables researchers to have proof of their peer reviews such that they don’t need to rely on journals for this proof. Want to learn more about TLDR? Watch Tim’s new video explainer on VitaDAO’s Youtube and check out the TLDR proof of concept website. 

Governance: Parter & DAO2DAO Development

Updates: VitaDAO's Institutional Genesis Raise 

Last month, Pfizer Ventures, L1 Digital, and Shine Capital applied to participate in VitaDAO’s Institutional Genesis Raise to contribute capital and participate in the governance of VitaDAO using $VITA tokens. This month, SpaceshipDAO, BeakerDAO, and Healthspan Capital applied to VitaDAO's Institutional Genesis Raise.

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VDP 54.4: SpaceshipDAO Expression of Interest

SpaceshipDAO, a member-owned investment DAO supported by Tribute Labs, proposed to contribute $50,000 to participate in the governance of VitaDAO. They proposed to support VitaDAO with access to deal flow, domain expertise, awareness, and commercialization efforts of IP. 

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VDP 54.5: BeakerDAO Expression of Interest

BeakerDAO proposed to contribute $75,000 to participate in the governance of VitaDAO. They proposed to support VitaDAO with community support and expertise in the DeSci space.

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VDP 54.6: Healthspan Capital Expression of Interest

Healthspan Capital proposed to contribute $100,000 to participate in the governance of VitaDAO using $VITA tokens. Healthspan Capital proposed to support VitaDAO beyond capital contribution with deal flow sharing, diligence notes comparing, support for newco formation and incubation, IP diligence, and industry partnering.

Live On Snapshot: Funding VitaDAO Fellows

VDP-57 proposes that VitaDAO donate $10,000 USDC to fund VitaDAO Longevity Fellows with micro-grants of up to $2k. VitaDAO’s fellowship program supports individuals who desire to dive deeper into learning about longevity. Previously, VitaDAO’s Fellowship was made possible by donors on Gitcoin. Due to the positive feedback from the broader community, as well as hearing from unfunded applicants, VDP-57 requests financial support for a new batch of fellows.

Key Working Group Contributor: Estèfano Pinilla

Estèfano Pinilla is a long-term VitaDAO working group contributor, who first joined VitaDAO in May 2021. He is a postdoctoral researcher, studying Cardiovascular Pharmacology, at Aarhus University in Denmark. His interests include longevity, extracellular matrix, and fibrosis. 

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How did you first get involved with the VitaDAO community/ in DeSci?

I first stumbled upon VitaDAO on Twitter, a month before the initial token auction. I wasn’t very interested in the blockchain back then, I only saw the financial applications and it seemed too self-referential to catch my interest. However, I am familiar with trying to bring research from the lab to the patients and with the limitations of the current patent system. As a researcher, I immediately could see the potential of the IP-NFT concept, and the idea of a community of scientists, professionals, and longevity enthusiasts getting together with the mission of extending healthy life sounded extremely exciting. I was impressed with how honestly the project was communicated as an experiment, and I decided to jump right in and started contributing. I’m always in for a cool experiment! 

Can you walk me through what your position in VitaDAO entails?

As a Longevity Working Group contributor, I have shepherded several projects as well as assisted other shepherds as a squad member. Being a shepherd consists in serving as a bridge between the community and the applicants, coordinating the evaluation of the projects, putting all the information together, and writing the proposal for the community to vote on. In the Comms and Awareness Working Group, my main activity has been organizing the second season of the Longevity Journal Club, where we discussed the latest research papers in Longevity in an accessible way for the non-technical audience.

What has surprised you the most about VitaDAO?

What has surprised me the most is the diversity of backgrounds and expertise of the members of our community. It’s great to be able to lurk around the Discord group and see what is being discussed in the chats from the different working groups, I have learned a lot and accessed information that I wouldn’t have otherwise just by doing that. Also, it’s amazing to see ideas from community members growing into full-fledged projects in real-time. The worst part is not having the bandwidth to participate in all of them!

What are you most excited about in VitaDAO’s future?

There is so much potential and so many exciting projects on the horizon that it’s difficult to pick a single thing. One of the things I’m most excited about is the possibility of seeing biotech companies coming out of the projects we fund, companies trying to bring medicines to market in which the researchers have more upside and a diverse community of stakeholders have much more control over the assets. 

Any closing thoughts for readers? 

I would like to encourage other researchers to join the DAO and apply for funding, we are always looking for cool new ideas with the potential to extend healthy life and reach the patients. The collective knowledge of the community is impressive and we have a lot of passion to bring projects forward!

VitaDAO in the Media: Vitalik discusses VitaDAO

Should VitaDAO be a DAO? In a recent essay titled “DAOs are not corporations: Where decentralization in autonomous organizations matters” Vitalik Buterin, co-founder of Ethereum, explores DAOs as a first-order organization and discusses VitaDAO. 

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Theo Beutel spoke on behalf of VitaDAO as a part of Tally's video interview series. He covered the power of crypto funding, VitaDAO’s governance, and VitaDAO’s IP NFT mechanism. 

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At VitaDAOxPolygonDAO AMA, VitaDAO members Laurence Ion, Catthu, Jesse, and Time Peterson discussed VitaDAO’s achievements, the challenges of scientific funding, and VitaDAO’s future plans. 

Upcoming Events: A Second VitaDAO symposium & more 

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October 10-13th at 11 AM EST- Our members, Tim Peterson, Max Unfried & Laurence Ion,  will be speaking at Targeting Metabesity 2022 Virtual Conference! 

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October 17th at 11 AM EST- Swing by VitaDAO’s monthly community call, hosted on TwitterSpace. Learn more about what is going on in VitaDAO behind the scenes! 

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October 19th at 10 AM EST- (Recurring weekly on Wednesdays)- Join a VitaDAO onboarding session! Here, you can ask questions about VitaDAO, meet others interested in the DAO, and learn about VitaDAO’s working groups. 

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October 20th at 9 AM EST- Join hosts Max Unfried and Eleanor Sheekey at VitaDAO’s second VitaDAO Crypto meets Longevity Symposium. The symposium will serve as a chance for scientists, blockchain experts, and longevity professionals from internationally recognized institutions to connect and learn more about the intersection of Web3 and longevity. 

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October 28-30th & 4-6th Nov  - VitaDAO Hackathon - hackathon focusing on longevity is a strong requirement for the future of the longevity field. VitaDAO Hackathon registration is now open! Register here

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Join Us! 

Have a special skill set? Anyone can contribute to VitaDAO and receive $VITA in return. Join the VitaDAO community on Discord and stay up to date on Twitter!  

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Enjoyed this newsletter? Subscribing is the best way to guarantee you stay up to date with monthly VitaDAO updates. 

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The transfer of technology (TT) is essential in turning intellectual property (IP) generated from innovative research into real-world applications that benefit the general public. New drugs, materials, and software often take this route on their journey from the lab to the consumer market. As with most legacy systems, leveraging emerging technology will improve this process through which scientific innovation is used for the public good.

Breakthroughs in science do not immediately benefit the general public. They must first be ushered from the labs in which they originate into the commercial marketplaces. This essential act of ushering is commonly overseen by a Technology Transfer Office (TTO). The goal of these entities is pure, though their centralized nature of operation has produced significant inefficiencies. Building on the successes of the TTO, a modernized Decentralized Technology Transfer (DTT) system would untether researchers and investors from these inefficiencies to pursue scientific innovation more purely. We will describe DTT fully below but its purpose is to enable the researcher to operate outside of their institution and leverage other institutions’ resources.

Introduction

In 1980, the U.S. Government passed the Bayh-Dole act which stated IP ownership rested in the hands of the institutes receiving federal funding to conduct the necessary research. Between 1998 and 2006, this act saw over 4,000 new products, 6,500 new companies, 280,000 new jobs, and $450 billion in U.S. gross industrial output (DiMasi, 2016). For context, the National Institutes of Health (NIH) invests $32 billion per annum in health-based research. Thus, it could be said that the US govt. recoups what it invests as a result of the Bayh-Dole act.

The success of the Bayh-Dole act brought a new need for institutes to develop proficiency in translating IP generated from research into real-world products that generated revenue (Sampat, 2006). From this need arose the TTO entity whereby IP rights are transferred, licensed, and otherwise made accessible to the real world.

TTOs go by several names and are common among universities and corporations alike. They have helped facilitate this remarkable surge in scientific innovation but, like other legacy systems in need of modernization, now stifle innovation as much as facilitate it. Research suggests that, in some cases, TTOs actively impede the progression of IP getting to market.

For example, a 1997 survey of more than 2,000 life science faculty from 50 universities found that dramatic delays in publication stemmed from concerns over patent rights. More than 400 surveyed researchers described experiencing a delay of at least 6 months to accommodate patent applications, unfavorable results, or even resolve disputes over IP rights. An even more discouraging by-product of the TTO model was described by nearly 200 researchers admitting to refusing to share results with researchers at other institutes for similar concerns (Blumenthal, 1997).

Another concern is the inability of smaller TTOs to establish and maintain a profitable business model. A 2013 report by the Brookings Institution notes that profitable TTOs are statistically the exception — rather than the rule. This report describes a great inequality in gross IP-related revenue generated by top-earning TTOs compared to the average. The top 5% of earners account for 50% of all licensing income from Universities with TTOs. The top 10% account for nearly 75% of total IP-related revenue (Valdivia, 2013). This describes a system in which the majority of TTOs are unprofitable — hinting at what is, perhaps, a flaw in the very nature of the TTO system.

Much like the traditional taxi-driven ride system was revolutionized by ride-sharing companies like Uber; much like the traditional rent-from-an-agency system evolved into companies like Airbnb; much like the talent agency system has been largely superseded by the gig economy; so too is the TTO model positioned for the next stage in its evolution.

Herein, a candidate for such disruption to the TTO model is discussed — the DTT system. With DTT, researchers retain IP rights, a broader range of investors are given access to early-stage research, a network of scientists is empowered economically, and modern technology is leveraged to improve upon the shortcomings of the TTO model. Before we dig into the DTT model, let us first better understand the core issues of the TTO model.

Technology Transfer Offices Take IP to Market

TTOs are billed as the vehicles by which scientific breakthroughs enter into markets for the benefit of the public. TTOs accomplish this by shepherding IP from researchers to an entity, such as a pharmaceutical company. This company can then apply the IP to create, market, and sell products and services on commercial markets.

IP is the “product” of academic research that attracts funding, kindles industry partnerships, and incentivizes innovation. IP is the legal vehicle in which scientific innovation is most likely to be assured of its due economic gain. Drug patents, new materials, and even computer algorithms are all representative of IP generated from research.

Governing bodies such as the United States Patent Office (USPTO) and the European Patent Office (EPO) outline IP rights such that they can be legally enforced. In other words, IP ensures a company can be the exclusive seller or grantor of licenses to sell products resulting from their research and development efforts.

In addition to attracting funding, IP rights can also be used to stimulate greater academic and scientific innovation. A 2003 study of more than 102 U.S. universities found that those institutes paying higher royalty shares to scientists realized more inventions and revenue from generated IP. After performing rigorous statistical analysis, researchers concluded that an increase in royalty share of 10% would increase resulting revenue by as much as 58% in private institutions and 16% among public ones (Lach, 2003).

TTO Structure

TTOs operations embody two primary stakeholders: researchers and management. Researchers are more likely to be motivated by the pursuit of gaining knowledge, recognition among peers, and scientific autonomy. By contrast, TTO management is more likely to be motivated to develop IP-generating projects to drive industry partnerships and royalty revenues (O’Kane, 2014).

The market performance of IP generated by universities, and the magnitude of resulting revenues, can be discussed in the context of these two primary stakeholders. Together, these account for the human, institutional, intellectual, and financial capital that defines the effectiveness of university IP performance (O’Shea, 2005).

Where TTOs are involved — there will always be a struggle against the individual scientists. Managing stakeholders are incentivized to prioritize projects and partnerships deemed best in the strictest economic sense — rather than an academic one.

TTO Performance

The performance of any single TTO can be understood by the relationship between its research and financial-based interests. A TTO more adept at transferring IP to industry is more likely to attract more favorable industry attention, generate larger revenue, and be more effective at supporting research programs (O’Kane, 2014; O’Shea, 2005). Thus, the TTO is incentivized to act in a manner pursuant to the greatest gain for all partners, not just researchers.

The TTO must consider the needs of industry partners, performance metrics, and existing IP needs. In contrast to the TTO, the researcher need only focus on innovation and discovery.

Research has shown that businesses straying from the traditional bottom-line-first model — adopting a more socially-aware model — generate more revenue (Bouichous, 2022). While not strictly related to the TTO model, if the core business model of modern corporations can successfully evolve there’s no reason to believe a more appropriate model for funding research than the TTO can’t also emerge.

Introducing Decentralized Technology Transfer

Inefficiencies in the TTO model arise for many reasons. A TTO either works or does not work based on local stakeholders and office priorities. A common characteristic among all TTOs — ranging from efficient to inefficient — is that they are centralized entities operating without autonomy.

In the traditional TTO system, the TTO itself represents a centralized stakeholder in the system. A TTO acts as an overseer of transfers of fledgling IP to shepherds within the industry or outright licensers of market-ready tech to manufacturers, marketers, or even retailers in some cases. This central authority, by design, makes decisions for individuals with the perspective of the ecosystem in mind. As such, a breakthrough of one researcher might be deemed competitive to another —  even within the same university.

The DTT model presents a modernized incentive structure whereby individual researchers, laboratories, and publishers are freed from the bureaucracy and often conflicted interests of traditional TTO processes

A DTT would address the inefficiencies of TTOs through the empowerment of individual researchers. This process doesn’t cast economic benefit aside to favor pure scientific interest. On the contrary — the DTT model presents a modernized incentive structure whereby individual researchers, laboratories, and publishers are untethered from the bureaucracy and often conflicted interests of traditional TTO processes. The DTT makes a bold claim, let’s discuss.

The diffusion of research from private and public institutions is often delayed for indirect reasons such as the demands of industry partners, broader concerns for ongoing patent applications, or even publisher delays. Without discarding the TTO model, DTTs can exist in cases where research diffusion is prioritized. That is —  individual researchers can take their research to the public outside of the traditional route via coordinated, decentralized means, while also being compensated.

That last point is essential — DTT does not assert abandoning IP. Rather, DTT is a framework by which IP can be unshackled from the often bureaucratic and opaque pipeline of TTOs and placed firmly among researchers and direct partners.

The Best of Both Worlds

For a decentralized transfer of technology to take place, many aspects of the traditional TTO process need to remain. IP-generating experiments still need to occur —  researchers, labs, and even patent attornies are all still integral. The main difference is that actors in a DTT system are sovereign, act in their own interest, and face no indirect pushback. That’s to say — researchers own their IP, decide when something goes to market, and have sole discretion over their research.

Court cases have established that, even in the case of federally-funded Universities, patented inventions vest first with the inventor (pdf). This ruling is contrary to many interpretations of the underlying legal framework used to argue such cases, such as the 1980 Bayh-Dole Act. The history of such IP cases illustrates that, even in the face of what many regard to be clear legislation, IP ownership is uncertain.

The core feature of the DTT is to place research into the hands of third parties such that a university or commercially employed researcher retains IP rights. This is a simple but powerful distinction in how research is conducted in the DTT model. The DTT model opens the doors for broader financial support since the resulting IP can be licensed or shared freely.

Under this model, researchers are no longer bound to the labs of their respective employers, and IP is no longer bound to the bureaucracy of TTOs. This opens the doors for new scientific innovation as well as new opportunities for investors. The next two sections elaborate on these concepts in greater detail — outlining how a DTT might operate and also detailing VitaDAO’s VDP-45 measure to implement a DTT in the real world.

An Example Case of DTT

Consider a research team with an idea for a promising new therapy to help extend the human lifespan. This team intends to rapidly advance an existing therapy and take the resulting research to market as fast as possible to elicit as much benefit to as many people as possible.

Research conducted in the university’s labs is likely to fall under the purview of that university’s TTO. In this case, any resulting IP could be delayed — or even shelved — based on any number of broader concerns. For the DTT model to work, research needs to be conducted in an unbound capacity.

The unburdening of IP from the clutches of the traditional TTO path would make an entirely new ecosystem of research funding opportunities possible in which all actors receive fair compensation for their efforts

A Contract Research Organization (CRO) provides the same robust scientific tooling needed for robust modern research without asserting any ownership on the resulting IP. The CRO gets paid for services rendered and the initial researcher retains rights to any resulting IP. By working through a CRO researchers will, unless stated otherwise in their employment contracts, retain full rights to any resulting IP.

These researchers don’t have the financial resources to contract the CRO however and need to look to outside investors. Since the researcher will retain full rights to the resulting IP, they can incentivize outside investors, such as VitaDAO. For example, the researchers might enter an agreement with VitaDAO to serve as paid consultants such that VitaDAO bears the responsibility for contracting the CRO with partial rights to the IP in exchange.

Under this arrangement, commercial benefit from the resulting IP is shared among VitaDAO and the original researchers. VitaDAO would likely handle the IP by transferring it to a Real World Entity (RWE) holding company whereby it can enforce IP rights within existing legal frameworks that exist today. With these pieces, an entire network can be developed whereby researchers would post projects, scientific advisors would review them, and VitaDAO would vote whether or not to fund them.

The unburdening of IP from the clutches of the traditional TTO path would make an entirely new ecosystem of research funding opportunities possible in which all actors receive fair compensation for their efforts. All this is possible in an on-chain, fully-decentralized, and community-driven system.

VDP-45: Decentralized Tech Transfer

VitaDAO illustrates a possible outside investor in the DTT model. To gain greater insight into how this might work let us consider several aspects of the recently-passed VDP-45 governance proposal.

VDP-45 outlines VitaDAO’s approach for supporting researchers via a DTT model as such:

1. Identifying researchers within projects.
2. Pay the selected researchers as consultants on the project.
3. Use CROs at organizations and universities to which the researchers have no affiliation to ensure IP rights are retained.
4. Providing investment opportunities to outside researchers during the funding process.

VDP-45 notes this approach to DTT could be used to support research in any field. VitaDAO would, however, be more focused on research aligned with its core mission of promoting longevity. Another aspect of VitaDAO’s approach would be the formation of the RWE to hold the resulting IP within an existing legal framework. The text of the VDP-45 also notes that likely outside investors getting “upside” would be community members.

The long-term vision of VDP-45 is to support more automation and less restriction by traditional university-bound bureaucracy. In pursuit of greater automation, a network on which researchers submit proposals, qualified reviewers assess, and on-chain voting by community members help decide funding decisions. Immediately, VDP-45 describes establishing a researcher network and a CRO network.

The research network will be comprised of individuals willing and able to take lead on projects in the DTT model. Above all else, a qualifying point will be that such researchers will have no contractual obligations with existing organizations whereby resulting IP rights would be contested or forfeited.

The CRO network will be constructed in partnership with LabDAO and initially be facilitated via a Master Agreement with the Washington University in St. Louis’ Center for Drug Discovery. This facility supports both medicinal chemistry and high-throughput screening capabilities. The details of the financial terms of such contracts between VitaDAO and LabDAO will be determined by community governance in a later proposal. Check out the Snapshot proposal for more details.

Final Thoughts

The shortcomings of the TTO model should not be thought of as a failure of science, funding, or the institutions in which they’ve been housed. Rather, the TTO model should be looked to for its successes as researchers, investors, universities, and corporations modernize their incentive models.

Autonomy, IP retainment, and globalized research networks are now a very real possibility, more than ever before. The Decentralized Technology Transfer model seeks to leverage innovative new technologies to support the next generation of scientific funding with organizations like VitaDAO and LabDAO leading the way.

Zack West is a marketing professional with 10+ years of experience in design, development, and digital marketing. He holds a BSc in Graphic Communications from North Carolina State University and is currently a BSc Computer Science candidate at Western Carolina University. He is passionate about natural systems and the nature of consciousness.

References

Blumenthal, David, et al. “Withholding Research Results in Academic Life Science: Evidence From a National Survey of Faculty.” JAMA, vol. 277, no. 15, Apr. 1997, pp. 1224–28. doi:10.1001/jama.1997.03540390054035.

Bouichou, Said Id, et al. “How Corporate Social Responsibility Boosts Corporate Financial and Non-financial Performance: The Moderating Role of Ethical Leadership.” Frontiers in Psychology, vol. 13, 871334, May 2022, doi:10.3389/fpsyg.2022.871334.

Cohen, Wesley M., et al. “Links and Impacts: The Influence of Public Research on Industrial R&D.” Management Science, vol. 48, no. 1, Institute for Operations Research and the Management Sciences (INFORMS), Jan. 2002, pp. 1–23. doi:10.1287/mnsc.48.1.1.14273.

DiMasi, Joseph A., et al. “Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs.” Journal of Health Economics, vol. 47, Elsevier BV, May 2016, pp. 20–33. doi:10.1016/j.jhealeco.2016.01.012.

Lach, Saul, and Mark Schankerman. “Incentives and Invention in Universities.” National Bureau of Economic Research — Working Paper Series, May 2003, doi:10.3386/w9727.

O’Kane, Conor, et al. “University Technology Transfer Offices: The Search for Identity to Build Legitimacy.” Research Policy, vol. 44, no. 2, Elsevier BV, Mar. 2015, pp. 421–37. doi:10.1016/j.respol.2014.08.003.

O’Shea, Rory P., et al. “Entrepreneurial Orientation, Technology Transfer and Spinoff Performance of U.S. Universities.” Research Policy, vol. 34, no. 7, Elsevier BV, Sept. 2005, pp. 994–1009. doi:10.1016/j.respol.2005.05.011.

Sampat, Bhaven N. “Patenting and US Academic Research in the 20th Century: The World Before and After Bayh-Dole.” Research Policy, vol. 35, no. 6, Elsevier BV, July 2006, pp. 772–89. doi:10.1016/j.respol.2006.04.009.

Valdivia, Walter. “University Start-Ups: Critical for Improving Technology Transfer.” Brookings, 29 July 2016, www.brookings.edu/research/university-start-ups-critical-for-improving-technology-transfer.

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Welcome back to our monthly newsletter! This month we are excited to bring you an interview with Dr. Marco Demaria who has made some significant contributions to our understanding of cellular senescence. 

For those of you not well-versed in senescence, here's a little intro….

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It used to be thought that given the correct culture conditions human cells would be able to proliferate indefinitely, however some pioneering experiments from Leonard Hayflick showed this was not the case and eventually cells would permanently  stop dividing - this phenomenon was coined 'cellular senescence'. Traditionally thought of as a tumour suppressor mechanism, research has shown that senescence is involved in a range of functions from development, to wound healing (Marco Demaria!). However, senescent cells have also been shown to elicit a pro-inflammatory response (senescence-associated inflammatory response - SASP) thought to attract immune cells to clear them. But as we age, an increase in the number of cells entering senescence, coupled with a decline in the ability of the immune system to clear them, leads to an accumulation of senescent cells and a chronic SASP which can paradoxically lead to a pro-tumourigenic environment and is associated with numerous diseases. Genetic and pharmacological removal of senescent cells has been shown to attenuate age-related diseases and extend lifespan in mouse models. Efforts to target/suppress senescent cells in humans (senolytic/senotherapy) have therefore gained significant traction both in academia and industry.

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For some up-to-date perspectives and cutting edge research on cellular senescence (as well as other topics) check out our hot picks below!

Longevity Literature Hot Picks

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So many fascinating papers were published this month that, in addition to our hot picks, we’ve had to include a Further Reading section for you at the bottom of this issue - enjoy! 

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Nuclear morphology is a deep learning biomarker of cellular senescence

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

A universal marker for cellular senescence has yet to be discovered. However, research from the Scheibye-Knudsen laboratory has utilised machine learning to detect senescent cells by nuclear morphology alone, with up to 95% accuracy in human fibroblasts, when compared to a cocktail of canonical senescence markers.

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Cellular senescence: the good, the bad and the unknown

https://www.nature.com/articles/s41581-022-00601-z

Senescence and cancer — role and therapeutic opportunities

https://www.nature.com/articles/s41571-022-00668-4

Cellular senescence: a key therapeutic target in aging and diseases

https://www.jci.org/articles/view/158450#.YuhXTn-A0M4.twitter

Cellular senescence and senolytics: the path to the clinic

https://www.nature.com/articles/s41591-022-01923-y

Above are 4 reviews on senescence which each give unique perspectives ranging from our mechanistic understanding of the senescent phenotype, to its role in cancer and other diseases, to how we can target senescent cells and efforts to translate this to the clinic.

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Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis

https://www.cell.com/cell/fulltext/S0092-8674(22)00790-5?rss=yes&utm_source=dlvr.it&utm_medium=twitter

Dysregulated mitochondrial homeostasis can result in switching cell death modalities and direct immune outcomes. The inflammasome is activated in Lrrk2 gain of function macrophages. Mitochondrial ROS directs the pore-forming protein gasdermin D to mitochondrial membranes, leading to inflammasome activation.

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Naked Mole-Rat Hyaluronan Synthase 2 Promotes Longevity and Enhances Healthspan in Mice (under review)

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4185135

High molecular weight hyaluronic acid (HMW-HA) is known to aids cancer resistance and possibly healthspan the naked mole-rat. Overexpressing hyaluronan synthase 2 resulted in lower cancer incidence, increased lifespan and improved healthspan, likely by affecting inflammation, response to ROS and enhancing the gut barrier with age. 

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Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00313-8#.Yv_gSYZ1KU8.twitter

With the aim to study the drivers of Alzheimer’s disease, the study identifies a metabolic switch to aerobic glycolysis in induced neurons from AD patient fibroblasts. Cancer associated PKM2 isoform was essential for this change and if chemically modulated to prevent nuclear translocation, neuronal metabolism was restored.

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Astrocytic traffic jams in the aging brain

https://www.nature.com/articles/s43587-022-00270-4

Three distinct clusters of astrocytes were identified in aged mice hippocampi. One of them is novel and previously unrecognised, which was characterised with disrupted proteostasis. This contributed to a defective astrocyte morphology, synaptic maintenance and protein trafficking.

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Cyanidin-3-O-glucoside promotes stress tolerance and lifespan extension of Caenorhabditis elegans exposed to polystyrene via DAF-16 pathway

https://www.sciencedirect.com/science/article/abs/pii/S0047637422001051?via%3Dihub

Microplastics are a growing pollutant in our environment and food chain. The effects and toxicity of a common microplastic polystyrene (PS) were explored in worms. As expected PS was toxic and decreased lifespan, which was mitigated by cyanidin-3-O-glucoside (C3G) treatment.

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Chill out: environmentally relevant cooling challenge does not increase telomere loss during early life

https://www.sciencedirect.com/science/article/pii/S0016648022001332?via%3Dihub

Stressors early in life can have both positive (damage resistant) or negative (damage promoting) effects later in life. Timing and context is crucial for deciding the effect of environmental challenges. In birds, cooling has no effect on telomeres, but brood size and growth rate during nesting stage affect telomere shortening.  

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Dose-response association between the daily step count and all-cause mortality: A systematic review and meta-analysis

https://www.tandfonline.com/doi/full/10.1080/02640414.2022.2099186

Getting in your 10,000 steps a day has become as popular a health target as eating your “5 a day” of fruit and vegetables. However, metrics such as these are often criticised for being too arbitrary. Now a meta-analysis of all-cause mortality shows a non-linear inverse relationship between the number of daily steps and chances of dying - so keep moving!

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Measuring biological aging in humans: A quest

https://onlinelibrary.wiley.com/doi/10.1111/acel.13080

Biomarkers to quantify biological age are required in order to test the efficacy of interventions aimed at delaying the onset of age-related diseases. This review highlights the known hallmarks of ageing, their link to morbidity and how being able to quantify biological age could lead to a therapeutic revolution. 

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Promotion of Hair Regrowth by Transdermal Dissolvable Microneedles Loaded with Rapamycin and Epigallocatechin Gallate Nanoparticles

https://www.mdpi.com/1999-4923/14/7/1404

Rapamycin - a drug which inhibits mTOR (one of the central regulators of metabolism) has been shown to be able to extend lifespan in numerous model organisms. New research shows that injection of rapamycin-containing nanoparticles can increase hair growth in mice in just 7 days, evidenced by increased hair follicle density and higher hair shaft growth rate. 

Clinical Trial Updates

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Unity Biotechnology

Unity announced positive data from their Ph 2 BEHOLD study of UBX1325 in diabetic macular edema. The 12- and 18-week results are a promising step in validating their senolytic platform and supports the potential of UBX1325 in retinovascular diseases.

https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-announces-positive-data-phase-2-behold-study

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New / Active Rapamycin Human Clinical Trials (related to Aging)

https://www.rapamycin.news/t/new-active-rapamycin-human-clinical-trials-related-to-aging/2650

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News

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Peter Adams and collaborators at UCSD been awarded $10.6M from @NIH_CommonFund to join SenNet, an initiative to create a comprehensive atlas of how and where aging cells accumulate. 

Read more: https://bit.ly/3vVCTwd

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LongevityTech.fund II launches – now accepting new investors

https://longevity.technology/news/longevitytech-fund-ii-launches-now-accepting-new-investors/

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BioAge Partners With Age Labs to Decipher Healthy Longevity Using Samples and Data From a Preeminent Northern European Biobank

https://www.businesswire.com/news/home/20220823005823/en/BioAge-Partners-With-Age-Labs-to-Decipher-Healthy-Longevity-Using-Samples-and-Data-From-a-Preeminent-Northern-European-Biobank

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Longevity Resources

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Age-related Disease Spreadsheet

https://docs.google.com/spreadsheets/d/19wPcWmW868mmMvugL_N4DJjMLt0WpnLB3o7D6RaiGP8/edit#gid=0

The Norn Group has curated this useful resource containing an overview of age-related diseases with data on biology, epidemiology, clinical landscape, animal models and market research!

Articles

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Decentralized investor communities gain traction in biotech

https://www.nature.com/articles/s41587-022-01459-z

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Epigenetic ‘Clocks’ Predict Animals’ True Biological Age

https://www.quantamagazine.org/epigenetic-clocks-predict-animals-true-biological-age-20220817/

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As billionaires race to fund anti-aging projects, a much-discussed trial goes overlooked

https://www.statnews.com/2022/08/09/anti-aging-projects-funding-much-discussed-trial-overlooked/

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Martin O’Dea: longevity is burning bright in Ireland

https://longevity.technology/news/martin-odea-longevity-is-burning-bright-in-ireland/

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40,000 pet dogs, one big question

https://www.theatlantic.com/science/archive/2022/07/senior-dog-aging-project-brains/671008/

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These Six Biotechs are Winning the Race to Get AI-Designed Drugs to the Clinic

https://www.insideprecisionmedicine.com/artificial-intelligence/these-six-biotechs-are-winning-the-race-to-get-ai-designed-drugs-to-the-clinic/

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The Opposite of Death Is Youth

https://tomhyde.substack.com/p/the-opposite-of-death-is-youth?r=hf6xj&utm_medium=ios

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With advances in medicine, could 80 become the new 40?

https://www.cbc.ca/radio/spark/with-advances-in-medicine-could-80-become-the-new-40-1.6427495

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Lengthening a woman's fertility may extend her life as well, research finds

https://edition.cnn.com/2022/08/20/health/extending-fertility-aging-life-itself-wellness/index.html

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Book 

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Methuselah's Zoo: What Nature Can Teach Us about Living Longer, Healthier Lives

Book by Steven N. Austad

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Newly published book delving into the biology of long-lived organisms and what they can teach us about the biology of ageing. Check out an article written by the author Steven N. Austad in ‘The Atlantic’: 

https://www.theatlantic.com/science/archive/2022/08/clams-bivalves-long-lifespan-ming/671107/

Also, a review of the book by Prof. Charles Brenner: 

https://www.science.org/doi/full/10.1126/science.add9130?fbclid=IwAR0HCk6DOpclwY27gR9x0m0de3lA30sXwfQjdum7bKDdHxdzphjcpE2jhrk

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Upcoming conferences

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Longevity Summit Dublin 2022

September 18th-20th, Dublin

https://longevitysummitdublin.com/

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Longevity Investors Conference

September 28-30, 2022, Gstaad, Switzerland

https://www.longevityinvestors.ch/

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7th International Cell Senescence Association (ICSA) Conference

September 29th - October 1st, Groningen

https://www.icsa2022groningen.nl/

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The Rejuvenation Startup Summit 

October 14-15, 2022, Berlin, Germany

https://forever-healthy.org/summit/

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2nd VitaDAO Crypto meets Longevity Symposium

October 20th, Online

Check out our 1st symposium here: https://www.youtube.com/watch?v=GJ-rJAfjhBE

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The Longevity Summit 2022

December 7th-8th, Buck Insitute for Aging, US

https://longevitysummit.io/

Funding Opportunities

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Life Extension Ventures

https://www.lifex.vc/

A new $100 million fund that is focused on life extension for "people and planet."

Job board

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Research Associate Position, Ochre Bio, New York, US

Ochre Bio works on chronic liver health challenges, from reducing cirrhosis complications through metabolic stress, metabolism, and regeneration programs.

https://jobs.lever.co/ochre-bio/c8da319b-f300-4945-9a1d-1cfc97fc9c29

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Post-doc Position in Dr. Marco Demaria’s Lab - ERIBA Labs, Groningen, Netherlands

https://www.linkedin.com/feed/update/urn:li:share:6963462684604252160

The Demaria lab are looking for a motivated postdoc to lead a project on chemotherapy-induced senescence.

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Post-doc Position in David James’ and Mark Larance’s Lab - Charles Perkins Centre, University of Sydney, Australia

Interested in healthy ageing? David James and Mark Larance are looking for a motivated postdoc with experience in proteomics.

Please apply to David.james@sydney.edu.au

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PhD Studentship in Dr. Ina Huppertz’s Lab - Max Planck Institute for Biology of Ageing, Cologne, Germany

https://www.ageing-grad-school.de/phd/host-lab-proposals/dr-ina-huppertz

Seeking a PhD student with a strong interest in RNA biology and metabolism.

Interview with Dr. Marco Demaria

Dr. Demaria gained his PhD in Molecular Medicine from the University of Torino, Italy where he researched the role of cellular metabolism and chronic inflammation on tumour progression. He then joined Prof. Judith Campisi's lab at the Buck Institute where he developed tools and methods to analyse senescent cells in vivo and made the important discovery of the role of transient cellular senescence in wound healing. He is now an Associate Professor at the ERIBA Labs and Group Leader of the Cellular Senescence and Age-Related Pathologies laboratory.

What inspired you to enter longevity research?

From a personal perspective, growing up living in close contact with my grandparents exposed me to the understanding of the ageing process very early in life. From a professional perspective, I began to do biomedical research on cancer. Looking for potential cancer drivers in the tumor microenvironment I encountered cellular senescence. I decided to join the laboratory of Judith Campisi to study it, and learned how senescence might be implicated in virtually every age-associated disease, not only cancer. This eventually inspired me to focus on the possibility that we might be able to target age-related mechanisms to extend quality of life and healthy longevity.

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

I have always been a supporter of antagonistic pleiotropy. I find it quite logical that evolution selected traits related to optimal fitness at young age without caring of the detriment that they could provoke in post-reproductive stages. I think the main topic of my research, cellular senescence, well fits that theory. While less convinced by the experimental evidence, I do not discard the idea of programmed aging. This is mainly driven by the fact that certain ageing mechanisms seem to follow a very regulated and reproducible trajectory.

How has the field changed since you started?

When I started in the field, pharmacological approaches to reduce age-associated features and to extend healthy longevity were very sporadic. Only when the hallmarks of aging started to become popularized, mainly thanks to the review in Cell in 2013, the pharma industry realized there were specific mechanisms to target. Also, more funding opportunities from public and private sources became available to researchers, thus boosting aging research. The field is exponentially growing, and we are just scratching the surface of understanding how ageing works. Exciting times.

What mistakes do you think the longevity field has made?

I think the longevity field has been too quick to move interventions forward, and there are too many parallel efforts in this direction with no standards and minimal exchange of knowledge. We risk to find that targeting individual hallmarks of ageing is only minimally impactful, and also to be unable to compare different studies. But making mistakes is not a problem if we learn something from them. In this case, a failure would direct towards a better standardization of how we read out ageing and towards development of combinatorial and synergistic approaches.

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

Several discoveries from outstanding laboratories worldwide related to understanding basic mechanisms have been instrumental to improve our knowledge on how organisms age. In terms of therapeutic approaches, besides the concept that elimination of senescent cells can delay onset and progression of tissue dysfunctions, the idea that we can reprogram cells has been revolutionary for its potential in regenerative medicine.

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

First, try not to rush to conclusions. We are just starting to understand how various age-associated traits interact, and we should invest more resources for fundamental research in this area. Moving too quickly to interventions is risky and might jeopardize the current interest in the field. Second, let’s be more collaborative and collegial. I’m starting to see too many people pushing their ideas and not sharing with peers. Too many scientists talking about compound a and compound b without disclosing any detail. This can harm progress and knowledge.

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

As mentioned before, the formal description of the hallmarks of ageing popularized longevity research. However, this is an oversimplification. We should not think we have fully understood how ageing works, and we should invest more resources in doing basic science, not only in developing therapeutics. Finally, it is important to note that the current pharmacological approaches are mainly derived from what we are learning on the mechanisms engaged by good lifestyle choices – mainly diet and physical exercise. We need to think that these approaches might not work on individuals that are already taking good lifestyle choices. More attention should be taken in understanding what can further delay ageing on already long-lived organisms, and support more research in this area.

Is ageing a disease?

No, aging is a condition that increases our predisposition to develop diseases.

You have made significant advances to the field of cellular senescence. Could you summarise your discovery of the role that senescent cells play in wound healing and what the potential therapeutic implications could be?

Senescent cells are transiently induced during tissue damage and they promote optimal tissue repair. Currently, we know this phenomenon is happening in the heart, liver, kidney and skin but we think it might be an event occurring in every tissue. Because of this function, pro-senescence therapies, in particular interventions that can switch cell fate from death to senescence, can have an enormous potential to improve recovery from acute tissue injury and to avoid pathological sequelae.

There still lacks a universal marker for senescence – what do you think are the most robust markers discovered so far?

The three most senescence-associated markers remain activation of the lysosomal enzyme bgal, induction of the cell cycle inhibitor p16 and loss of the nuclear protein LaminB1. All these markers are not 100% specific, so combinations of them have the highest chance to reveal senescence in biospecimens. It is becoming more and more clear that different subtypes of senescent cells express subset-specific markers. Studies on senescence should start to incorporate such markers to identify the exact subpopulations.

Although senescence can be thought of as a tumour suppressor mechanism, research from you and others has highlighted the detrimental effect senescent cells can have. What do you think are the most promising senolytic strategies and what are the potential negative impacts of removing senescent cells?

There are several strategies to eliminate senescent cells, most of them leading to activation of apoptosis. Most of these approaches are based on re-purposed small molecules or natural compounds. The advantage is that they normally have a well-characterized safety profile in humans, and thus are more ready to enter clinical trials for a new indication. The disadvantage is that these compounds have senolytic properties but also additional senescence-independent on-target effects. This might lead to unwanted side effects and adverse reactions. Senolytics with increased targeted activity are under development, and promising results are shown by using senescence-specific peptides and gene therapy strategies. The potential negative impacts of targeting senescent cells might be reduced tumor immunosurveillance and impaired ability to repair acute tissue damages.

Outro

Thanks for your interest in the space and joining us yet again for VitaDAO’s Monthly Longevity Newsletter!

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Don’t hesitate to contact us to let us know what you want to see next and give any feedback. We would love to hear from you! Until next time and if you’ve missed this month’s highlights, check this out on YouTube:

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The Longevity Prize Opening Ceremony | with VitaDAO, Foresight Institute & the Methuselah Foundation - YouTube

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Further Reading

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Cellular senescence in neuroinflammatory disease: new therapies for old cells?