June Longevity Research Newsletter
Introduction
Welcome back, Vitalians! This month we’re celebrating VitaDAO’s 3rd birthday! It’s been an exciting journey, and we’re thrilled to share our progress and future plans with you. In the past three years, VitaDAO has evaluated over 200 projects, funded 23, and deployed over $4.5 million USD in funding.
In June 2023, VitaDAO launched the first intellectual property token pool, offering governance to the VitaDAO community (VITA-FAST). Building on this momentum, VitaDAO has since introduced a second intellectual property token (VITARNA), marking another significant milestone in our mission.
As we look forward, we're more excited than ever about the future and our role in advancing the longevity field. The best is yet to come, and we can't wait to share 100 more birthdays with all of you!
As we celebrate another milestone, let's dive into the fiery debate that has our interviewees and experts in the field at odds: "Is aging a disease?" - our most hated question in the whole interview. The responses ranged from diplomatic nods to outright defiance, making this one of our most engaging topics yet. While some argue that aging is a natural process, others see it as a gateway to disease, begging the question—can we treat aging itself? Find a snapshot of where they clash and converge below as well as the answers from many aging scientists.
Longevity Literature Hot Picks
Preprint Corner in collaboration with
The Longevist is a preprint overlay journal spotlighting the most promising longevity studies each quarter.
Check out these latest preprints, which have all been entered into the 2Q24 longlist to be in the running to receive a coveted place in The Longevist. As always, you can refer preprints for consideration in The Longevist and the person who recommends the highest-voted preprint of the quarter will receive a prize of 200 VITA!
Neuron-type specific aging-rate reveals age decelerating interventions preventing neurodegeneration
Circadian clock disruption and lack of sleep harm cells and organs by activating the DREAM complex, which de-regulates essential cellular processes. Inhibiting DREAM restores cellular health and homeostasis despite persistent clock dysfunction, making it a potential therapeutic target for mitigating the adverse effects of circadian disruptions.
Long-term NMN treatment increases lifespan and healthspan in mice in a sex dependent manner
Nicotinamide adenine dinucleotide (NAD) is crucial for various enzymatic reactions, including energy metabolism and DNA repair, and its levels can decline significantly with age. Long-term administration of the NAD+ precursor nicotinamide mononucleotide (NMN) in mice increased activity, maintained youthful gene expression, reduced frailty, improved metabolic health in males, and extended median lifespan in females by 8.5%, without increasing cancer risk, highlighting the potential of NAD+ boosters for age-related conditions and the importance of considering sex-specific effects in studies.
Comprehensive evaluation of lifespan-extending molecules in C. elegans
The nematode C. elegans, a key model organism in aging research, is ideal for high-throughput experiments due to its short lifespan and small size, yet consensus on the most effective lifespan-extending compounds remains elusive, partly due to confounding drug-bacteria interactions. This study evaluated 16 frequently reported compounds, confirming robust lifespan extension with many and revealing some synergistic effects, while also demonstrating that several compounds extend lifespan in the fly D. melanogaster and identifying new lifespan-extending molecules in C. elegans.
Systemic low-dose anti-fibrotic treatment attenuates ovarian aging in the mouse
The female reproductive system ages early, causing infertility and endocrine issues, with the aging ovary developing a harmful fibro-inflammatory environment. This study found that systemic delivery of the anti-fibrotic drug Pirfenidone, but not the anti-inflammatory drug Etanercept, reduced ovarian fibrosis and improved ovarian function and gene expression in mice, suggesting that modulating the ovarian environment can extend reproductive longevity.
Integrative epigenetics and transcriptomics identify aging genes in human blood
Recent studies have identified many genomic regions with age-related methylation changes, but their functional consequences remain unclear, while age-related gene expression changes have shown limited consistency across populations. By integrating high-resolution epigenetic and transcriptomic data, this study identified multi-omic aging genes in blood, which are enriched for adaptive immune functions, replicate robustly across diverse populations, and are strongly associated with aging outcomes, suggesting they may be targets for epigenetic editing to promote cellular rejuvenation.
Programmed telomere shortening limits tumorigenesis by inducing replicative senescence, which is solely triggered by the ATM kinase. This study shows that ATM inhibition can delay senescence, allow normal cell divisions in some senescent cells, and that low oxygen conditions extend replicative lifespan by diminishing ATM activity, revealing how primary human cells detect shortened telomeres and the molecular mechanisms of the telomere tumor suppressor pathway.
Circadian clock disruption engages the DREAM complex in suppressing cellular health
Circadian clock disruption and lack of sleep harm cells and organs, with mechanisms involving the DREAM complex as a key health repressor activated by clock impairment. Inhibition of DREAM restores healthy cellular homeostasis and alleviates dysfunction in clock-impaired systems, suggesting DREAM as a therapeutic target to mitigate the negative health effects of circadian disruptions.
Published Research Papers
Previously VitaDAO-funded Korolchuk lab, have published a new study in Dev Cell, showing that age-dependent downregulation of mitophagy drives senescence and cell aging - phenotypes which can be rescued by restoring mitophagy levels.
TERT activation targets DNA methylation and multiple aging hallmarks
Insufficient telomerase activity, due to low TERT gene transcription, leads to telomere dysfunction and aging pathologies. A TERT activator compound (TAC) has been identified that upregulates TERT via the MEK/ERK/AP-1 cascade, promoting telomere synthesis, reducing cellular senescence and inflammation, and enhancing cognitive function in aged mice without evident toxicity, highlighting TERT's crucial role in aging and potential therapeutic applications.
Biological age clocks should predict mortality and provide insights for healthy aging. By applying principal component analysis to clinical data, we developed PCAge and LinAge clocks, identifying signatures of metabolic, cardiac, renal dysfunction, and inflammation predicting unsuccessful aging, with potential for drug intervention impacts. These clocks, including a tailored version for the CALERIE study, show that mild caloric restriction reduces biological age, highlighting the value of integrating biological markers for preventative medicine and promoting healthy aging.
Caloric restriction (CR) in mice, achieved by cold-induced metabolism with matched protein intake, resulted in reduced body weight, lean and fat mass, leptin, IGF-1, and TNF-α levels, along with improved survival compared to ad libitum-fed mice. These findings suggest that the longevity benefits of CR are mediated by energy imbalance rather than low energy or protein intake alone.
Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial
People with peripheral artery disease (PAD) experience increased oxidative stress, impaired mitochondrial activity, and poor walking performance. A 6-month randomized clinical trial showed that oral nicotinamide riboside (NR) significantly improved walking distance compared to placebo, with NR alone improving the 6-minute walk test by 31.0 meters among those adhering to the regimen, while resveratrol did not provide additional benefits.
Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony
In aging, physiological networks decline at different rates among individuals, resulting in varied lifespans, with 70% of lifespan variance unexplained by genetics. Using Asynch-seq, a new method to study gene-expression heterogeneity, researchers created a detailed atlas of non-genetic variation in Caenorhabditis elegans, identifying the decoupling of mRNA content between germline and soma as a major source of aging variability, suggesting that targeting pleiotropic genes can reduce lifespan disparities.
Sex-dependent regulation of vertebrate somatic growth and aging by germ cells
Germ cells influence somatic growth and aging differently in male and female Nothobranchius furzeri, a short-lived vertebrate model. Removing germ cells shortened lifespan and altered estrogen and IGF-1 signaling in females, while in males, it improved health via increased vitamin D signaling, highlighting sex-dependent pathways in regulating growth and aging.
Mitochondria are vital for many biological processes, but methods to study their heterogeneity at the single-cell level are limited. This study optimized the DNBelab C4 single-cell ATAC sequencing workflow for mitochondrial sequencing (C4_mtscATAC-seq), validated its effectiveness in HEK-293T cells, and applied it to mouse spleen and bone marrow tissues, revealing higher mitochondrial DNA content and fewer mutations in young tissues compared to aged tissues, with specific mtDNA variations linked to differential gene expression.
Epigenetic predictors of species maximum life span and other life-history traits in mammals
By analyzing 15,000 samples from 348 mammalian species, researchers developed DNA methylation (DNAm) predictors for maximum life span, gestation time, and age at sexual maturity. These predictors reveal an innate longevity advantage for females in some species, remain unaffected by caloric restriction or partial reprogramming, and show that maximum life span is determined by an epigenetic signature intrinsic to each species, distinct from individual mortality risk.
Published Literature Reviews, Hypothesis, Perspectives and more
The human gut microbiome and aging
The human gut microbiome changes throughout life, influenced by factors such as birth method, diet, environment, geography, medication, and aging, with its composition impacting aging and age-related diseases. A diverse microbiome, particularly one producing anti-inflammatory metabolites like short-chain fatty acids, is consistently linked to healthy aging globally, suggesting universal features that could be targeted for interventions to promote health and longevity.
Cellular senescence in normal physiology
Cellular senescence has been shown to contribute to the pathology of numerous age-related diseases, and thus there are numerous therapeutic efforts attempting to eliminate them. However, this perspective takes a deeper look at how senescence cells also perform a number of healthy physiological roles and thus emphasising our need to fully understand this phenomenon.
SenNet recommendations for detecting senescent cells in different tissues
As mentioned above, cellular senescence is now recognized as playing both beneficial and detrimental roles in various biological processes across species. The SenNet Biomarkers Working Group offers recommendations for identifying and characterizing senescent cells in tissues, based on a comprehensive analysis of senescence markers in 14 tissues from mice and humans, aiming to support both experienced researchers and newcomers in the field.
Therapy-induced senescence through the redox lens
Therapy-induced senescent tumor cells drive tumor recurrence and disease relapse, with reactive oxygen species (ROS) playing a crucial role in initiating and establishing this senescence. The review explores how ROS and redox dynamics influence these processes and discusses potential interventions, such as senotherapeutics, to target these pathways and reduce disease relapse.
Regulation of cell function and identity by cellular senescence
Senescent cells, accumulating during aging and various contexts like embryonic development and cancer, play key roles in pathophysiological functions beyond just loss of proliferation. The discovery of the senescence-associated secretory phenotype (SASP) revealed that senescent cells also promote gain-of-function effects, influencing cell identity and impacting pathophysiology either beneficially or deleteriously.
Gene regulatory networks in disease and ageing
Precise gene expression control is crucial for cellular homeostasis and function, with its decline contributing to age-related physiological changes and diseases. Gene regulatory networks, representing molecular interactions governing gene expression, have been inferred with high precision thanks to advances in experimental and computational technologies, aiding our understanding of cellular aging and disease mechanisms.
Neuronal senescence may drive brain aging
Senescence was traditionally thought to be a phenotype affecting proliferating cells, however numerous studies have now shown that post-mitotic cells can also undergo senescence. This perspective examines the role of senescent neuronal cells and their impact on neurological aging.
Psychogenic Aging: A Novel Prospect to Integrate Psychobiological Hallmarks of Aging
Psychological factors are crucial predictors of healthspan and longevity but are often overlooked in aging research. Psychogenic Aging, a new branch of biogerontology, aims to integrate these psychological influences into geroscience, advocating for their inclusion in the Hallmarks of Aging framework to enhance understanding and development of anti-aging therapies.
Job Board
Did you know Retro Bio offers an accelerated PhD program?
They are also looking for a Facility Manager.
Some Hevolution funding opportunities
- Hevolution Foundation Postdoctoral Training in Geroscience Program (HF-PTG)
- Hevolution/AFAR New Investigator Awards in Aging Biology and Geroscience Research
- 2024 Hevolution Foundation Saudi Arabia Postdoctoral Fellowship for Aging Biology & Geroscience (HF-SAP)
The AbuGoot lab is hiring for a number of grad, postdoc and scientist positions for exciting new projects in the aging/AI spaces. We leverage high-throughput screening tools to understand aging and AI to interpret the results, and then build new rejuvenative therapies.
Announcing COHORT 5 of the Longevity Biotech Fellowship! Join +600 hardcore engineers, scientists, entrepreneurs, investors, and operators working to solve aging.
David Vilchez is looking for a motivated postdoc to study the links between aging and amyotrophic lateral sclerosis. The project combines disease modeling using patient-derived iPSCs and C. elegans models. Apply here or contact David Vilchez directly.
News and Media
New Drug Restores Telomerase, Improves Cognition in Mice
New Study Reveals Way to 'Significantly Reduce' Biological Age
Reviewing What is Known of the Aging of the Gut Microbiome
Daily multivitamins do not help people live longer, major study finds
Hevolution Foundation: Transforming Healthspan Science with Unprecedented $400M Funding Surge
Resources
People in Aging (agingbiotech.info)
Check out the who’s who of longevity research!
A comprehensive list of interventions that are being explored to help healthy aging.
Machine learning-aided generative molecular design
Review of generative AI in small molecule chemistry
Conferences
26-30th August, Copenhagen, Denmark
4th-6th September
La Jolla, CA. 10th-11th Sep 2024. Molecular and Cellular Aging. Registration link coming soon.
9th International Cell Senescence Association (ICSA) Conference
7th - 9th November, Puerto Varas, Chile
The ICSA are offering 2 Travel Fellowships for an ECR to attend the conference.
ICSA DEI Travel Fellowship Application
Tweet of the Month
Could Blue Zones be a hoax?
https://x.com/DoctorTro/status/1813181976414704125
@DoctorTro
How statisticians and researchers arrived at the conclusion that the BlueZones are a FRAUD. 🤔
🔑 Thread with key excerpts
Podcasts and Webinars
NUS Medicine’s Healthy Longevity Webinar Series
Check out the latest episode of The Sheekey Science Show, where Eleanor features the top 3 preprints from the current Longevist edition.
Longevity Acceleration Podcast Episode 003 with Professor Jean Hebert of the Einstein School of Medicine
New organ system clock developed with Yale (TruDiagnostic) SymphonyAge webinar
AI For Longevity Drug Discovery: Breakthrough and Challenges Webinar
The Optispan Podcast with Matt Kaeberlein:
Global Enlightenment? The Wild Effects Of An Age Cure
Interview flashbacks “Is Aging a Disease”
Our experts agree that aging and disease are intricately linked, but the classification of aging as a disease remains contentious. Some see aging as a natural, inevitable process, while others argue it’s the ultimate risk factor for a host of diseases. The consensus? Whether we call it a disease or not, targeting the biology of aging could revolutionize how we approach health and longevity.
Andrea Maier: “Yes! Yes, it absolutely is a disease. And we all have it!
Referring to aging as a disease might be counterproductive when communicating with the general public. However, as a physician, you require a clear diagnosis and treatment plan for your patients.
By treating the underlying mechanisms and consequences of aging, we aim to optimize the overall health and well-being of your patients. Diagnosing aging-related deterioration and assessing biological age allows you to tailor interventions and treatments accordingly. It provides a framework for addressing the physiological and pathological changes associated with aging.
In the medical field, having a clear understanding of aging and its impact on health is crucial for establishing effective practices and offering appropriate interventions to enhance patients' quality of life.”
Irina Conboy: "In my view, we notice aging specifically because tissues, organs and eventually organisms become unhealthy, e.g., it is accumulation of diseases."
David Barzilai: "Innumerable arguments have been made, with publications and conference symposium panels all focused on this issue. The answer is simple: It depends on how we choose to define aging, and how we choose to define disease. The bottom line is this: Aging biology can be argued to be the ultimate risk factor for not one, but a wide multitude of diseases. At the very least, we can observe that something in the aging process- and its molecular underpinnings- is permissive to the development of disease. Thus ultimately, if we are interested in mitigating the negative impact of disease, targeting biologic aging is a sensible approach. Precisely because biologic aging is intertwined with not one, but a wide multitude of diseases and poor health states (including frailty and lack of resilience), targeting aging biology before it deviates from the state of youth holds the potential to reduce the overall burden of chronic disease."
Matt Kaeberlein: “That’s the wrong question. It just distracts from what’s important. Aging biology is modifiable, and we can treat it to prevent disease and maintain health.”
Michael Klutstein: "No. In other words - it’s not a bug, it’s a feature."
Björn Schumacher: “Ageing is a physiological process but not a disease. However, it is the cause of all chronic diseases for which age is the primary risk factor. Therefore, we need to target the ageing process itself to prevent age-related diseases. Given the demographic change this is our only option for a future with 2 billion elderly whose active participation in society to a significant degree depends on their health. It is as urgent as fighting climate change to fight the multimorbidity that is affecting a growing proportion of the population. We need to boost ageing research now!”
John Speakman: “As far as we understand it, from an evolutionary standpoint, ageing and death happen as part of an adaptive program. We stop reproducing at a certain point in our lives, and there is no evolutionary selective pressure to invest in effective somatic maintenance programs to preserve us into old age. Mutations in genes leading to improvement in those features in later life never get passed on. Without that selective pressure to evolve physiological processes that sustain our systems they slowly fall apart. Should we call that a disease? To be honest I don’t think it matters. It is something that negatively affects all of us, creates enormous personal, economic and societal costs, and therefore there will always be an impetus to try and stop it. Interestingly the first ever written document (the story of Gilgamesh) is about discovery of anti-ageing therapeutics. We have always been interested in avoiding ageing and extending lifespan. Whether we call it a disease or not won’t change that. There is an argument that if it isn’t classed as a disease then the FDA would not grant a licence for drugs that aim to retard ageing in general, rather than specific components of it. Calling it a disease then is just a pragmatic solution to a practical hurdle. It’s not something that I think scientists should spend their time agonising over. If (when?) an effective anti-aging drug appears that needs approval, a billionaire will pay a very well paid lawyer to argue the case that ageing is a disease, and then the path will be open for FDA approval.”
Tom Kirkwood: “For me, ageing isn’t a disease in the sense I would usually apply to this term. It’s a normal process. But by its very nature it involves the generation of molecular and cellular abnormality. This feeds into multiple kinds of dysfunction. When a particular kind of dysfunction – which may have causes additional to ageing – passes a threshold recognised by clinicians, it gets a diagnosis of disease.”
Alex Cagan: “Aging certainly raises the risk for a number of diseases. Whether or not we define aging itself as a disease I would consider largely a semantics issue, though with implications for how we think about our lives and how we fund aging research. I enjoy considering different perspectives on aging, whether it is something we should ‘accept’ or ‘conquer’ or ‘cure’. Such conversations remind me of Sophocles’ lines about humanity from Antigone ‘Numberless are the world’s wonders, but none more wonderful than man; …from every wind he has made himself secure — from all but one: In the late wind of death he cannot stand.” It is awe inspiring and humbling to think that there is a realistic prospect that aging itself could be overcome through human ingenuity. Though we are currently far from reaching this point I think it’s important that as a society we begin to have conversations about what the implications of this would mean.”
Barry Bentley: "There is little agreement amongst gerontologists on how to classify aging, mainly because aging is such a catch-all term that refers to many things: biological age, as a sociological status or marker, chronological advancement, appearance, etc. Personally, I think the debate is somewhat counterproductive. Regardless of how we use the term, and whether we call it a disease, the fact remains that people become sicker as they get older. My own approach is to focus on those aspects that make people sick: the underlying aging-related pathology."
Nicole Ehrhart: "Modern medicine is based upon detection and subsequent diagnosis of a specific condition which is then treated. However, changes in our cells and tissues are occurring with the passage of time. We call this “aging”. Older bodies are made up of older cells that are less and less able to repair from the wear and tear of everyday function or damage. Subsequently, when enough unrepaired damage accumulates within an organ or body system, the system fails to work properly. We recognize this end dysfunction as a “disease”. So maybe the question is: are accumulating changes that are upstream of the onset of a disease diagnosis also part of the “disease”. My answer to this is “yes”. Aging is a modifiable process that occurs over time and we should not wait until the dysfunction is so severe so as to put a specific name on it to treat it."
David Vilchez: "Aging is a natural and progressive stage in the life cycle of any animal. However, aging is a primary risk factor for multiple diseases. The key focus lies in the potential to delay aging to enhance our quality of life and prevent multiple diseases simultaneously."
Marco Demaria: “No, aging is a condition that increases our predisposition to develop diseases.”
Adam Freund: "Whether a condition is generally considered a disease vs “normal aging” is primarily based on the prevalence of that condition in the general population: an isolated group whose members all harbor presenilin-1 mutations would characterize Alzheimer’s as “normal aging” because it would be universal. This controversy, therefore, reduces to a question of reference point (shameless plug for a thought piece I wrote on this topic). Irrespective of how we label it, aging is a process that can and should be therapeutically altered."
Vera Gorbunova: “From the evolutionary standpoint aging is not a disease. However, we have to approach it as a disease to develop treatments and interventions.”
Matt Yousefzadeh: "This is how you start a fight over beers when you get a bunch of aging researchers together. I think it is a disease, but also a natural and omnipresent condition. A very milquetoast take right? Realistically it probably sits in between the two states. Some people feel very strongly about it, but I’d rather focus on the science rather than semantics."
Tim Peterson: “I get that this matters to the FDA, but I’m not sure I have much to add to this debate other than people should have more rights to try new medicines.”
Joao Pedro de Magalhaes: "That’s a good question, but I suppose it depends on the definitions of aging and of disease. As such, I think it’s more of a semantics question than a biological one. Regardless of the definitions, aging is a trigger for diseases, and it should be targeted therapeutically."
ChatGPT: “Aging is a highly complex and multifaceted process. A plausible approach would be to tackle it from both a biological and a sociocultural angle:
Biologically: Focus on cellular and genetic levels. This could involve targeting senescent cells, managing telomere length, and improving proteostasis, along with employing genetic engineering techniques like CRISPR to modify or replace genes linked with aging.
Socioculturally: The intersection of technology, lifestyle, and health would have to be addressed. Integrative health systems would become a priority, where AI, human medical expertise, and regular health monitoring would ensure that people stay in the best health possible.”
Peter Fedichev: “This is a hard question that is probably more politically and emotionally charged than scientifically justified. From what we see in human and animal data, I believe aging can be slowed down and even stopped, not reversed. In this sense, this “disease” can not be fully cured but may be prevented. A huge entropic component in human aging makes aging more like a syndrome (multiple diseases leading to the same symptoms). To me, this does not matter.
I am trying to avoid this conversation since it quickly gets murky and is dangerously close to scholastics. I believe that aging must be stopped, and once this is demonstrated, the technological solution will be covered by governments and insurance regardless of whether it addresses a disease. The potential upside is huge. It is so huge that new business models will emerge if the existing payers fail to recognize the opportunity. If I am correct on this, we must forget about politics and focus on demonstrating an effective solution.”
Shahaf Peleg: “No, it’s worse. Studying aging is currently the second most unattainable and important quest of mankind (I’ve ranked space travel as first). Aging is more complicated, inevitable, and lacks any treatment in comparison. Moreover, it is the primary cause of a large number of diseases, and slowing down aging can delay many of them. Aging is a fundamental process that gradually 'kills' us.”
Viktor Korolchuk: “If we are ever able to delay or cure human ageing, it will become a disease from the past for generations to come.”
Outro
Thank you for being part of our journey. Here’s to another year of exploring the fascinating world of longevity research! We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!
Further Reading
NLRP1 inflammasome promotes senescence and senescence-associated secretory phenotype
Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age
mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process
The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
Excessive STAU1 condensate drives mTOR translation and autophagy dysfunction in neurodegeneration
Stress-resilience impacts psychological wellbeing as evidenced by brain–gut microbiome interactions
Testing the amount of nicotinamide mononucleotide and urolithin A as compared to the label claim
Linking Aging to Cancer: The Role of Chromatin Biology
Brain responses to intermittent fasting and the healthy living diet in older adults
Mechanism and role of nuclear laminin B1 in cell senescence and malignant tumors
Improved resilience and proteostasis mediate longevity upon DAF-2 degradation in old age
Senescence and tissue fibrosis: opportunities for therapeutic targeting
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