Introduction
Welcome back Vitalians, it’s been an eventful month in longevity and DeSci.
Please join us in congratulating the TransFidelity team for passing the VitaDAO token holder vote. This proposal will allocate $50,000 to TransFidelity, a project focused on preventing neurodegenerative diseases by improving the accuracy of protein synthesis, thereby reducing the formation of harmful protein aggregates.
VitaDAO-backed Oisín Biotechnologies raises $15M Series A led by AbbVie Ventures. Oisín Bio aims to advance genetic medicines for age-related conditions, focusing on muscle-building to combat frailty.
We are also excited to share that the BIO Genesis event is underway. BIO creates a permanent, global pool of capital and talent, aiming to revolutionise biomedical science and creating a permissionless layer to back scientific projects with decentralized funding, liquidity & incentives.
This month also brings the sad news that renowned Professor Leonard Hayflick, a legend in the aging field, has passed away. We’d like to dedicate this issue to honor the extraordinary life of Professor Hayflick, a visionary whose relentless pursuit of knowledge redefined our understanding of life itself. Hayflick was not just a scientist; he was a pioneer who dared to challenge the status quo, forever altering the landscape of biology and medicine.
For over half a century, there was a scientific dogma that human cells could proliferate indefinitely, until Leonard Hayflick performed some pioneering experiments in the early 1960s which showed this was not the case, and after a reproducible number of divisions, later coined the “Hayflick Limit” cells would permanently stop dividing. The cessation of cell division is now known as cellular senescence, and the study of this phenomenon has blossomed into a scientific field in its own right. With several papers showing genetic or pharmacological removal of senescent cells can increase lifespan in mice, there is now a huge academic and pharmaceutical effort to further understand and target this process in an attempt to improve human healthspan and lifespan.
In addition to discovering cellular senescence, Prof. Hayflick developed the WI-38 cell line which became a cornerstone of modern vaccines, safeguarding the health of billions worldwide — a testament to his enduring legacy. Furthermore, he also developed the first inverted microscope for use in cell culture research, the design of which is still used today in modern microscopes.
But Leonard Hayflick’s journey was not without its trials. He faced controversies and opposition, yet he stood firm, driven by a belief that science must serve humanity, no matter the personal cost. His courage in the face of adversity and his unwavering dedication to truth inspired generations of scientists to question, explore, and innovate. Leonard Hayflick’s life was a beacon of inspiration, reminding us all that true progress is born from curiosity, courage, and a deep commitment to making the world a better place. As we commemorate his life, we celebrate not only his remarkable achievements but the spirit of perseverance and passion that defined his work. His legacy will continue to inspire and guide us, a shining light in the ever-evolving quest for knowledge.
At the end of this newsletter you’ll find some thoughts and quotes from him as well as a few words from his esteemed colleagues and students.
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!
Inhibition of the insulin/IGF/mTORC1/Ras network, particularly through drugs like trametinib and rapamycin, can extend lifespan and improve health in mice, with combined treatment showing greater benefits than either drug alone. This suggests that repurposing these drugs for geroprotection in humans may have significant translational potential.
The Emergent Aging Model: Aging as an Emergent Property of Biological Systems
The Emergent Aging Model (EAM) suggests that aging is an emergent property of complex biological systems, such as gene networks, where aging arises at the system level even if individual components do not age. EAM explains aging as an increase in mortality rate over time and aligns with observed stochastic influences on aging, providing a framework consistent with models like the Gompertz model and applicable to various biological species.
Published Research Papers
Inhibition of IL-11 signalling extends mammalian healthspan and lifespan
This study has received a huge amount of press attention and discussion from the scientific community. The research demonstrates that IL-11, a pro-inflammatory cytokine, negatively impacts age-related diseases and lifespan by regulating the ERK–AMPK–mTORC1 axis as mice age. Deletion or inhibition of IL-11 significantly extends lifespan and improves health in aged mice, suggesting that anti-IL-11 therapy, currently under trial for fibrotic lung disease, could potentially mitigate aging-related pathologies in humans.
An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging
The study reveals that CD38, an NAD+-dependent enzyme, facilitates hematopoietic stem cell (HSC) proliferation in young mice by promoting mitochondrial Ca2+ influx and metabolism, but its aberrant upregulation in aged mice leads to HSC deterioration through disrupted NAD+ metabolism and impaired mitochondrial stress responses. Pharmacological inactivation of CD38 mitigates these aging effects, underscoring an NAD+ metabolic checkpoint that balances mitochondrial activity to maintain HSC function across the lifespan.
This study shows that overexpressing mitochondrial fission or fusion genes in C. elegans leads to increased mitochondrial fragmentation but unexpectedly extends lifespan and enhances stress resistance, despite not maintaining a youthful mitochondrial network morphology. This suggests that enhancing mitochondrial dynamics, rather than preserving their youthful structure, is key to promoting resilience and longevity.
The study reveals a shared transcription factor binding site (TFBS) signature between aging and development, where early-life cis-regulatory elements (cCREs) lose accessibility over time, driven by a redistribution of transcription factors (TFs) towards AP-1-rich cCREs. This shift, coupled with a mild downregulation of cell identity TFs, alters gene expression, suggesting that AP-1-linked chromatin remodeling, initially promoting maturation, is later co-opted in aging to disrupt cell identity and function.
Disrupting the mitochondrial fission gene drp-1 significantly extends the lifespan of daf-2 insulin/IGF-1 signaling mutants in C. elegans. This lifespan extension is linked to increased mitophagy, enhanced mitochondrial and peroxisomal connectivity, and improved energy production, while specific tissue knockdowns and ROS levels are not affected.
Obesity and risk of diseases associated with hallmarks of cellular ageing: a multicohort study
This multicohort study found that obesity significantly increases the risk of developing diseases associated with cellular aging, such as those linked to mitochondrial dysfunction, telomere attrition, and stem cell exhaustion. Obesity-related cellular aging processes contribute substantially to increased mortality, suggesting that targeting these aging mechanisms could help mitigate the health impacts of the obesity epidemic.
An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo
This study introduces the CellPopAge Clock, a novel epigenetic clock designed to accelerate the discovery of anti-aging compounds by accurately monitoring the aging of human primary cell populations in vitro. The clock successfully detected slowed cellular aging when cells were treated with known longevity drugs like rapamycin and trametinib.
Blood protein assessment of leading incident diseases and mortality in the UK Biobank
This study analyzed 1,468 proteins in 47,600 UK Biobank participants, finding 3,209 associations between 963 proteins and 21 age-related diseases. The researchers developed ProteinScores that significantly improved the prediction of 10-year disease onset compared to traditional factors.
The correlation between CpG methylation and gene expression is driven by sequence variants
Researchers identified 189,178 regions where methylation was significantly depleted, with 41% of these regions associated with cis-acting sequence variants, termed allele-specific methylation quantitative trait loci (ASM-QTLs). Further analysis using RNA sequencing showed that ASM-QTLs largely drive the correlation between gene expression and CpG methylation.
Effects of walking on epigenetic age acceleration: a Mendelian randomization study
Higher usual walking pace is significantly associated with a deceleration in the acceleration of epigenetic aging, as measured by four classical epigenetic clocks (GrimAge, PhenoAge, Horvath, and Hannum). However, other walking behaviors, such as walking duration and frequency, did not show a significant impact on EAA.
Published Literature Reviews, Hypothesis, Perspectives and more
Why cancer risk declines sharply in old age
Recent research suggests that the sharp decline in cancer risk after the age of 75, particularly for lung cancer, may be linked to the role of certain genes that influence how the body ages and responds to cancerous changes.
Why do eggs in ovaries last for decades? Long-lived proteins may be key
Mammals are born with a set number of oocytes, which can remain viable for decades. Recent mouse studies suggest this longevity may be due to ovarian proteins that last nearly as long as the organism itself, potentially supporting long-term fertility.
Microbiota-bone axis in ageing-related bone diseases
This review highlights the crucial role of gut microbiota in maintaining bone homeostasis, particularly in the context of aging. It explores how the gut microbiota influences bone metabolism through various mechanisms, including its effects on the endocrine and immune systems and the production of gut microbiota-derived metabolites.
The complexity of coffee and its impact on metabolism
Coffee contains various bioactive compounds, including caffeine, which is metabolized into paraxanthine in the body. Paraxanthine, though not present in coffee, shares many of caffeine’s effects and likely contributes significantly to coffee’s impact on metabolism. While coffee consumption increases metabolic rate by 5% to 20%, individual responses vary due to factors like caffeine clearance, genetic differences, age, and body composition.
The role of cellular senescence in ovarian aging
This review examines the link between ovarian aging and the accumulation of senescent cells, as well as the potential of senolytic drugs to extend reproductive longevity. Ovarian aging, marked by a decline in ovarian reserve, leads to reduced fertility and menopause.
Senolytic Prodrugs: A Promising Approach to Enhancing Senescence-targeting Intervention
This review highlights the potential of senolytic prodrugs as a solution to the side effects of traditional senolytic therapies. These prodrugs, designed to selectively eliminate senescent cells by targeting the SA-β-gal biomarker, are categorized into galactose-modified senolytics and bioorthogonal activation approaches. The development of these prodrugs, including methods like PROTACs and photodynamic therapy, aims to safely translate senolytic therapies into clinical practice.
Job Board
David Vilchez’s lab in Cologne is recruiting a postdoc/lab manager position. The position is initially until December 2025 with the possibility to be extended until December 2032
Postdoc position in cellular senescence and age-related pathologies in Prof. Marco Demaria’s lab.
News and Media
BioAge Announces First Patient Dosed in the STRIDES Phase 2 Clinical Trial
Evaluating Azelaprag as a Novel Treatment for Obesity in Combination with Tirzepatide
A Molecular Reason Why Exercise Fights Senescence
Cells Across the Body Talk to Each Other About Aging
‘Dream come true’: study suggests drug could extend women’s fertility by five years
Cellular Reprogramming Improves Cognition in Aged Rats
Vegan Diet Lowers Biological Age in a New Study
Resources
LongevityGPT — designed to answer any aging/longevity/health/medical questions. Check out this Tweet to get more information.
Conferences
26–30th August, Copenhagen, Denmark
4th-6th September
Molecular and Cellular Aging Meeting in San Diego
La Jolla, CA. 10th-11th Sep 2024
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
The Cambridge Society of Ageing and Longevity Research term card for Michaelmas 2024 is here!
Tweet of the Month
A breakdown of the IL11 paper by Martin Borch Jensen
Podcasts and Webinars
NUS Medicine’s Healthy Longevity Webinar Series
David Sinclair at the Aspen Institute
David Sinclair shared some unpublished animal study results. These include:
- Reversing Alzheimer’s symptoms: Preliminary findings suggest potential for reversing symptoms in animal models.
- Hearing loss: Animal studies indicate progress in reversing hearing loss.
- ALS (Amyotrophic Lateral Sclerosis): There’s encouraging data on alleviating ALS symptoms.
- Glaucoma: Sinclair anticipates clinical trials by 2025, following positive outcomes in monkey models.
- Rejuvenating skin, kidneys, and liver: Results show signs of rejuvenation in these organs.
Additionally, the FDA has approved Tet-inducible partial reprogramming gene therapies. Life Bio is nearing clinical trials, having shown promising results in monkeys, particularly in eye stroke models (NIAON) and a glaucoma model.
In memory of Professor Leonard Hayflick
Here is a collection of some of his most memorable quotes, reflecting his insights, wit, and wisdom throughout his remarkable career:
“It is astonishing to realise that the human species survived hundreds of thousands of years, more than 99 percent of its time on this planet, with a life expectancy of only eighteen years.”
“The purpose of research is to ask questions. Don’t be afraid to challenge accepted wisdom, and have the courage to defend your findings and, where necessary, to challenge accepted dogma.”
“The suggestion I made that the finite lifetime of cultured normal cells relates to aging was dismissed by many as foolish, but it’s been confirmed thousands of times since, worldwide.”
“Had I patented the cells, I might own the world’s supply of WI-38, which would make me sufficiently wealthy to buy London, I think.”
“My recollection is that while the paper was in press, our electrical freezer failed, and we lost everything.”
“I put all my several hundred ampoules into a liquid nitrogen container and strapped it to the back seat of my Pontiac sedan. Two of my children sat next to it, and off we went to California.”
“The cells couldn’t be patented because in the early 1960s, the patent laws in the United States and most other countries prevented patenting of living materials. So I delivered ampoules of WI-38 worldwide freely to most virus vaccine manufacturers.”
These quotes capture the essence of Leonard Hayflick’s character — his relentless curiosity, boldness in the face of opposition, and his enduring impact on the world of science.
Outro
We appreciate you sticking with our research newsletter for another month and hope the content we curate is useful in helping you to keep up-to-date with all the exciting longevity-related developments. See you next month!
Further Reading and Viewing
Sleep is associated with telomere shortening: A population-based longitudinal study
