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.
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.
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.
VitaDAO-funded Research Projects
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.
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
Longevity Literature Hot Picks
Preprint Corner
Check out this month’s longevity preprints - will any receive a coveted spot in the Q2 Issue of the Longevist? Watch this space!
Premature Aging and Reduced Cancer Incidence Associated with Near-Complete Body-Wide Myc Inactivation
Measuring C. elegans Ageing Through Non-Invasive Monitoring of Movement across Large Populations
The blood has something to say: A hematology-based clock to measure aging in mice
Cognitive Rejuvenation In Old Rats By Hippocampal Oskm Gene Therapy
Developmental mitochondrial Complex I activity determines lifespan
The Role of Respiratory Complex IV in Lifespan Length and Quality
The molecular clock in long-lived tropical trees is independent of growth rate
Uncoupling of lifespan and reproductive tradeoffs by dietary methionine and one-carbon metabolism
Measuring C. elegans Ageing Through Non-Invasive Monitoring of Movement across Large Populations
Published Research Papers
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.
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.
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.
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.
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.
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.
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.
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.
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.
Published Literature Reviews
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.
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.
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.
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.
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.
And finally -
a special FEBs issue of reviews and research articles on Senescence in Ageing and Disease
Job board
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
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.
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
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.
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.
News
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
Dr. David Sinclair Assumes Presidency of the Academy for Health and Lifespan Research
Police got called to an overcrowded presentation on “rejuvenation” technology
Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution
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!
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.
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?
Should I worry about my VO2 max?
Meet Rapamycin, the Drug That Could Delay Menopause
Time-restricted feeding makes the mouse run like a pro
Defining a longevity biotechnology company
Transformer-based aging clock provides insights into aging
Navigate the emerging field of longevity
How seeing corpses reduces the lifespan of flies
Fasting Mimetics: Health And Longevity Benefits With Dr. Valter Longo
The billion-dollar search for immortality
Finding joy at age 100: Talking to centenarians about living their best life at any age
Conferences, Workshops and Webinars
World Aging and Rejuvenation Conference (ARC)
17-18 July, Frankfurt, Germany
10-11 August, NY, USA and virtual
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
7-9 September, LA, CA, USA
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
Balaji: CHEATING DEATH IS GOOD
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.
Also check out this interesting thread from Healthspan on Blagosklonny's theory of cellular hyperfunction
Podcasts and Videos
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.
Interview with Prof Joao Pedro de Magalhaes
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.
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!
VITA-FAST — Revolutionizing Governance in Longevity Research
Further Reading
Association between infectious exposures in infancy and epigenetic age acceleration in young adulthood in metropolitan Cebu, Philippines
Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing
Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria
Does omega-3 supplementation improve the inflammatory profile of patients with heart failure? a systematic review and meta-analysis
Curcumin, Inflammation, and Neurological disorders: How are they linked?
Epigenetic and Metabolomic Biomarkers for Biological Age: A Comparative Analysis of Mortality and Frailty Risk
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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