Introduction
Welcome to 2024, Vitalians! We hope your holiday season was wonderful, and that you're returning recharged and ready for another year of exciting developments in longevity science!
I know it seems so far away already but here is what happened in December, plus an insightful interview from Dr. Bernadette Carroll - who shares her thoughts on the longevity field as well as discussing her research on nutrient sensing, lysosomes and their role in senescence and aging, enjoy!
Longevity Literature Hot Picks
Preprint Corner in collaboration with
The Longevist is an overlay journal spotlighting the most promising longevity studies each quarter through a collaborative and transparent process, leveraging insights from a panel of global experts in the longevity space.
With Q4 now over, The Longevist editors are currently finalising the shortlist of preprints to put forward to our curators for the next on-chain vote. In the meantime, check out the 3rd issue of The Longevist and look out for our newly assigned ISSN!
Check out these latest preprints, each of these will be entered into the Q1 2024 longlist to be in the running to receive a coveted place in The Longevist. They are also available to review on our reviewing platform The Longevity Decentralized Review (TLDR) for a bounty of 50 VITA per review.
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.
The germline regulates longevity and somatic repair in a sex-specific manner
Epigenetic Clocks and Programmatic Aging
Epistemic uncertainty challenges aging clock reliability in predicting rejuvenation effects
Extensive remodeling of the ubiquitination landscape during aging in C. elegans
The molecular landscape of premature aging diseases defined by multilayer network exploration
From Churchill to Elephants: The Role of Protective Genes Against Cancer
Published Research Papers
DNA methylation rates scale with maximum lifespan across mammals
A new statistical framework was developed to compare DNA methylation rates at conserved age-related sites across mammals, revealing a negative correlation with maximum lifespan in both blood and skin tissues. This indicates methylation rates might be a constraint on maximum lifespan, affecting diverse mammalian lineages.
Organ aging signatures in the plasma proteome track health and disease
Analysis of organ-specific aging in humans using blood plasma proteins, finding significant variations in aging rates across different organs and predicting increased disease risks. The approach offers a novel method for assessing individual aging processes and their impact on health, using plasma proteomics data.
Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype
Iron accumulation is a key factor in cellular senescence and fibrosis in mice and humans, suggesting iron metabolism as a potential target for treating senescence-associated diseases. It also highlights the possibility of using magnetic resonance imaging to non-invasively assess fibrotic diseases.
Aged intestinal stem cells propagate cell-intrinsic sources of inflammaging in mice
This research explored inflammaging in the mouse intestinal epithelium, discovering that aged intestinal stem cells (ISCs) play a key role in this process by upregulating major histocompatibility complex class II genes and exhibiting an intrinsic inflammatory memory. It highlights that inflammaging is driven by a cell-intrinsic mechanism, dependent on STAT1 signaling, and leads to a disruption in immune homeostasis.
The effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer
A ketogenic diet, compared to standard mouse chow, effectively reduces breast tumor growth and increases lifespan in a mouse model, particularly when combined with the anti-cancer drug rapamycin.
The study introduces a detailed RNA-seq dataset from multiple organs of the African turquoise killifish, highlighting that age significantly affects gene expression more than sex. This resource is pivotal for investigating aging and sex-related gene expression in this short-lived vertebrate model, especially noting the increased expression of transposable elements in the brain with age.
Published Literature Reviews, Hypothesis, Perspectives and more
The Information Theory of Aging
Biological information is stored in two ways: the genome as a blueprint, and the epigenome which regulates gene expression. The Information Theory of Aging suggests that aging results from losing epigenetic information, and its retrieval through reprogramming could reverse aging.
Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming
Recent developments in anti-aging research involve using nuclear reprogramming factors to reverse age-related deterioration in mouse and human models. The study also explores the challenges and potential of epigenetic rejuvenation strategies in practical applications for treating aging and age-related diseases.
Telomeres, cellular senescence, and aging: past and future
The review commemorates over fifty years since Alexey Olovnikov's theory of the end-replication problem, exploring the complex role of telomeres in cellular senescence and aging, and their impact on age-related diseases.
There are significant limitations of predominantly using the inbred C57BL/6 mouse strain in aging research, advocating for the diversification of mouse strains to better understand variations in lifespan and healthspan. They emphasize the need to select mouse strains based on specific research questions and an understanding of genetic diversity to bridge the gap in translating findings to human aging.
A thermodynamic model to predict lifespan changes in mice under calorie and protein restriction finds that increased restriction reduces entropy generation and potentially extends lifespan. This model aligns with precision gerontology goals and could help identify anti-aging interventions.
Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement
The review analyzes recent aging research, focusing on cellular and molecular hallmarks, their links to age-related diseases, and major biochemical processes, aiming to advance understanding of aging mechanisms and challenges.
Job Board
PhD Studentship: Blood-based Biomarkers of Frailty and Ageing
PhD Studentship: Exploring Valid Approaches to Breath VOC Analysis for Diagnostic Research with Prof Alexandra Stolzing
Postdoctoral Position in Genome Stability: The Institute for Genome Stability in Aging and Disease at the CECAD Research Center, University of Cologne. DNA damage in aging and the regulation of the inheritance of stable genomes with Prof Schumacher
The Kohler Mito Lab are recruiting a Post-doc and a PhD student to study Mitochondrial Protein Quality Control Umeå University, Sweden
Interested in cellular senescence? Apply for this fellowship to join Ana O’Loghlen’s lab in Madrid!
The Sandri Lab are hiring - 18 months postdoctoral fellowship to work on developing RNA-based therapies in vivo for modulating signaling pathways involved in protein degradation, bioenergetics/mitchondria and protein synthesis. University of Padova, Italy.
News and Media
$200 Billion in Revenue: How an Aging Drug Will Conquer Pharma
Hevolution Foundation Grant Expands New Investigator Awards in Geroscience
New tests promise to tell you if you have the cells of a 30-year-old or a 60-year-old. Here’s what to know about them.
Bridging Generations: Our Ageless Future
Turn Bio, backed by the VitaDAO Community, achieves a milestone in RNA therapeutics by successfully delivering mRNA to the skin, a significant step beyond liver-targeted therapies
Not all organs age the same. ‘Older’ ones may predict your risk of disease
The RAPID Clinical Trial are recruiting volunteers to take part in a clinical study to treating periodontal disease by targeting mTOR
Death Becomes Her, or Why Aging is an Epigenetic Program
Insilico Medicine announces AI drug discovery milestone achievement in pharma collaboration
Venture Capital Giants In The Billion-Dollar Quest For Longevity Breakthroughs
Frontiers in Aging are accepting submissions on the research topic “Longevity Worldwide: A Collection on Centenarian Studies” until 31st January
The Biggest Breakthrough in Longevity may Start with Menopause
Light color is less important for the internal clock than originally thought, study finds
Conferences
Jan 29-30, CECAD Cologne
Young ICSA 18th & 19th March
Oriel College Oxford - Register here by 19th January
Vitalia.city has officially launched. It will host 4 bi-weekly conferences on different topics, 2 of which will be on longevity:
Longevity & Human Improvement (Jan 15 - 21, Summit: Jan 20)
- The Bioscience of Longevity
- Business Models for Longevity Companies
- Economics and Incentives of Healthcare Systems
- Philosophical Views and Ethics of Life Extension
Startup Societies & Crypto Cities (Jan 29 - Feb 4, Summit: Feb 3)
AI & Technological Progress (Feb 5 - 11, Summit: Feb 10)
Pathways to Life Extension (Feb 19 - Feb 25, Summit: Feb 24)
- New Drug Development
- Clinical and Healthcare
- Biohacking and Self-Improvement
- Incentive Design Solutions
Tweets of the Month
From Artemy Shumskiy, what do you think?
Aging hallmark I dislike: telomeres
Aging hallmark I begrudgingly respect: splicing dysreg
Aging hallmark I think is overrated: senescence
Aging hallmark I think is underrated: altered intercell comm
Aging hallmark I like: inflammation
Aging hallmark I love: epi alterations
Some pearls of wisdom from The Terminator (Arnold Schwarzenegger)
I heard that the way you go viral on this site is by making a big list of things you have to do. Let me try.
-You should mostly eat food you know is healthy, there is no magic food.
-You should also occasionally let yourself eat delicious food you know isn’t healthy. Otherwise what’s the point?
-You should be training with some kind of resistance (your bodyweight works), no matter your age
-You should do something to get your heart going and get a schvitz a few times a week
-You should know there isn’t a magic pill, a hack, or a diet and most of that crap people put in their lists is just mean to confuse you so you pay them to figure it out for you with whatever they are selling
-You should also know my daily newsletter is free, is allergic to bullshit, and includes weekly workouts, the latest health and fitness news, and motivation from me.
-Don’t worry, if you paid one of those people to tell you jumping in cold water or taking 29 pills every morning will get you fit, I’ll still be here in three months when you decide it’s time to try something that works. The only trick I know is that you have to work, it hasn’t changed in 76 years and it won’t change.
Podcasts and Webinars
NUS Medicine Healthy Longevity Webinar
Cellular Senescence and Mitochondria | Prof Joao Passos
Gene Therapy Insights Podcast
Energy Replacement in the Light of Aging with Dr. Shahaf Peleg
The Desci Podcast by Molecule
Keith Comito's Insights on Aging Research and Lifespan Extension
The Sheekey Science Show
Can taurine and vitamin B12 improve your health?
Interview with Dr. Bernadette Carroll
After completing her PhD at Imperial College London, Dr. Carroll worked in Viktor Korolchuk’s laboratory at the Newcastle University Institute for Ageing and Health where she published numerous papers on nutrient sensing, mTOR, autophagy and their role in senescence and aging. She now runs her own research laboratory at The University of Bristol, focusing on mechanisms controlling the spatial regulation of nutrient homeostasis in health, senescence and cancer. She has recently published a paper discovering a key mechanism of how lysosomal biogenesis is required for cell survival during the onset of senescence.
What inspired you to enter longevity research?
I will admit that my entry into longevity research was not entirely by design. I originally trained as a cell biologist, and I have always been interested in the spatial organisation of our cells, asking questions such as how and why are proteins recruited to specific sites in the cell, and what happens if this localisation becomes dysregulated? For my postdoc, I moved to Newcastle University to work in the lab of Dr Viktor Korolchuk, a key contributor to the VitaDAO community. My project was focused on understanding how the localisation of the main regulator of cell growth, called mTOR is controlled. Over time, through research seminars, coffee chats and a pint (or several), I was won over by the enthusiasm and passion of researchers in the longevity field. It was well established in the field that mTOR signalling drives several senescence phenotypes, and so I got onboard and used my expertise to take a closer look and explain in more detail exactly how mTOR is dysregulated in senescence.
Which of the current theories of ageing do you think are the most convincing?
I see immense value in developing theories of ageing. As an experimentalist who relies on a bottom-up approach, these theories give us new ideas to test using hypothesis-based science. If we can rescue senescence phenotypes by identifying and modifying dysregulated mechanisms, this gives us hope that one day we will be able to develop new anti-ageing interventions. Currently, I particularly favour programmatic theories rooted in the development, where processes like mTOR play an important role.
How has the field changed since you started?
The field has become a lot more mainstream. There is increasing appreciation that a comprehensive understanding of all aspects of fundamental and applied biology is required to explain the ageing process. This is undoubtedly a positive, there is more interest from the public, from governments and from biotech industry which has led to increased, dedicated funding, increased initiatives to promote collaboration and more research teams focused on longevity. This increased focus however also presents its own challenges as we come to fully realise the complexity of understanding longevity, integrating topics from biochemistry, to physiology, psychology, and sociology. I think it will require some out-of-the-box thinking going forward to tackle longevity research effectively and collaboratively. That’s why communities like VitaDAO are so important.
What mistakes do you think the longevity field has made?
Ageing is a complex, multi-factorial and multi-scale process and I think the longevity field is guilty of approaching the question from a reductionist angle. This is a natural result of the short-term funding strategies of most national and international funding schemes that don’t necessarily support high-risk or more preliminary projects. While labs working on model organisms such as yeast, flies and mice have been true trailblazers in identifying key signalling or metabolic pathways involved in longevity, translating these findings to humans has been very limited. Instead, we are still at the stage of generating theories of ageing, essentially a thought process. The next few decades however promise an explosion of fundamental, translational, and clinical research in longevity which will inevitably push the field forward in a practical way.
Other than your own, what do you think have been the biggest/important discoveries in the field?
As cell biologists, we work exclusively with human cells that have been removed from their natural environment in the body and are instead exposed to different nutrients and stressors. There is always the worry therefore that the many of the phenomenon’s we study could be artifacts that have little or no physiological relevance. That is why the seminal work from the Mayo clinic demonstrating that the selective clearance of p16-positive senescent cells can alleviate ageing phenotypes was fundamentally important for researchers working on senescence.
What advice would you give to people currently working in longevity research?
Collaborate. I believe the biggest rewards will come from those who can step out of their comfort zone to embrace different approaches and ways of thinking about longevity. Also keep an open mind about new potential directions. Getting involved with communities like VitaDAO is a really positive move to facilitate collaborations and generate new ideas.
Your research focuses on the interplay between nutrient homeostasis and cellular processes in the context of aging and cancer. What inspired your interest in this area?
We are what we eat, and as such I believe that a lot of the answers about how well we age and how likely we are to develop age-related diseases lies in our diets and in the way our bodies are able to handle nutrients. There are so many intriguing questions in this area, both in terms of fundamental mechanisms of nutrient sensing as well as in terms of practical applications. For example, despite decades of nutritional research, we are still unclear about how to combine the beneficial effects of dietary restriction with the need to maintain active and fit bodies, especially in old age. In the lab, we are developing cell- and tissue-based models of human ageing and believe that these will provide new answers to the long-standing questions in the field.
mTOR is often referred to as a master regulator of cell growth and metabolism and heavily implicated in the aging process. You previously published work showing that mTORC1 activity can be regulated by the amino acid arginine, through control of the TSC2-Rheb signalling pathway. Could you summarise these findings?
Several decades of research have revealed that the activity of mTORC1 is controlled via its subcellular localisation in the cell. Specifically, the availability of specific amino acids is sensed to dictate whether mTORC1 is localised to the cytoplasm or to the surface of the lysosome (the degradative compartment of the cell). When I started my postdoc, the mechanisms via which leucine and glutamine controlled mTORC1 had been identified but we found over and over again in our cell system, that arginine was having a very strong effect on mTORC1 signalling and cell growth. We identified that rather than regulating the localisation of mTORC1, arginine is important for controlling the localisation of the inhibitor of mTORC1, called TSC. This large protein complex inactivates another protein, called Rheb which is the master activator of mTORC1 signalling. We found that in the absence of arginine, TSC is localised on the lysosome, binds to Rheb and prevents the mTORC1 activation. As such, the mechanism by which arginine is sensed is conceptually different to other amino acids.
Do you think the positive effects of dietary restriction on healthspan/lifespan could be due in some part due to lowered arginine availability, and would this be worth testing? Considering leucine and glutamine have also been shown to affect mTORC1 activity, do you think any other amino acids could also play a role?
The regulation of amino acid uptake, utilisation and synthesis is complicated and very context dependent. There are 20 natural amino acids which are the building blocks of proteins and play key roles in metabolism. Human cells can make 11 of them, the other 9 amino acids, including leucine are referred to as essential amino acids which means they need to be ingested in our diets. Leucine is a particularly potent growth-promoting amino acid; you might have noticed high levels of leucine advertised on protein shakes aimed at gym-goers trying to boost muscle mass. Glutamine and arginine, along with several other amino acids are referred to as conditionally essential, that means our cells can produce them but that at certain times, for example during development or during tissue/wound healing, our cells might not be able to meet demand and diet supplementation is necessary. It’s true that exploiting changes in amino acid metabolism can have clinical benefits in some settings; for example, tumours auxotropic for arginine (i.e. tumour cells that have lost the ability to synthesise their own arginine) can be treated with circulating arginase to degrade circulating arginine and thus essentially starve the tumour cells. However, as of yet, we have not identified any specific defects in senescent cells that would allow us to target them in this manner.
Evidence from fly models would also suggest that starvation of any single amino acids may not yield any discernible longevity benefits, except perhaps for methionine starvation. So rather than any specific amino acid, it’s more likely that caloric restriction has a beneficial effect through a combination of reduced protein synthesis-related stress (less burden on ribosomes and ER folding machinery) and increased levels of autophagy.
Senescent cells have dysfunctional lysosomes and you recently published a paper identifying the mechanism by which senescent cells increase their lysosomal content to cope with this decreased function. Could you briefly explain these findings and what the potential therapeutic implications could be?
Lysosomes are the degradative organelle of the cell and they play an essential role in degrading unwanted, or damaged cellular contents. Despite the fact that an increase in lysosomal content is one of the hallmarks of senescence (measured by senescence-associated ß-galactosidase staining), the driving mechanisms and cellular consequences were poorly understood. We identified that lysosomes in senescence are dysfunctional. Their pH is increased which is important because low pH is required to maintain the activity of the degradative enzymes in the lysosome. As a result, the lysosomes are less active, and less able to degrade cargo. We propose that senescent cells compensate for this reduced lysosome activity by increasing their biogenesis, specifically by activating transcription factors of the TFEB family. Increased lysosome content therefore allows continued degradation of damaged and surplus cellular contents and support senescent cell survival.
What’s next for the Carroll lab?
The work us and others demonstrated that inhibiting lysosome biogenesis or modulating dysregulated mTORC1 signalling can promote senescent cell death, which indicates we could one day be able to develop interventions to target these pathways and promote healthier ageing in vivo. With this ultimate goal in mind, we are continuing to work towards a better mechanistic understanding of lysosomes and their interplay with mTORC1 signalling in senescence. We have some exciting data on changes in lysosomal lipids in senescence coming through, so watch this space :).
Outro
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
Capsaicin inhibits A7r5 cell senescence via the mitochondrial carrier protein Slc25a12
NADase CD38 is a key determinant of ovarian aging
DNA repair-deficient premature aging models display accelerated epigenetic age
Successful Aging: The Longer One Lives, the Better One Has Eaten?
NMN: The NAD precursor at the intersection between axon degeneration and anti-ageing therapies
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