Introduction
Welcome back Vitalians!
Following our successful fundraise of $4.1 million (check out the Forbes article), a new wave of projects are in the pipeline to be funded. First up in 2023 is Brain Tissue Replacement Therapy with Jean Hebert - see his latest paper on rebuilding neocortical tissue in our hot picks below.
The VitaDAO community also voted to develop a brand new overlay journal - The Longevist - a curation of the most impactful longevity research every quarter, as voted on by a large body of key opinion leaders. Stay tuned as we aim to launch our 1st issue in April!
There are a plethora of different theories as to why we age, often with overlapping ideas that make it hard to separate the relative contributions of each factor. This month, we are excited to bring you an interview with Prof. John Speakman - a world leader on energy expenditure - who recently published his “Live cold, die old” paper, with some elegant experiments providing evidence that body temperature is a greater driver of ageing than metabolic rate in two species of small mammals. Check out the interview as Prof. Speakman discusses this and how it affects our understanding of calorie restriction interventions, free radical damage, and how temperature and entropy could be key to understanding biological ageing (recall our previously featured preprint from Dr. Peter Fedichev: Aging clocks, entropy, and the limits of age-reversal). Enjoy!
Longevity Literature Hot Picks
Preprint Corner
This month we are featuring 7 new preprints which are all available to review on our reviewing platform The Longevity Decentralised Review (TLDR) in return for a bounty of 50 $VITA each. Simply follow the above link to the TLDR page and get reviewing! What's more, we will be continuing the 50 $VITA bounty for reviewing any of the preprints featured in January's longevity research newsletter.
p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells
NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype
Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging
Insulin-mTOR hyperfunction drives C. elegans aging opposed by the megaprotein LPD-3
The human pathome shows sex specific aging patterns post-development
Aging Atlas Reveals Cell-Type-Specific Regulation of Pro-longevity Strategies
Biological Age Estimation Using Circulating Blood Biomarkers
Published Research Papers
Photoactivatable senolysis with single-cell resolution delays aging +
A senolytic strategy integrating multiple technologies delays aging (research briefing)
Senolytics have been shown to promote longevity but precise and trackable senolysis is still a challenge. An interesting approach to tackle this is described here - a photosensitive senolytic drug targeting the enzyme substrate of SA-β-gal with fluorescence tag for the precise tracking.
An In Vivo Platform for Rebuilding Functional Neocortical Tissue
While advances in stem cell transplantation have been made, the functionality of transplants remains a challenge. This in vivo transplant platform resulted in functional graft with differentiated layers of neurons, vascularization within a week, electrophysiological activity in a month and it responded to visual stimuli.
Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice
The study provides evidence for transgenerational epigenetic inheritance, a long debated subject. They show the CpG island reprogramming in the parental generation was maintained and transmitted across multiple generation alongside the phenotypic traits.
The DNA methylation of 220 subjects with obesity randomized to 25% CR or ad libitum for 2 years were assessed but resulted in inconclusive results. There was a striking difference between DNAm tests with DunedinPACE showing slowed pace of aging, while PhenoAge and GrimAge showed no change in biological age.
HGPS is a premature aging disease and there has been a growing body of evidence that mitotic defects play a role. A core spindle assembly protein BUBR1 had decreased levels and the remaining protein was anchored. A unique peptide prevented binding and increased expression, showing potential for progeria therapeutics.
Correlated evolution of social organization and lifespan in mammals
Phylogenetic comparative analysis of over 1000 species compares solitary vs group-living species and concludes that group-living species generally live longer than solitary-living, suggesting correlated evolution of social organisation and longevity.
Telomere-to-mitochondria signalling by ZBP1 mediates replicative crisis
Dysfunctional telomeres were shown to activate immune responses as a mechanism for telomere mediated tumour suppression. The process is dependent on mitochondrial telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres forming oligomers with ZBP1 (Z-DNA binding protein).
Mitochondrial DNA mutation rate and accumulation significantly differed across aged tissues. This was not correlated to tissue function and mitochondrial content. An unexpected lack of mutations linked to oxidative damage were found, suggesting dynamic clearance.
Job board
A two-part role including being the Executive Director of XPRIZE’s Health Domain and Director of the upcoming “Healthspan XPRIZE”
To help with research on aging and age-related diseases.
SenNet Consortium Underrepresented Student Program Summer 2023 Application
Summer undergrad research internships at the NIH cellular senescence research consortium! Deadline 15th March 2023.
A Postdoc (Research Fellow, RF) and Ph.D. position in Biology of aging are available in the Sorrentino laboratory at NUS in Singapore. The projects explore the interconnectivity and possible therapeutic targeting of the cellular hallmarks of the aging process, with a particular focus on mitochondrial dysfunction, protein aggregation and alterations of NAD+ metabolism.
Are you interested in cardiovascular research and aging? Apply for a PhD position and join a research team part of the VASC-HEALTH Flagship Project at the Medical University of Graz
News
A4LI is proud to announce the founding of the Congressional Caucus for Longevity Science.
The formation of the “Longevity Science Caucus” is a transformational moment for the longevity biotechnology industry and the movement to increase healthy human lifespans.
Targeted degradation: putting autophagy to work
Autophagy inducing biotech company Casma Therapeutics closed a $46 million round with the aim to develop novel treatments for cancer, inflammation, neurodegeneration, and metabolic disorders
Articles
Antiaging talk: Is red wine good for the skin?
Global longevity investment hit $5.2 billion in 2022
The puzzling gap between how old you are and how old you think you are
Mapping out the longevity investment landscape
Anti-ageing scientists extend lifespan of oldest living lab rat
Restrict calories to live longer, study says, but critics say more proof is needed
Young female mice exposed to scents from older females live longer
Study reveals how exercise turns back the clock in aging muscles
Conferences, Workshops and Webinars
Two-day cellular senescence symposium at Cancer Research UK - Cambridge Institute! A great opportunity for PhD students and postdocs.
Workshop: Midlife Stress and the Hallmarks of Aging
Researchers at all career stages from academia, industry, and government with an interest in the impacts of stress on aging in human populations and animal models of stress and/or aging.
Podcasts and Videos
Bryan Johnson's Blueprint, Spotify Enters Health and VitaDAO Raises $4M
The intake of legumes—beans, chickpeas, split peas, and lentils—may be the single most important dietary predictor of a long lifespan. But what about concerns about intestinal gas?
Interview with Prof. John Speakman
Professor John Speakman is a leading expert on metabolic activity and energy expenditure and was instrumental in the development of doubly-labelled water (DLW) technique. He has made numerous significant contributions to our understanding of factors that govern variation in food intake and energy expenditure, and the consequences for fat storage (obesity) and ageing. He currently runs 2 research laboratories and is Head of Integrative Physiology at the University of Aberdeen, and a professor at the Chinese Academy of Sciences in Shenzhen.
What inspired you to enter longevity research?
My PhD in the 1980s was to study energy balance and metabolic rates in wild animals. At the time there was a lot of interest in among species scaling relationships for all sorts of things – one of which was lifespan. Bigger animals live longer, and one idea why that was the case was because they have lower metabolic rate: the ‘rate of living theory’. This was also a potential reason why calorie restriction exerts its effects – by lowering metabolic rate. It was a pretty old idea from the 1920s and in the 1950s it got a boost by the idea that higher metabolism leads to greater production of free-radicals and therefore the reason we age is because of free-radical damage that stems from our metabolism. By the 1990s this idea had enormous traction among biologists studying ageing. Many of them were taking large amounts of vitamin C and E daily to quench their free-radical damage. Since I knew something about metabolism, I got interested in this idea that lifespan depends on metabolism and free-radicals, and that we have a fixed amount of lifetime expenditure of energy. I also started taking antioxidant vitamins daily. At the time in the 1990s however almost all the work on the idea was correlational and inter-specific. I figured that we could probably do intra-specific experiments to test the ‘rate of living/free-radical damage’ idea, by making animals expend more or less energy, and giving them anti-oxidants, and then looking at how long they live. I applied for money to the UK BBSRC to do such experiments as part of their first special topic on ageing and was successful. I recruited an amazing post doc (Colin Selman) who eventually became a great gerontology professor, and we did some interesting work together. The general outcome of our work was that the rate of living/free-radical damage model was not sustainable. Voles given antioxidants for example lived shorter lives. It had at least one direct human consequence, in that I personally stopped taking antioxidant vitamins. These studies eventually led to my groups work on calorie restriction which has dominated my work on ageing ever since.
Which of the current theories of ageing do you think are the most convincing?
I quite like the idea from the Nobel prize winning physicist Erwin Schrodinger in the 1930s that he presented in a short book called ‘what is life?’. In it he posited that organisms are incredibly complex low entropy systems that naturally have a tendency to increase in entropy because it needs a constant and large flow of energy to sustain their low entropy state. For a while it is advantageous in terms of reproduction for us to invest in holding back the increase in entropy in our soma, and we do so, but then eventually it starts to accumulate (ageing). This becomes self-reinforcing because the cost to repair the system starts to get larger and larger. Eventually entropy accumulates to the point where the system is overwhelmed, and that overwhelmed state is what we call death. Many other theories of ageing are potentially just restatements of the entropy principle – eg mutation accumulation, free-radical damage, senescent cell accumulation. What I like about the entropy idea is that it is very non-specific, so the reasons people die are probably all slightly different and depend on the stochastic nature of the system falling to bits. This not just explains why living things age and die but why any complex system fails. If you go around a scrap yard and look at the cars in there they are all in there for slightly different reasons but fundamentally for many of them they are there because investing more money in stopping them falling to bits was too expensive. I think what this tells us is that chasing down a single problem (like accumulation of senescent cells for example) is unlikely to be very effective as an overall anti-aging strategy because there will always be another problem that arises reflective of the increasing entropy. In other words as we all know there are multiple hallmarks of ageing. Ultimately, then, I think the solution will be to increase the activity of the systems that keep entropy low when we are young. This will really mean intervening when that system starts to decline which is probably in our twenties or thirties, not our sixties and seventies. By then its probably already too late.
How has the field changed since you started?
I guess the major recent change in the field is the fact that the boomer generation has finally realised that they are all going to die and they are not happy about it. So now there are very large sums of money being poured into ageing research by very wealthy people in their late 50’s early 60’s and that has given ageing research a tremendous boost. The money invested in Calico by Google, the Hevolution project and into Altos labs by Bezos and colleagues is enormous. Whether they will see a practical return on this investment in their lifetimes is an interesting question. Most of them in my view have left it too late already.
A second big practical difference is the interventions testing program in the USA. I think that was a real landmark achievement to set up an integrated multi-lab platform to test compounds that might have lifespan impacts in rodents. This program has saved a lot of time and effort chasing down false leads that would have been based on underpowered small studies.
What mistakes do you think the longevity field has made?
For cost purposes medical science in general has placed enormous efforts into understanding model organisms like yeast, C. elegans, Drosophila and mice. I think this has generally led to some important insights in many fields, but the benefit to cost ratio of understanding what causes ageing in C. elegans or yeast is very low. The translational benefits of working on ageing in mice are already not great because mice are not little people. Once you get into ectothermic animals, and single cell organisms that reproduce a-sexually, with fundamentally different physiology (eg ability to go into Dauer states in C. elegans or generate ethanol in yeast) the translational potential of such work is effectively zero. A recent review by Bene and Salmon in Geroscience showed that there was virtually no translation from C. elegans to mouse for life extending therapeutics. Studies of ageing in these organisms have led us down several expensive blind alleys, perhaps most notably the sirtuin story which is now starting to completely unravel.
The key issue though is that as you get closer to humans and the translational potential increases there are increasing ethical issues. Moreover, as the lifespan of the organisms under study get longer, the required experiments get longer as well, until we get to a point where nobody can do the required experiments within a single career of one scientist and progress is phenomenally slow. It is a hard nut to crack in a world where people want answers yesterday. I think this impatience for answers is basically what continues to fuel C.elegans work on ageing irrespective of its likely utility.
Other than your own, what do you think have been the biggest/important discoveries in the field?
I have found it really intriguing the very simple observation that if you transfuse blood from a young mammal to an older one you can slow down its ageing. I think this will turn out to be an incredibly important and practically significant observation. Is it because the young blood contains life promoting compounds, as some recent work suggests, or does it just dilute life shortening compounds in the old blood. Either way I think this has the most exciting potential for an immediate practical intervention.
What advice would you give to people currently working in longevity research?
Apart from finding out what is going on with young blood, if someone was just starting out a career then I think my advice would be to focus on ageing of the brain. You can envisage that for pretty much all our bodily functions it will eventually be possible to replace them with mechanical substitutes. In fact this is already true for many of our organs and musculo-skeletal systems. Recently exoskeletons were developed to augment declining muscle strength, thereby allowing elderly people to retain mobility and avoid falls. These days as people age we routinely swap out parts of their failing bodies and replace them with man-made mechanical alternatives – like heart valves and hip replacements. Although hip arthroplasty has a history dating back to the 1800s it only became a widely used and available procedure with minimal complications in the 1970s. Prior to that if your hips wore out you were basically crippled or bed-ridden and had a very low quality of life until you prematurely died. Nowadays, understanding the processes that lead to our hip joints failing as we get older is pretty much pointless because that problem has already been solved as far as practical aspects of hip ageing is concerned – although may give us insights into bone degeneration more generally. That will become increasingly the case as more and more mechanical replacements are developed. The one system, however, that I don’t see us ever being able to replace mechanically is the brain. That is the fundamental thing in your body that harbours what we identify as you. If it was possible to combine the head of a person grafted onto the body of a different person, we would identify the resultant being from the head (brain), not the body. Therefore, preserving the brain and preventing brain ageing is really the whole key to preventing ageing in the very long term. That, and inventing mechanical substitutes for all the other systems.
Which aspect of longevity research do you think requires more attention?
Brain ageing – see above.
Is ageing a disease?
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.
You recently published your “live cold - die old” paper - would you be able to summarise your findings?
In general when endothermic animals like humans reduce their metabolic rate they reduce their heat production and this can lead to them having a lower body temperature. During calorie restriction for example it is pretty widely agreed that metabolic rate goes down (whether on a whole animal or normalised for body size basis) and that body temperature is also lower. Formally then because these two things go in tandem its not possible to separate which (if any) is a causal factor in the observed life extension. To separate the effects of metabolic rate and body temperature you need a situation where they change in opposite directions. One such situation in small rodents is when you change the housing temperature from below thermoneutral (around 20 oC) to the top of the thermoneutral zone (32.5 oC). When you do that metabolic rate goes down at the same time that body temperature goes up. Looking at that effect on lifespan in mice and hamsters at these temperatures allowed us to separate the effect of body temperature from that of metabolic rate. If lower metabolic rate was important then they should live longer when hotter, if body temperature drives the effect they should live shorter. The answer was that when you made the animals hotter their lifespan declined. We then showed that if you blow air over the animals in hot conditions you can prevent the rise in body temperature without altering metabolic rate, and when you do that you can rescue the lifespan effect. It seems that body temperature is more important than metabolic rate. In the press release we used the bumper sticker ‘live cold, die old’ to promote the work. Interestingly this may be a much more general principle than just organismal ageing. For example, the duration that transistors ‘live’ until failure is related negatively to their operating temperature. I suspect temperature is related to entropy change. When complex things are hotter entropy accumulates faster and they fail more quickly.
Do you envisage that cooler environments / increased convection would benefit humans? / Do you have any plans to test this?
Living in a colder environment will generally not reduce your body temperature much compared with the environments we currently seek out just below thermoneutral so that isn’t probably going to work. Similarly increased convection probably won’t be very effective either. It worked in the mice and hamsters to cool them down from a much higher temperature. We have recently completed some preliminary tests getting people to drink cold water and monitoring the impact on their body temperature as a pilot study to get the necessary data to perform power analysis for a randomised clinical trial. I like the idea but I didn’t start drinking cold water everyday myself yet.
Which other non-therapeutic interventions do you think hold promise for improving human healthspan/lifespan?
Although fraught with some ethical issues I think blood transfusion from young to older people holds a lot of promise based on the mouse work.
Outro
Thank you for staying with us till the very end and as always we encourage you to reach out to us about content you’d like us to discuss in our next issues. See you next month!
Further Reading
The association between body height and longevity: evidence from a national population sample
High Investment in Reproduction Is Associated with Reduced Life Span in Dogs
