Introduction
A multitude of discoveries and inventions throughout history have been made by people who were initially trained in one domain, but were able to make a significant contribution to a different field due to their ability to look at a problem with a unique perspective. Would Charles Darwin still have conceived the Theory of Evolution if it were not for his background in Geology and appreciation that for geological processes to have occurred, Earth must have been around for a vast amount of time!
The contributions of physicists in particular to our understanding of biology have been immensely valuable over the past century. Great thinkers such as Szilard, Schrödinger and Crick, compelled to find out what life is and how it works, were able to provide humanity with novel ideas and trailblazing discoveries in molecular biology.
Take this month’s issue as a tribute to the novel insights provided from physics with a few newly published papers, pre-prints and an interview with Dr. Peter Fedichev - highlighting the power of cross-disciplinary thinking to help advance longevity research!
Longevity Literature Hot Picks
After another month of overwhelming amounts of great longevity research being published, we hope to make it easier for you to keep up with it all by presenting some of our favourite papers from the field (and remember our Further Reading section at the bottom of this page for even more new longevity papers).
While we normally pick peer-reviewed published papers, there were a few interesting pre-prints this month which sparked a lot of debate that we couldn’t ignore!
Unsupervised learning of aging principles from longitudinal data
What is the relationship between physiological changes with age and lifespan? To answer this question analytical and machine learning tools were employed to design deep artificial neural networks with auto-regression model, identifying a relationship between physiological state during aging and a variable named “dynamic frailty index” or dFI. dFI increased exponentially with age and predicted lifespan from mouse blood samples. It also responded accordingly to know life-shortening and life-extending interventions.
Aging clocks, entropy, and the limits of age-reversal
https://www.biorxiv.org/content/10.1101/2022.02.06.479300v2
A single variable called thermodynamic biological age (tBA) tracks entropy produced, and hence information lost, with age. As tBA increases with age it reduces resilience, and drives the exponential acceleration of chronic disease incidence and death risks, which is a linear and irreversible drift, setting severe constraints on age reversal possibilities. But wait, not all hope is lost. We might be able to figure out how to “cool down” the organism, control entropy and reduce the rate of aging in humans.
F1F0 ATP Hydrolysis is a Determinant of Metabolic Rate, a Correlate of Lifespan, and a Weakness of Cancer
https://www.biorxiv.org/content/10.1101/2021.10.28.466310v3
F1F0 ATP hydrolysis generates metabolic heat in an organism. A drug that can selectively inhibit ATP hydrolysis, but not synthesis, is explored here, and hypothesised that it could extend lifespan by slightly lowering body temperature. In 12 different species, decreased F1F0 ATP hydrolysis correlates with greater maximal lifespan. Anti-cancer properties were also observed in vitro.
Dietary restriction fails to extend life in stressful environments
https://www.biorxiv.org/content/10.1101/2022.10.17.512576v1
Dietary restriction has been shown to extend lifespan in numerous model organisms, however here the authors show that this effect is lost in fruit flies which are also under stress due to cold or hot living environments. This raises the question of whether laboratory-tested interventions will translate to animals living in more natural environments.
Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice
https://www.nature.com/articles/s43587-022-00304-x
Aging leads to the accumulation of hematopoietic stem cells with reduced regenerative potential. The mechanisms behind this are unclear but this study shows that inactivation of the plant homeodomain factor 6 (PHF6), a single epigenetic regulator, rejuvenates mouse aged hematopoietic stem cells.
The commentary on the article:
Is the philosopher’s stone to rejuvenate blood stem cells an epigenetic regulator?
https://www.nature.com/articles/s43587-022-00305-w
Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms
https://www.mdpi.com/1422-0067/23/20/12325/htm
A new take on CR mimetics with Sodium-glucose cotransporter 2 inhibitors (SGLT2-i), which lower glucose by elimination through urine, and actually induce a net loss of calories, fostering ketones and fatty acids utilization as glucose-alternative substrates. This process modulates major nutrient-sensing pathways held to drive aging, such as mTOR and resembles CR. Preliminary data also shows that it can inhibit cellular senescence and inflammaging.
Circadian transcriptional pathway atlas highlights a proteasome switch in intermittent fasting
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01403-6
Intermittent fasting has gained traction among the longevity community as a safe lifestyle intervention hoping to improve healthspan and increase lifespan. The authors set out to discover if there was an internal "timer" to respond to fasting duration. They found that in mice, the hepatic proteasome switches leading to transcriptional resonance which is reversed upon re-feeding. It will be interesting to investigate if a similar mechanism is conserved in humans and what fasting duration is required to induce the switch.
The role of gut microbiota in liver regeneration
https://www.frontiersin.org/articles/10.3389/fimmu.2022.1003376/full
Unlike other human organs, the liver has an amazing ability to regenerate itself.
Check out this review exploring how gut microbiota play a role in liver regeneration through regulating the liver immune microenvironment thus modulating inflammatory signalling at different stages of the regenerative process.
Combining stem cell rejuvenation and senescence targeting to synergistically extend lifespan
https://www.aging-us.com/article/204347/text
The 2012 Nobel Prize for Physiology or Medicine was awarded for showing that differentiated cells could be reverted back to stem cells by activation of 4 transcriptional factors, now eponymously known as Yamanaka factors. This led to huge interest in the field including the founding of the multi-billion start-up Altos Labs. Another longevity target are senescent cells, the removal of which by either genetic or pharmacological means can increase lifespan in mouse models. Here the authors show that combining Yamanka activation with senescence removal has a synergistic effect on lifespan, with the largest effect resulting from transient treatment of both interventions.
Clinical Trial Updates
A Randomized Clinical Trial showing that a sustained low-carbohydrate diet might be a useful dietary approach for preventing and treating type 2 diabetes.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797714
Meta analysis of aerobic exercise improving intelligence and cognitive function in patients with Alzheimer’s disease
UNITY Biotechnology Announces Positive 24-Week Data from Phase 2 BEHOLD Study of UBX1325 in Patients with Diabetic Macular Edema
News
JPMorgan Launches Life-Sciences Venture Group
Crypto entrepreneur Justin Sun, founder of Tron, donate’s 51k USD to the Longevity Prize
https://www.longevityprize.com/
Journal eLife eliminates reject/accept decisions from their review process
https://elifesciences.org/articles/83889
Articles
MIT Technology Review - The Mortality Issue
https://www.technologyreview.com/magazines/the-mortality-issue/#features
Featuring:
The debate over whether aging is a disease rages on
https://www.technologyreview.com/2022/10/19/1061070/is-old-age-a-disease/
Why the sci-fi dream of cryonics never died
https://www.technologyreview.com/2022/10/14/1060951/cryonics-sci-fi-freezing-bodies/
How scientists want to make you young again
https://www.technologyreview.com/2022/10/25/1061644/how-to-be-young-again/
Modern Vampirism: “Young Blood” Transfusions
Blood from young mice has rejuvenating effects on old mice, but it’s too early to translate these results into treatments for humans.
Upcoming conferences
A lot of us are conferenced-out for this year but there is one more meeting with an impressive line up we’d recommend:
The Longevity Summit
December 6-7 | Buck Institute for Aging | Novato, CA
While we’re waiting for more exciting conferences, make sure you’re caught up with the recordings from ARDD and VitaDAO’s own crypto-longevity symposium.
https://www.youtube.com/channel/UClOnplI2mzpJlwdX3vlOMJA
https://www.youtube.com/watch?v=-70SgGJPzTo
Evotec Webinar series focusing on 3 key areas:
- Therapeutic approaches for aging and age-related disease
- Aging and precision medicine
- Why older adults should not be underrepresented in clinical trials.
https://news.evotec.com/a-spotlight-on-aging-webinar-series
Funding Opportunities
Hevolution Foundation Announces Pilot Grants Program for Top Healthspan-Related Research in the United States
Job board
The Schumacher lab is looking for a postdoc to join them at the Institute for Genome Stability in Ageing and Disease, CECAD-Cluster of Excellence in Aging Research, University of Cologne
https://schumacher.cecad-labs.uni-koeln.de/open-positions
Vita therapeutics, a cell engineering company using iPSCs, have two open positions - research associate and a quality assurance director:
https://www.vitatx.com/careers#openpositions
Head of Ops for Longevity Fund - $150K+ salary, higher if you’re significantly experienced. Looking for someone smart and capable with 3+ years of operating at a fast-paced startup or VC firm
email laura@longevity.vc if a fit! $10K referral bonus if you find someone great :)
Longevity Tweet of the Month
Even if you don’t use Twitter, it must have been near impossible to escape the news and debate surrounding Twitter’s new owner Elon Musk and his plans to charge for verification. The author Stephen King took umbrage to this and threatened to leave the platform. Alex Zhavoronkov had an amazing response, leading to the inauguration of our new ‘Longevity Tweet of the Month’:
Alex Zhavoronkov: “I will pay @StephenKing's $20/month twitter for the rest of his life if he writes his scariest book titled "The Biology of Aging" (the concept is so horrifying that after 40, you do not need a costume for Halloween anymore). With @davidasinclair as the savior protagonist 🎃👻💀”
https://twitter.com/biogerontology/status/1587477303671816192
Interview with Dr. Peter Fedichev
Dr. Peter Fedichev describes himself as a "physicist in drug discovery land". With a background in condensed matter physics, biophysics and bioinformatics he has been able to provide a unique perspective to longevity research, for example the 2 papers highlighted in this month's issue. He is currently the CEO and co-founder of the longevity biotech company GERO.
What inspired you to enter longevity research?
I am a physicist by training and did my studies in the field of strongly interacting and correlated systems. I am fascinated with phase transitions and emergence - the ability of complex systems to develop properties that do not exist on the level of their constituent parts. “More is different,” in P. Anderson's words, and we find novel interesting phenomena whenever it applies. Living systems and their gene regulatory networks fall into this category. Somebody brought my attention to negligible senescence (slow or no-aging in some species). I immediately recognized that such aging-resistance might also be an example of emerging property.
Since then, we followed this lead and developed a set of ideas casting the “normal” Gompertzian aging and negligible senescence as two distinct phases of gene regulatory networks differentiated by dynamic stability properties. I am increasingly convinced that negligible senescence is the most important discovery in the field of aging studies. I also see that physics lends great tools for understanding this phenomenon and that achieving negligible senescence is a great scientific, humanitarian, and technological goal.
Which of the current theories of ageing do you think are the most convincing?
Let me answer this question by bringing up the following analogy. In physics, there is the Standard Model. This is by far the best theory ever made. Until very recently (2018), there’s been no single experiment contradicting the theory. Even now, with only a few experiments in neutrino physics falling from the scheme, the discrepancy between the theory and the experiment is abysmal. Nevertheless, the Standard Model is a model, not a theory. This is because everyone knows it is inconsistent and thus can not be a complete theory.
Compare this to the situation in aging sciences. We have a dozen of “theories” of aging. Such an impressive number of “theories” tells us that we do not have a theory of aging. It may look bad, but it is exciting too. Other fields of science lived through the times of such a “zoo” of theories. The physics literature was full of unrelated forces and particles not long ago. We need the grand unified theory of aging, and it will come in due course.
How has the field changed since you started?
The field matures. People do clinical trials. More people in science and the general public believe that lifespan is modifiable. We have more and increasingly better-trained people with diverse scientific and entrepreneurial backgrounds coming into the field (think, for example, of physicists, AI engineers, and crypto-activists joining biologists and medics).
What mistakes do you think the longevity field has made?
There’s been tremendous progress both in understanding aging and translating the growing fundamental knowledge into preclinical and clinical trials. However, most currently developed solutions will produce small effects on par with the effects of lifestyles. For many, this strategy seems to reduce risks. But any working solution in biotech takes 10 years at least to develop fully. Working on weak interventions is a waste of resources and years of life. I would also think of hopes and expectations here. The public and policymakers have high hopes and may end up frustrated if the longevity biotech ends up with “statistically significant” and, at the same time, miserable results.
Other than your own, what do you think have been the biggest/important discoveries in the field?
To my taste, the discovery of negligible senescence - the discovery of advanced animals, such as mammals, that defy Gompertz mortality law is the biggest discovery in the field of aging. This is a very important demonstrator proving that aging is not evitable. Reducing mortality acceleration to almost zero may increase human lifespan a few fold.
What advice would you give to people currently working in longevity research?
Think big - avoid solving unimportant problems even if those lend you a paper in a good journal.
Which aspect of longevity research do you think requires more attention?
Negligible senescence
Is ageing a disease?
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.
Can you explain what you’ve found in your research to be the major difference in the ways different species age (e.g. mice, naked mole-rat (NMR), humans)?
This is a great question. We published two Nature Comms works (a week ago, Unsupervised learning of aging principles from longitudinal data | Nature Communications, and a year ago, Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit | Nature Communications) suggesting that humans and mice belong to two distinct classes of regulatory networks function. Mice are dynamically unstable; their organisms amplify damage, the damage does more damage, and this vicious loop leads to the exponential accumulation of damage. We found that the damage accumulation rate is the same as the mortality rate doubling time, and therefore the inability of the regulatory systems to control damage is the cause of exponential mortality acceleration. On the positive side, aging in mice appears to be mostly reversible.
On the other hand, humans control the damage very well for the most time up until late in life. The transition from the stable to the unstable phase occurs stochastically at some age around 60 due to the gradual loss of resilience, the ability of the organism to regain its homeostatic equilibrium after a shock.
If this is true, aging in mice is the model of late-life morbidity and mortality in humans. Drugs acting in mice and extending their lifespan will improve lifespan beyond healthspan. Since resilience is lost late in life, the effects of such drugs on the human lifespan will be limited.
To develop drugs that could let people live in good health for 150–200 years, we must confront the loss of resilience. This is especially challenging since the resilience is already lost in mice by the age of 25 weeks, if not earlier. This forms what we would call a “preclinical trap”: to convince investors and peer scientists, you have to select drugs that work best in mice. Such interventions, however, could only help people late in life. Unfortunately, the same drugs will provide small effects in healthy people and likely would not affect resilience.
What are the fundamental principles and mechanisms behind negligible senescence in some animals (like NMR) and what causes them to die if there is no increased risk of mortality or frailty over time?
This is an open question. Our models suggest that NMRs and other negligibly senescent animals die of the same diseases. Just the incidence of those diseases (and hence death) does not grow exponentially as we age. Our last publications hint that humans are already almost negligibly senescent. In contrast to mice, humans control the hallmarks of aging for dozens of years until resilience is lost, and all hallmarks of aging and chronic diseases start appearing simultaneously. I believe that humans and NMR belong to the same class of aging systems. NMRs lose their resilience way slower than us, and I want to learn how they do it. Or, better, how to make humans stop losing their resilience.
Could human biology be modified in a way that it utilises those underlying principles of negligible senescence?
The short answer is yes. People are working to find out how. This is what Gero does, and answering this question is my personal scientific goal.
What do you consider “true aging”? And in order to extend healthy life, should we intervene before cellular and organismal loss of resilience?
As I said, we observe that humans are very resilient. More is different, we are not talking at the level of cells. We are describing and measuring the resilience on the level of the organism as a whole. We work with very large datasets of human data and find that it’s very hard to die before resilience is lost. Curiously, according to our measurements, the number of people demonstrating the loss of resilience increases in the population exponentially and doubles every eight years, exactly as fast as the mortality rate doubles. Once the resilience is lost, like in mice, you have just a few years of life left.
Therefore, the loss of resilience is the most fundamental aging phenotype in humans. We call it “true aging” and it is different from the classic hallmarks of aging driving late-life mortality and morbidity. Our worst nightmare came true: this year, we put up a preprint, Aging clocks, entropy, and the limits of age-reversal | bioRxiv, suggesting that the loss of resilience is driven by a thermodynamically irreversible process. If this is true, true aging in humans can not be fully reversed but only stopped. This is the least fortunate outcome of our research, and we had to be very careful trying for a few years to disprove this conclusion.
Our approach is human-centric. We are applying modern AI/ML tools for identifying markers and genetic determinants of true aging in human data. In this way, we aim at the disentanglement of aging and diseases. This helps in two ways. First, it helps people who look for cures for specific diseases. We work with pharma companies to identify novel targets, targeting reversible processes leading to transformative medicines.
Most importantly, we track true aging in real-world medical and genetic data to find genetic factors modifying the rate of true aging. We are making good progress and hope to initiate experiments to test the theories in practice.
Our goal is to make humans negligibly senescent species.
Outro
Thanks for reading our November issue of VitaDAO's Monthly Longevity Newsletter!
Once again, if there is anything you would like us to feature in future issues, please get in contact.
This time we leave you with a thought provoking article in Science from 1972 by Nobel prize winner in physics Philip Anderson - More is Different because even though it’s 50 years old it’s still relevant today. There Prof. Anderson challenges the hierarchical structure of sciences - from physics to biology - and argues that “at each level of complexity entirely new properties appear”:
https://cse-robotics.engr.tamu.edu/dshell/cs689/papers/anderson72more_is_different.pdf
Further Reading
Healthy Aging: Strategies to Slow the Process
https://www.sciencedirect.com/science/article/abs/pii/S0030666522000809
Association of sleep duration at age 50, 60, and 70 years with risk of multimorbidity in the UK: 25-year follow-up of the Whitehall II cohort study
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004109
Does Abdominal Obesity Increase All-Cause, Cardiovascular Disease, and Cancer Mortality Risks in Older Adults? A 10-Year Follow-Up Analysis
https://www.mdpi.com/2072-6643/14/20/4315/htm
A long-term obesogenic high-fat diet in mice partially dampens the anti-frailty benefits of late-life intermittent fasting
https://link.springer.com/article/10.1007/s11357-022-00678-1
Lipid hydroperoxides and oxylipins are mediators of denervation induced muscle atrophy
https://www.sciencedirect.com/science/article/pii/S2213231722002907?via%3Dihub
The time is now: Regular exercise maintains vascular health in aging women
https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP282896
One-year aerobic exercise increases cerebral blood flow in cognitively normal older adults
https://journals.sagepub.com/doi/abs/10.1177/0271678X221133861?journalCode=jcba&
Mitochondria dysfunction and impaired response to oxidative stress promotes proteostasis disruption in aged human cells
https://www.sciencedirect.com/science/article/pii/S1567724922000861?via%3Dihu
The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside
https://www.frontiersin.org/articles/10.3389/fragi.2022.1005322/full#.Y1SIjLKuaWo.twitter
Attenuation by Time-Restricted Feeding of High-Fat and High-Fructose Diet-Induced NASH in Mice Is Related to Per2 and Ferroptosis
https://www.hindawi.com/journals/omcl/2022/8063897/
