30 replies to this topic

[albedo]

This is a highly original and insightful preprint, hopefully to be peer-reviewed soon (1^st version dates Feb 2022). It is highly technical and requires time to follow through the many details both in biology and mathematical modeling (imported from the physics of dynamical systems).

 

Please post here in case you have insight into the paper and know of good discussions going on elsewhere.

 

“We analyze aging signatures of DNA methylation and longitudinal electronic medical records from the UK Biobank datasets and observe that aging is driven by a large number of independent and infrequent transitions between metastable states in a vast configuration space. The compound effect of conguration changes can be captured by a single stochastic variable, thermodynamic biological age (tBA), tracking entropy produced, and hence information lost during aging. We show that tBA increases with age, causes the linear and irreversible drift of physiological state variables, reduces resilience, and drives the exponential acceleration of chronic disease incidence and death risks. The entropic character of aging drift sets severe constraints on the possibilities of age reversal. However, we highlight the universal features of configuration transitions, suggest practical ways of suppressing the rate of aging in humans, and speculate on the possibility of achieving negligible senescence.”

 

Tarkhov AE, Denisov KA, Fedichev PO. Aging Clocks, Entropy, and the Limits of Age-Reversal. Systems Biology; 2022.

 

There are several good videos on YouTube by one of the authors, Peter Fedichev (CEO of Gero), and also a recent interview on Lifespan.io explaining the main points of his theory of aging, e.g. here: https://www.lifespan...heory-of-aging/

 

[albedo]

Google Scholar provides the following 5 citations:

 

https://journals.bio...io059750/287042

https://www.frontier...23.1129107/full

https://link.springe...439-023-02529-1

https://www.biorxiv....509592.abstract

https://www.frontier...022.828239/full

[albedo]

I wonder why this paper is not discussed more in the community. Possibly its technicality or maybe that is fundamentally wrong? I also wonder why it is taking so long to publish! Maybe all of this ....?

[albedo]

One telling comment from Brian Kennedy:

 

 kennedy fedichev.jpg   138.72KB   0 downloads

[Rocket]

Everything is reversible. You can even reverse air to make fuel and uncook eggs.

[albedo]

Gero approach and theory explained here in general terms by Dr. Peter Fedichev, CEO:

 

https://www.lifespan...heory-of-aging/

 

[albedo]

The paper in my original post above (still not published) is a bit too synthetic and highly technical for a good understating.

 

The team has published a lot too and you need to navigate through a lot of material, if interested.

 

In my view and if I can be of any guidance the insight and more easily readable content can be found here:

Fedichev PO. Hacking aging: a strategy to use big data from medical studies to extend human life. Front Genet. 2018;9:411329.

 

The more fully developed technical formalism is here and in the references therein (particularly [54], [55])

Podolskiy D, Molodtcov I, Zenin A, et al. Critical dynamics of gene networks is a mechanism behind ageing and Gompertz law. arXiv:150204307 [physics, q-bio]. Published online November 23, 2016.

 

I am fascinated by these ideas which I am trying to assimilate.

[albedo]

In general there is a disagreement between Aubrey and Fedichev, but i guess this is in general regarding the interpretation and both approaches (I love both..) are necessary to fight a common enemy. The image is from a thread on Reddit

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[albedo]

The recent Gero-Foxo agreement might bring validation to the theory developed in the paper:

 

(Aug 2023) "...The firms are now coming together first to validate some of Gero's earlier work, with the hope that a collaboration could eventually inform clinical studies, according to Foxo CSO Brian Chen.

Fedichev and two Gero colleagues published a preprint on BioRxiv last year that explored the notion of a "thermodynamic biological age" that they based on DNA methylation signatures and longitudinal electronic medical records gleaned from UK Biobank.

"This is cooperation with the goal to better understand the dynamics of human aging [with] one of the most variable sources of data, which is DNA methylation," Fedichev said.

The epigenetic data Gero used to this point has been cross-sectional. The company was attracted to Foxo because like UK Biobank, the latter has a collection of longitudinal DNA methylation data, according to Fedichev.

"They have some biological insights that they've discovered through other datasets, and they would like to first apply that to our longitudinal datasets," Chen explained.

Foxo has both long-term and shorter-term longitudinal data, from a variety of sources, the largest of which is the Physicians' Health Study, a large-scale trial initiated by Brigham and Women's Hospital in 1982, according to Chen.

"That allows us and Gero to look at how resilient or how persistent or how stable certain measurements are over time, especially in relation to some sort of … anti-aging intervention or any other lifestyle interventions," he explained. "And that gives us insights as to whether we could actually change these measures or if there's an inherent state that's very stable."..."

https://www.genomewe...xo-technologies

[albedo]

The paper in my original post above (still not published) is a bit too synthetic and highly technical for a good understating.

 

The team has published a lot too and you need to navigate through a lot of material, if interested.

 

In my view and if I can be of any guidance the insight and more easily readable content can be found here:

Fedichev PO. Hacking aging: a strategy to use big data from medical studies to extend human life. Front Genet. 2018;9:411329.

 

The more fully developed technical formalism is here and in the references therein (particularly [54], [55])

Podolskiy D, Molodtcov I, Zenin A, et al. Critical dynamics of gene networks is a mechanism behind ageing and Gompertz law. arXiv:150204307 [physics, q-bio]. Published online November 23, 2016.

 

I am fascinated by these ideas which I am trying to assimilate.

 

Compared to the second link I posted here, the section "Aging and critical dynamics of the organism’s state (the summary of theoretical results)" of the following paper published in Nature Communications provides a simplified version of the main theoretical results. Yet the link I cited contains the in depth full formalism derivation.

 

Avchaciov K, Antoch MP, Andrianova EL, et al. Unsupervised learning of aging principles from longitudinal data. Nat Commun. 2022;13(1):6529.

https://www.nature.c...YZTbZoKJdfC8q4Q


 

[albedo]

I recollected and compared a couple of readings from my previous research.

 

The following paper in Nature, somewhat countered by Aubrey here , seems to reach similar conclusion as Fedichev’s work. I compared two excerpts (a) and (b)

 

(a) From Dong X, Milholland B, Vijg J. Evidence for a limit to human lifespan. Nature. 2016;538(7624):257-259.

 

“…Hence, in contrast to previous suggestions that human longevity can be extended ever further1, our data strongly suggest that the duration of life is limited. In the past, others have suggested that human lifespan is limited. For example, in 1980 Fries argued that increased prevention of premature deaths would lead to a compression of morbidity owing to a finite lifespan10. However, his arguments for such a limit to life, that is, the lack of a detectable increase in centenarians or in the maximum reported age at death, while correct at that time, have been refuted since2,6. Ten years later, Olshansky et al.11 estimated the upper limits to human longevity based on hypothetical reductions in mortality rates, concluding that life expectancy at birth would not exceed 85 years. Like Fries, Olshansky et al. also suggested a biological limit to life based on the lack of an increase in the age of the verified longest-lived individual. However, as they mention, insufficient data prevented them from drawing definite conclusions. Now, more than two decades later, such data are becoming available. With the caveat that the ages at death of the supercentenarians in our present study are still noisy and made up of small samples, we feel that the observed trajectories in Fig. 2 are compelling and our results strongly suggest that human lifespan has a natural limit…”

 

(b) From Tarkhov AE, Denisov KA, Fedichev PO. Aging clocks, entropy, and the limits of age-reversal. bioRxiv. Published online October 11, 2022:2022.02.06.479300.

 

“… In agreement with Eq. 2, the extrapolation shows that the inverse variance of DNAm-PC3 hits zero and hence the variance of DNAm-PC3 diverges at approximately 120 years (see the solid line in Fig. 1d). The estimations of the limiting age from the behavior of DNAm-PC3 mean and its variance are comfortably close. Hence, our calculations support the existence of a critical point in the age range of 100-150 years…”

 

“…we demonstrated that linear log-mortality predictors built from complete blood counts (CBC) and physical activity [17] also exhibited diverging fluctuations and a vanishing recovery rate at about the same limiting age tmax 130 years…”

 

Moreover, the mortality deceleration might also be explained by Fedichev’s et al research:

 

 Screenshot 2023-11-04 210908.png   63.49KB   0 downloads

 

https://arxiv.org/abs/1502.04307

 

or here too:

 

 Screenshot 2023-11-05 121155.png   68.88KB   0 downloads

 

https://www.nature.c...YZTbZoKJdfC8q4Q

 

 

There was also a related topic related to the mortality slow down also touched here:

 

https://www.longecit...ndpost&p=827494

 

 

Thank you in advance for any comment you might provide!

 

 

[albedo]

Clearly there is a point which would need to be addressed (epigenetic reprogramming and Shannon's observer as pointed by D Sinclair with his Information Theory of Aging). So far I did not find much by the team and would appreciate if you could provide additional resources:

 

 Screenshot 2023-11-05 123207.png   296.91KB   0 downloads

 

 Screenshot 2023-11-05 123532.png   57.23KB   0 downloads

 

 

[albedo]

Clearly there is a point which would need to be addressed (epigenetic reprogramming and Shannon's observer as pointed by D Sinclair with his Information Theory of Aging). So far I did not find much by the team and would appreciate if you could provide additional resources:

 

Screenshot 2023-11-05 123207.png

 

Screenshot 2023-11-05 123532.png

 

After a little of research some elements of reply maybe are here (by some of same authors)

 

"...

It is important to note that our analyses are limited to the process of functional aging, and do
not consider the effects of rejuvenation therapies on the epigenome48–50. Stochasticity of
age-related epigenetic changes does not imply the impossibility of reversal, as is the case
for epigenetic reprogramming protocols resetting the DNAm patterns. At the same time,
stochasticity behind the process of accumulation of epigenetic changes with age does not
preclude programmatic behavior, a quasi-program of aging, defined by the developmental
biology predisposing species to follow a particular aging trajectory. Moreover, components of
the stochastic part of epigenetic clocks would be predetermined by development and
biological organization of the organism. The sites that were initialized in the hypo- or
hyper-methylated states by the end of early development would tend to stochastically gain or
lose methylation with age, hence they would make good candidates for epigenetic clock
CpG sites. Thus, the developmental program initializes the epigenome into a state that later
stochastically decays during aging. Therefore, the multispecies epigenetic clocks51 may work
well because closely related species, such as mammals, share the associated
developmental biology setting them into similar initial states of the epigenome. Overall, the
effects of early embryonic development on aging need to be further investigated30,52.
The question of the biological meaning of existing epigenetic clocks deserves separate
discussion. The causal relationship between the molecular changes during aging and
functional decline resulting in mortality is also the subject of an ongoing debate. A highly
desirable feature of aging clocks is the ability to predict mortality events and lifespan;
however, the state-of-the-art epigenetic clocks continue ticking in immortalized cell
cultures18,19 and in naked-mole rats20,21, where mortality exhibits minimal changes with age.
These observations raise questions about the use of epigenetic clocks for the prediction of
mortality. At the same time, the absence of a mechanistic explanation behind epigenetic
clocks impedes their clinical use as aging biomarkers..." (red mine)

 

Tarkhov AE, Lindstrom-Vautrin T, Zhang S, et al. Nature of epigenetic aging from a single-cell perspective. bioRxiv. Published online October 29, 2023:2022.09.26.509592.
https://www.biorxiv.....09.26.509592v2
 

Edited by albedo, 26 November 2023 - 10:52 PM.

[Mind]

I wonder why this paper is not discussed more in the community. Possibly its technicality or maybe that is fundamentally wrong? I also wonder why it is taking so long to publish! Maybe all of this ....?

 

My opinion about why this theory/finding is not discussed more is that it does not say anything fundamentally new about aging or its possible reversal. I could summarize:

 

Entropy always increases - second law of thermodynamics.

 

The entropy of our body - physical state - will increase after puberty leading to aging, death, and decomposition. We know that the body has regenerative capability. We just have to figure out a way to keep that going (activate it) as we age. This requires energy input, to reverse (or lower) entropy.

 

Rejuvenation researchers are working on the problem. Talking about how "entropy increases" seems like an unimportant side show.

[albedo]

@Mind. I am of the opinion to first understand things before acting. If we want to have a chance to fight aging to me is first try and understand what it is, increasing of entropy is almost a tautology, and while the paper is a conjecture which might be refuted it looks to have a high explication power. My issue is rather with the robustness of the theoretical model.  It might explain why PC1 out of the PCA analysis goes linearly, why variance goes linearly, why time to recovery goes down, why Gompertz's law works at all, why we might have a deceleration of mortality, why several theories of aging might converge, why acting on one of the aging hallmarks might impact others, why epigenetics clocks might work, why mouse might be not the best animal model, and others which I need to get my head around. So I think it is unfair to say it says nothing news and is just a restatement of a 2nd law of thermodynamics applied to aging, that is to be quite obvious. They are trying to recast aging as a dynamics of complex non linear interacting systems using physics and mathematical framework (its is called also synergetics) which has an extraordinary explication power in a large range of disciplines quite far from each other at first sight. And yes it agrees with the entropy view of aging going back to Hayflick. Also I think you would agree it is not only a matter of energy input but also and foremost of information input (read for example epigenetics): even when you are burned at death you are having a massive input of energy not clearly bringing you back to life, what is needed is an addition of information and organization as well ...

Edited by albedo, 27 November 2023 - 03:49 PM.

[Mind]

@Mind. I am of the opinion to first understand things before acting. If we want to have a chance to fight aging to me is first try and understand what it is, increasing of entropy is almost a tautology, and while the paper is a conjecture which might be refuted it looks to have a high explication power. My issue is rather with the robustness of the theoretical model.  It might explain why PC1 out of the PCA analysis goes linearly, why variance goes linearly, why time to recovery goes down, why Gompertz's law works at all, why we might have a deceleration of mortality, why several theories of aging might converge, why acting on one of the aging hallmarks might impact others, why epigenetics clocks might work and others which I need to recollect from some of the production the authors had. So I think it is unfair to say it says nothing news and is just a restatement of a 2nd law of thermodynamics applied to aging, that is to be quite obvious. They are trying to recast aging as a dynamics of complex non linear interacting systems using physics and mathematical framework (its is called also synergetics) which has an extraordinary explication power in a large range of disciplines quite far from each other at first sight. And yes it agrees with the entropy view of aging going back to Hayflick. Also I think you would agree it is not only a matter of energy input but also and foremost of information input (read for example epigenetics): even when you are burned at death you are having a massive input of energy not clearly bringing you back to life, what is needed is an addition of information and organization as well ...

 

Yes. Information and energy are inextricably linked through the mathematical formulation of the 2nd law of thermodynamics.

 

The human body is an extremely complex system and "systems analysis" of aging is probably a good thing in order to measure the effectiveness of any therapies. I am only afraid that focusing too much on high-level complex theories of aging instead of getting results from human trials (even if it is a "trial and error" approach) will delay the development of beneficial therapeutics and strategies that could be used right now.

[albedo]

Related ...

https://pubmed.ncbi....h.gov/38102202/

[albedo]

Two works citing the original work I posted and somewhat supportive:

Pridham G, Rutenberg AD. Dynamical network stability analysis of multiple biological ages provides a framework for understanding the aging process. arXiv:230910005 [q-bio]. Published online December 27, 2023.

Pridham G, Rutenberg AD. Network dynamical stability analysis reveals key “mallostatic” natural variables that erode homeostasis and drive age-related decline of health. Sci Rep. 2023;13(1):22140.



 

[albedo]

Also related and somewhat supporting generally the original post work:

 

Nielsen PY, Jensen MK, Mitarai N, Bhatt S. The Gompertz Law emerges naturally from the inter-dependencies between sub-components in complex organisms. Sci Rep. 2024;14(1):1196.

 

Cohen, A.A., Ferrucci, L., Fülöp, T. et al. A complex systems approach to aging biology. Nat Aging 2, 580–591 (2022). https://doi.org/10.1...587-022-00252-6

 

[albedo]

A new preprint is just out building on the OP paper:

 

Perevoshchikova K, Fedichev PO. Differential responses of dynamic and entropic aging factors to longevity interventions. bioRxiv. Published online February 28, 2024:2024.02.25.581928.

Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz law’s description of mortality acceleration. This signature is the manifestation of the dynamic instability in the organism’s state that drives the aging process in mice. It aligns closely with regression-based aging clocks and responds to interventions such as caloric restriction and parabiosis. Additionally, we identified a linear DNAm signature, indicative of a global demethylation level. Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.

 

[albedo]

A new preprint is just out building on the OP paper:

 

Perevoshchikova K, Fedichev PO. Differential responses of dynamic and entropic aging factors to longevity interventions. bioRxiv. Published online February 28, 2024:2024.02.25.581928.

Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz law’s description of mortality acceleration. This signature is the manifestation of the dynamic instability in the organism’s state that drives the aging process in mice. It aligns closely with regression-based aging clocks and responds to interventions such as caloric restriction and parabiosis. Additionally, we identified a linear DNAm signature, indicative of a global demethylation level. Through single-cell DNAm (scDNAm) data from aging animals, we demonstrate that this signature captures the exponential expansion of the state space volume spanned by individual cells within an aging organism, and thus quantifying linearly increasing configuration entropy, likely an irreversible process. Consistent with this interpretation, we found that neither caloric restriction (CR) nor parabiosis significantly impacts the entropic feature, reinforcing its link to irreversible damage.

 

Here is what the corresponding author (Peter Fedichev) posted on LinkedIn about the new results:

 

"Ladies and gentlemen, two years ago, we theorized that aging results from a mix of "wear and tear" - an entropic, seemingly irreversible process, and a dynamic instability of the organism state. We suggested human aging is mostly of the first kind - entropic, whereas in mice, the dynamic instability dominates. If the proposed picture is correct, most known treatments would primarily target the dynamic aspects. We believed entropic aging couldn't be reduced, as entropy naturally resists decrease (I know you are kidding about open systems), though its pace might be slowed.

Two years on, we were able to test some of those ideas and found that: (a) mice also experience entropic aging, evidenced by a linear pattern in DNA methylation (DNAm); (b) aging clocks largely detect dynamic aging features, seen in the exponential pattern of DNAm; © the linear DNAm pattern's entropic nature is verified through single-cell DNAm analysis; (d) dynamic aging features are mitigated by anti-aging interventions; however, (e) such interventions don't affect the entropy production in aging mice (see https://lnkd.in/ePtJVZBG).

For half of the people this sounds obvious. Remarkably, this half is almost always not from the geoscience circle. Entropy in data has a distinct look and feel, or even smell. It does not smell well, if you want to control such a process by means available to modern biotechnology. While single-cell analysis is insightful, in the retrospect, it's not essential for confirmation. Achieving complete age reversal in humans will be profoundly difficult - I am sorry for that."

 

[albedo]

Interesting ...

Author's lay terms explication on the OP paper is from about the mid of the podcast:

https://www.vitadao....science-podcast

Edited by albedo, 05 May 2024 - 12:16 PM.

[albedo]

A paper from A Tarkhov (co-author of the OP paper) has made its way into Nature:

 

Tarkhov AE, Lindstrom-Vautrin T, Zhang S, et al. Nature of epigenetic aging from a single-cell perspective. Nat Aging. Published online May 9, 2024:1-17.

 

and two also in Nature are related and published at the same time:

 

Meyer DH, Schumacher B. Aging clocks based on accumulating stochastic variation. Nat Aging. Published online May 9, 2024:1-15.

Tong H, Dwaraka VB, Chen Q, et al. Quantifying the stochastic component of epigenetic aging. Nat Aging. Published online May 9, 2024:1-16.

 

I need to dig on each but they look basically cross-confirming each other.

Edited by albedo, 10 May 2024 - 09:54 PM.

[albedo]

Aubrey de Grey and Peter Fedichev (co-author of the OP paper) debate - 28 05 2024

 

[albedo]

I think, in the context of this thread, Fedichev's reply to a known 2017 paper in PNAS by Nelson & Masel (https://www.pnas.org...pnas.1618854114) on the inevitably of aging is important:

 

https://medium.com/h...ng-8b677d9b7d69

 

Also this counters the somewhat "negative" feedback which the OP paper has stirred.

Edited by albedo, 03 June 2024 - 10:12 AM.

[albedo]

OP: peer-reviewed and published:

https://agingcelljou...lume2/20240031/

[kurt9]

This suggests the appropriate approach to age reversal is not epigenetic reprogramming of cells. But rather a replacement technique. I believe the "Turnbuckle" protocol, elsewhere on this forum, and an example of one such technique.

[QuestforLife]

I am not sure this is an fruitful line of enquiry. Of course a body cannot be maintained against entropy indefinitely. But entropy doesn't care if it wins in 10 years or 1000 years, but that makes a big difference to me. 

[albedo]

@Questfor Life. Of course I agree with you. However, if I interpret correctly your thoughts and the paper, the latter justifying to slow entropy increase (any maybe stop it) your comment and the paper should be in agreement, IMHO.

[albedo]

OP: peer-reviewed and published:

https://agingcelljou...lume2/20240031/

 

The main equation in the text, refer to it for the explication of symbols and interpretation of this model of aging and supportive data:

 Screenshot 2024-11-03 103234.png   94.18KB   0 downloads