Epigenetics and the Direction of Anti-Aging Science

Dear Readers –

It’s been a deeply gratifying year for me.  Twenty years ago, I first started writing that aging is something the body does to itself, a body function, rather than deterioration or loss of function.  Journals would not even send my submission out for peer review.  Journal of Theoretical Biology sent me the considered opinion of their anonymous reviewer, “JTB shouldn’t touch this topic with a ten-foot pole.”  The conflict with prevailling evolutionary theory was just too deep.

But in the interim, the evidence has continued to pile up, and many medical researchers have taken the message to heart in a practical way, setting aside the evolutionary question and just pursuing approaches that seem to work.  The most promising developments in anti-aging medicine involve changing the signaling environment rather than trying to “fix what goes wrong” with the body.

My popular book exploring the evolutionary origins of aging (and implications for medical science) came out in June, and an academic version of the same content came out in October.  Gandhi taught me,

“First they ignore you…
then they laugh at you…
then they fight you…
then you win.”

The paradigm of programmed aging passed this year from stage 2 to stage 3, with prominent articles arguing against the possibility of programmed aging [Kirkwood, de Grey, Vijg & Kennedy].  Current Aging Sciences devoted a full issue to the question.  I welcome the discussion.  This is a debate that colleagues and I have sought to initiate for many years.  There are powerful theoretical arguments on one side, and diverse empirical observations on the other.  The scientific community will eventually opt for empiricism, but not until theory digs in its heels and fights to the death.  A basic principle of evolution is at stake, and many theorists will rise to defend the basis of their life work; but a re-evaluation of basic evolutionary theory is long overdue.

The idea that fitness consists in reproducing as fast as possible is no longer tenable.  For plants, this may be approximately true.  But animal populations cannot afford to reproduce at a pace faster than the base of their food chain can support.  Animals that exploit their food supply unsustainably will starve their own children, and there is no evolutionary future in that.  This is a principle that links together entire ecologies, and the foundation of evolutionary theory will have to be rewritten to take it into account.

 

The Programmed Aging Paradigm: Is it a Cause for Optimism in the Quest for Extended Human Life?

For many years, I put forward the argument that programmed aging means there are genes that serve no other purpose than to hasten our death, and that medical research should be targeting the products of those genes.  (Once a pathway has been identified, pharmaceutical science knows well how to block it with engineered drugs, like beta blockers and MAO inhibitors and serotonin re-uptake inhibitors.)

But in recent years, epigenetics has eclipsed genetics as the major theme in molecular biology.  Everything that happens in the body is determined by which genes are expressed where and when.  The vast majority of our DNA is devoted not to coding of proteins but to promoter and repressor regions that control gene expression with exquisite subtlety.

There has been a growing recognition of aging as an epigenetic program.  As we get older, genes that protect us are dialed down, and genes for inflammation and apoptosis are dialed up so high that healthy tissue is being destroyed.  Many epigenetic scientists have discovered this, and they find it natural to see aging as a programmed phenomenon.  (Most have never been to graduate courses in evolutionary science, where they would have been indoctrinated into the perspective of the selfish gene.)

At first blush, it seems that an epigenetic program is just as amenable to pharmaceutical intervention as a genetic program.  A few years ago, I wrote about transcription factors as the key to aging.  Transcription factors bind to DNA and turn whole suites of genes on and off in a coordinated way.  If we can restore a youthful transcription environment in an older animal or human, the body knows how to repair damage and re-create a younger self.  The model I had in mind was based on a small number of powerful transcription factors controlling expression of a much larger number of genes, controlling a yet larger population of metabolites.

I no longer believe in this model.

This summer, I had a chance to work in a worm genetics lab and consult closely with people who know the experimental details.  I learned that there is no clear line between functional proteins and transcription factors, that many proteins have multiple functions, and that metabolites feed back to control gene expression.  Instead of a pyramid, I should think of a web of causes and effects.

The entire system is primed for homeostasis, meaning that it responds to any intervention, seeking to move the system back toward its previous state.  Of course, it is this capacity for recovery that makes life robust; but it also means that there is no “command central” which can be tweaked to move the whole system at once toward a desired state.

I still believe that there are one or more aging clocks that inform the body of an age-appropriate metabolic state, and synchronize the aging of different systems.  Telomere length is one such clock.  If we can reset an aging clock, the body will repair and clean itself up.  If we can reset several clocks, the body may be able to restore itself to a younger state.  But I recognize the possibility that the clock is diffused through the detailed epigenetic status of a trillion cells, and may be beyond the reach of foreseeable technology.

A few years ago, Steve Horvath of UCLA gave us the most explicit picture of an aging clock.  He found it in one particular epigenetic marker: the pattern of DNA methylation.  The Horvath clock is distributed over 353 sites.  This is a clock that can be read for any given cell, but can it be changed or adjusted in each of the body’s trillions of cells?  The prospect is daunting, and we do not yet know how to go about it.  2016 saw the first use of CRISPR technology for therapy in a living human.  CRISPR could, in principle, be used to alter gene expression, one gene at a time.  To re-regulate the expression of 353 genes in one treatment would probably require new concepts and new discoveries.

Short of resetting the aging clock, there are several technologies just over the horizon that should offer substantial life extension benefit.  I believe the best prospects are senolytics (ridding the body of senescent cells), telomerase activators (rejuvenating old stem cells), and adjusting blood levels of key hormones and cytokines that increase or decrease with age.

 

The Bottom Line

Programmed aging is the right model to keep in mind as we search for interventions that slow the aging process and lessen the incidence of heart disease, cancer and Alzheimer’s all at once.  Prospects are good for real breakthroughs, perhaps as soon as 2017, but I am no longer as optimistic as I was just a few years ago that complete rejuvenation is on the horizon.

Wishing you health and vitality for the coming year,

 

 

 

– Josh Mitteldorf

43 thoughts on “Epigenetics and the Direction of Anti-Aging Science

  1. Michael Fossel has similar opinions about aging and he is studying the mechanisms of aging for over 35 years… but he got funds and research grants and now he is very close to solve the mystery and cure all so called age-related-diseases. I had interviewed him twice and he told me that.

    • Michael is a friend of mine but let’s wait and see what the data shows us before we jump to any conclusions. For my money Hallmarks of Aging is the most accurate picture of what aging is because it incorporates aspects of damage and program including epigenetics and telomeres unlike SENS.

  2. Aging and Immortality: Quasi-Programmed senescence and its Pharmacologic Inhibition 2006, Blagosklonny, set forth the idea that aging is not programmed at all but plays out as a quasi-program, a program that after completion of program doesn’t get turned off.
    As stated by Kirkwood, “If genes program aging, they do so only very loosely. This is in sharp contrast to the developmental process, which is so precisely regulated.” Kirkwood concluded, “either the program for aging is extraordinarily robust or that it does not exist at all.”
    The idea that aging is programmed is the opposite of modern aging theory; at least as expressed by Blagosklonny for past 10 years.

  3. Josh, I agree with you that aging is clearly programmed. Otherwise the widely different lifespans of different species could not occur. But I still keep my model more like a pyramid than a diffuse net.

    What I think about your proposal here is that it lacks trying to explain why different animal species have so different longevities . And that is the most important point if we want to go up from just 1.4 fold to 2, 4, 6, or 10 fold life extension.

    Between species lies the “big effect”. The one needed to understand how nature varies so much the endogenous aging rate.

    Studying, or thinking in just one single species, or comparing only what happens from young to old in a single species (does not matter if it is TFs, epigenetics or whatever) is not the answer to the most important thing we need to know. We will never understand aging thinking and working on a single species model.

    In addition, most changes in old age (including epigenetics, et cetera) are consequences of aging, not its causes. So the classic young vs. old approach generates much confusion. The fundamental cause/s of aging are there already in the young. They should be looked for in the young. They occur in the young rat at a 30 fold quicker pace than in the young human.

    Comparing young with old only works if the parameter we measure is the thing/s that irreversibly accumulate during aging and causes de final irreversible damage and loss of function and homeostasis. Such old vs. young approach should be restricted to those parameters (I mean, for people who is truly interested in defeating aging)

    • Aging is clearly not programmed and the evidence supports a model closer to the Hallmarks of Aging than either extreme. Clearly the aging process includes timed processes such as thymic involution, telomere attrition which are more predictable but it also includes stocastic elements like epigenetic changes, genomic instability, inflammaging and crosslinks which are stocastic in nature. I dont see why some researchers have to insist its one extreme or the other when the data suggests its a mixture.

      • The program causes many of those apparently stochastic changes. That is why they occurr at absolutely different speeds in different species.

        • Crosslinks are a purely stochastic process and so are things DNA damage and mtDNA mutations.

          Yes altered intercellular communication plays a significant role in housekeeping and the immune systems decline is a somewhat timed process as is stem cell depletion but that does not make the entire process a program.

          As I said previously, aging is clearly a mixture of program and damage with them both interacting closely. One look at Hallmarks of Aging and related works makes that very clear.

          • Unless of course you can present supporting evidence that crosslinks, DNA mutations and mtDNA are not random. However the weight of clinical evidence thus far does not support that.

            Telomere attrition, immunosenescence and a number of processes are clearly regulated but that only further reinforces the idea that aging is a mixture of the two and is not one extreme or the other.

            The recent SALK research shows epigenetic changes are part of the process and these changes are influenced by altered intercellular communication which again supports the idea that there are stochastic and more regulated processes at work here.

        • Exactly Josh. Altered intracellular communication and epigenetics is a big part of the puzzle here and they clearly can change phenotype whne changed. I certainly dont think aging is exclusively damage or program because to my eye there are elements of both here.

          I expect the recent SALK work pleased you as it proves epigentics has a big influence on lifespan and was for me vindication of Hallmarks which said they believe it does but there was no evidence in 2013?

          • What is called aging is basically the interaction of two different processes:

            1) Epigenetic program
            2) “Post-aging diseases”

            The latter consists of stochastic damage already occuring in early childhood, resulting in diseases like Amyloidosis, Lipofuscinosis etc. on a time-dependent basis.

            Of course both phenomena interact with each other!

  4. All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident. – Arthur Schopenhauer.

    Jeff Bowles hypothesizes that our body uses vitamin D as a proxy for food availability on an annual basis. When food is scarce (winter) our body is miserly with our nutrients and puts our body into a hibernation-like state. Repair work is deferred until summer when there is more food (and vitamin D).

    I hypothesize that vitamin A is used as a proxy for food availability on an lifetime basis. Vitamin A is found in the liver. When humans capture an animal to eat there is only so much liver to go around. If the population is large then the elderly won’t get as much liver to eat as when the population is small. This way evolution doesn’t have to kill off the old people when there is sufficient food to sustain a larger population.

    We know that both vitamins A and D cause thousands of genes to switch on or off. I’m going to be sure to keep my body’s level of fat soluble vitamins (A, D, E, K2) in the high end of normal.

    Does less sun mean more disease?
    https://youtu.be/5tglP1YJdMc

  5. I enjoyed Josh’s Cracking the Aging Code. But I have a comment I’ve been itching to make, which regards the impact of any mutation that resulted in greater longevity.

    First, if a parent remained healthy and fertile past the age of sexual maturity of offspring, the offspring would most likely mate with the parents since they are close by. That would immediately negate the advantages of sexual reproduction.

    If a parent remained healthy but infertile, the offspring would mate with the parents without producing a new generation. In animals that engage in mating based on appearances, you need infertility to be on display as unattractive.

    Thus is no mystery that super longevity genes have not evolved; they would destroy themselves. So I don’t think it requires any group selection.

    If we do find a way to stop or reverse aging, we’ll have to rely on morals to prevent inbreeding.

    • Bill –
      You raise questions that have no simple answers. People’s definitions of group selection varies. At one extreme, some define it as the same as kin selection. At the other extreme, some people define it in a way that by definition it can’t exist.
      Instincts that keep siblings and parent-child from mating are many and diverse in different species. Yes, it’s important enough that evolution has paid a lot of attention. No, it doesn’t require senescence to keep parents from mating with offspring. Think of deer that produce a couple of fauns every spring. By the next spring, the fauns are mature and could mate with each other or with their parents, but they don’t.
      – Josh

      • It’s true that effects like the westermarck effect and other inbreeding avoidance mechanisms can generally deal with inbreeding to an extent.

        But the presence of members the previous generations, has other effects. Not only can this result population collapse if the birth rate and death rate are not highly in tune, but it also presents the fact that the older organisms are competing with the younger organisms.

        In animals that learn, an older organism with far more experience, cannot be expected to be as likely to die as a younger organism with less experience.

        There is also several potential problems to genetic quality and genetic diversity.

        One a certain subset of animals barring aging would be the least likely to die, and this would continue to be so indefinitely, their lineage would likely share these traits, and outcompete most of the rest of the population overtime composing more and more of the population, probably even within reasonably short evolutionary time. You can imagine that as this fraction outcompeted the rest, eventually genetic similarity would result.

        Two inbreeding avoidance may work with direct kin, and slightly indirect kin, but it would likely get weaker as the number of generations between increased.

        Three, unless gamete quality was kept indefinitely, it is conceivable that mutation accumulation in the rapidly dividing germ line could result in decreased genetic quality of the population, thus you’d have fit organisms that would be the longest lived outcompeting the less fit yet reducing the fitness of the population by introducing ever more errors into the gene pool as they grew older but outcompeted most(note they and their direct lineage would be the least likely to die, and the population would be in danger as they continued to damage the gene pool).

        Two things, first even very minor detriment to young animals from having to compete with previous generations would likely be selected against. Two, if gamete quality declines age related dependent manner, as we saw with inbreeding avoidance, mechanisms can come into play to ensure gene pool quality is maintained, rather than evolve drastically increased germ line repair and maintenance to avoid decline in progeny quality(something that may slow or hamper evolution which is dependent on mutation.), it may be easier to evolve a mechanism to kill the adult organisms.

    • Not quite…. if we keep in mind that we already passed through doubling the lifespan several times in the last 2000 years… first from slaves era when the average was about 20 years to dark ages when it was 40 years and then since 1850 (the end of the Little Ice Age) until present doubled again to 80 years…. The genes did not destroyed themselves… however, the problem, from my perspective, is the speed of change, not the age itself… We are going to double the lifespan again, not in 1000 years, not in 200 years but in less then 50 years…. We would not have the infrastructure ready to create jobs, homes, things we need… Michael Fossel told me in the interview that we should create our own business and jobs and not wait for someone else to give them for us… yet, on the other hand … we cannot be all 7 billions entrepeneurs, businessman, developers… so obviously some of them should thinks for the others who may not have the skills to create their own jobs… The other question raised here I also asked Michael in my interview, regarding if we would be really having the capability of sexual reproduction at an age like 120 years-old or more…. and he said “I don’t know” … so first we have to answer this question in order to understand if we would rather mate with our own parents when they would be “like” us, visually… Metaphorically the movie called “In Time” …. has a good illustration … o society where time is a product and is selling in excgange for work… and you got some extra “hours” or days,… the very rich men got “centuries” …. so on. Please watch both of these parts here and shortly in few weeks I’ll upload the other two parts interview in the same area https://www.youtube.com/watch?v=8DCbrNe0PbM&index=1&list=PLm7uyPwcHexJsTNrrzJnA5jq3GQg4p8Hg

      • Things have to be taken in the context of technological progress. It is likely that within a century full automation will be possible, no one will be forced to work to live, they will work, but it won’t be necessary for society, and they will do so optionally.

        Now, as to whether we will be able to reproduce, I’ve heard gamete quality declines over time, it is likely mutations would accumulate, either more thorough repair and maintenance mechanisms would have to be put internally in place, or we’d have to perform external repairs on a person’s reproductive cells. Right now, sperm and egg cells, iirc, have been generated from other cells in the body of animals. So, it’d be extremely unlikely that we’d lose reproduction ability considering technological future progress.

        That said, if we reduce death from disease, crime, accident, and all causes near zero, it is obvious the birth rate must go near zero too. And that is basically impossible voluntarily, so eventually as medicine progresses and eliminates more and more diseases, as we automate things like driving, and as we make everything safer to account for our increased longevity, we will have to regulate reproduction.

        If reproduction is regulated, indefinite lifespans can be sustained indefinitely.

        • I don’t imagine a society in which, those who only choose as an option, not to work, they’ll also get food and shelter for free… Today’s society is one based on money… if you can’t produce a work which get money in return, then you just cannot exist within the society… it’s a money based society… in my country, such “options” will not be available for hundred of years or ever…. I know how things works here… and we see the others as an impediment and not a useful workforce … that’s why the rate of unemployed is huge, criminality rate rising… Alzheimer patients now almost 3% of the entire 20 millions – that is between 500-700 thousands has this disease…. Over 7 millions have back pains, chronicle back pains uncurable…. and now we double the life span without knowing how all these people will have any resources for living, no jobs, no pensions, lower living level…

          • Christian, currently 2,024,180 americans are employed as laborers within the transport sector. Many of these jobs will be lost due to automation during the next 10-20 years. It is unrealistic to think that we can just up-qualify a truck driver to become e.g. an IT engineer or biochemist. Are we going to see these people sick and starving in the streets. I don’t think so. Lets be realistisc..

  6. Great article and comments. In your section on anti-aging technologies, you did not mention what we can do personally to improve our chances of a longer life. Some of them involve supplements (such as weak telomerase activators, Vitamin D, …), aerobic exercise and likely periodic fasting. I think the combination of these likely offers at least several years of anti-aging benefit. Of course these are covered in your excellent recent book.

  7. “But animal populations cannot afford to reproduce at a pace faster than the base of their food chain can support. Animals that exploit their food supply unsustainably will starve their own children, and there is no evolutionary future in that. This is a principle that links together entire ecologies, and the foundation of evolutionary theory will have to be rewritten to take it into account.”

    Nope, evolution doesn’t work that way. The unit of selection is the individual, not the population. If you have a population with a low fertily rate and inside it an individual with a high fertility rate, then that individual has an advantage to its peers, and its genes related to fertility will spread faster than those of its peers. It’s that simple. Even if a low fertility rate would be better for the population as a whole, it will not happen. Simply, population dynamics don’t work that way.

    Consider for example sex ratios. The better for the population would be to have few males and a lot of females. That way, progeny is maximized wrt resource use. Instead of that, we have a 50/50 ratio in most species, because that is what happens when individuals can benefit instead of the group.

      • Well, I have not much time to analyse it in detail now (I have a tight deadline in my job now), but I will comment on some parts. Also, sorry for my English, since it’s not my mother tongue.

        “but all considerations of group benefit have been dismissed because they violate the prevailing paradigm of neo-Darwinism, a.k.a. The Selfish Gene. […] But aging genes are not ‘selfish genes’, and cannot be explained within the Standard Model.”

        AFAIK, the selfish gene is not the prevailing paradigm of neo-Darwinism. Today, I think most biologists admit there can be evolution at different levels, from genes to populations, so, to some extent, parts of the selfish gene theory are integrated into mainstream current evolutionary theory (call it neo-Darwinism, Standard Model or whatever), but it’s not its main component, nor it’s group selection either. I think most biologists admit group selection in some cases (for example, for somewhat closed family groups competing with one another), but it’s not the main part of evolutionary theory for most people today. So I think the identification of Standard Model with the Selfish Gene is a gross exageration, and thus the Standard Model can’t be attacked on that basis.

        Now, on the Second Law of Thermodynamics. The fact that the Law can’t be applied to living beings because they aren’t closed systems doesn’t imply that some kind of opposite law can be applied to them, namely, that, since they aren’t closed systems, they can’t suffer stochastic damage. Yes, they can use external energy to repair themselves, but that doesn’t imply that repair mechanisms must be perfect. And we know that they aren’t perfect: mutations accumulate with time (most are repaired, but not all), glucosepane accumulates and it’s not eliminated, etc.

        “If the problem is oxidation, why do anti-oxidants seem to make the problem worse?”

        ROS not only cause mutations in mtDNA, they also have other functions, like signaling. So, when you externally provide some anti-oxidant or elevate natural levels of it by genetic means, it doesn’t decrease mutation rate (since the metabolism compensates the decrease in signaling molecules using another pathway that also produces ROS, or, for some antioxidants, because they don’t reach mitochondria) or is somewhat harmful (because it affects other pathways).

        “More fundamentally, the question that cries out for explanation is why the body should permit damage to accumulate”

        Basically, because selective pressure lowers with age.

        “If animals were ‘wearing out’ with age, we would expect exercise to shorten life span. The opposite is true. We would expect that the bat, with its high activity and fast metabolism, should burn itself out faster than the mouse. But mice live about two years and bats about thirty.”

        Predatory pressure it’s very different for them. The same happens with birds. They live longer than non-flying vertebrates of the same size because there is comparatively less predators for animals that can fly (and thus less pressure to reproduce early). Indeed, bats and birds are more resistant to ROS than other species:

        http://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-016-3227-8

        http://online.liebertpub.com/doi/abs/10.1089/rej.2008.0676

        So yes, they should produce more damage, and they do produce it, but they also have more repair mechanisms, due to their predatory pressure.

        “Hormesis is a concept that was controversial for years, because it flies in the face of wear-and-tear theories of aging.”

        Hormesis is not incompatible with aging-as-damage theories. The main point is that the body can’t repair all the damage. Hormesis increases repair, but not to 100%, so the theories still hold.

        “Even osteo-arthritis, which was formerly understood as a cumulative effect of abrasion on cartilage, is now described as an effect of excessive inflammation, not essentially different from rheumatoid arthritis”

        So what? Inflammation can be caused by immunosenescence, that fits inside aging-as-damage theories.

        “1. The Declining Force of Natural Selection: Mutation Accumulation and the Genetic Load”

        The declining force of natural selection doesn’t only affect mutation accumulation (that its, the number of mutations an individual accumulates in its lifespan) but also the evolution of repair mechanisms, etc.

        I think the next two sections also deal in some way with the idea of the decline of natural selection with age, but again restricting it to only very particular mechanisms (antagonistic pleiotropy and the disposable soma). I don’t think aging can be explained by only one of those three mechanisms, but still I think the general principle holds: selective pressure lowers with age. That explains why mutations accumulate, why there are antagonistic pleiotropy genes and why there is a balance between resources used for reproduction rate and resources used for repair. But there is absolutly no need to choose only one of the three as the only cause of aging, and there are more mechanisms influenced by that principle.

        • Antonio –

          I’ve heard too often the argument that “repair mechanisms can’t be perfect.”

          There’s nothing perfect about a newly-minted young adult. The body was grown from a single cell. When it becomes damaged, it can be rebuilt the same as before, or even stronger, or not as strong. The ultimate proof that aging is not inevitable is that there are some animals and many plants that don’t age. If “aging” is defined as an increasing probability of death, then it is common for trees to “age backwards” for many decades at a stretch.

          – Josh

          • “When it becomes damaged, it can be rebuilt the same as before, or even stronger, or not as strong.”

            Do you mean the “cleaning” and rejuvenation that happens when a new germline is created? But and egg is not an human! It can’t have AGE-crosslinks, nor amyloid deposits, etc. That’s useless as an aging treatment.

            “The ultimate proof that aging is not inevitable is that there are some animals and many plants that don’t age.”

            The only cases where we are sure of negligible senescence (i.e., excluding lobsters, naked mole rats, etc., that we don’t know for sure whether they are simply long lived or negligibly senescent) are very simple living beings, like single-celled organisms that reproduce by mitosis, or multi-celled organisms like the hydra, where every cell can create a new whole organism. They are very different from us, and nobody has found a way to apply their anti-aging mechanisms to vertebrates. Probably those mechanisms are very similar to what we use for our germline, so the above argument applies.

            And, anyway, the debate here is not whether aging is inevitable, but whether it’s programmed or not. I think we all here think that aging can be cured or treated. The question is how to cure it, and which research avenue to pursue.

            “If ‘aging’ is defined as an increasing probability of death, then it is common for trees to ‘age backwards’ for many decades at a stretch.”

            We also “age backwards” before puberty, but that is also useless as an antiaging therapy.

  8. Gentlemen,

    I am not a specialist on these matters.
    However I saw (on internet videos or TV!) that it is common in zoos (from the necessity of getting offsprings?) to mate some birds with one parent and at least one case of orang-outang which was mated repeatedely with its offsprings.
    Maybe the information on these cases – or similar – might interest you.
    Hope this helps.

  9. Hi Josh,

    I agree with you that the evidence is strong that aging is programmatic, I feel you have made a strong case for this in your writings. However I would like to offer you an alternative to the concern you present here that hemostatic influences, as you present in your diagram above, force us into a complex network model of the aging mechanism, one that is not amenable to easy manipulation. Is it reasonable to view aging as part of a homeostatic state? It seems to be the antithesis of homeostasis in that it represents consistent change over time to the cells and organ systems?

    Additionally, as I propose in my paper “Sexual Selection and Diseconomies of Scale Theory of Aging” (referenced below), senescence is part of the developmental program. The advantage here is that development is also the antithesis of homeostasis in that it drives profound change in the organism and it does not appear to be defined or regulated by the kind of network diagram you provided.

    Nick Lane describes in his book “Life Ascending” it appears that apoptosis evolved as an arms race between bacteria and bacteriophage which results in the network you present. Yes I agree with you that apoptosis, when used as a defense against viral infection for example, is subject to the network effects described in your diagram, but apoptosis has another major use in organism development. It appears that evolution has found ways to co-opt apoptosis for use in developmental processes and impose a hierarchy of control over this network. Developmental processes make individual animals sensitive to individual signaling molecules that can precisely drive apoptosis activity in very specific tissue domains, for example. I think you will agree that It is well known that developmental processes are often very sensitive to single mutation events and other hierarchical control structures.

  10. Kevin – Yes, I agree that these are promising indications. Perhaps you can follow a path from these observations toward suggestions of anti-aging strategies that might be tried in practice.
    – Josh

  11. Hi Josh,

    Thanks for commenting on my last response to your blog post, I know that you are busy these days and it is difficult to take the time to respond to as many of the comments being made to you as you do.

    I feel that it is likely that a developmental clock is the metronome for aging and that it resides in the hypothalamus or its analog in other species. I think that the hypothalamus is likely communicating its timing via a signaling peptide, perhaps like oxytocin as you have described in previous blog posts, or other compounds that operates via the endocrine/immune systems, and as such is not very amenable via supplementation in the conventional sense. I do feel that that the descriptions you have provide on the varying approaches, from synolitics, to thymic regeneration peptides that you have presented on this blog over the last few years has been very instructive and insightful.

    Perhaps I am more optimistic on the probability of rejuvenation than you are, but I feel that you and I mostly differ as to the type of selection that functions as the primary driver of the evolution and persistence of aging. You propose and advocate for group selection and I being focused on sexual selection as the primary driver. I think that either of these two types of selection are capable of evolving programmatic aging capable of producing the attribute that we see in nature. Additionally I agree with you that standard “survival of the fittest” or “de-selection by death” or call it the “standard model of Neo-Darwinism” is not capable of evolving persistent programmatic death mechanisms as you have so aptly pointed out over the last decade.

    I think that you are doing a great service in your speaking out against the standard Neo-Darwinist model because your scholarship and perspective will over time change minds and as a result foster faster advancements in the laboratory based on a more rational model of evolution.

  12. Hi Josh,

    In your book you recommend taking a daily aspirin and also the diabetic drug metformin. I am 38 years old, from what age do you recommend taking both?
    What about resveratrol?

    Thanks in advance for your advice.

    • You can take resveratrol any time. For metformin and aspirin, I see no benefit in taking them before age 50 for most people. Exception is if you are pre-diabetic or if your inflammatory markers are already high.
      – Josh

  13. Josh:

    As I understand the fundamental issue, even Darwin was concerned that the Theory of Evolution predicts that humans should have a process for repairing the accumulated damage that leads to the progressive loss of function over time. After 150 years of effort, and numerous variations on the two primary schools of thought, no one has come up with an acceptable rationale to explain why humans don’t have a maintenance process. I would suggest that the reason you can’t explain the absence of the maintenance process is because we have one. It doesn’t go away over time. Adults just fail to activate it.

    I’m not a scientist, so until quite recently I was blissfully unaware of these weighty scientific issues. However, because of a family history of early death (my dad died at 50), I am acutely aware of my own mortality. So I tried the standard lifestyle adjustments – no smoking, reasonable diet, steady state exercise (running). And I achieved the predicted results – in my mid-fifties I was in better health than most people my age, but was certainly starting to feel certain infirmities of aging. But about 10 years ago, at the age of 54, I started doing intense exercise on a regular basis. Since then, the functioning of each organ and system in my body has progressively improved. Today, at the age of 63, I am healthier, stronger, fitter, smarter, etc. than I have ever been.

    Life scientists, and people in general, tend to ignore or reject data that doesn’t fit with their preconceived notions. But before you dismiss my observations, you should be aware of the following: (i) prior to the 21st century, hardly anyone (pretty much only athletes and other professional performers), and certainly no one over the age of 40, engaged in intense exercise on a regular basis; and (ii) today, thousands (but only thousands) of ordinary men and women in their 50s and 60s are engaging in intense exercise on a regular basis, and all of them are experiencing the same results as I described in the previous paragraph. In the fitness community, these results are now taken for granted.

    I decided to try to find out what it was about intense exercise that made it qualitatively different from steady state exercise – why does intense exercise have the effect of reversing loss of function? Conventional medical researchers universally acknowledge that exercise dramatically reduces the risk of all chronic degenerative diseases, but have never bothered to investigate the underlying mechanisms. However, there have been a large number of recent studies of high performance athletes (conducted by scientists who have no interest in chronic disease or aging) that describe the chemical changes that occur when one exercises at high intensity levels.

    A multitude of studies confirm that whenever a healthy human of any age exercises at a level of intensity that raises blood levels of lactate (that is the technical definition of intense exercise), his or her pituitary gland secretes human growth hormone. HGH is associated with muscle development and the growth and health of all organs other than the brain. A number of other studies confirm that whenever a healthy human of any age exercises at a level of intensity that raises blood levels of lactate, his or her blood levels of brain derived neurotrophic factor increase in proportion to the levels of lactate. BDNF can be likened to HGH for the brain – it triggers the growth of new neurons and helps repair and protect brain cells. Numerous other studies confirm that elevated levels of lactate in the blood also trigger elevated levels of other growth hormones, stems cells and other progenitor cells, steroids, AMPK and a number of other substances.

    The same stimulus – elevated blood levels of lactate – activates the release of dozens of substances that are associated with growth, repair and rejuvenation. It happens every single time and in proportion to the amount of lactate in the blood. Thus it was obviously a distinct, coordinated process. Many of the substances involved are ineffective in the absence of the others, and some are harmful if not metabolized quickly. The presence of elevated levels of these substances is incompatible with homeostasis. Thus, this process must be a discrete process that occurs quickly.

    So, it was apparent to me that the reason that intense exercise had such a dramatic effect on me was that it triggered a complicated chemical process that repairs the damage that leads to loss of function – something that sounds an awful lot like a human maintenance process.

    After reaching the conclusion that intense exercise activates the human maintenance process, I decided to review the literature to see how the existence of that process fit in with current theories of aging, the treatment of chronic degenerative diseases, etc. Imagine my surprise when I discovered that 150 years of research and analysis have been devoted to a fruitless effort to explain why a process that I deliberately activate several times a week doesn’t exist.

    The critical point is that the process must be activated, and, in adult humans, that activation occurs only when one engages in exercise at a particular level of intensity. Since, prior to the last fifteen years, no human of advanced age engaged in such exercise on a regular basis, it appeared to Darwin, as it has appeared to you and to every other scientist who has looked at the issue, that humans have an “incapacity to avoid senescence decay.”

    The Theory of Evolution is correct is predicting that humans are genetically designed to function perfectly throughout their lifespans, and evolution has provided us with a maintenance process to repair the damage that results in the loss of functionality over time. However, environmental factors cause phenotype (what we are) to differ from genotype (what we are genetically designed to be). The aging process results from that deviation increasing over time. The key, uncorrected environmental factor is intense exercise (the type of exercise engaged in by the evolutionary precursors to humans – any mammal subject to the forces of nature must engage in frequent intense physical activity or die). In the absence of that type of exercise, the body does not activate the maintenance process.

    By the way, the existence of a human maintenance process in no way precludes the possibility that humans have a programmed aging process. The maintenance process I describe does not regrow lost teeth or turn grey hair back to black or brown. It doesn’t even reverse hearing loss or bad eyesight (I have perfectly healthy ears and eyes; I just can’t hear or see very well). But as far as I can tell, it does reverse any other condition that you would consider an infirmity of aging.

    • Mark –
      Longer life under hardship is what you’re describing, and it has a name. It’s called “hormesis”.
      In my book, I have a full chapter devoted to the idea that hormesis can only be explained in the context of programmed aging. If Evolution didn’t want us to die, then it would be easier to keep us alive longer in the ABSENCE of hardship.
      – Josh

      • Josh:

        Thanks for the prompt response. Sorry I couldn’t be as prompt with my reply, but I had to do some research into what “hormesis” is.

        If I were talking about steady state exercise, you would be substantially correct in applying the “hormesis” label. The benefits of steady state running (that means running at an intensity level that one can sustain for more than a minute or so – i.e., below the lactate threshold) in large part result from the repair of the damage done by the exercise. And the benefits are generally restricted to the heart, other working muscles and circulatory system – whatever is damaged in the exercise process. As I noted, that’s the type of exercise that I did until I was in my mid-50s. And although I did note health benefits relative to peers who did not exercise, I still suffered from the infirmities that one would expect of someone in his mid-50s. Steady state exercise has no appreciable effect on the aging process.

        Distance running may be considered a hardship/hormesis because it applies unnatural stresses to the body. But short bursts of intense exercise are something different. A slow, weak or lazy mammal that is subject to the forces of nature is a dead mammal. Thus, frequent short bursts of intense exercise are as much a part of the normal evolutionary environment as is food, air or exposure to sunlight.

        There is a qualitative difference, in terms of chemical processes, between steady state exercise and exercise at an intensity level that exceeds the lactate threshold. The chemicals that are released in conjunction with intense exercise confer direct benefits on organs, such as the brain, that have nothing to do with the exercise itself. By the way, exactly the same set of chemicals is involved in fetal growth and the growth of infants and children. Growth/maintenance is inconsistent with homeostasis and thus is not an automatic process at any stage of human existence. A specific set of chemicals must be present in the bloodstream.

        Regardless of whether the “hormesis” label is applicable or not, you need to take into account the following new empirical data. Thousands of normal people in their 50s, 60s and older have been able to reverse the infirmities of aging through intense exercise. That number, and the age cohort, goes up significantly each year. You may or may not be correct that I have a genetically predetermined termination date. But if I can improve functionality in all modalities as I advance into my late 60s, the loss of functionality experienced by those who choose not to exercise and preprogrammed death must be two separate phenomena.

        • Mark – You and I are on the same page concerning the benefits of high-intensity exercise. I would just counsel you to be careful with broad statements, because there are always exceptions and surprises in biology.

          “frequent short bursts of intense exercise are as much a part of the normal evolutionary environment as is food, air or exposure to sunlight.”

          There are mammals that have no predators (whales, bats, giraffes). There are mammals that live with much less air (naked mole rat, porpoise) and with hardly any sun (nocturnal rodents, moles, bats).

          “You may or may not be correct that I have a genetically predetermined termination date.”

          I don’t believe I ever said that.

          I think you’re right about the benefits of high-intensity exercise, but it’s hard to get clean statistics because the ability and the will-power to do it form a highly selected group.

          About the hormonal basis for the benefit: Biochemical explanation and evolutionary explanation work on two different levels. I would like to understand aging on both these levels, and a biochemical explanation doesn’t obviate the need for an evolutionary explanation.

  14. I read recently that half of centenarians smoked and 1/3 drank regularly. As far as I know they still haven’t found any lifestyle factors that significantly contribute to very long life. Also, that there is evidence of a significant genetic component to aging.

    What aging theory does this evidence support? I suppose it could be spun to support any or all of them depending on the mechanisms. But if the damage theory is true, then it has to be highly regulated and controlled by something other than lifestyle.

  15. I post the amazon link to your book on every Facebook friend’s page on their birthdays (or “telomere shortening day” as I call them).

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