Is aging inevitable?

A new study has appeared to support an old idea: Aging is inevitable and immutable, so anti-aging research is doomed in advance to failure.

In 1957, George Williams wrote

This conclusion banishes the “fountain of youth” to the limbo of scientific impossibilities where other human aspirations, like the perpetual motion machine and Laplace’s “superman” have already been placed by other theoretical considerations. Such conclusions are always disappointing, but they have the desirable consequence of channeling research in directions that are likely to be fruitful.

In 2002, three prominent aging scientists wrote (in Scientific American):

No Truth to the Fountain of Youth:
…no purported anti-aging intervention has been proved to modify aging…We find it ironic that a phony anti-aging industry is proliferating today…Some [researchers] Some assert that aging’s complexity will forever militate against the development of anti-aging therapies.

One of the three was Len Hayflick, who is most famous for having discovered and documented one of the clearest and most preventable mechanisms of programmed aging.

In 2017, Joanna Masel wrote

“Aging is mathematically inevitable. Like, seriously inevitable. There’s logically, theoretically, mathematically no way out.”

This new study is based on statistical analysis of human and primate populations. Among the 42 authors (!) who signed it, I am chagrined to find the name of J. W. Vaupel. Et tu, James? Over several decades, Vaupel has been the optimist of demography, telling us that somewhere in the world, human lifespan is always continuing to increase, as it has done since 1840, at the rate of about 1 year of new lifespan for every 4 years that passes. For the first 130 years of this advance, the improvement in lifespan was predominantly about preventing infant mortality and combatting infectious disease. But since about 1970, lifespan improvements have continued to benefit the elderly. My informal index is the number of 80-year-olds I see on the tennis courts. Vaupel and his former student, Annette Baudisch, also were prime movers in a comprehensive 2013 study of Aging Across the Tree of Life, which catalogued species that don’t age at all for decades at a time, and others that become demographically younger.

This new computer modellike all computer modelsis a translation into mathematical language of a set of assumptions about a natural phenomenon. The crank turns, and out pops a prediction. The sleight-of-hand, the conjuror’s trick, is that we are tempted to look at the mathematical machinery to see where these predictions come from. But equally important is to look at the assumptions on which the mathematics is built.

In this case, the assumption is that natural selection has been trying to maximize lifespan, because the longer an individual lives, the more opportunity it has to reproduce. And reproductive output is the measure of success in neo-Darwinian logic.
But if we look at the biology of aging, it’s clear that evolution has not been trying to maximize lifespan. As we get old, genes are turned on that destroy us with inflammation and autoimmunity, and this epigenetic change shows every sign of being under the body’s control. As we get old, genes are turned off that rebuild and protect the body against chemical damage, most famously from free radicals. Again, it appears that this is deliberate. It is a product of natural selection, not a constraint on natural selection.
How can this be? How can a variety with lower reproductive success prevail in evolutionary competition against other varieties with higher reproductive success? This question has been the primary focus of my own research for 25 years, and my answer is the necessity to preserve stability of ecosystems.
My answer may be right or wrongit is still a minority opinion. But what is clear is that the lifespan of almost all living things is under epigenetic control. That is, aging is a programmed phenomenon. Aging is not the accumulation of damage. Aging is not the body wearing out. Rather, aging derives from processes of self-destruction that are under the body’s control.
In this perspective, aging looks a good deal less inevitable than this article claims. And indeed, there is cutting-edge science that appears to be turning back the clock of aging, turning old rats into young rats.
Specifically, what does the new study find? Looking at populations of humans and other primates, they find that longer average lifespans are associated with less variability in lifespan. In other words, the short-lived primates have deaths that are spread out, with some living much longer lives; but in the longer-lived primates, age-at-death is clustered up near the high end. This gives the appearance of some kind of wall at the high end of lifespan.
And where, specifically, is the flaw in the new paper?
“Understanding the nature and extent of biological constraints on the rate of ageing and other aspects of age-specific mortality patterns is critica…”
The implicit assumption about “biological constraints” is that the constraint is physical, or that in some way it is beyond the reach of evolution. The assumption is that natural selection has pushed against these constraints, and hit a brick wall. The alternative view (a view that is shared by some of the most prominent researchers who have studied physiology and biochemistry of aging) is that these “constraints” are actually baked in by natural selection itself. Far from being constraints on evolution, these constraints are actually the product of evolution. This is to say that the constraints are not fundamental physical limits, but features built into the epigenetic cycle of growth, development, and aging. The “constraints” become malleable as we tinker with the signaling mechanism by which the body imposes aging on itself.

A crucial caveat

I believe that as we understand more about epigenetics and the signaling mechanisms that control biological age, it will become increasingly feasible to manipulate lifespan. Indeed, we’re already doing this to a huge extent in lab worms and, to a good extent, in rodents.
But evolution isn’t so dumb. Limits on lifespan have been put in place to help protect against population overshoot. And (my opinion) humans are already in a state
of severe population overshoot, in the context of sustainable limits of Earth’s biosphere. I believe that whether or not biological science succeeds in further extending lifespan, it is an urgent matter for survival of our species (and many other species) that we shrink the human footprint on the biosphere and on the soil, water, and atmosphere that support Earth’s ecology. I think that living well with less is a relatively simple technical problem. We need only implement all currently known efficiency improvements in the use of resources, and continue to discover new ones. But it is a huge political problem that we have barely begun to confront, and I don’t have any good ideas how to make these changes a political reality. I’m going to stick to the science, and count on others who are more adept at politics than myself. As we extend human lifespan, there is an urgent need to move toward sustainable agriculture and to adopt energy-efficient technologies.

151 thoughts on “Is aging inevitable?

  1. Exactly the opposite argument has been made from that kind of data, on – that the fact there is a cut-off means aging cannot be random damage:

    “The age-vs mortality curves for members of species do not represent those which would exist if aging was caused by random damage or any other random process. It they did we would have a tiny handful of 600+ year old people and 75 year-old house cats, 100 year old dogs and 15 year-old mice. The same would be true if aging was the result of randomly-operating vestigial developmental programs. More precisely, the statistical distribution for any random process results in a Poissonian distribution curve, one with an infinitely long tail. The same is true for distributions representing combinations of random process. The lifespan curves for all species have cut-off tails.”

    • I wonder how this relates to the work of Geoffrey West, which I’d not heard of previously but recently came across.

      “Visionary physicist Geoffrey West is a pioneer in the field of complexity science, the science of emergent systems and networks. The term “complexity” can be misleading, however, because what makes West’s discoveries so beautiful is that he has found an underlying simplicity that unites the seemingly complex and diverse phenomena of living systems, including our bodies, our cities and our businesses.”-Wallstreet journal

      He too came with mathematical reasons for aging, but from the perspective of the mathematical laws governing networks, all the way from individual cells, to companies, cities and societies and how many seem destined for a finite duration.

      The book
      Scale: The Search for Simplicity and Unity in the Complexity of Life, from Cells to Cities, Companies to Ecosystems, Milliseconds to Millennia
      discusses his ideas, but a brief overview can be found in the following google talk

      I’ll be reading the book to see his arguments in more detail. But if anyone’s familiar with his works perhaps they can comment on what such mathematical laws say about aging and whether these too are refuted.

    • Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:

      I LIKED MUCH YOUR reasoning (new to me). I thnk thinking about various species at a time is a most fruitfull approach in aging, and studying only young vs old (ª99% of what one sees are concequences, not causes of aging) asnd only one species as medical doctors, pharmacysts, chemicals etc usually do will never solve the aging problem.
      Combining the experimental qwirth the comparative approach in the biogerontology area is most fruitful. I have a 4 decade long experience on that.
      our last 3 papers U(plus one review in FESB J) with this comparative approach is a good example on how fast and inexpensive it is this method to clarify what parameters can or cannot be causes of aging:

      -1) Mota.Martorell et al. Redox Biology (2020) finding NDIFV2 (FeS cluster) plus possibly NDUFV1 (we are evaluating it with FeSN3 and the FMN) as responsible for the mitROSop causing mito-derived aging, as well as VDAC (mPTP member?) involved not only in pathologies but also aging.

      -2) Pamplona & Barja FESBE J (2021) oreview on the ndufv2 topic above

      -3) Gredilla et al., Geroscience (2020) For the first time mitBER is positively correlated with species longevity in mammals (nuclear-“genomic” BER is negatively correlated with longevity: see Stuart and Vilhelm Bohr work at NIA/NIH Maryland Bethesda 2010, -stuart et al, and 2004 FASEB J. paper signed by Vilhelm.

      .-4) Mota-Martorell et al., Geroscience (2020) First study ever on mTOR complex between species with different longevity. Results absolutely fit with CR, PR and MetR and rapamycin experimental results mTORC1 protein. mTORC1 negatively correlates with mammalian longevity accross species. The mTOR regulator activators are negatively regulated too (and the inhibitors are positively regulated)

      -5) Barja Exper. Gerontol. (2019) Towards a Unifyied Mechanistic (Programmed) Theory of Aging (I had to take out “Programmed” from the title..I consider this one my best paper among the around 200 ones that I have published. It is essential to understand the previous opnes. Most published information appearing after 2019 almost always fits with the Fig. 2 cheme of nuclear aging program afferent and efferent arms. For internal structure of the nuclear aging program please see the theoretical proposal from 13 years back:

      -6) Barja, Biogerontology (2008) The Gene Cluster of Aging and Longevity

      • Prof Barja has my vote for one of the great researchers in aging theory. The 2019 paper he says is his best and the dozen references to his other papers in that seminal 2019 paper are must reading for understanding aging.

        Big up to Josh;
        It is like Roger Federer just dropped in at your local tennis club.

        • Gustavo Barja, Professor of Physiology, UCM Univ. Madrid Spain. Head of the LRMG (Longevity Research Multidisciplinary Group) composed by 10 Proffesors from 5 different Spanish Universities. on said:

          Thanks Alan.
          And: I had to autocensor that paper:
          1) Eliminating the word “Program” from the tittle
          2) Cutting the 2nd part of it (approx. 50%) about Extraclelular and whole organism aging because it was considered too long a ms. by the reviewers. I hope to publish that 2nd part soon at a good gerontology journal at USA.

          3) I Had to cut the single 1 page dedicated to Evolutionary Theores of aging on which I critiziced the three non-programmed still mainstream ones

          4)The original ms. was originally written in 2015 for a USA very good editorial by the editor died the night previous to deadline. Afterwards it passed through 2 more USA journals where I received clearly to me biased unfair criticisms. Finally it was fortunately accepted at Exper. Gerontol. It was good because I was so upset that I was thinking of sending it ti be published at Russia where a open minded journal concerning evolutiol of aging exhists. The critics in the journals refusing to publish it at USA sumply stated that non-programmed was THE EVOLUTIONARY THEORY OF AGING as if it were a dogmatically stablished truth that I coul not dare to challenge, instead of an alternative hypothesis oppossed to the other one: programmed aging fir which there are huge number of both field snd laboratory support. To my it has beeb clear from the beginning (in 1988 I entered the aging field)
          that aging must necessarily be programmed, the most important reason why being the huge difference in longevity amlng animal species, from less than 1 day in some insects to 16.000 years in a sponge (more than 1 million fold difference!) whereas animal are mostly composed of the same kinds of biological molecular and structural components whuch makes wear-tear theories and entropy randomness driven processes (like those of innanimate objects) non sense.

          I am finishing a other article to objecively comparing the many proofs for and against both PA and NON-PA hypotheses of aging aleeady available in a systematic way.

          • Prof Barja
            what in your opinion is the reason behind not using statistical distribution to test for randomness in age spans, disease occurrence etc to prove aging is programmed, by various aging researchers.
            I mean there is so much data on chain smokers and lung damage across age spans. That data can easily be put through statistical analysis to show that even after excessive abuse of the lungs at a fairly young age(after sexual maturity), incidence of lung disease occurs fairly late in the age span, indicating a presence of a centrally mediated program

          • Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:

            sorry I always use statistics on my work.
            But I assume you are referring to the main paper alluded by Josh in this blog which I COULD NOT STILL READ

    • Exactly, Instead of theories like selfish gene, antagonistic pleiotropy and many others propounding that mother nature is clueless after development has ended and therefore aging is random damage.
      Statistics is used in almost all sciences to prove or disprove hypothesis, but in the case of aging, random distribution analysis has not been applied to age spans, disease incidence after development/sexual maturity, in spite of this data being in public domain.
      Without even this statistical analysis, any layman can see that age spans, disease occurrence is non random.
      The mere evidence of non randomness is evidence of an aging program.

  2. Josh realization that evolution intentionally constrains life span for betterment of species was great contribution to aging theory and has moved from lone voice to widely accepted view.

    However, within maximum life span of species there in room to tinker and up to 40% increase seems possible. More than 40% would need different genes.

    It would be easy to built a human that would live to 250 years. Just don’t use membranes with unsaturated fatty acids. That is how some species of clams live to 500 years. However, humans living 250 years would be a very bad thing. How would young people get a top level job if the retirement age was 200.

    • Human membranes in mitochondria significantly oxidation resistant, part of what is said to give us our extraordinary lifespan.

      The question of whether we need new genes or not for vast changes depends on how difficult increasing lifespan significantly is. On the one hand you have Aubrey’s view that nature exhausted all the easy tricks and we have herculean tasks ahead to meaningfully extend lifespan. And on the other the idea that the longer a species lives the closer it is to negligible senescence, and perhaps the fewer the changes necessary to yield significantly greater lifespan and achieve negligible senescence.

      We know that mouse neurons transplanted into rats live twice as long as mouse do, and iirc I think the researchers behind that experiment commented that perhaps in another hosts the neurons would live even longer, potentially indefinitely, that is nature had achieved immortality at the cellular level in a nondividing high metabolism cell. All cells with dna have full genome and all the same genes as these apparently immortal cells.

      Experiments seem to have shown simple compounds can even affect the expression of critical elements such as telomerase lengthening telomeres meaningfully. There is no telling the limits of what combinations of nutraceuticals and drugs can achieve, especially in a species as long lived as ours which should be closer to negligible senescence.

    • In 50 years (most likely less), neither young nor 250 years old people will need to find a job. Robots will do all the work, and humans will do what they choose to do.
      Already some governments are experimenting with minimum guaranteed income that will provide for a comfortable living.

      • do you beleive that?
        Or they will try to get rid of the non-productive people who expends and does not contribute to society
        Unless capitalism is substituted by a better more social system I am afraid ways (vaccines or not) to eliminate these not working people will be invented by the greedy satanic ones in power

        • @gustavo barja
          I have no doubt in my mind that technologically it will be possible.
          Of course, I cannot predict if the “powerful” will not eliminate the “useless”. Or if robots will not eliminate humans altogether. Or that humanity will not disappear due to other causes.
          I was just responding to the “jobs” issue.

          • Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:

            Ok Zisos, I understand
            I heard this year Davos members (the powerful ones on Earth have declared for the first time that they a minimum of money will be given (eg. 500 Euro per month) for those who will be left without job due to robots..
            I acnnot imagine a world with two classes of people
            -Those wealthy with job and integrated in society
            -Those trash people left on the side to survive with 500 euros per month…
            Half human kind will be despised denigrated left to depression or , suicide or crime?
            I am happy that I will die soon so not having to see that dirty world.
            I hope capitalism is substituted by a more humane system that knows how to share work and wealth among all citizens.
            I think disgusting how those dirty people in power segregate and segregate their own brothers behaving like Cain who killed his own brother Abel…

            If there is no job for all only for half of the people, the only just think will be everybody forbid working more than 4 hours a day, or 10 hours per week so that everyone has a job and everyone has a social inclusion in society with dignity.
            If capitalism is non-compatible with that, then it is capitalism we must get rid of, not the poor people, unless you are greedy little sons of satan

          • I was not aware of the proposal for 500 Euro to those that lose their job to robots.
            For today’s technological capabilities, I find it very good (even though insufficient to live on)
            In less than 50 years, robots will produce all we need, and 99% of the population will not need to work, but instead do what they like. Will 99% of the population be the society or the 1%? I personally prefer to be one in the 99%, with a much higher than 500 Euros that technology will be able to secure then.
            Needless to say, I am much more optimistic than you, and I would love to live much longer, to have many more experiences in better health, than to die soon, after going through illnesses. If I don’t like the “system” then, I can always suicide.
            My main concern for humanity is that it might be overtaken by robots (Artificial Intelligence).

          • I Am nopessimostic at all. That’s why I have worked 65 hours a weak without rest for 41 years and I fimally fo d the gene/s responsible for around 1/3 of human aging rate: the mitochondrial nuclear coded gene ndufv2 which regulates mitROSp and thus the rate of mtDNA fragments integration into genomic DNA and thus aging.

            But optimism does not svoid me to know the crude truth. Just read history an you will understand present day politics…
            99% happy and wealthy? That is a tale for children. They cheated you the “wise very bad guys I, one of the samurays on Earth , fight hard…
            Until the 3 parts GB utopy is fullfilled:

            1-Only 1 country in whole Earth
            2- All mixed together (through sex): all color “coffe with milk”.
            3- Never agan one man will exploit (employ) another man to extract “plusvalue” from him

            Until this is not accomplished we are in strong danger of dying all from atomic war or climate change or whataver…

            There is no time left any more…

            Now we produce 10 times more per person or more than at the XIXth and still ee hsve the excluded poor and hungry and cokd without refugee at New Yorl and at Madrid, ehich unfortunately? Each time is more similar to Madrid.
            The huge increase in efficiency benefits the rich not the poor..
            The sane will happen for the robots…
            The history repeats again and again…
            The real gold that brings men to hades is POWER
            POWER IS SATAN

    • They would wait till they’re 150 yo. Or better, they would build new organization. Regardless, should we maintain the suffering of old age so that we can maintain the existing economic structures and cycles?

      • Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:

        YOU SAID: “However, within maximum life span of species there in room to tinker and up to 40% increase seems possible. More than 40% would need different genes.”

        WE HAVE EVIDENCE THAT THAT IS NOT CORRECT. We have found differences in gene expression (of the same gene) across species with different longevities for ndufv2 gene (FeSN1a at NDUFV2 polypeptide is responsible for mitROS production explaining part of the aging rate) and VDAC mitochondrial polypeptide amount (Mota-Martorell et al. Redox Biology (2020), also for mitBER enzymes (Gredilla et al. Geroscience (2020), as well as for mTORC1 (gene expression too) and regulatory metabolites (Mota-Martorel et al., Geroscience, 2020).
        Therefore, it is likely that it will be possible to modify longevity to an extent similar to that which took place during evolution of species with different longevities (between 3,5-4 years in rats and mice and 46 years in horses, by ONE ORDER OF MAGNITUDE without the need to modify any gene. It would be sufficient to modulate the gene expression of the same genes. Good news since many countries like Spain do not allow human gene modification but do not say anything about modulation of gene expression (which occurs every day as a result of simple common activities like eating different foods or doing exercise. It os a question of knowing which genes must we to modulate its expression and in what relative proportions. Most likely we will have to modulate the appropriate master genes at intermediate levels in the aging program which in turn modulate the gene expression of various target genes of interest in that program (Barja, Biogerontology, 2008; Experimental Gerontology, 2019) .

        • 1 country on earth with every ethnicity mixed? Doesn’t sound like Utopia to me. Sounds like a sure recipe for a civil war.

          Ludicrous optimism here expecting robots to replace all human work. Stop reading sci-fi from the 1950s.

          Most likely the human race is due an almighty crash. If we’re lucky we’ll solve aging before that happens and won’t have to buildback up for another 100 generations.

          • Hi Mark
            If you refer to my conviction that robots will be able to do 99 percent of human jobs, please note that I have never read a science fiction book. Maybe I should start now.
            My conviction is based on statements of people much smarter than me, such as:
            Stephen Hawking (dead now)
            Elon Musk
            Ray Kurzweil
            They all predicted that AI will surpass human intelligence. The first two are pessimists. They expressed the opinion that AI is the biggest threat to humanity
            Ray Kurzweil is an optimist. He predicts that the machine will pass the “Turing Test” (i,e, reach human level intelligence) before 2030. He also predicts that Longevity Escape Velocity will be reached in the 30’s by the general public. He has been more than 90 percent accurate with his long term predictions.
            While this comment appears to be “off topic”, I believe it is not. Because if someone accepts Kurzweil’s prediction, we only need to stay relatively healthy for 15 more years in order to reach LEV.

          • Hi, I’ve read Kurzweil and I found his ideas intriguing, but I don’t believe he is correct. The pace of progress in science has dramatically slowed, especially in physics the most fundamental science where it has basically been on the wrong track since the early twentieth century. We’ve had lots of apparent advances, like smart phones, but really that is just putting a computer (20th century invention) in charge of a radio (19th century invention). Elon Musk is great, I wish he’d been about when I was growing up and dreaming about Space. But again its just 1960s rocketry with computer control to help it land itself. There’s been no fundamental breakthroughs like real clean energy, or new methods or space propulsion. We can’t even make a Concorde anymore. Biology has been catching up because of the access to computing tools, but that has downsides too, like too much modelling and too little experimentation. Will we really have AGI soon? I certainly hope not…

    • Alan:

      Maybe society will have to rethink employment, if lifespan is extended.

      Perhaps higher pay could/should be performance or production based.

      A high level worker should not be chosen simply based upon age or years of service.

      Experience is important but it is only worthwhile if the employee is able to tap into that experience in a productive performance based way that is beneficial to the employer.

      In addition, a high-level employee can be chosen simply because he/she enjoys the challenges presented by the job, rather than having a primary interest only in a higher pay level.

  3. Overshoot prevention makes sense as a reason natural selection gave us the wall.
    Another theory: The wall may also have been built to rid a population of extra mouths to feed that weren’t pulling their weight. Neurogenesis declines after maturity. Yet a lot neurogenesis is exactly what a species needs to adapt to new realities and solve problems. In balancing priorities (eg which “mouths to feed” ) the mouths attached to a brain that is able to generate new neurons and thus new tools for adapting to a dynamic world, would be prioritized.. and the others programmed to die.

    Greg Kieser
    Author, Dear Machine.

      • Aren’t neurons the only tissue that does not regenerate? Is it possible that chronological age = biological age in neurons?

        • The hippocampus produces around 1000 neurons a day. Even in older people. That was a big surprise just few years ago.Yes, there is neurogenesis during all our life, despite some tissues in the brain slow it down.

          • Yes neuron mitosis in the hypocampus. That’s well knonwn. But, what about most of the other brain regions :> 95% of Brain?

        • The hippocampus produces around 1000 neurons a day. Even in older people. That was a big surprise just few years ago.Yes, there is neurogenesis during all our life, despite some tissues in the brain slow it down.

  4. Hi Josh, I believe aging, the passage through later, high-mortality life-stages (jointly called old age) is a pre-programmed part of development. A life has (for the most part) a beginning and end. The best ‘the modern synthesis’ of aging science can do is slow it down a bit.
    That there are non-aging animals, and there are – so, therefore, by all the rules of science, the hypothesis that aging is inevitable, must be rejected. A single exception is grounds for rejecting the hypothesis.
    Our group and several others have successfully demonstrated rejuvenation; using young blood, Nakayama factors, or in our case plasma-derived factors, to reverse aging. Steve Horvath certified the changes with several of his “clocks”, which means the rejuvenation takes place at the deepest cellular levels but translates (as in many experiments of others) to improved performance in higher-level tasks. Improved cognition following heterochronic plasma exchange was published by Saul Villeda a decade ago. So aging is inevitable, biological time does not stand still, but unlike chronological time, it can be slowed (where nearly all of today’s anti-aging medicine aims), or much, much better, it can be reset and reset again.

    • Hi Harold – non scientist here with an engineering background. Maybe the better way to look at it moving forward is to not equate ‘aging’ with ‘degradation’ but instead with ‘evolution’ or ‘progression’. As was already stated, there is no escaping menopause, my wife is dealing with it right now and although hormonal creams help I wonder if even E5 would be capable of halting, let alone reversing, the chain reaction of hormonal changes we refer to as menopause.

      Let’s say E5 delivers as expected and gradually rejuvenates the body including all organs and down to the bones over the course of a decade. Would that also reverse those hormonal changes and perhaps my wife would become fertile again? To be honest I have serious doubts about that as that would truly count as turning back the clock on aging.

      How about things like presbyopia? I’m really feeling that now at 55 and how would E5 reverse that without some type of local intervention? Many similar questions arise once you follow this line of thinking. Looking younger is one thing – truly being younger and reorganizing tissue that has degraded over the course of decades is another.

      So while I am hopeful about extending my active lifespan I am also realistic when it comes to my expectations. In other words I don’t expect to ever ‘look and feel like’ I did when I was 25 or even 35. For one my hair won’t grow back and I also don’t think whatever is left will go dark again. At best we’ll probably look like very well preserved 50 year olds – and honestly I’m fine with that 😉

      • Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:


      • Why would anyone have high hopes for E5 when it has not yet been demonstrated to work in long lived species? With E5, we have one non-peer reviewed study found a 54% life extension in mice conducted by the inventor of E5. Even if the E5 study is valid for mice, short lived species are not good substitutes for humans. By way of example, one calorie restriction study showed an approx 50% life extension effect in mouse lemurs, but was later shown in other studies to have little or no effect on life span in longer lived animals (monkeys).

        • Brad,
          CR and E5 have a very different mechanism. CR induces hormesis which has been added by Nature to deal with low gradient stress arising from environmental factors and gives a boost within a limited range. E5 works at epigenetic level as evidenced from the Horvath clock measurements. Major changes in the epigenome can have much greater impact on our biology.

          • In my opinion E5,CR, Exercise all have the same mechanism, i.e. they are modulating Autophagy, because my opinion is that Autophagy is central to aging and a Gene network which is activated at puberty controls the gradual decline in the autophagy mechanism through Dnmt. However, It might be that E5 regulates Autophagy by perturbing the Gene network which controls autophagy through Dnmt and hence epigenetics.
            Exercise, CR, NAD+ all activate the diminishing autophagy mechanism, which results in healthy aging, but they cannot reverse aging because they cannot propagate their effect beyond a certain point.
            It is the decline in Basal autophagy which leads to cell senescence and it is the decline in autophagy which results in stem cell quiescence

          • Interesting point Kunal. I agree that autophagy is one of the most important repair and recycling systems in our biology. Whether it is the main or only reason for aging? Probably not. The program of aging is multi modal. For example Morimoto in his seminal paper “Repression of the heat shock response is a programmed event at the onset of reproduction” shows us that just after puberty the ubiquitin proteasome system that supports the production of protein collapses significantly as a programmed event conserved across species. Protein and protein production too is critical for our biology. Repression of the Heat Shock Protein occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. Something like E5 should be able to decrease the marks to reactivate the stress response to a better efficiency. The loss of autophagic efficiency too would have a similar mechanism with the production of agonist proteins being repressed. But this too can be reversed. But you are doing good Research and I like your comments here. The importance of autophagy can be ascertained from this paper:
            “High autophagy in the naked mole rat may play a significant role in maintaining good health.” citing more resilient autophagy as the secret behind Naked Mole rats extra long lifespan versus other rats.

          • Hi Akshay, I am a fellow indian from Bombay and eagerly waiting for E5.

            I think you might find this paper interesting

            ‘Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk’

            Nature 2020

          • Hi Kunal,
            So are you studying or working in biotech? I would not pay too much attention to studies where they induced situations. As those results are not reliable. In real life we do not get complete inhibition of autophagy. Its efficiency gradually winds down. Hope you have read Tony Wyss-Coray’s, Prof Hayashi from Tsukuba Uni’s, Morimoto’s and Jean Pierre Issa’s papers?

          • Autophagy is just the breakdown of biological molecules for disposal or recycling. All biological molecules apart from DNA are automatically broken down and replaced. Aubrey and Co believe that even when you’re young this turnover rate is insufficient (although it undeniably falls with age), hence accumulated damaged molecules and aging follows. Therefore anti-aging is just a complicated clean-up operation. But to me to me this suggests that DNA is the source of aging and if we can keep DNA pristine (methylation, histone compaction, telomeres) the body will be returned to youthful turnover of all other molecules.

          • Thanks Akshay for the suggestion, I read the papers on mitochondrial defects, proteostasis and epigenetic drift by their respective authors.
            In the process, I found that newer studies show that Autophagy pathway has a role to play in the above. In fact Autophagy also has a role to play in cell cycle, DNA repair, ubiquitin proteasome system.

          • Kunal autophagy is shown to have distinct roles. It isn’t all encompassing. So for example in ubiquitin proteasome system it can help in clearing aggregates of unformed protein but it can’t replace the role of chaperones and heat shock proteins. What do you do if HSP transcription is silenced? Many scientist have tried to identify any one aspect of aging to be the only one or main one like telomeres or drop in NAD+ in mitochondria or senescent cells build up. But program of aging is much more multi-modal, dynamic and complex. It hits us by lowering efficiency of many important pathways.

          • I completely agree that the program of aging is multi-modal, and I really feel that the term Autophagy is a misnomer, because it ascribes specific function to the autophagy related genes, whereas new roles are being discovered even now. There should be a term for the cell house keeping function which should reflect the multi modality and complexity of process regards to aging

          • Kunal we agree to disagree. Now you are changing the definition of autophagy. Even if one takes it as housekeeping there so many specific repair systems that all can’t be governed by autophagic genes. Another example is DNA repair: it has base excision repair, nucleotide excision repair, mismatch repair, homologous and non homologous recombination. How can autophagy implement this when there are specific genes for DNA repair?

          • Autophagy Roles in the Modulation of DNA Repair Pathways
            Autophagy and DNA repair are biological processes vital for cellular homeostasis maintenance and when dysfunctional, they lead to several human disorders including premature aging, neurodegenerative diseases, and cancer. The interchange between these pathways is complex and it may occur in both directions. Autophagy is activated in response to several DNA lesions types and it can regulate different mechanisms and molecules involved in DNA damage response (DDR), such as cell cycle checkpoints, cell death, and DNA repair. Thus, autophagy may modulate DNA repair pathways, the main focus of this review. In addition to the already well-documented autophagy positive effects on homologous recombination (HR), autophagy has also been implicated with other DNA repair mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Given the relevance of these cellular processes, the clinical applications of drugs targeting this autophagy-DNA repair interface emerge as potential therapeutic strategies for many diseases, especially cancer.

          • Kunal what you have discovered through this review is that everything is connected in some way in our biology. Thats why when one symptom of aging is addressed and we get some benefit overall from the cascading effects. It does not mean that autophagy is DNA repair or autophagy is ubiquitin proteasome system. I can write a review article where I can show you Nrf2 interplay with everything you pointed too.

          • I agree, all I am saying is that innumerable papers point to autophagy having a very big role in aging and Horvath’s paper mentioning that the sites that are tracked in epigenetic age are primarily cell house keeping functions, which include autophagy, ubiquitin proteasome system etc. And now many papers are showing that these are inter related and therefore the complexity.

          • Kunal yes now we are in agreement. Autophagy indeed is very powerful and critical. There are other similar pathways. All systems are intricately interrelated. There is indeed incredible amount of complexity. There is so much yet to be discovered. Aging interventions that may lead to extended lifespans need to be effective across every cell and system. The era of addressing individual systems and symptoms no matter how powerful is over. Are you a researcher at University or industry?

          • Tom there is a very interesting paper that explains the molecular mechanism of action of spermidine and resveratrol in inducing autophagy. They also did dose analysis and found that only 10% of the dose is required to induce autophagy if both are taken together: 2.5 mg/kg resveratrol or 5 mg/kg spermidine.

          • Thanks greatly. A study shows that pterostilbene has twice the effect on SIRT1 as resveratrol, so I am taking that.
            Kahyo, T., et al., A novel chalcone polyphenol inhibits the deacetylase activity of SIRT1 and cell growth in HEK293T cells. Journal of pharmacological sciences, 2008.

          • As I understand, Extra Virgin Olive Oil (EVOO) has a similar effect to Resveratrol.
            In Mediterranean countries, we consume EVOO on a daily basis. Does this mean that spermidine can be combined with EVOO, instead of Resveratrol?

          • Zisos unless there is study that has confirmed the exact same mechanism of action as resveratrol one can not be certain about similar synergy. Typically any conjugation with fat improves the bioavailability of most natural extracts.

          • Hi, Tom:
            They say they will contact the buyer to confirm that it is for research only.
            How can someone get around that? Just by stating so?
            Or does someone need to explain/prove?

          • Spermidine can be obtained as an over the counter supplement. Just look on amazon or any supplement site.

            I could be wrong about this, but I seem to recall a discussion of a mouse study whereby too much spermidine (obtained from a supplement) becomes a negative. Spermidine is easily obtainable from food and food spermidine, in my opinion, is likely a lot safer than a supplement.

          • By my calculations, you need about 10mg/day. Lab spermidine costs 0.02$/mg. Amazon gets around 2.00/mg

          • Thank you, Tom.
            I like your experiment LOL.
            And I agree, the spermidine sold as a supplement is outrageously priced.
            And it is the exact same thing sold by the lab!
            Can you please explain how you arrive at 10mg/day?
            I currently take about 1mg/day by consuming wheat germ, and probably a bit more through other sources. Getting 10mg through food is difficult.

          • Both, exercise and intermittent fasting, which I practise extensively, are known to increase autophagy.

            I’m wondering how much autophagy is too much?

            Would I benefit from supplementing with spermidine or overshoot?

          • Autophagy and senolytics can be dangerous. Removing too much senescent cartilage can lead to pinched nerves and worse.

          • Article

            Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length

          • Yes Spermidine is very interesting. I wrote about Spermidine and Urolithin A 5 years ago. Already used in my animal study of repair systems agonists quite successfully.

          • Akshay

            I tried to visit your blog ‘’
            But i am getting error ‘NET::ERR_CERT_COMMON_NAME_INVALID’.
            Is there another way to access your blog

          • Article

            Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions

            While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.

          • Kunal I am glad that blood borne interventions are unable to rejuvenate HSCs otherwise E5 wouldn’t have much value. Can aged HSCs be rejuvenated? Yes they can. This paper covers many ways they can be: Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging.
            E5 will do some of things mentioned here on HSC rejuvenation. Read the cited papers.

        • If it works in other mammals, we’re not certain that it will work in humans , but if it fails in rodents, it will almost certainly Not work in us.

  5. Of course aging is inevitable but that’s a false argument to discuss living forever, rather let’s discuss slowing down the rate of aging, that’s where all the research is aimed at. From n=1 experiment done on myself that seems to work well. There’s no way for me to know if that experiment will become successful. Since you can’t prove it…

  6. Actually it is menopause that prevents population overshoot in humans…Aging eventually stops males from reproducing…but 1 male can repopulate the whole group….So this is kind of a much waeasker selected force than menopause..
    (I am just thiking out loud here Assuming that population control is evolution’s goal for selecting for aging ..which is debatable…)
    Also death and starvation reverse population overshoot.
    Now if you include menoause as an aging phenomenon then Josh’s statement would not need modification.

  7. Narrow minded two dimensional thinking. Dunning/Kruger applies. We are at the down of a new age and we don’t even know what we don’t know yet. Meaning 10 years from now, 30 years from now, 50 years from now we’ll have access to technologies and insights into the process of aging that we cannot even fathom yet today. We are all prisoners of our own era.

    I’m in the finance and quant trading field and have seen more lofty predictions in my career than I could shake a stick at. The majority of them proved to be completely false and if they held true then it was only for a brief amount of time. But of course memories are short and then the next generation of analysts repeat the cycle in a similar fashion. It’s the one lesson that humanity refuses to learn: It’s tough to make predictions, especially about the future (Yogi Berra).

    It’s human nature to think on the basis of the here and now – to imagine things in mostly linear terms. It’s very hard for most of us to appreciate or imagine exponential change, and for that reason the pessimists are going to continue to be proven right until one day (hopefully not too far in the future) they will suddenly be proven horribly wrong.

    TL;DR: let’s ignore the naysayers and soldier on, there’s much work to be done.

    Akshay: we are all rooting for you 😉

  8. This blog summarizing the study is full of errors and states things that are not even present in the study:

    – Epigenetic aging is the direct consequence of DNA double strand breaks and not a programmed process.

    The loss of telomeres is not there to make us age but to protect us from cancer. It is only when this system is deregulated (persistent cell senescence) that this poses a problem. ( potential rejuvenation strategys ) Cellular senescence ( therapeutic opportunity )

    – Aging cannot be directly programmed for 2 reasons:

    1: The selection cannot act on the genes which manifest their effects after the breeding period.

    2: Selection works at the level of the individual and not at the level of the species.

    Aging is harmful for the individual and as, by definition, the natural selection must eliminate all that is bad for the individual, it cannot actively hold back such a harmful process, which in addition, manifests itself well after the period reproduction and in a very isolated way (very few individuals live long enough to suffer the harmful effects of aging )

    3: The theory which stipulates that aging serves to make room for young people has been dead for 130 years and since, unanimously rejected because its author, August Weismann, could not explain a concrete mechanism explaining how such a mechanism could target old people and how it could be maintained over time.

    He therefore suppressed his theory a few years after having published it.

    And then, if aging was really programmed, we would all age at the same rate and die at the same age, no matter what our lifestyle, and then, if evolution was really able to actively limit lifespan, it Rather, I would have chosen an instant death after a certain age has passed rather than a long decomposition, because this way individuals can continue to survive and reproduce properly. ( Naked mole-rats eventually die, but like other species , they do not age. ) ( The same goes for the bigmouth buffalo ) ( There is no reason in the eyes of evolution to select the progressive deterioration of the organism, unlike programmed death )

    • Thanks for these thoughts, Donovan – You summarize very well the arguments I have been up against for 25 years. Yes, I’ve been thinking about this subject for a long time, and I have answered all these objections along the way. They’re adressed in my books. Here’s the academic version and the popular version, with Dorian Sagan. Most of the points are addressed at some point or other in previous editions of this blog.

    • The changes that lead to epigenetic drift involve predictable silencing and activation of genes. If DSBs are sole cause then getting exact changes in which genes are silenced and which genes are activated can not be possible as DSBs do not occur at exact spatial and temporal planes. Horvath clocks and Wyss-Coray’s 2020 papers give evidence of a pattern of spatial and temporal changes. For example the methylation changes are so predictable that accurate bioage clocks have been constructed. These predictable changes ensure death but it need not be at exact same age even if it is thus programmed as Nature has included cheat codes: a reward for the active, productive and penalty for gluttonous and lazy. This creates the variance in age of death. But no matter how healthy lifestyle one leads or supplements one takes we are unable to prevent death. This has been mathematically captured by the authors of this and many other papers including the Hayflick limit to espouse biological constraints to lifespan. These calculations do not factor therapies that address those biological constraints. The epigenetic drift is caused by regulatory factors and not DSBs. The temporal transcription of these factors provide the predictable trend of dysfunction. The paper is correct that by addressing the symptoms of aging like depletion of NAD+ or increase in senescent cells one can’t extend lifespan. But if there are interventions that address the regulation than there is scope to extend lifespan. I have given this example before of Gingko Biloba tree only because Prof Richard Dixon has conducted scientific research to arrive at his findings. A 20 year old tree and a 1,000 year old tree have only a 5% difference in their gene expression. Its autophagy, immunity, photosynthesis were as efficient as in the young. It was able to replenish its stem cells. Somehow the tree is able to freeze the epigenome thereby becoming immortal in a young state. A lot of the most highly regarded papers have been written with only a tiny view of our biology. Till recently 98% of our genome was considered junk even by the most respected scientists. Now we know that there is incredible amount regulatory factors transcribed in the non coding part of our DNA. Most of them are yet to be characterized. So we can’t take these papers to be the final word on lifespan. There are many exciting biological discoveries that are coming and some of them will lead to possibility of longer maximum lifespans.

      • Good point Ashkay.
        I agree that we should focus more on eigenetic control of/by the Aging Program. But we must also focus on knowing the steucture and internal hietarchical regulation of the nuclear Aging Program itself (please see my paper Barja Biogerontology 2008 on the AP internal regulation to see in more detail what I mean).
        Without knowledge on how tge nuclear AP is organized epigenetics study will be almost useless to us.

        That’s why I like to finish my papers “shouting”: “Please, Look at the Nucleus!!!”

        • Gustavo I am in agreement. Epigenetic changes are one of the many changes effected by regulation that arises from nucleus over time. I also liked your reply on entropy 🙂

          • Blog has a serious problem regarding the posting. For example, if you try to press reply on the notification on your email address it will show up but if you just press the comments, you will only see the old ones.

  9. Bravo!

    You might have added that it political impediments are in no small way dictated by economic forces. With traditional proletarian communist internationalism on the rocks, we await an alternative economic system that systemically ensures continued ecological harmony and sustainability, plentitude, substantial socio-economic equality, cultural diversity, and peace. Curiously, it appears that biological immortality (pessimists aside) will prove easier than secure humanitarian social structures.

  10. Josh. I have a political idea on how to avoid the disaster of climate change:
    Urge tge so iologidts to think of a better system than classical capitalism which is absolutely incompatible with your proposal of livibg well with less plus efficiency. I agree with these but it is not enough.
    Capitalism is rooted on individualism and kndividual profit. USA us a excellent exsmple of this abtisocial system oposed to well fare state at EU in the Zlste XXth century. Now neoliberals snd right are trying hard to bring us back towards savage capitalism. USA itself is savage capitalism compared to EU well developed states like France on the past (?now its social aspects destroyed by neoliberal selfish ideology focusing only on self interest benefit snd greediness (socoal hate amkng individials within a society which you know well, like Darwin said in The Descent of Man, weakens the group. The best group is the one with 100% love towards inside (and 100% hate towards otside, towards other groups).
    So Gaia needs our social systems to evolve towards better kinds of society (classical capitalism is no good). The problem is we lack sociologists courageous or clevar enough to sit and study a new better kind of social system.
    Some phylosophers are starting to think if the chinese have really created a little step forward or not in this sense with their:

    -A) Fully Competitiveness based economy
    Balanced by?:

    -B) More than us Collaborative in the internal political side? (I have never been in China but of course inviding their own Capitol as it happened in USA or menacing our own Ministers with bren gun bullets to kill then and family- as it happened in Spain is unthinkable in China. Here at West there is much more Hate towards inside our groups than in China (it is healthy to recognize this).

    If A plus B were correct they would be more “balanced” (internally) than clasical capitalism (mainly focused on Competition among individuals).
    I heard some specialized thinkers say that the Chinese put SOCIAL HARMONY as superior to INDIVIDUAL SELFISHNESS (selfish gene theory in Biology is a good example of how wrong thst can be!.

    In case that would be correct , could it perhaps explain the FACT that China has already “won” the intergroup race with USA to be the next empire worldwide?
    I see a lot of nervousness in President Biden about China. But I think his aggressi e attitude towards Russia (the third small but well ARMED party of the 3 big “brothers” of this poor earth). Trump seemed to have a better politics trying to atteact the Russians towards his side (although his despising Europeans was a huge mistake too in my opinion).
    But now Biden does the reverse. His move leads to a classical confrontation of USA+EU against RUSSIA + CHINA.
    That can only finish in the East winning the cold war. Unless he is so crazy as to wonder going to the warm one if in despair of loosing for ever the USA empire. I hope he does not go so far away..
    Until now, when any empire ĺost his economic power it always just durrendered, Egypt, Rome, Spain, France,England, did it. I do not see any reason why USA and his satlites would not co tinue this rule and surrender peacifully instead of bringing all humankind to hell….

    • It is no good just trying to dream up some better politic system. Many clever Europeans came up with communism and look at the horrors that caused; far worse than the worst of capitalism. Of course individualism was the making of the West and also it’s downfall. I don’t think China is as strong as you suggest,they have terrible demographics and anyway owe all their economic growth to sponging off the West. I suspect the USA will hold onto their crown for the foreseeable.

  11. Josh:
    My thought is that the study actually demonstrated the ability of the various aging “clocks” to adapt to species specific requirements and therefore the fact that they are amenable to change. If we study the differences which lead to divergent aging rates in various species it should be a direct path to control.

  12. Josh
    what is the “new study” absurdly pretending that aging is inevitable? I did not find tge citation.Can you state it please?

  13. Josh, I forgot to add that relying only in competition instead of in competition+colaboration (much better balanced future sociological system for humankind?!) is obviously inferior.
    A good example us the vaccination campaign in the West (in EU a desastrous one) with 4 compsnies in competition..
    the result of which was the disaster of the mRNA-based vaccines risking corrupting the cellular DNA of half of the population. Only competition can explain such gross mistake that will no doubt accelerate aging in the West but not in China!
    The more safe vaccines are no doubt the 3 chinese ones because they are based on the attenuated virus which is the classical vaccines used for around one century and with a lot of experience on their safety. Even if the mRNA ones were not bad in the end why to incurr in such a risk at 1,000 million people level! Only the bad outcome of compettitiveness and looking for company benefits (greediness) can explain such a huge mistake. Unless one thinks it is a mistake done on purpose…I cannot beleive any organization can be so globally criminal. I do not believe in that. I think it is a mistake out of greediness and our classical capitalist system allows such a hugely wrong thing to happen whike in China it did nlt because the vaccines where under the control of the State.

  14. Are these people who say aging is inevitable the same people who said that HCQ and Ivermectin were useless against covid-19? Are they the same people who said that covid-19 could not possibly have come from the Wuhan lab?

  15. I have worked in biological sciences long enough to one thing for sure. Any scientist who is sure you can’t do something is in the wrong field. You can lead a whore to culture, but you can’t make him/her think.

  16. I think we can safely ignore papers where everyone and their dog gets a credit.

    Reduction in variance of lifespan with increase in lifespan is just due to the removal of external causes of death. Nothing more. Clearly shorter lifespan is not only a neutral, but an actual advantage when external causes of death are high, as it allows more iterations of generations within a given time frame, so adaptation to a faster changing environment is possible.

    We not in Kansas anymore. We don’t care what evolution wants. Whatever mechanisms nature has employed to constrain human lifespan can be overcome. As Alan and Josh have said, this will cause problems. But they won’t be as bad as half the population living in a retirement home with dementia, and the other half destitute to pay for it.

  17. Just curious – it seems there are 28 comments but I only see one (by Leo June 17). Same on two pc’s and my phone. Is private login required? Thanks!

  18. It seems that if we could maintain signals and nutrients in plasma at youthful levels, we could live to 200

  19. Gustavo Barja. Professor of Physiology (UCM Univ. Madrid, Spain) and Academic of RANF (The Royal National Spanish Academy of Pharmacy), and head of the LRGM Research Group composed by five Professors from Seville, Lleida & Madrid Universities on said:

    You said: “My main concern for humanity is that it might be overtaken by robots (Artificial Intelligence).

    Zsisos, do not be afraid. For the moment there is no “Artificial intelligence at all”. That is a¡just another fake to make business.

    I agree, however, that it will be a huge problem for humans the day true artificial intelligence is created. but that is still far in the future.

    We do not understand how our human brain works. Even the best knowledge in neuroscience is gross. Complexity of synaptic connections in human brains are much more combinations than stars in the galaxy. That is why artificial intelligence does not exist (specialists on the field know it and some tell it openly).

    I predict that humankind will be succeed in producing 300 years old and 1,000 years old “super-humans” (socially speaking in Friedich Nietzsche terms) much earlier than true artificial intelligence (I mean “intelligence” of a similar or higher level than the human one).
    The problem is that too many people in the badly called a”rtificial intelligence only annoher kind of sellers looking for gold, or are so absorbed by technology that do not have time for reading intelligent things like Phylosophy…so their idea of “intelligence” is a very low level one, similar to the one they practice on their culturally empty heads…
    I cannot imagine any present day machine being light-years far from the intelligence of people like Aristotles or Plato. But to be near the intelligence of our Madrid fascist president…that is at hand of more than the already existent machines perhaps je je

  20. Besides ecosystem stability, there are a few other reasons why ageing could be programmed. Like it is in the analogous process of cellular apoptosis in multi-cellular organisms.

    For example, limiting HOMOZYGOSITY of deleterious alleles, which is what tends to happen in small populations through in-breeding.

    The idea being that the offspring of a few individuals could dominate the gene pool. I recall some studies comparing the age of sexual maturity and maximum lifespan and there being a good deal of correlation, at least in higher animals.

    Connected to this idea would be MAXIMISING GENE DIVERSITY within a population, so that it can better adapt to a changing environment. The more diverse the gene pool is, while still remaining capable of cross-breeding, the more the chances and the speed at which a group can adapt to a new niche (and balloon their numbers thereafter).

    This is connected to the idea of EVOLVABILITY. That is, increasing adaptability and outcompeting other species.

    Another more unconventional idea that I haven’t seen elsewhere, is that ageing facilitates more effective SEXUAL SELECTION. With the passage of time a multi-cellular organism’s germ line will accumulate mutations, further separating the somatic phenotype (which itself would have accumulated mutations, but those would not be passed down anyway) from inheritable features. It could be that continuing the “developmental process” that ageing seems to be, serves to signal the actual age and the the germ line may have drifted far away and not be as fit as it would otherwise.

    Another reason, related to the one above, is that ageing serves to STRESS-TEST an organism. Similar to how silver back gorillas signal full sexual maturity with “grey hair”, ageing tests the ability of an individual to survive. Thus sneaky mother nature not only counts on external forces to shape evolution, but also provides an endogenous stress force through ageing.

    • I completely agree with your thoughtful analysis Adrian.

      Intermixing of genes is paramount in a fast changing environment. A shorter lived species will always be able to out-evolve a longer lived species, hence why prey species have (or develop) shorter lifespans than those who prey upon them. This is a highly adaptable process whereby stressful conditions induce earlier breeding, favouring those who can grow to maturity quicker (with consequent shorter lifespans) but also permitting loss of any adaptations for longer lifespan if these conditions are sustained. The way that this is achieved may well have commonalities between species, for example the MTOR complex, and may also have completely different effector mechanisms, like ROS in mice, or telomeres in humans. The argument about whether it is ‘programmed’ or useful ‘neglect’ is semantics to me; nature achieves it without giving it a name.

      • Mark,
        Why do you say ” different effector mechanisms, ROS in mice and telomeres in humans” if:
        A) There is repeatedly confirmed evidence of involvment of mitROSp in aging both in short- and long- lived animals? (In fact the strongest among all possible aging mechanisms apart from double bond index of fatty acids)
        B) There is ample involvment of many strong evidences against telomere shortening as causal to aging (including in himans) because: B1) calculations indicate that you reach telomere full length shortening only well after 120 years
        B2 ) Telomere shortening does not occur in cells that do not or very scarcely divide under natural conditions: neurons, cardiomyocites and skeletal muscle cells, the post-mitotic cells, the most important for aging no matter how in fashion mitotic mother stemm cells are…

        • I say it because I know a great deal about telomeres, that’s why. Telomeres shorten in mice and humans; it’s irrelevant whether they shorten sufficiently to reach replicative senescence. Real biology isn’t binary; ‘senescent enough’ to divide more slowly is all that’s required for deleterious effects. As for quiescent cells, in every case they are supported by dividing cell lines.

          • Mark, you will find this paper interesting:
            ‘Potential Role of ‘Junk DNA’ Sequence in Aging and Cancer Identified’
            It confirms my hypothesis about non coding transcription regulating important age related changes. The enhancer function to telomerase transcription they mention must be wound down as we grow older. What is fascinating about cancer is that from what is available in our biology/body it is able to engineer an immortal cell. If we keep aside its manic replication, how cleverly it reorients and metamorphosizes all the constituents of the cell to serve its various purposes is awe inspiring. It tells us we don’t need any synthetic therapy. We can create immortal, resilient cells from what is already present in us.

  21. Humans couldn’t fly, until they built airplanes. Like it or not, longevity technology is coming fast and doesn’t care about our natural constraints, whatever they may be. The rest we’ll just have to figure out.

  22. And humans couldn’t fly, until they built airplanes . Longevity technology is coming fast, like it or not, and the rest we’ll just have to figure out.

  23. The inevitability of aging does not exclude that temporarily rejuvenation is not possible but only temporarily. These old rats turned into young rats only
    temporarily. After 1 year (if not dead) the rats would be older.
    It is the same as with the entropy. The entropy of a system could be decreased only temporarily with the intervention from outside.

    Besides this, the rejuvenation of the rats was measured using only physiological parameters.
    I am 58 years old and I’ve done one year ago a complete medical check (130 tests !). The biological age that resulted from that tests was 39 years.
    But I do not feel, by far, like when I was 39 years old. At most like when I was 50.

    So what’s the use that a 90 years old man have the biological parameters of a 50 years old when he feels as at most 75?

    • It’s funny to me when people tout their “biological age” from these aging clock tests when they actually look much closer to their chronological age. I do think these testing methodologies are likely misleading and inaccurate.

    • Florentin. I agree with you except for one detail: we animals are energetically OPEN systems. That’s why our entropy does not have NECCESARILY to increase AT ALL. Aging is not due to “entropy”. That is tru of chairs and other innanimate objects. Not of living things that co tinuously ingest foid (energy) and use it to autoorganize ourselves. If there is aging in spite of this fact is because we the animals produce aging internally on purpose to age at a speed tipical of each species. Forget ablut “entropy” when discussing animal aging.

    • Florentin – I ask you to be more specific about the word “temporarily”. There are clams that live 500 years. There are redwoods that are 3000 years old. There are Aspen groves, grown from a single seed, that have continued to propagate through underground root systems for 30,000 years. All these living things have managed to “temporarily” avoid aging.

      If all that you mean is that we will all die evenutally, I agree. Nothing lasts forever. If I live long enough, I will die in a traffic accident. The earth will be engulfed by the sun as a Red Giant. All life is temporary. Stars and even galaxies don’t last forever. Black holes evaporate in a googol years.

  24. Josh posted comments and even received a reply on my comment but they can not be seen here. Can please you look into this?

    • If you click on “reply” on any post, it will reveal all hidden posts. It doesn’t really fix the problem, but it works.

  25. Perhaps the microbiome is the clock? A new paper.

    “Here, however, by comparing gene expression profiling of Drosophila raised either conventionally, or free of bacteria, we show that ∼70% of these conserved, age-associated changes in gene expression fail to occur in germ-free flies. Among the processes that fail to show time-dependent change under germ-free conditions are two aging features that are observed across phylogeny, declining expression of stress response genes and increasing expression of innate immune genes. These comprise adaptive strategies the organism uses to respond to bacteria, rather than being inevitable components of age-dependent decline. ”

    • The capacity to show “Adaptive responses” is programmed in the genome.
      Almost all body physiology is Programmed in the genome. We call itHomeostasis (regulation) without which we will be deade like “non prigrammed chairs” (the one obeying wear ant tear necessarily wrong “theories” (just wrong hypotheses) of evolutionary aging.

      Such programmed regulation wiil be also responsible for ourcapacity to live for 1,000 years (at mininum) in the future. If cells renew themselves continuously (turnover that chairs do not have) why not we live indifinitely?
      Because some of the programed regulations include the determination od spexies-specific life span. That s why sckentist must study the nucleus of neurons, cardiomyocytes and sk. muscle cells, the ones most important for aging. Biology knows almost nothing about the functioning of those nuclei. Almost all mother cells stem cells etc and similar wrong approaches (in fashion) to aging are done in very diffrent cultivated cells like fibroblasts which mislead the researchers.
      PLEASE LOOK AT THE NUCLEUS OF THE POSTMITOTIC CELLS! (just in case you know how to do that, much more difficult than population doublings etc

  26. With all the DNA/mRna studies being done it is being said by scientists that ageing is a hiccup in our genes and that ageing (now being recognized as a disease) may be more easily “fixed” than many cancers.
    Also it is more recognized that “underpopulation ” may be a more imminent threat than what we have been warned about for years. Look at the “fertility rates” of almost all nations, including so called third world countries.
    Countries like Japan, South Korea and Thailand are under1.0 replacement rates. Europe has been taking in immigrants for years.
    I’ve seen where the USA is at 1.7 and falling below the 2.1 to keep the population at the current number.

    • Hiccup is quite an understatement. It’s programmed at a deep level, but I agree it is easier to slow aging than to cure cancer.

      Overpopulation seems already to be a problem, and we either need to change our habits to use resources far more efficiently or agree to limit everyone’s individual right to reproduction. Either of these requires changes in culture that I don’t know how to approach.

      • Regarding the overpopulation problem, it looks like this is being caused by a fall in death rates rather than rise in birth rates. In under developed African countries going through the transition to low child mortality this is most pronounced as birth rates have not yet fallen to developed levels, but to a lesser extent it is being mirrored in developed countries at the other end of the age range with far more older people surviving for longer in a dependent state. My little town in central England only has 1000 people living there, but has 2 large old peoples’ accommodation. Solving aging would make these people productive again, but would make the overpopulation problem even worse. But in England birth rate are low and drifting lower. Can we even contemplate rolling out such a treatment to countries with high birth rates?

        • This assumes that nations with high fertility will continue to have high fertility after getting access to anti-aging therapies. High fertility is ultimately economic. The opportunity costs of having children skyrocket as societies become more prosperous.

          • Very true, but as I pointed out there are rocketing populations in countries transitioning from high to low fertility, and I’d expect something similar in countries transitioning to an ageless society.

      • In general as soon as women are educated tend to give birth to less children if any at all. in some cases In South Korea the birth rate per woman is 0,95 kids. This is far less than one.
        In Europe birth rates go down steadily. So they do everywhere except some countries in Africa (where women are uneducated, just give them time, if you check gapminder you’ll see that even those high birth rates are not as high as they use to be, and decrease every year, as they are being mitigated by women’s education, just like they have been in other countries).
        In Africa kids are still working force and old age insurance for the parents, which is absolutely undesirable. Most of governments try to take action on that.
        For good or for bad, many of my girl colleagues from the Polytechnical University are childless, or have just one kid. Personal decision, most of times.
        It is something unthinkable for me, but many women seem to be comfortable with that.

        Besides I have the feeling that many people think that we are solving death, and I think the pandemics show us clearly that we are not solving that.
        The fact is that developed countries have aged amazingly and the pandemics have been the cause of death of at least 4 million people in the world. Seem few, and every death is a loss, and a drama, and I lost my mother just before pandemics and every time I read about the death of the elderly by COVID was a painful reminder of her loss.
        But I think that we are being too optimist too fast, E5 might be the amazing discovery of the Century (and probably would broke many fertility clinics, as most of them treat women with age related issues, that would get pregnant easily otherwise), but society has changed a lot concerning childbearing and many women do it late, because of social pressure and many times are unsatisfied with motherhood. Again we think that we have to assume that not everybody is willing to reproduce like rabbits.

        And that next pandemics may not hit the elderly only.

        • Everything you are saying about female education and motherhood is well known and accepted, and I take no issue with it. But the key point is that regardless of reduced fertility, there is a significant lag during which population rockets. This is evident in many developing countries. It does not matter in the short term that women’s fertility drops, because it does not drop as fast as childhood deaths do. I see something similar happening with civilisation after aging is solved. There will be a decade or two whilst it is being rolled out and everyone realises that there is no longer a time limit on motherhood. In that time population will go up. It is another discussion whether we are really about to solve aging or whether it will take another 100 years. But I think we need to have the discussion before it is upon us.

  27. Josh have you seen this?

    Molecular epidemiologists have observed that mutations within the Sars-CoV-2 spike (S) protein of these emerging, more infectious lineages are converging to the same genetic sites, a phenomenon that coincided with a major evolutionary shift in the landscape of naturally selected Sars-CoV-2 mutations (1).

    Significant convergent evolution(*) of more infectious circulating Sars-CoV-2 variants is not a neutral, host-independent evolutionary phenomenon that merely results from increased viral replication and transmission but is strongly suggestive of natural selection and adaptation following a dramatic shift in the host(ile) environment the virus is exposed to (1).

    Molecular epidemiologists fully acknowledge that the pandemic is currently evolving Sars-CoV-2 variants that “could be a considerably bigger problem for us than any variants that we currently know in that they might have any combinations of increased transmissibility, altered virulence and/or increased capacity to escape population immunity” (1). This is to say that phylogenetics-based natural selection analysis on circulating Sars-CoV-2 lineages strongly suggests that viral variants resistant to spike (S)-based Covid-19 vaccines are currently expanding in prevalence and highly suspicious of causing future epidemic surges globally.

    Deployment of current Covid-19 vaccines in mass vaccination campaigns combined with the ongoing widespread circulation of Sars-CoV-2 can only increase immune selective pressure on Sars-CoV-2 spike protein and hence, further drive its adaptive evolution to circumvent vaccine-induced humoral immunity. In this regard, the expectation of an increasing number of vaccinologists matches the current observation made by genomic epidemiologists in that S protein-directed immune escape variants are highly likely to further spread and expedite the occurrence of viral resistance to the currently deployed and future (so-called ‘2nd generation’) Covid-19 vaccines.

  28. Hi All followers of this blog. Just heard the very sad news of Josh’s accident on Wednesday. For all who don’t know he is in ICU. Let us pray for his speedy recovery.

  29. Ok just received a very sad update from his friend Walter who is in touch with Josh’s daughter Sarah:
    Josh was hit and run on his bicycle. Hip, leg, arm, etc. broken. Already had several surgeries. Much internal bleeding, but he’s awake and safe now. Will probably be in the ICU for two more weeks, according to his daughter, and will probably never be able to run or hike again, etc.

  30. A bit off topic but I really need a right information if you could help me. Do you know if Sulforaphane and DIM interfere with antibiotic doxycycline?

    • Nanaka:

      It appears that broccoli & Kale may reduce the ability to absorb the Doxycycline. It will at worst make the doxy less effective.

      Can you take the nutrients apart from the Doxy, by eight hours or at least a four hours to avoid decreasing absorption to much?

      If not, it may be best to stop taking them temporarily, while using the Doxy, to maintain the drugs full effect

      Dim and Sulphoraphane Both are found in Brassica vegetables

      Iron supplements and iron-rich foods — such as liver, sardines, beef, lamb, eggs, canned salmon, legumes, tofu, wholegrain cereals, kale, broccoli, spinach and certain seeds and nuts — may also affect your body’s ability to absorb doxycycline.

      Dim: (3,3′-Diindolylmethane) is a compound derived from the digestion of indole-3-carbinol, found in cruciferous vegetables such as broccoli, Brussels sprouts, cabbage and kale.

      The elimination half life of doxycycline is between 16 to 22 hours (for healthy adults). This is the time it takes for your body to reduce the plasma levels by half.

        • Nanaka:

          just noticed that Heather didn’t mention dairy products, which should be avoided prior to taking doxycycline (most likely also mentioned in the package leaflet).

          You probably already knew that, but just to be on the safe side.

          • Hi Nanaka:

            I did not know that. Sorry to hear that that type of lack of knowledge is worse outside the USA.

  31. Akshay,
    I have a couple of questions. A couple of months ago you indicated in a post that the Blue Gel would come in a 30ml unit size, and that to participate in the systemic effect trial, you would need to apply Blue Gel two times per day. In a more recent post you indicated that the unit size would be 100ml, and that the Blue Gel would need to be applied 3 time per day. Have you changed the formulation? Has the price per unit changed?

    I saw the update for your E5 longevity trial on the “Modern Healthspan” Youtube channel. The results for IL-6 and TNF-alpha were impressive. Congratulations! Are you testing other parameters than the above two that you have already shared?


    • Hi Rick,
      As many of you wrote to me about doing a fully body application self conducted trial with cytokine readings before and after 30ml would be too less per bottle. So on Amazon both 30ml and 100ml will be available for the soft launch to our community we will keep only 100ml.
      Yes we were really happy to see the results of the ongoing lifespan study. We have also done grip strength and are in the process of sending DNA samples to Horvath Lab/Clock Foundation. Interestingly for the first time next week we will be administering a 3rd dose. Really keen to see results on these subsequent doses to see if there is any cumulative effect or if at some dose aging stops.

  32. I dont know if my reply to Rick Davis was posted so here goes:
    Hi Rick,
    As many of you wrote to me about doing a fully body application self conducted trial with cytokine readings before and after 30ml would be too less per bottle. So on Amazon both 30ml and 100ml will be available for the soft launch to our community we will keep only 100ml.
    Yes we were really happy to see the results of the ongoing lifespan study. We have also done grip strength and are in the process of sending DNA samples to Horvath Lab/Clock Foundation. Interestingly for the first time next week we will be administering a 3rd dose. Really keen to see results on these subsequent doses to see if there is any cumulative effect or if at some dose aging stops.

  33. ” As we extend human lifespan, there is an urgent need to move toward sustainable agriculture and to adopt energy-efficient technologies.”

    And even more urgently to spread human civilizations off planet Earth.

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