Universal Clock implies Universal Clockwork

A new methylation clock works in 128 different mammal species, using the same methylation signals. This is the latest evidence that at least some of the mechanisms of aging have been conserved by evolution—strong evidence that aging has a useful function in ecology, so that natural selection actually prefers a finite, defined lifespan.


Einstein taught us that time is relative. Indeed, there are rodents that live less than a year, and Bowhead whales that live more than 200 years. Some of this is just about size and has a basis in physics; but it is well-known that size is only part of the story. Bats and mice are the same size, but bats live ten times longer. Humans are much smaller than horses, but live three times as long.

The first time I met Cynthia Kenyon was circa 1998. She offered me a one-line proof that aging is programmed: the enormous range in lifespans found in nature defies any theory about damage accumulation, because no conceivable process of chemical damage could vary so widely in its fundamental rate. (Think mayflies and sequoia trees.) My own one-line proof is that yeast and mammals share in common some genetic mechanisms that regulate aging, though the last common ancestor of yeast and mammals is more than half a billion years old. These mechanisms include sirtuins and the insulin metabolism.

These intuitions about aging rate and evolutionary conservation have recently come to the world of big data. In this new BioRxiv manuscript, Steve Horvath collaborates with an all-star cast of biologists the world over to compile evidence that there is a universal mechanism underlying development and aging in all mammals, and it is a pan-tissue epigenetic program, not a process of chemical damage.

Brief background on methylation: It is increasingly clear that aging has a basis in gene expression. The whole body has the same DNA, and it doesn’t change over time. However, different genes are turned on and off in different times and places. Turning genes on and off is called “epigenetics”, and evolution has devoted enormous resource to this process. One of many epigenetic mechanisms is the presence or absence of a methyl group on Cytosine, which is one of the 4 building blocks of DNA (A, C, T, G). There are over 20 million regulatory sites in human DNA where methyls can appear or not. Of these, several thousand have been found to consistently correlate with age. The correlation is so strong that the most accurate measures of biological age are now based on methylation. There is (IMO) a developing consensus in the community that methylation changes are an upstream cause of aging, and there remains strong resistance to this idea on theoretical grounds. More background here

The team assembled tissue samples from 59 organs across 128 species of mammals, and looked for commonalities in the progression of methylation that were independent of species and independent of tissue type. They found thousands of methylation sites that fit the bill, attesting to an evolutionarily-conserved mechanism “connected to” aging. It is a short leap to imagine that “connected to” implies a root cause.

How did the authors map age for a mouse onto age of a whale? Just as I might say, “I’m only 10 years old, in dog years,” a year for a whale might be a hundred “mouse years”. The authors took three different approaches. (1) Just ignore it, mapping chronological time directly. (2) Adjust time for the different species based on the maximum lifetime for that species. (3) Adjust time for the different species based on the time to maturity for that species.

Predictably, (1) produced paradoxes; (2) and (3) were similar, but (3) produced the best results. What they didn’t do — but might in follow-on work — was to optimize the age-scaling factor individually for each species to target the best fit with all the other species. Even better would be to choose two independent scaling factors to optimize the fit of each species. Ever since the original 2013 clock, Horvath has divided the lifespan into two regimes, development and aging: In development, time is logarithmic, moving very fast at the beginning and slowing down at the end of development. In the aging regime, time is linear. So it would be natural (optimum, in my opinion) to choose two separate scaling factors that best map each species’s life history course onto all the others. Mathematically, this is (roughly) as simple as matching the slopes of two lines. Horvath has told me he is interested in pursuing this strategy but for some species the existing data doe not cover the lifespan sufficiently to support it.

“Cytosines that become increasingly methylated with age (i.e., positively correlated) were found to be more highly conserved (Fig. 1a)  …Interestingly, although there were 3,617 enrichments of hypermethylated age-related CpGs [i.e., increased methylation with age] across all tissues, only 12 were found for hypomethylated [the opposite] ones.”

Interpretation: with age, we (and other mammals) tend to lose methylation, i.e., to turn on genes that shouldn’t be turned on. There are more sites that demethylate with age than that methylate with age. But the sites that gain methylation tend to be more highly conserved between species. I presume a lot of demethylation is stochastic. It’s easy for a methyl group to “fall off”, but attaching one in the right place requires a specialized enzyme (methyl transferase). What we are seeing here is stronger genetic determinism for the process that requires active intervention.

Question: Would it be useful to develop a methylation clock based solely on sites that gain methylation? What we would thereby avoid is the situation where the age algorithm combines a great many large positive numbers with a great many large negative numbers to make a small difference. This characteristic makes the algorithm overly sensitive to bad data from one or a few particular sites. We can see from the figure above that (red) sites from the top half of the plot have stronger evidence behind them than the (blue) sites from the bottom. What we would lose would be diversity in the basis of the measurement. If retaining that diversity is desirable, it would be possible to design a clock algorithm with both red and blue sites in such a way that all coefficients are relatively small, and no one site contributes inordinately to the age calculation, even if data for that site is completely missing.

Speculation for statistics geeks: I think the methodology that has become standard for developing methylation clocks is not optimal. The standard method is to identify N sites (typically a few hundred) where methylation is well-correlated with age, then derive N coefficients such that you can multiply each coefficient by the corresponding methylation, add up the products, and you get an age estimate*. The way I would do it is with a more complicated calculation, from a methodology called “maximum likelihood”. The idea is to choose the age that minimizes the difference between the expected methylation and measured methylation for the collection of the N sites. To be more specific, minimize the sum of the squares of the z scores for each site, where z is the number of standard deviations by which the measured methylation is different from the expected methylation.It may sound like a complicated calculation to find the age at which this number is a minimum, but it is not. Yes, it’s a guessing game; but the algorithm called “Newton’s method” allows you to make smart guesses so you home in on the best (min Σz2) age within four or five guesses. The calculation is more complicated to program, but it would still execute in a tiny fraction of a second. My proposed method requires maybe 10 or 20 times as many fixed parameters within the algorithm; but the data submitted from each sample is the same.
Caveat – This is all theoretical on my part. I don’t know how much performance would be improved in practice.
————————
*Two footnotes: (1) A constant is also added. (2) In case the subject is young, below the age of sexual maturity, what you get is a logarithm of age, not age itself.

“Importantly, age-related methylation changes in young animals concur strongly with those observed in middle-aged or old animals, excluding the likelihood that the changes are those involved purely in the process of organismal development.”

These plots are adduced as evidence that aging and development are one continuous process under epigenetic control. They come from EWAS=epigenome-wide association studies. Start by asking which sites on the methylome are most closely correlated with age, across many different animals and different tissues in those animals. Start with just the young animals (different ages, but all before or close to sexual maturity. Arrange all the different sites according to how they change methylation with age (increasing or decreasing), just in this age range. Then repeat the process, re-ordering the sites according to how they change with age during middle age.

The left plot above includes a dot for each methylation site, ordered along the X axis according to how they change during youth, and along the Y axis according to how they change during middle age. The point of the exercise is that it is largely the same sites that increase (or decrease) methylation in youth and in middle age.

The middle plot shows the corresponding correlation between middle age (X axis) and old age (Y axis). The right-hand plot shows the correlation between young (X axis) and old age (Y axis). (I believe the labeling of the figure on the right is a misprint.)

This evidence points to a conceptual framework that views development and aging as one continuous process. Development is a lot more complicated than aging. Consequently, most of the sites in the clock are developmental.  Maybe a clock could be optimized for aging only, and it would be more useful for those of us who are using the clocks to assess anti-aging interventions.

“The cytosines that were negatively associated with age in brain and cortex, but not skin, blood, and liver, are enriched in the circadian rhythm pathway”

Here we see again the intriguing connection between the brain’s daily timekeeping apparatus and the epigenetic changes that drive development and aging.

“The implication of multiple genes related to mitochondrial function supports the long-argued importance of this organelle in the aging process. It is also important to note that many of the identified genes are implicated in a host of age-related pathologies and conditions, bolstering the likelihood of their active participation in, as opposed to passive association with, the aging process.”

Another theme in the set of age-correlated genes that the team discovered is mitochondrial function. Mitochondria have an ancient association with cell death, and a long, conserved history with respect to aging. The simple damage themes associated with the free radical theory have yielded to a more complex picture, in which free radicals can be signals for apoptosis or inflammation or enhanced protective adaptations.

The big picture

“Therefore, methylation regulation of the genes involved in development (during and after the developmental period) may constitute a key mechanism linking growth and aging. The universal epigenetic clocks demonstrate that aging and development are coupled and share important mechanistic processes that operate over the entire lifespan of an organism.”

This is cautiously worded, presumably to represent a consensus among several dozen authors, or perhaps to appease the evolutionary biologists looking over our shoulders. The statement is akin to what Blagosklonny has for years called “quasi-programmed aging”, to wit, there are processes that are essential to development that fail to turn off on time, and cause damage as the organism gets older. In the version put forward in this present ms, it is not the gene expression itself but the direction of change of gene expression that carries momentum and cannot be turned off.

Evolutionary theory

Modern evolutionary theory began with Peter Medawar, a Nobel laureate and giant of mid-century biological understanding. (He was 6 foot 5.) Medawar’s 1952 monograph contains the insight that launched all modern theories for evolution of aging. His fundamental idea was that it’s a dog-eat-dog world in which very few few animals live long enough for aging to be a factor in their death. The three main branches of evolutionary theory in response to Medawar are called Mutation AccumulationDisposable Soma, and Antagonistic Pleiotropy. According to Medawar’s thought (and all three theories that followed) old age exists in a “selection shadow” so random processes are at work in old age. It follows that we would expect the aging of a bat and a bowhead whale to be subject to very different random processes. If it is a burden of recently acquired mutations that natural selection has not yet had time to weed out, these should be different for different species. Or if it is about tradeoffs (pleiotropy) between needs of the young animal and the old animal, we would not expect the bat and the whale to be subject to the same tradeoffs.

The Medawar paradigm and its three popular sub-theories all predict that there should be little overlap between the genetic factors involved in aging of species that are adapted so differently. Therefore, the present work documenting a common epigenetic basis of aging is a challenge to the established evolutionary theories of aging.

As I see it, the expression of genes is exquisitely timed for many purposes, so we must view gene expression as subject to tight bodily control. “Accidents” or “mistakes” or “evolutionary neglect” are implausible. For some genes, methylation changes from minute to minute in a way that is adaptive and responsive. Blagosklonny’s idea that there are genes turned on for development and then the body forgets to turn them off doesn’t feel right. Equally, the idea that certain genes are being turned on (or off) progressively through development and then, after development has ended, the process has a momentum of its own so the body can’t stop further turning on (or off) of these same genes is equally implausible. I assume the body is adapted to do exactly what it wants with gene expression, and if the body expresses a combination of genes that causes aging, it’s because that’s what natural selection has designed the body to do. Of course, this looks to be a paradox, as aging is completely maladaptive according to the notion of Darwinian fitness that became accepted in the first half of the 20th century; but evolutionary biologists have broadened the notion of fitness since then, and I’ve written volumes concerning this paradox.

The bottom line

For personal application to individuals who want to know how well they are doing and their future life expectancy, I recommend Horvath’s Grim Age clock as the best available. (Elysium has done a lot of work on their Index product, and it may be as good or better, but it’s impossible to evaluate unless they release their proprietary methodology.) For application to studies of anti-aging interventions (including my own project, DataBETA), the choice of clocks is not clear, because it depends not just on statistics but on theory. We want a clock that is not only accurate, but that is based on epigenetic causes of aging, not epigenetic responses to aging. The multi-species clock is a welcome contribution, precisely because epigenetic processes that are conserved across species are more likely to be linked to the root cause of aging. For the future, I’ve made suggestions above for ways the multi-species clock might be made even better.

200 thoughts on “Universal Clock implies Universal Clockwork

    • No – DataBETA is in final stages of negotiating with a lab to do be our primary service supplier. When they’re ready, we’ll be ready. It should be less than 2 months, but I have no credibility because I’ve been saying that for too long.

  1. If age clocks really existed, there would have to be something that adds methyl groups at regular intervals. Even if the methyl groups could be removed, thus altering the activities of the enzymes to their original young state, the organism would still not rejuvenate. It would only get rid of chronic diseases such as obesity, diabetes, increased enzyme activity such as: aromatase, monoamino oxidase, etc.

    When a person takes antiobesity drugs, aromatase inhibitors, monoamine oxidase inhibitors, he looks a little younger. But signs of old age such as pigment spots on the skin do not disappear.

    • This is Josh’s forte due to his background. A very insightful review of a brilliant paper that makes some evidence backed conclusions that will please all those of us who believe in programmed lifecycle including aging. Josh’s review is interspersed with gems of his own.
      Any sequenced program needs temporal guns that make the required changes to execute the program. This artillery is transcription. We have spent decades focused only on coding genes correctly assuming that the translated proteins run all our systems. But there is higher force than gene expression. The temporal changes effected by regulatory transcription. Gene expression, protein translation and even post translation is regulated by the product of this transcription. Data from ENCODE suggests that more than 75% of the human genome is transcribed into RNAs but only 3% of these RNAs are from protein coding genes (Djebali et al., 2012; Ecker, 2012; Pennisi, 2012). The non coding transcription has not been studied as assiduously. They are the guns of the program of aging. Methylation is just one of the secondary tools used to lock these changes. Hope in future we see more research on transcription in the non coding part of our genome.

      • Yes, I always laughed when my teachers back in the day referred to this as “junk DNA”

        What a moniker and irony from “non-religious” evolutionists

  2. Thank you for this report. I found it very informative and exciting. I believe that human life is similar to an incomplete software program that just hangs up after the logarithmic growth stage. Perhaps if we had an additional metamorphosis stage, similar to that of a butterfly, we could understand aging further.

  3. I would be interested in your opinion about the potential use of Methylene Blue (MB) as a means for adjusting your “methylation clock”.

    Low doses of MB have been reported to have many favorable effects on mitochondrial activities and cellular senescence, and on many biochemical markers related to aging.

    But how can I know — if I start taking a low dose of MB — whether I am activating, de-activating, or re-activating, the “right” genes?

  4. Thanks for this report Josh. Very interesting.

    I’m still a little unsure of whether these (species conserved) methylation changes really are UPSTREAM of aging. If you look at the expected methylation pattern of an aged person, it would be a perfectly reasonable argument to say that this pattern is what enabled them to reach such an advanced age. Because the link between methylation changes and actual gene expression is so tenuous, we end up falling back on such logical arguments.

    Having said that, it is clear that development and aging are linked – although I for one still hanker for a actual, solid mechanistic explanation, such as the faster you grow up, the faster you use up your stem cells. For example, if you take supplement X that allows stem cells to maintain a greater degree of pluripotency, and this then leads to a reversal in some methylation measurement of your aging, we are on common ground. But that doesn’t necessarily imply it is the methylation changes that cause the aging.

  5. Is there any study which would predict the clock CpG sites based on surrounding sequence?
    I like the ML idea. I would go one step further, I would apply a neural network model on the CpG sites that would predict age/tissue type based on surrounding sequences.

      • A bit off-topic but I also liked very much Lachs’s comment on “COVID-19 and aging, a tale of two pandemics.” in the same Nature issues.
        BTW, the commentary from Josh to this major work is particularly insightful. I read the paper before reading Josh’s post and intuitively guessed the link to Blagosklonny which I happy happy he confirmed 🙂

  6. Josh you were right,

    Of the 12 genes turned off, a quick check showed they were involved in aging such as:

    mTORC1 ,
    circadian oscillations,
    neurogenesis,
    toxin metabolism,
    hypoxia,
    skin,
    telomeres maintenence,
    Muscle,
    cancer inhibition,
    DNA-repair,
    etc…

    It would be interesting to see the effect of Harold’s elixer on this latest clock.

    • But that doesn’t agree with Josh’s hypothesis – he is saying the aging program (if there is one) is mainly about genes that become (intentionally) methylated, not demethylated. The only way to get agreement with the 12 cytosine locations you say are associated with such important pathways, is to say that these locations become demethylated as a consequence of other locations becoming methylated. This is possible, but I haven’t (yet) seen any evidence this is the case.

      • Hi Mark,

        Thanks for catching that, the 12 genes were hypomethylated not hypermethylated.

        I guess I thanked Josh too soon, although I think he does deserve a lot of thanks for this blog.

        This blog is a bright positive point for myself in the generally dark times we all face.

        The areas that the genes are active in I got from wiki pages, genecard, etc…

        My point in listing the areas affected was to show we are fishing generally in the right waters.

        Harold’s elixer testing is the next big thing that I am aware of that might shed light on the new clock.

        If Harold’s elixer is shown to affect both longevity and the new clock it should help determine what is critical versus noise.

        Also food for thought…

        The 128 different mammal species that were tested in this clock would broaden the range of animals that Harold’s elixer could possibly be used to treat.

        • You are right.The biological tools involved in Harold/Akshay therapeutic are the same across mammals across most living things so I think that gives us a lot of encouragement that its effect could be miraculous.

    • It is very interesting that the commonly hypomethylated sites are so closely associated with such important genes. It would be very interesting do as Josh suggests, and separate out the changes during development from those that occur only during aging. It might be that the changes common to both development and aging are less important than we think.

      • Mark,

        Yes, I agree that splitting out the fast development phase from the slower aging phase would help.

        Then we would need to account for the 3 aging waves at 34, 60 and 78 years.

        Do the other 127 species also have these aging waves?

        Josh’s blog on top down approach might make a lot of sense in this case.

        What is driving the aging waves from a top down prespective?

        Perhaps Levin’s group might shed some light on this?

        Has the signal that determines something is an eye degraded to something else?

        I read that his group is developing tools to look into the aging process.

  7. ICD (diagtor.com.ua) it was found that malic acid stabilized by MAS allows to stop human aging. This result was obtained in an experiment, when the telomeres of all the main organs did not change for 6 years. MAS is obtained by informational activation of common malic acid. In MAS, the number of molecules in a cluster is 9, and in ordinary malic acid there are 12 molecules. In addition, an electromagnetic field with a frequency of 10 to 11 degrees of hertz arises in the clusters of the MAS, which directly affects the human body and the surrounding nature. For example, soaking grains in a VAS solution stimulates grain and plant growth until it ripens.

  8. “She offered me a one-line proof that aging is programmed: the enormous range in lifespans found in nature defies any theory about damage accumulation, because no conceivable process of chemical damage could vary so widely in its fundamental rate.”

    Doesn’t lifespan correlate with metabolic rate? If so, damage accumulation cannot be ruled out.

    • It does. Also, the faster the time to maturity, the shorter the lifespan – in general, though of course there are exceptions. If you rush the growth phase, then the adult with be less durable. Which tells me that aging probably is caused by the build up of various undesirables produced during the growth phase, and to a lesser extent, once we are mature.

      Of course this can be mitigated by any evolved repair or ‘cleaning’ mechanisms, depending on the selection pressure on that species, for example if it is beneficial to stick around to look after your children.

      This is supported by the recent paper in which the Conboys caused rejuvenation by replacement of half of the plasma of mice with saline and 5% albumin. See ‘Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin’. So ‘cleaning’ the blood, helps the rest of the body to repair. I expect that the similar effects achieved through tgf-b suppression, or addition of gdf11 or oxytocin, operate in a similar way, activating pathways suppressed by metabolic byproducts.

      • Yes, since this is such a PC world but everyone knows better, I always thought of the proverbial black athlete (west african descent) and thought of pleiotropy here, a universal. It is more common to see guys like arguably the greatest athlete of all time (Bo Jackson) become fat slugs after 50 years of age than to see them maintain like Herschel Walker, whose longevity still must be compromised because of universal realities. And there is no problem with this, it’s just how it is.

        It’s also a universal that early maturation is associated with a lower ceiling overall, which describes male/female differences to a large degree, as well.

        • 2 new paragraphs added to the end of this artilce that might be of interest>>>
          https://jefftbowles.com/a-unifying-theory-of-the-evolution-of-sex-and-aging-via-predator-selection/

          “And finally another interesting insight- if we assume the phenomenon of menopause evolved to stop/limit a female’s contribution to the gene pool to preserve the gene pool’s diversity, let us look at some other parameters that are linked to menopause (aka declining litter size in other animals) :

          These folowing factors are all linked across species…Length of pregnancy (gestation time), age at menarche (puberty), litter size, age of decline in litter size, and maximum lifespan. When you increase the maximum life span in a species, it pulls all the other paramters along with it: It increases the gestation period (this decreases the number of offspring possible in a lifetime) it increases the age of menarche (puberty) (this also decreases the number of offspring possible in a lifetime), it decreases litter size (this also decreases the number of offspring possible in a lifetime)- starting to see a pattern here?”

        • It probably is true that racial differences are a result of different selection pressures, but this is a taboo subject and we are not permitted to discuss such things.

    • “She offered me a one-line proof that aging is programmed: the enormous range in lifespans found in nature defies any theory about damage accumulation, because no conceivable process of chemical damage could vary so widely in its fundamental rate.”

      “Doesn’t lifespan correlate with metabolic rate? If so, damage accumulation cannot be ruled out.”

      Lifespan correlates with a host of things not just metabolic rate. In any case the quote that no conceivable process of chemical damage could vary so widely is missing the point. Damage differs widely and the programmed responses against those damages differ widely also adding to the difference. The damage does not exist in isolation. Thinking damage is a major player in aging does not mean one thinks programming has no influence. Programming is of course involved, it’s just influencing the damage rather than being the fundamental cause of it.

  9. “The whole body has the same DNA, and it doesn’t change over time.”

    That’s close to true but definitely not entirely true. The DNA is in fact quite mosaic between different cells and this increases with age due to mutations that arise during cell divisions or various stochastic events that damage DNA. DNA damage accumulating with aging is just one pathology that contributes to aging that is not fixed by any interventions that reverts back the epigenetic clock.

    • I expect this will be the ultimate limit on human lifespan, once all other mechanisms (such as epigenetic) have been solved. I do not think genetic mutations play a strong role in aging in current human lifespan, outside of the impact of cancer. But this is the reason there is such a strong selection pressure for healthy sperm before the embryo is formed. After all the germline is otherwise immortal, so only needs fear harmful mutations.

      The only way I can think of solving this in a mature adult is to gradually replace all the stem cells in our bone marrow with ones made to order. But as I say, there are other more proximal causes of aging.

      • I don’t think DNA damage will be the ultimate limit. There are lots of other problems that would become limiting way before DNA damage would become so. I do agree with you that DNA mutations don’t play a large role in aging or life span of humans with the exception of those that are unlucky enough to get cancer.

        “The only way I can think of solving this in a mature adult is to gradually replace all the stem cells in our bone marrow with ones made to order.”

        That’s a start but that would only replace a small subset of stem cells and tissues in the body. Most of the tissues would not be replaced by merely replacing the bone marrow stem cells because they aren’t produced by the bone marrow in the first place.

        • Actually the majority of stem cells do come from the bone marrow. It is a common misconception that the bone marrow only supply red and white blood cells. If these BMSCs were all replaced, and there are ways of doing this, eventually these stem cells would appear throughout the tissues of the body.

          But I agree that there are plenty of other problems to fix first, and that brand new stem cells probably won’t work to fix aging until the other issues are addressed. But it is interesting to think that designer stem cells could keep someone going indefinitely. We might also be able to make them immune to cancer. The next question would be, how much would you then want to change your DNA, or would you be content with an immortal version of your current self?

          • “Actually the majority of stem cells do come from the bone marrow. It is a common misconception that the bone marrow only supply red and white blood cells.”

            I don’t think that is true. Sure in addition to hematopoietic stem cells (that produce the blood cells) they do supply stromal stem cells that can produce fat, bone and cartilage cells, but that’s it and that is still quite limited. They do not contain the stem cells needed to produce cells of the various other organs and tissues of the body.

            “If these BMSCs were all replaced, and there are ways of doing this, eventually these stem cells would appear throughout the tissues of the body.”

            No they wouldn’t, at least not to any great extent. If this would happen you would see leukemic patients that underwent bone marrow transplants having donor stem cells in all kinds of tissues and organs besides the bone marrow and in many ways they would probably age a lot faster because these stem cells in many cases are older like the donor.

            “But I agree that there are plenty of other problems to fix first, and that brand new stem cells probably won’t work to fix aging until the other issues are addressed. But it is interesting to think that designer stem cells could keep someone going indefinitely.”

            They definitely won’t keep someone going indefinitely even if they were designed to be rejuvenated and remarkably potent. The reason for that is that differentiated cells in tissues do get old and do not get replaced by stem cells just because they are old. Another major reason is that the body is a lot more than just cells. If you just fix the cells you won’t stop or reverse aging completely.

          • But stem cells from a donor DO appear in multiple recipient organs. Look up multiple papers on sex mismatched bone marrow stem cell transplants.

            I agree that they replace damaged tissues only very slowly, and this is why recovery from heart attack, for example, is so poor. That is why I said quite clearly other things need to be fixed as well. The parabiosis experiments give me hope that this is achievable.

          • I think you are overestimating the degree to which stem cells from bone marrow transplants appear in other organs than the bone marrow. I agree that a small fraction may appear in other organs but I found no evidence of this happening to a large degree and in many different organs. Even if it did the cells are hematopoietic stem cells and cannot serve as precursor for stem cells in a lot of other organs like the heart as an example.

            “I agree that they replace damaged tissues only very slowly, and this is why recovery from heart attack, for example, is so poor. That is why I said quite clearly other things need to be fixed as well. The parabiosis experiments give me hope that this is achievable.”

            The problem isn’t just that they replace things very slowly in many cases. The problem is more that there are several things they don’t replace at all. If you are 80 years old and get a heart attack some of the most damaged cells will be replaced by stem cells thus fixing part of the damage. However the rest of your heart cells, some of which did not suffer great damage, they will not be replaced at all. Also if you are 80 years old and have a poor functioning heart your body won’t just go and replace the old heart cells with younger ones, even if you had several infusions with young stem cells you would still have an old heart. The problem is the stem cells go and fix damage, they don’t just go and replace old cells which is what is really needed if stem cells would be some kind of a universal treatment for aging. The parabiosis experiments give me hope too, but for them too there is a lot they do not fix at all even if they will be improved upon.

          • There is clear evidence of stem cells appearing in multiple tissues. Here is an example in the liver, from sex mismatched transplants (‘Liver from Bone Marrow in Humans’, https://pubmed.ncbi.nlm.nih.gov/10869283/). This paper shows that female livers are partially replaced (up to 43%) over time (up to 13 months) by male hepatocytes from the bone marrow of the male recipient.

            The real question is why replacement is insufficient. Or perhaps, even with replacement, why such cells are not rendered fully ‘young’.

            It could be there are insufficient stem cell numbers, they could have suffered telomere loss, they might have become senescent themselves. It might be a systemic issue, as the tissues requiring rejuvenation have become more senescent over time, the initial helpful signalling might have become pathological, effectively locking what would be stem cells into a differentiated or damaged state. The stem cells might have aged epigenetically themselves because of the signalling of the surrounding tissue or blood. The latter is certainly something these various blood borne factors (or simply replacement of blood with new plasma and saline, as has been demonstrated) could help with.

          • Thanks for the reference Mark. That’s an interesting study and shows a greater chimerism than I would expect. However I very much doubt that this applies to other organs also. Note that the liver is in a league of its own in terms of regeneration. It has far greater ability to regenerate than most other organs. Also my literature research on various stem cells indicates that they need to be of the same type as the tissue they are supposed to regenerate. Hematopoietic stem cells aren’t likely to regenerate many other types of tissues.

            “The real question is why replacement is insufficient. Or perhaps, even with replacement, why such cells are not rendered fully ‘young’.”

            Problem is the body doesn’t usually try to replace cells that are merely old. And that’s not strange. It would be very difficult for it to do so in case of tissues that normally don’t regenerate much. Stem cells usually respond to signals of severe damage and home to areas of tissues that have suffered a lot of damage such as cell death. To replace a cell that is merely old but otherwise not dead the body would have to decide to kill it with apoptosis and then get rid of it and replace it with fresh stem cells. This is not something that normally occurs in tissues where cells are usually not replaced at all. The reason why the cells are not rendered fully young is likely because it is dangerous to reprogram the cells because if the reprogramming gets a little too far it can cause high risk of cancer.

            “It could be there are insufficient stem cell numbers, they could have suffered telomere loss, they might have become senescent themselves. It might be a systemic issue, as the tissues requiring rejuvenation have become more senescent over time, the initial helpful signalling might have become pathological, effectively locking what would be stem cells into a differentiated or damaged state. The stem cells might have aged epigenetically themselves because of the signalling of the surrounding tissue or blood. The latter is certainly something these various blood borne factors (or simply replacement of blood with new plasma and saline, as has been demonstrated) could help with.”

            Most tissues of the body have simply not evolved to replace themselves with fresh stem cells when the cells are old. We have evolved to have somatic cells that are long lived and only resist damage sufficiently to live a pretty long life but not evolved to age super slowly or remain youthful for much longer than a normal lifespan. If you inject a lot of fresh stem cells into animals they usually just die within a short while. Some of them may go to highly damaged areas and replace some cells there but most will just die. They don’t just go and replace older cells, unfortunately.

    • I think DNA damage might not be limiting for a very long time. A newborn has like 100 brand new mutations, a centenarian has accumulated like 400 mutations in some of the fastest dividing stem cell lines. That is not too dissimilar in a genome of billions of bases.

      Any cell with a catastrophic mutation will most likely die, ensuring only cells with less harmful mutations propagate through time, by the time a century passes you should have several cells with a number of less harmful or harmless mutations similar to a newborn.

      • I agree that DNA damage is not likely to be limiting for longevity for a very long time. The point I was making was made more to emphasize that there are plenty of stochastic damages that occur and contribute to aging that will not be fixed by merely reverting the epigenetic age of cells back. Many of these are far more limiting than DNA damage is at the edge of normal human life span.

      • DNA damage is why stem cells like to mostly remain quiescent and let other cells do most of the dividing. But eventually they do acquire mutations. At some point we will have to address this issue, because mutations to stem cells are inherited by all the cells that descend from them. Mutations in stem cells might also act like a form of natural selection, whereby as you age you are left with stem cells that don’t like to differentiate. This would gradually starve tissues of replenishment.

        • “DNA damage is why stem cells like to mostly remain quiescent and let other cells do most of the dividing. But eventually they do acquire mutations. At some point we will have to address this issue, because mutations to stem cells are inherited by all the cells that descend from them. Mutations in stem cells might also act like a form of natural selection, whereby as you age you are left with stem cells that don’t like to differentiate. This would gradually starve tissues of replenishment.”

          I agree, we definitely need to address the DNA damage issue, and there are lots of other issues that need to be addressed that are not influenced much at all by the DNA or epigenetics simply because those problems are found outside of cells and the defenses against them do not exist. Proponents of programmed aging and cellular rejuvenation tend to forget that the human body is made of more than just cells. If you rejuvenate all the cells you don’t fix everything or stop aging of the body. Fixing just the cells and ignoring everything else is like trying to keep a city in good condition for ages by just fixing the houses in it while completely ignoring the gardens, roads, sidewalks, electricity, water, sewer system and all the infrastructure. Fixing the houses is going to make it livable much longer but the deterioration of everything else will bring it down eventually if that problem is avoided. Same with the body.

  10. no matter how much you turn the epigenetic clock backward, there are other kinds of ‘turn-off-the-life’ biological and ‘end-of-resource’ processes more or less independent of methylation that limit the lifespan. Lysosome waste accumulation, AGEs degenerating tissues, telomere shortening turning cells pre-cancer and killing the organism among them.

    • Actually some of the problems you mentioned are fixed mostly by epigenetic rejuvenation of cells, but you’re absolutely right in that there are still several problems that will not be fixed by any kind of cellular rejuvenation. It must not be forgotten that the body is not made of just cells.

  11. both DNA methylation and histone modification are epigenetic programming ways, why epigenetic clocks are only built on DNA methylation, not histone modification?
    DNA methylation is far more important than histone modification?

    • It may or may not be more important than histone modification. It is MUCH better studied because there are cheap tests that can be computerized and mass-produced that measure methylation. There are no such technologies for histone modification.

      The other thing we CAN do cheaply is to measure the proteome that is the net result of all the epigenetics as a composite. This technology is developing fast, and may catch up and overtake methylation clocks. Stay tuned. https://joshmitteldorf.scienceblog.com/2020/12/21/what-to-look-for-in-a-biological-clock/

    • I am guessing that histone modifications change more frequently than DNA methylation. I always think of DNA methylation as a final seal, that is very hard to remove, where histone modifications as decoration that can be removed and put back at ease.
      I guess DNA binding motif occupancy changes most frequently that represent the current expression profile. Histone methylation primes chromatin for motif occupancy possibilities. Methylation finally closes any chance of histone modifications or binding factor occupancy.
      But nevertheless histone modification is also expensive to study.

      • Methylation of histone residues is very important to controlling access to DNA. This type of methylation does not appear to be permanent, but is controlled somehow and therefore available for us to manipulate. I don’t think any ‘clocks’ have looked at this type of methylation; maybe it is too variable to be useful, I don’t know.

        • I have read some papers about polycomb switch bewteen DNA methylation and polycomb repressive complex 2. in cancers, the unmethylated CpG originally masked by PRC2 switch to hypermethylation by DNMT due to loss of PRC2. and the methylation plasticity is greatly reduced.

          since H3K27me is the target of PRC2, histone status indeed impact DNA methylation a lot. and it seems hypermethylation is not always a good thing.

  12. ‘We want a clock that is not only accurate, but that is based on epigenetic causes of aging, not epigenetic responses to aging’, this is key. To isolate these genes, we have to test gene expression at peak maturity/youth and thereon. Because the aging clock starts at peak youth or more precisely near puberty, whereas all the clocks are being studied from birth.
    will increasing growth factors or decreasing those factors which gradually impinge growth factors, is the solution to age reversal also needs to be investigated.

  13. If development and aging is one continuous process, but involving different sets of genes which initiate and control them, then basing a clock on monitoring gene expression from birth is conceptually flawed. A clock which is monitoring genes from birth cannot uncover genes which initiate and maintain aging of the organism. Maybe a different approach is required.

    • Jeff, your conclusions in that article are absurd. It is not new that evolution influences aging and longevity. It influences every parameter of the animal that interacts with its ability to pass its genes on and the longevity of the individual of the species is just one of all those parameters. It does not follow from this that aging is programmed. Just because the genetic and epigenetic programming influences aging doesn’t mean it is the cause of it. There are lots of causes of aging and there are lots of things that contribute to aging that are not under the control of genes at all and will not be fixed by even fully reverting the gene expression of all the cells of the body back to their most youthful levels. Why so many proponents of programmed aging keep ignoring this is beyond me. Can you not think of at least a few things that deteriorate with time and contribute to aging but will not be fixed by tinkering with the gene expression of your cells?

      • I would not normally respond to a post like this..I’ll just say many people have/had trouble understanding my first paper and probably this article-there are a lot of moving parts and a lot to digest… (Just ask Josh-it took him about 14 years to write his paper on epigenetics after he had read my 1998 paper which he originalyl described as a paper by a self-taught biologist of uneven quality-sprinkled with gems of evolutionary wisdom..)..well that papert made many crazy predictions that turned out to be true..the greatest test for any theory. anyway…Just take a look at what Horvath says at the end of his abstract of his study….
        ” Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species – a notion that was long-debated without the benefit of this new and compelling evidence.”

        note the phrase “is indeed evolutionary conserved”

        I think I’ll go with Horvath’s judgement over your “absurd” judgement anyday..

        • “I would not normally respond to a post like this..”

          Well I wouldn’t be surprised if you didn’t. The times I have confronted proponents of evolutionary theories of aging they have such strong beliefs in their position that they close their mind and evade answering my questions when I give them examples of things that are clearly not controlled by programming yet are a contributory factor in aging. Matter of fact is you have to ignore some fundamental physics to think aging is programmed. Those that think that other theories (like damage theories or whatever) are the cause usually have a more open mind and certainly do not deny the importance or influence of evolution and programming on aging.

          “I’ll just say many people have/had trouble understanding my first paper and probably this article-there are a lot of moving parts and a lot to digest… (Just ask Josh-it took him about 14 years to write his paper on epigenetics after he had read my 1998 paper which he originalyl described as a paper by a self-taught biologist of uneven quality-sprinkled with gems of evolutionary wisdom..)..well that papert made many crazy predictions that turned out to be true..the greatest test for any theory. anyway…”

          Frankly I don’t think I have trouble understanding it. What I have trouble understanding is why people that believe (yes I say believe because they often ignore logic) in aging being programmed refuse to answer simple questions or evade responding when I give examples of things that contribute to aging and are obviously not programmed or when I give examples of age-related changes that will not and can not be fixed by any kind of tinkering with gene expression. This last is a simple proof that it isn’t programmed since if it were programmed you could fix everything and stay rejuvenated and young indefinitely merely by fixing the programming (your gene expression) and maintaining it in perfect young state. But this is not possible for obvious reasons.

          “Just take a look at what Horvath says at the end of his abstract of his study….
          ” Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species – a notion that was long-debated without the benefit of this new and compelling evidence.””

          I think you are reading too much into what he said. Yes it is evolutionary conserved I have no disagreement with that but evolutionary conserved does not mean it is programmed. All organisms have to battle entropy and all of them evolve to pass their genes on in all kinds of ways including in terms of optimizing the fitness and longevity of the individual of the species in whatever ways will give him the biggest evolutionary advantage. That does not mean that evolution is the cause of aging. Aging is in many ways caused by stochastic entropic processes and all organisms fight this to stay alive (that’s programming) but the evolution is a response to the stochastic processes not the other way around. There are lots of processes going on in your body that are contributing to aging of your body and are not under any genetic control at all. If you deny this then you are ignoring entropy and fundamental physics. I repeat I am not saying evolution and programming isn’t of huge importance and isn’t a major influence on aging. But evolution and programming is ultimately a response to fundamental physical events not the cause of them. Aging is an interplay of stochastic processes and the programmed responses against them.

          • ‘evolution and programming is ultimately a response to fundamental physical events not the cause of them. Aging is an interplay of stochastic processes and the programmed responses against them.’

            I agree wholeheartedly with this statement.

            However, we do have to look at, say a salmon, who has lots of babies and then dies, a human, who has less babies more slowly and then hangs around a while, and a turtle that has lots of babies, and then just gets bigger and more fertile with age, and we have to at least concede that evolution seems to exercise a great deal of control over stochastic processes that drive decay and deterioration. It is also at least conceivable that aging could be beneficial to the species, even as it sacrifices the organism.

          • “However, we do have to look at, say a salmon, who has lots of babies and then dies, a human, who has less babies more slowly and then hangs around a while, and a turtle that has lots of babies, and then just gets bigger and more fertile with age, and we have to at least concede that evolution seems to exercise a great deal of control over stochastic processes that drive decay and deterioration. It is also at least conceivable that aging could be beneficial to the species, even as it sacrifices the organism.”

            I agree with everything you said above Mark. Programming has major influences on aging and lifespan and aging can be beneficial for a species and there is a lot to learn from animals that live exceptionally long. None of that means aging is fundamentally programmed however (this last comment is not directed at you).

      • If aging were not programmed, the decline of functionality of organisms across species would be uniform after attaining maturity, that it is not so is a verifiable fact and conclusively proves aging is programmed

        • Differing metabolic rates between species vary the rate of damage accumulation. The (programmed) response to that damage also varies between species.

          But that doesn’t prove individuals are programmed to die. More like they are programmed to last as long as it is a benefit to the species for them to live.

        • “If aging were not programmed, the decline of functionality of organisms across species would be uniform after attaining maturity, that it is not so is a verifiable fact and conclusively proves aging is programmed”

          That’s not true for two main reasons. The first one being that the processes that cause damage differ widely in depending on the conditions the organisms live in. The second one is that damage does not exist in isolation, while it isn’t caused by programming it is still greatly influenced by programming and the programming differs enormously between different animals meaning their defenses against various kinds of damages differ greatly.
          Reply ↓

          Mark
          on January 29, 2021 at 10:44 am said:
          Differing metabolic rates between species vary the rate of damage accumulation. The (programmed) response to that damage also varies between species.

          But that doesn’t prove individuals are programmed to die. More like they are programmed to last as long as it is a benefit to the species for them to live.

          • ‘stochastic entropic processes’ will affect all species at the same rate, since they are made up of same biomolecules. But that does not happen, entropy affects different species at different rates, because the rate of decline of the repair function decides the aging in a particular species, and which has been selected. Since the rate of decline of the repair function is malleable and independent of entropy, it can be concluded, that it is programmable.

        • “‘stochastic entropic processes’ will affect all species at the same rate, since they are made up of same biomolecules.”

          That statement makes no sense. That’s like saying all cars will deteriorate at the same rate because they are all made of metal which obviously is a gross oversimplification and isn’t true. Species are not made of the same biomolecules. They differ widely in their composition and thus their propensity to entropic decay.

          “But that does not happen, entropy affects different species at different rates, because the rate of decline of the repair function decides the aging in a particular species, and which has been selected.”

          Again that’s wrong. Hell you could take cell free extracellular matrix of different species and it would get damaged at different rates under the same conditions in vitro all because of different matrix compositions and it has nothing to do with repair because it’s cell free. Also the rate of repair greatly influences aging of a particular species but it does not decide it. The degradation of lens proteins in vitro is a great example of degradation that cannot possibly be influenced by repair because there is nothing there to repair it. The same is true for lots of things in animals. Only some biological components have repair mechanisms in place. Many have none and that keeps getting ignored by proponents of programmed aging. If you disagree with me please tell me where is the repair mechanism for glucosepane cross-links in humans, or mice or rats? It does not exist unfortunately and that’s just one example of many problems with no repair.

          • why do glucosepane cross-links not create a problem when we are young. Has there any study done in your knowledge which has tackled the problem of glucosepane cross-links with pre puberty young blood /growth factors.
            How can you be so sure that pre maturity growth factors cannot tackle the ECM degradation, do you have any evidence to prove it.

          • “why do glucosepane cross-links not create a problem when we are young. Has there any study done in your knowledge which has tackled the problem of glucosepane cross-links with pre puberty young blood /growth factors.
            How can you be so sure that pre maturity growth factors cannot tackle the ECM degradation, do you have any evidence to prove it.”

            Think about why wearing out of tires or rusting of metal doesn’t cause a problem with your bicycle or car in the first week or month after you buy it. It’s not because the tires don’t start wearing out and the metal starting to rust right from day one, it’s because the damage is so small in the beginning it is hardly noticeable and far too small to result in a significant problem. The same is true for cross-link accumulation and various other types of damages. Many such damages start to accumulate even before you are born but the damage doesn’t become great enough to result in noticeable problems until much later when the accumulation has proceeded for long. I’m not the one that needs to prove that the growth factors or whatever cannot fix the ECM. I’m not the one making unreasonable claims of reprogramming fixing everything. The burden of proof lies on you, the people that claim that cellular reprogramming will somehow magically fix everything even when there are no reasonable mechanisms to explain how it could be possible. If we had good explanations and mechanisms that have been shown in vitro to lead to repair of all the problems in the ECM surrounding rejuvenated cells then sure maybe I would be the one needing to offer proof that that would not happen in vivo. But there are non good explanations or good reasoning for how cellular rejuvenation would fix the extracellular matrix so any belief that it would do so is based more on belief not science.

            “why doesn’t entropy happen in childhood, why doesn’t the lens degard in the young.”

            Entropy does happen in childhood and the lens does degrade in the young even before birth. The degradation is just so small at young ages that it fails to cause noticeable problems with eyesight. Just like the tires on your bicycle will start wearing out form the first minute you ride it even though the wearing won’t be great enough to cause noticeable problems until much later.

          • All species are programmed by the DNA and RnA molecules and by your argument, the DNA and RNA should be affected by entropy at the same rate for all species within a controlled environment such as captivity, but that does not happen.

          • You are saying ‘Entropy does happen in childhood and the lens does degrade in the young even before birth’ and the Lens overcomes it and grows in size.

          • ‘I’m not the one that needs to prove that the growth factors or whatever cannot fix the ECM. I’m not the one making unreasonable claims of reprogramming fixing everything. The burden of proof lies on you’
            But it is already proven that when we are growing, the ECM overcomes any degradation as claimed by you and acquires additional 95% mass at maturity and I am assuming it is because of certain growth factors.

          • “All species are programmed by the DNA and RnA molecules and by your argument, the DNA and RNA should be affected by entropy at the same rate for all species within a controlled environment such as captivity, but that does not happen.”

            The DNA and RNA is effected by entropy but that does not mean all kinds of damages appear at the same rate for all species. There is a huge variation in the design and environment of different species and also in their ability to defend against entropy. It seems like you don’t understand what entropy is.

            “You are saying ‘Entropy does happen in childhood and the lens does degrade in the young even before birth’ and the Lens overcomes it and grows in size.”

            I think you need to learn more about what entropy is. The fact that the lens grows in size doesn’t mean that it overcomes entropy. The entropy of the lens actually increases as it grows. And it will continue to accumulate damage as it is growing and when it has stopped growing.

            “But it is already proven that when we are growing, the ECM overcomes any degradation as claimed by you and acquires additional 95% mass at maturity and I am assuming it is because of certain growth factors”

            Overcoming degradation isn’t overcoming entropy or damage. Those are very different things. The ECM is subject to entropic damage and such damage is accumulating in the ECM both while it is growing in size during development and after development has finished.

          • ‘The DNA and RNA is effected by entropy but that does not mean all kinds of damages appear at the same rate for all species. There is a huge variation in the design and environment of different species and also in their ability to defend against entropy’
            In a controlled environment such as captivity, the DNA and RNA should be affected by entropy at the same rate for all species in that specific environment, that it does not happen is in their ability to defend against entropy, which what ‘programmed aging’ is.

          • ‘I think you need to learn more about what entropy is. The fact that the lens grows in size doesn’t mean that it overcomes entropy. The entropy of the lens actually increases as it grows. And it will continue to accumulate damage as it is growing and when it has stopped growing.’
            The young environment of the body does not overcome entropy, it goes about that in a different way, it just eliminates hard to reverse damage efficiently and goes about doing what it knows best, generating new tissue, whether it is the lens, The ECM, collagen etc

          • “In a controlled environment such as captivity, the DNA and RNA should be affected by entropy at the same rate for all species in that specific environment, that it does not happen is in their ability to defend against entropy, which what ‘programmed aging’ is.”

            You are missing the fact that the DNA and RNA is surrounded by different biological environments in different cells and different species. Therefore they are exposed to different entropic changes. They also are defended by different cellular mechanisms that differ in efficiency depending on the species and a host of other things.

        • “The young environment of the body does not overcome entropy, it goes about that in a different way, it just eliminates hard to reverse damage efficiently and goes about doing what it knows best, generating new tissue, whether it is the lens, The ECM, collagen etc”

          The young body is growing so of course there is growth of new cells and ECM when the organism is growing but when it reaches adulthood and many tissues have reached full development and size they completely stop growing. At that point the non-growing tissues start accumulating damage even faster than before they stopped growing. Resetting the cellular age will not lead to those tissues starting to grow again, in any case that would be harmful. You wouldn’t want your eyes to grow more when you as an adult have stopped growing and your skull has reached size. Lots of damage in these tissues is not being eliminated or reversed even in early life so there is no reason to think it would be in the cell of an adult that is rejuvenated to have the same age as that early life age.

  14. Sounds like you are the one with rigid thinking…

    you wrote- “This last is a simple proof that it isn’t programmed since if it were programmed you could fix everything and stay rejuvenated and young indefinitely merely by fixing the programming (your gene expression) and maintaining it in perfect young state. But this is not possible for obvious reasons.”

    It is odd that you follow this blog and apparently have never heard of Yamanka factors

    • I wouldn’t be so quick to judge people you don’t know. I have been involved in the longevity field since 2003 and I have read hundreds of papers on induced pluripotency, epigenetics, gene expression and the Yamanaka factors. I am very positive about Harold Katchers experiments and any methods to partially rejuvenate cells in vivo by partial reprogramming. However unlike some people (you perhaps) I am also very aware of the limitations of such therapies no matter how much we manage to perfect them in future. Controlling the programming is of great importance to solve aging, but it is not enough. There are lots of other things to fix besides that.

        • “ABSURD!”

          Tell me what part is absurd and why? Otherwise you’re just proving my point about evolutionary theory proponents evading questions.

          Regarding the jellyfish. If you’re referring to Turritopsis dohrnii which is sometimes said to be biologially immortal. Are you really comparing higher animals like humans to a jellyfish that reverts itself back to a polyp stage which basically involves apoptosis of a major part of its body and turning back to a primitive life stage? That is no evidence of aging being programmed anymore than the fact that you can create a healthy young baby with your sperm even when you yourself get old.

          • I guess you deny that Salmon aging is programmed like all the other deniers HAHAHA…they live 3 years and then rapidly age and die in 3 days after mating….but can live 7 years if castrated…
            You are a programmed aging denier!! And your conlcusions are absurdf!
            You probably haven’t seen the study where Atlantic Salmon undergo the rapid aging and death caused by thir aging program….which was found to occur along with a hige spike in LH..just like my htoery predicted would be the case…

  15. “I guess you deny that Salmon aging is programmed like all the other deniers HAHAHA…they live 3 years and then rapidly age and die in 3 days after mating….but can live 7 years if castrated…”

    Programming can influence aging obviously. It can slow it down and speed it up but it is not the fundamental cause. If it was programmed then the salmon wouldn’t just live 7 years if castrated, it would go on to live to dozens of years as long as it doesn’t mate and is lucky enough to not die from being eaten or other kinds of accidents. Also the salmon that dies at age 3 after mating was also aging before mating, it just wasn’t aging as fast as after mating. Programming influences aging, I’m not denying that. I’m denying that it’s the fundamental cause of it. No amount of reprogramming will cause this salmon to live thousands of years in captivity where it does not mate or get eaten or succumb to other kind of accidents.

    “You are a programmed aging denier!! And your conlcusions are absurdf!”

    I deny ignorance of fundamental physics. No amount of cellular reprogramming or epigenetic fine tuning will cause you to become biologically immortal and not age at all because your body is not just made of cells and also because your body’s cells are still exposed to DNA damage that isn’t always 100% repaired even in the most youthful cell.

    “You probably haven’t seen the study where Atlantic Salmon undergo the rapid aging and death caused by thir aging program….which was found to occur along with a hige spike in LH..just like my htoery predicted would be the case…”

    I don’t have to see it. It is simply a demonstration of aging being influenced greatly by programming which I never denied being the case. I am arguing against programming being the fundamental cause and being able to fix or stop all the processes that are involved in aging. Even a single induced pluripotent cell in cell culture maintained in a fully rejuvenated state will eventually after a very long time get damaged and age from stochastic processes such as DNA damage. You know well that the DNA contains the programming and if the DNA gets severely damaged there is no way to fix that with epigenetics.

  16. Jeff, I have a question for you. Do you think that cellular reprogramming therapies (such as a much more advanced version of Harold’s Katchers elixir) would be sufficient to make humans not age at all and become practically biologically immortal? I mean is it your opinion that with the perfect reprogramming methods and ways to repeatedly deliver them perfectly to every cell of the body as needed by that cell we would have everything we need to solve aging?

    • Probably…we will see…

      Somehow the Greenland Shark was able to evolve a 500 year lifespan…we can probably figure out how to tinker with the DNA to get there very soon..
      information doubles every 10 years or so.. I never thought I would see driverless cars..

      and I just was able to clone my recently deceased dog! things are progressing faster than anyone ever imagined

      • “Probably…we will see…”

        Come on, you know that accumulating DNA damage cannot be fixed with epigenetic programming because epigenetics come on top of DNA they do not change or fix the DNA damage that has already occurred and will continue to occur, and there are many other examples of damages that are not influenced by epigenetics.

        “Somehow the Greenland Shark was able to evolve a 500 year lifespan…we can probably figure out how to tinker with the DNA to get there very soon..
        information doubles every 10 years or so.. I never thought I would see driverless cars..”

        That shark is a whole different species. For us to get to 500 years would require much more than just tinkering with the DNA. What if the shark has some genes that protect it against aging that are not found in the human genome. You know well that no amount of tweaking can turn on a gene like that if it isn’t found in the genome in the first place. If you’re suggesting we modify the DNA not just the epigenetics, yes I agree that can get us much further than just tuning epigenetics, but it’s still not enough.

        “and I just was able to clone my recently deceased dog! things are progressing faster than anyone ever imagined”

        Good news about your dog. I’m glad to hear that you got to clone it. Things are indeed progressing faster than I imagined in some areas (in terms of cellular reprogramming) but in others they are progressing disappointingly slow IMO. As an example we have made almost no progress in the past decade or two on breaking cross-links in vivo and that is one thing that epigenetic reprogramming will not fix because those cross links are not even within the cells.

    • Aging has already been solved by some trees. In a study by Dr. Richard Dixon of U of North Texas of 15 year old and 667 year old Gingko Biloba trees concluded ‘Comprehensive evaluation of the expression of genes related to autophagy, senescence, and age-related miRNAs, together with analysis of leaf photosynthetic efficiencies and seed germination rates, demonstrated that the old trees are still in a healthy, mature state, and senescence is not manifested at the whole-plant level.’
      Why do stochastic damage and entropy not make it die like most of the other trees within 100 years?
      In this https://www.sciencemag.org/news/2020/01/how-ginkgo-biloba-achieves-near-immortality article in Science covering the study:
      The new study provides the first real genetic evidence for something scientists have long suspected: “The default condition in plants is immortality,” says Howard Thomas, a plant biologist from Aberystwyth University.
      Living things on this planet do have the ability to not age and remain in youthful prime. If Gingko Biloba figured it out why can’t we?

      • Hi Ashkay

        Hurry up with that elixir!!!! Yeah I worte a book about aging..The Unslefish Geneome….
        and have a whole chapter on long living plants there are lots of trees that are 10,000+ years old…the long living trees include of course the 3,000 year old redwoods, 5,000 year old bristlecone pine, 10,000 year old creoste bushes, and I think junipers and cyprus trees also like 10,000 years….
        You can tell which trees live the longest ..they make insect repellent mulch out of them!! or use them their sap to insect proof railroad ties and telephone poles (creosote) you need a good defense to predators to evolve a long life span!!

        • Jeff I do enjoy reading your books and blogs. I am on daily metformin and do occasionally take high dose vit d3 with k2 thanks to your blog on hormones. Yes I find these long lived trees fascinating. Prof Dixon concluded that “While elderly humans more easily succumb to disease, the immune system of a 1,000-year-old ginkgo tree essentially “looks like that of a 20-year-old,”
          Gene expression changes despite 980 year age difference under 3%. So it’s not just long lifespan but long lifespan in prime of youth. Imagine if humans could live that long in youth we could seriously consider space travel outside our solar system.

          • Akshay, can you please share how your high vit D3 and K2 intake look like?

            I take daily 10,000 IU vit D3 with 100mcg K2 MK-7 among other supplements. Do you think this is too high?

            I do not have access to Metformin but at the age of 65, I pump iron 5 times a week for 90 min and hike at an average of 250 km each month. ( like the way our species has evolved )

          • HI Stephan
            You should read my books onD3 avaiable at amazon..
            keep in moind that the ability to make d3 from the sun in aging skin drops by more than 50%
            And that light skinned people whnio sunbathe for 1/2 hour in the summer sin in the northern US…make about 20,000 IUs of d3 in their skin…I wohdl recommend 20,000 IUs a day to prevent COVID-19 infections and /or symptoms if infected..I recommend now days 800 mcg of the mk7 type of k2 for each 10,000 IUs of d3 whcih provides a 1:1 molecular ation of d3 to k2…IN my 2nd book I recommned that ytou also take the cofactor of D3 magnesium 80% of us adfre deficeint and high dose d3 uses up magnesium at a high rate…other cofactors include boron and zinc..

          • Stephan,
            Your exercise routine is difficult even for men half your age so my congratulations on that discipline. I bet you must be feeling great. Your d3 k2 seems more than adequate to me because you do seem to spend quite a lot of time outdoors. I was forced to stay indoors a lot due to Covid 19 work at home so started taking 60,000 IU of nano d3 with k2 once every alternate week. The one I have is one of the most delicious shots ever had. I do not take metformin I meant melatonin which I take 10mg every night just before sleeping thanks to the hormone blog I read of Jeff. I do take rapamycin 3mg once every 9 to 15 days. You may probably not need it as nothing beats that kind exercise routine that you do.

          • Hi Akshay. Could you please tell us how your and Dr. Katcher’s supplement protocols look like? Do you take only D3/K2, melatonin and rapamycin?

          • Leo I take andrograoholide with pterostilbene and curcumin 2 times a week. Olive leaf extract and lycopene few times a week with milk thistle.

          • Thank you so much for sharing your protocol, Akshay. Seems you do not like NAD boosters and AKG if we do not consider sirtuin activator Pterostilbene.

        • @Akshay, @Jeff, @Biological Age

          Akshay, I’m also committed to daily time-restricted eating 18:6 and every three months four days water fasting, which really boosts energy level, pain relief and overall wellbeing. For 25 years I’m committed to a Paleo-like diet and spend most of my time in nature. You notice the reasoning?

          BIOLOGICAL AGE

          I’m feeling great and still can physically satisfy my interests in life, but does my paleolithic lifestyle has any positive impact on my biological age? I don’t know! Therefore, I’m eager to participate in Josh’s DataBETA project.

          Jeff, I’m also supplementing with magnesium, zinc, copper, selenium. In addition, I take glucosamine to protect my joints, ligaments and tendons. Just bought your latest book on Vit D3, will be an interesting reading.

          • Stephan,
            One of the key accelerators of aging is stress. Your lifestyle seems to avoid that considerably. I would not be surprised if your biological age is substantially lower than your chronological age. You can be a very good case study.

          • Hello there

            one of the best things to take for your joints after age 40 is oral hyalruonic acid…if you cant find it you can eat rooster combs…YUCK
            but our bodies have about 15 grams of HA through age 40 we turn over 5 grams a day but we start losing 1 mg every day so by age 75 or so you only have about 20% of your HA left..doctors will tell you that you cannot absorb it orally-this is a lie …actualy you can absorb about 2% whcih is enough so taking 50 mg a day should stop the daily 1 mg loss of ha..take more to re[lensih your body..

            HA is the clear goo that lubircates your joints….also in your eyes and is under your skin and plumps it out….I suggest after age 40 to take mayube 500 to 1000 mg a day…you will soon see it plumps yout skin out and smooths out wrinkles seems to make hair grow out faster/thicker.. it is kind of hard to find but you can get the purre powder cheap at taked3.com whcih links to vitaspace where peter sells it..cheap and pure

          • Akshay, I’m not sure about your assumption about my stress levels.

            I live close to the Arctic Circle so I’m exposed to the cold 6 months a year. Also, I take daily hot/cold showers. A couple of times a week I eat canned tuna, which has higher levels of mercury. And as I mentioned food deprivation, all stressors to the body I believe.

            In addition, due to COVID-19, I lost my job almost a year ago and there are no signs that the tourism industry will recover anytime soon. There is a level of mental stress as well.

            A case model? Well, I would be willing to contribute to science.

          • Stephan,
            I am sorry to hear about your job. This will soon get back to normal. I know many who are dying for a trip, holiday. Cold weather, sauna are beneficial. Can’t you replace the canned tuna with something that wouldn’t have anything toxic?

          • Wild Salmon is full of D3 and very popular in Alaska and probabl;y why the Alaskans aren’t gettign impacted by covid-19

            they eat on average 70 kg of wild salmon and other cold water fish per year!!! vs 15 kg per person average per year in the lower 48

            it’s all in my book nbanned by Amazon about Covid-19 which I am gviing away fro free as a pdf..just send an email to jeffsbandn@gmail.com

          • Akshay, Jeff

            My salmon fishing spots in Alaska are just a few hours’ drive away, however, I’m living in Canada and there are travel restrictions in place that make a trip not feasible.

            Salmon runs in the Yukon a very low for almost 20 years, so no recreational fishing permits. Freshwater species are in decline as well due to overfishing and climate change.

            I revert to tuna on purpose due to its high amount of omega 3 and 6 as well as proteins. Regarding mercury, I remember some papers suggesting small amounts of poison now and then are beneficial for the immune system.

            No worries, I’m eating canned sardines as well which should be safe.

          • MAkw aure you take 20,000 IUs of d3 a day to virus proof yourself I dont think tuna or sardines have much d3…only deep dwelling cold water fish do…

            thats why farm raised salmon dont have much d3 they are too close to the surface and dont have to make their own…they le tt the sun make it in tgheir skin…

      • “Aging has already been solved by some trees.”

        “Living things on this planet do have the ability to not age and remain in youthful prime. If Gingko Biloba figured it out why can’t we?”

        I think it’s a big mistake to compare mammals to trees. There is a fundamental difference between trees and mammals that influences damage accumulation. Trees are continuously growing and this allows them to dilute damage that would otherwise accumulate in the cells and the body of the tree. Here is an analogy. Lets say you live in a house and you have no way to dispose of trash outside of it so all the trash that accumulates from your living in the house you throw away inside the house so with time your house will slowly fill up with trash until there is no way to live in it anymore. Lets say that after three months your first house is roughly 10% full of trash and that every three months you decide build a new house that is a replica of the first except that it has no trash and when you build the new one you take the trash from your first house and divide it between the old and new one, now each has half the trash that was in the original one. Lets say you then take each of the two houses and create a new house for each of them. You keep doing this every three months and your houses will never be full of trash because you keep diluting it. Organisms that continue to grow can do the same thing. We humans are not continuously growing therefore we do not have this benefit of being able to dilute accumulated damage in the same way as trees do.

        • You are wrong, The therapy they did works for all mammals, affecting the same way. I think you should read more about this study instead of commenting here every 5 minutes.

          • “You are wrong, The therapy they did works for all mammals, affecting the same way. I think you should read more about this study instead of commenting here every 5 minutes.”

            I have read the studies and I know it works on mammalian cells too but I keep having to point out that we are not made of just cells. Are you aware of all the extracellular damages that occur outside of cells and are not influenced at all by rejuvenation of cells?

          • Well, we don’t know for sure that cellular rejuvenation will not improve the composition of the ECM, as the ECM is built and broken down by cells, and more functional cells should do this more quickly. In this way decreasing cellular turnover can be seen as the reverse of animals that never stop growing and hence dilute damage – slower cellular turnover means less dilution, less clearance of metabolic waste products. But I take your point certain byproducts like glucosepane have no human enzyme to break them down due to their slow accumulation with age never requiring their clearance. We don’t know as yet what restriction this will have on lifespan once other things are solved.

          • “Well, we don’t know for sure that cellular rejuvenation will not improve the composition of the ECM, as the ECM is built and broken down by cells, and more functional cells should do this more quickly. In this way decreasing cellular turnover can be seen as the reverse of animals that never stop growing and hence dilute damage – slower cellular turnover means less dilution, less clearance of metabolic waste products. But I take your point certain byproducts like glucosepane have no human enzyme to break them down due to their slow accumulation with age never requiring their clearance. We don’t know as yet what restriction this will have on lifespan once other things are solved.”

            I agree we don’t know for certain that it won’t improve the composition of the ECM. It will likely improve some components of it to some degree but I think the improvements will be small and it is incorrect for people to assume that it will fix almost everything. I would love to see experiments on reprogramming one day becoming so successful that we will see exactly how much they leave left to fix.

        • Since Akshay could not post he has requested me to do so:
          Olafur,
          Your argument against comparing the conserved similarities between trees and humans does not explain why almost all of the trees have a much much shorter lifespan whereas very few live in full bloom of youth for thousands of years.
          Secondly Prof Richard Morimoto has given evidence of a change occurring just after puberty when there is no chance of stochastic damage accumulation:
          https://www.cell.com/fulltext/S1097-2765(15)00499-2
          This repressive mark on Heat Shock Response transcription dropping its initiation against stress by 60% to 80% just after puberty can only be an outcome of programmed intervention. Morimoto himself uses the word and says this fall in protein folding efficiency so early after puberty is conserved across species.
          Tony Wyss-Coray in this paper in Nature Medicine titled Undulating Changes in Human Plasma Proteome Profiles Across Lifespan tells us that they observed waves of proteome changes cresting at 34, 60 and 78 in 4,263 humans of different age. Such temporal coincidence can not occur in all participants by stochastic events.
          Regarding ECM it is not in isolation and it is wrong to assume that Elixir rejuvenation will not rejuvenate ECM. There is constant crosstalk between cells, ECM and plasma components:
          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767504/
          You will find Mina Bissell’s TED talk fascinating where she describes how a healthy cell in an old ECM turned cancerous and this cancerous cell in a young ECM turned normal again. Akshay.

          • Hello Akshay,

            I’m not convinced by your answer on ECM. Yes there are studies showing that the ECM has a crucial influence on the cells it harbors (making ECM aging a new hallmark?), but where are the proof that ECM can be rejuvenated by the environment? I’ve read quickly the study you posted, but it looks to me mainly one way, ECM > cells.

            Since even parabiosis experiments did not show infinite life extension, do we have any indications that the ECM can be rejuvenated by young blood/plasma/milieu/…?

            Thank you

          • Raphael I would recommend reviewing Dr. Mina Bissell’s papers. Start with her TEDx lecture. She has shown evidence on two way cross talk between cell and ECM. Cell can not be and remain rejuvenated unless the ECM is also rejuvenated.

          • Thanks Akshay, I will do. From what I understand ECM is actually composed of lots of components, some structural and some acting as signalling. It might be that not all the components might be rejuvenated, that some glycation is not cleared away. And that may or may not be very important.

            Anyway, time will tell, for those who have enough of it 🙂

          • The hypothesis is that young blood can improve the EcM by enhancing proteolytic digestibility of AGE’s and at the same time generating new Ecm. Young blood reduces epigenetic age, rebalancing gene expression across the board to a more youthful state.

          • “Your argument against comparing the conserved similarities between trees and humans does not explain why almost all of the trees have a much much shorter lifespan whereas very few live in full bloom of youth for thousands of years.”

            Some of the trees are designed and programmed to live shorter and not last long without dying while others are designed to last much longer. That’s just an example of programming influencing the development and the defenses against entropy. That’s not a reason to think the programming causes the entropic damage or can in any way completely defend against entropy.

            “Secondly Prof Richard Morimoto has given evidence of a change occurring just after puberty when there is no chance of stochastic damage accumulation:”

            Sorry I don’t see this study providing any proof that there is no stochastic damage accumulation after puberty, only that some such damages can be slowed down. There is no proof that all of them can be stopped or reversed.

            “Regarding ECM it is not in isolation and it is wrong to assume that Elixir rejuvenation will not rejuvenate ECM. There is constant crosstalk between cells, ECM and plasma components:”

            It is wrong to make bold claims about the Elixir rejuvenating the ECM when there exists no good evidence of how cellular rejuvenation could possibly do so. There exist several studies on epigenetic rejuvenation of cells by various methods like the OSKM factors but I have never seen evidence of such therapies having any major effects on the ECM in vivo. If you know of such evidence please show me. If you don’t then your claims are wishful thinking. I’m not saying the elixir won’t have any rejuvenating effects on the ECM, it probably will have some minor positive effects indirectly but in no way will it fix it in any major way because there are no mechanisms by which it could do that. And yes there is constant cross talk between the cells and the ECM but it is limited in what it can effect. The mere existence of such a cross talk is no reason to think that the ECM can completely rejuvenate the cells or the cellular reprogramming can completely rejuvenate the ECM. You got to give more evidence of how it would happen otherwise it’s just unsupported hypotheses.

          • 😂 I think you just need to calm down, please. Just wait a bit and you will see what does The Elixir do. If you know so much about aging just make your own solution and patent it. Of course, that’s a good to argue and show your thoughts but the facts say absolutely contrary to your beliefs.

          • “The hypothesis is that young blood can improve the EcM by enhancing proteolytic digestibility of AGE’s and at the same time generating new Ecm.”

            That could be the case to a small degree in some parts of the body resulting in a minor ECM rejuvenation in some tissues. But there are no good reasons to think this would happen to a great degree in most tissues of the body. There are simply too many ECM compartments that are not being digested at all for a good reason. In some cases digesting them would be very dangerous and harmful.

            “Young blood reduces epigenetic age, rebalancing gene expression across the board to a more youthful state.”

            Yes but epigenetic age is just a measure of cellular age not ECM age. Even a cell with the most perfect rejuvenated gene expression cannot break a glucosepane cross-link in its surrounding ECM. There are a lots of other things it can’t fix in its surroundings. They are not omnipotent.

          • “Raphael I would recommend reviewing Dr. Mina Bissell’s papers. Start with her TEDx lecture. She has shown evidence on two way cross talk between cell and ECM. Cell can not be and remain rejuvenated unless the ECM is also rejuvenated.”

            Yes I agree that the ECM has a lot of control over the gene expression and cells ability to rejuvenate. If anything that is even a stronger reason for the proponents of programmed aging to focus on fixing ECM aging since without addressing that problem it’s going to be hard to achieve more than a partial reprogramming in vivo. Again I emphasize the mere existence of a cross talk between cells and the ECM does in no way mean that cells and the ECM have capacity to fully rejuvenate each other meaning you just have to fix one of those and the other one gets fixed as a result. The cross talk is limited in its capabilities.

          • Olafur you are adjusting your theories constantly to go round evidence example being Morimoto’s cited research. Dr. Mina Bissell has given lifetimes work with irrefutable evidence that cell can not be rejuvenated without the ECM too being rejuvenated. You are refuting it without having any study, trial or paper on your name.

          • “Olafur you are adjusting your theories constantly to go round evidence example being Morimoto’s cited research.

            I’m not adjusting my theories. I am stating again and again that nobody has shown me evidence or very good reasoning for how cellular reprogramming would fix all the ECM in a fully developed animal like a human and until I see something like that I logically conclude that cellular rejuvenation will not fix the ECM completely. The mere existence of a cross talk (that I knew very well exists) does not mean that that cross talk can allow cells to completely rejuvenate the ECM. And that is true even if it is true that cellular rejuvenation is impossible without fixing the ECM.

            “Dr. Mina Bissell has given lifetimes work with irrefutable evidence that cell can not be rejuvenated without the ECM too being rejuvenated. You are refuting it without having any study, trial or paper on your name.”

            I never claimed that cells can be rejuvenated without the ECM too being rejuvenated to at least some degree. I’m not refuting that. What I’m doing is saying that that is no evidence for programmed aging and that if cells cannot be rejuvenated without the ECM too being rejuvenated then that is just one reason why it will be even harder to reprogram the cells in vivo because to do so you have to fix the ECM first and that has not been done in vivo. Also if the elixir is working I think it is only working to some degree and offering partial cellular rejuvenation. I don’t think it’s fixing the cells or the ECM completely. Even greater rejuvenation could be achieved by fixing the ECM more before using something like the elixir. I think that to completely reverse and stop aging we will need a combination of cellular reprogramming and methods to fix all the rest including the ECM.

          • Olafur, I bet you have not read Dr. Mina Bissell’s papers before replying. You probably do not understand what crosstalk means in biological terms. One doesn’t need to fix one thing at time. If the cell is rejuvenated so will the ECM. Ditto for vice versa. You pick one damage which doesn’t seem reversible and you are erroneausly making a major conclusion that it means aging is not programmed. You are intelligent there is no doubt but you must respect a great researcher like Bisset or Morimoto, read their work, examine in 3D the evidence they provide and make your comments reflect that. This will allow for greater growth for you on aging and reversal of aging. Unless you feel you know everything there is to know? Please put money where your mouth is to conduct studies to prove your point. I am always ready to change my opinion when I come across interesting evidence.

          • Hey everybody I updaed my article yet again after I did a quixck Pub Med search of Melatonin AND DNA AND methylation…it was like opening up a treasure chest!!>>>
            I aded this to the article >>>
            A quick Pub Med search of the terms “melatonin AND DNA AND methylation” gives you 96 studies , most of which show that melatonin is intricately involved with DNA methylation, and the decline of melatonin with age might be the reason for the global hypomethylated status of DNA in the elderly. Studies with titles such as>> Melatonin and sirtuins: A “not-so unexpected” relationship., or Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation ,Melatonin-induced demethylation of antioxidant genes increases antioxidant capacity through RORalpha in cumulus cells of prepubertal lambs, Melatonin-Mediated Development of Ovine Cumulus Cells, Perhaps by Regulation of DNA Methylation,Melatonin restores the pluripotency of long-term-cultured embryonic stem cells through melatonin receptor-dependent m6A RNA regulation (of Yamanaka factors) are not uncommon.

          • “If you know so much about aging just make your own solution and patent it.”

            I would if it were so simple. It’s wishful thinking that some one treatment like the elixir will fix everything. Aging is more complicated than that but lots of people can’t accept that because beliefs even if irrational give them the hope they need. I don’t think it’s a coincidence that many of the scientists I know that are the biggest proponents of programmed aging are well past middle age, they really need some magic solution otherwise they won’t make it till longevity escape velocity. The younger people usually have a more healthy balanced view on aging being open to both programming and stochastic damages being things that contribute to aging. The solution isn’t as simple as just some elixir. The solution is to realize that programming has a great influence on aging and therefore we should definitely find ways to take advantage of that (like by creating something like the elixir) while at the same time we should realize that cellular rejuvenation won’t fix everything therefore we should put focus on working on all the problems that won’t be fixed by cellular rejuvenation. I see solving aging as mainly a problem of finding ways to induce partial cellular reprogramming in vivo and combine it with ways to fix everything that such a treatment won’t fix. Of course after something like the elixir becomes available it will be more clear exactly what it can’t fix but it’s still good to start now with the knowledge we have of the limits of reprogramming.

            Note that it is very dangerous and costly to put all the faith in programmed aging. If you would be right then great, the elixir or something similar would save you and we wouldn’t need much else to solve aging, I would be super happy to be wrong because all I want in the end is to solve aging. But if you’re wrong then when we finally have the solutions to reprogram cells and see more clearly that it isn’t fixing everything it may be too late to start working on all the other problems. Many people past middle age can’t afford to be wrong here. I think it is more wise here to assume that aging isn’t programmed (although it obviously is influenced by programming) and then start working on the problems that won’t be fixed by reprogramming, while at the same time continuing working on reprogramming treatments. In that case if you find out you were wrong and reprogramming does fix everything, then great, you will probably make it to escape velocity. But if you find that you are right in that aging isn’t programmed then the fact that you started earlier working on solving all the problems reprogramming won’t fix could save your life. It’s not wise to make a bet you can’t afford to lose. Better be prepared for the worst so you will win either way.

            “Of course, that’s a good to argue and show your thoughts but the facts say absolutely contrary to your beliefs.”

            I don’t operate on beliefs. I operate on facts and logic and they pretty clearly show that programming cannot be the root cause of aging.
            Here are some facts:
            1) There are some damages in the ECM that no known mechanisms found in vivo are able to fix. There also exists no good logic for a mechanism by which they would be fixed in humans by merely tweaking gene expression.
            2) DNA damage in cells will not be fixed by cellular rejuvenation. Cellular rejuvenation acts by changing the expression of the genes, not changing or fixing the DNA itself. Even the programmed aging proponents know this but they choose to ignore it or say it doesn’t matter because DNA damage is only a tiny part of what results in aging, but no matter how tiny it is it’s still an example of a thing that won’t be fixed by reprogramming and therefore obviously refutes their theory that reprogramming will fix everything.
            3) As an example of things that cannot be fixed by cellular reprogramming I posed this question earlier: “Please provide evidence or well supported explanations for how fixing the cells by cellular rejuvenation will fix the cross-links in this extracellular matrix that surrounds those cells.”. Nobody here has been able to give evidence or good explanations for this! Those that have answered have mostly evaded the question by directing the discussion to other very different animals or offering vague theories with no direct relevance to the biology of human adults.

          • Somehow the fact that you can take a cell from a really old person clone it and turn it into a brand new baby suggests DNA damage is not going to be a problem..soution? just kill off the DNA damaged cells and replace them with non-damaged cells via mitosis.. So if there is a problem with ECM we will solve it when we get to it. Worst case..we grow new body parts..But aging and develpoment are obviously programmed that is now quite clear.

          • You are very right. Since we can not regrow teeth, it seems programmed thing too.

          • “Olafur, I bet you have not read Dr. Mina Bissell’s papers before replying. You probably do not understand what crosstalk means in biological terms.”

            I understand what crosstalk means in biological terms. Most importantly I realize that this crosstalk is not omnipotent. I don’t need to be an expert on computer hardware to know that several computer hardware problems cannot be fixed with a screwdriver. The crosstalk from cells to the ECM is limited largely by the DNA and whatever it encodes. The crosstalk from the ECM to the cells is similarly limited by the DNA.

            “One doesn’t need to fix one thing at time. If the cell is rejuvenated so will the ECM. Ditto for vice versa.”

            This is what I disagree with being proven or being reasonable. Although fixing the ECM can lead to rejuvenation of cells to a large degree it can’t do so fully, and although rejuvenating cells will have some effects on the ECM in some tissues mostly indirect it can in no way rejuvenate it to a major degree in most tissues in vivo. I have never seen evidence of cellular rejuvenation being able to completely rejuvenate the ECM in a non-growing organism like a mammal. Nobody has provided such evidence and it seems that nobody here can.

            “You pick one damage which doesn’t seem reversible and you are erroneausly making a major conclusion that it means aging is not programmed.”

            I have named more than just glycation and could name more types but it’s pointless to try to find all of them. Note that you only need one exception to falsify a rule. The burden of proof here does not lie on me but on those making the extraordinary claims that cellular rejuvenation can completely fix the ECM.

            “You are intelligent there is no doubt but you must respect a great researcher like Bisset or Morimoto, read their work, examine in 3D the evidence they provide and make your comments reflect that. This will allow for greater growth for you on aging and reversal of aging. Unless you feel you know everything there is to know?”

            I don’t feel I know everything. I am always learning more and never lack the thirst to learn more. I very much doubt these researchers claimed or provided strong evidence that cellular rejuvenation could completely rejuvenate the ECM or vise versa in vivo in a multicellular non-growing organism. If they do then sure I would like to read the relevant studies, but if not I’m taking this as somewhat of an evasion of my questions. This does not mean I don’t respect Bisset or Morimoto, I do, but I’m not interested in reading more and more things that are not directly related to the issues I have raised. It’s just not my priority among all the things I want to read about.

            “Please put money where your mouth is to conduct studies to prove your point. I am always ready to change my opinion when I come across interesting evidence.”

            I would if I were wealthy enough.

          • Olafur,
            Well Harold and I didn’t have money but we managed to do three studies so if you have a passion for research and do present a reasonable protocol you could find the resources. Start with family and friends till you have proof of concept.
            I do feel that although you do get many things right there are some gaps in some fundamental aspects of biology. First you implied that ECM is in isolation to cell and if cell is rejuvenated ECM won’t. Extracellular Matrix is created by the cells, is nebulously interwoven with it. Not only is there crosstalk between cells and its ECM but also between the plasma constituents and the ECM. There is only one way to close this argument: We will demonstrate rejuvenation of ECM in our next study. Then you mentioned to Kunal that if the cells are repaired it won’t improve DNA repair. Where do the enzymes and proteins that are part of the DNA repair machinery come from? They come from cell’s DNA. And when cells are rejuvenated it will result in improvement of DNA repair. One of the actions of programmed aging is to progressively silence genes that code for proteins that are involved in the repair systems. Part of cell’s rejuvenation involves resetting those genes to be coding again.
            I can easily get exasperated by your long, long posts here and give up like the others but in my busy schedule I do take out the time to respond because I believe that you do have a passion for this field. But you must continue to read a lot especially papers from brilliant aging researchers regardless of labels of programmed aging or wear and tear to continue your journey. Do not be profuse in comments be guarded and fully read before making a major statement otherwise you will be misunderstood as flippant. Besides Bisset and Morimoto I also suggest you read Tony Wyss-Coray’s recent papers. He has shown evidence of the incredible crosstalk and given evidence of synchronized waves of changes at specific time points in our lifespan. This is evidence of a program. One part that may not get repaired does not refute that, as such a fact has nothing to do with Tony’s data. Anyway you may accept or ignore my suggestions its up to you. Wish you all the best with your research.

          • “Somehow the fact that you can take a cell from a really old person clone it and turn it into a brand new baby suggests DNA damage is not going to be a problem”

            It will be a problem but quite a small one relative to lots of other problems. Fact is, yes if you clone cells you can create an adult animal that is healthy, however that animal will never be a complete clone. There will likely be dozens of mutations in the cell you use for the cloning and if you’re lucky none of the mutations are serious but if not some of them are. Even if none of the mutations pose any problems the clone is still slightly mutated because the reprogramming can’t fix the mutations.

            “soution? just kill off the DNA damaged cells and replace them with non-damaged cells via mitosis.. So if there is a problem with ECM we will solve it when we get to it. Worst case..we grow new body parts..But aging and develpoment are obviously programmed that is now quite clear.”

            Sure regrowing limbs or organs is a solution that I have high hopes for in the future. However that’s kind of besides the subject since that’s no longer reprogramming an adult body to fix it instead you’re replacing parts of it all together. Your limbs aren’t going to regrow by simply reprogramming your cells. It would require cutting off your old limb and replacing it with a newly grown one. The old one never got fixed.

            “You are very right. Since we can not regrow teeth, it seems programmed thing too.”

            The development of new teeth is programmed not the fixing of old ones. Adult teeth can be regrown but that requires mechanical removal of the old tooth and then implantation of stem cells in the right place to grow a new one similarly to what occurred during development. This is an example of development being programmed but aging not being programmed. There is no program to fix an old tooth but it will be possible to start development of new ones by combining removal of the old ones with stem cell treatment directed in a programmed manner. This is just one of the examples of things we need to do in addition to cellular reprogramming to fix aging.

          • “Olafur,
            Well Harold and I didn’t have money but we managed to do three studies so if you have a passion for research and do present a reasonable protocol you could find the resources. Start with family and friends till you have proof of concept.”

            I don’t have some major protocol to fully solve aging. I think some problems are simply not within reach and will require technology (advanced artificial intelligence and nanorobots) that does not exist yet and is not coming until at least a few decades. I think we need more things like cross-link breakers and I know there are some companies that have been looking for ways to break glucosepane but they haven’t found any. I suspect even if they find some enzyme capable of breaking it it won’t be very useful in vivo because the enzyme would have to be small enough to fit between molecules of the ECM and break the tiny cross links, something that would be hard to do.

            “First you implied that ECM is in isolation to cell and if cell is rejuvenated ECM won’t. Extracellular Matrix is created by the cells, is nebulously interwoven with it. Not only is there crosstalk between cells and its ECM but also between the plasma constituents and the ECM.”

            I never said there isn’t crosstalk between cells and the ECM. There is definitely crosstalk between them. What I said and think is that the crosstalk is limited in what it can do. Also while ECM is originally created by cells that doesn’t necessarily mean it can be fixed by cells. As an analogy, different tools are required to fix a broken car than were required to create it from scratch. If your car door gets rusty there is nothin in the toolbox of the factory that created the car that can remove the rust and restore the metal to its original state because there was no need to remove rust from the metal the car was created from because it was not rusty when it was manufactured. The best you could do would be to replace the door once it’s highly damaged from rust. While that is a great solution that’s not the same as repairing it without ever replacing it. In the body this would be akin to replacing an organ or a limb when it is so damaged that some parts of it cannot be fixed. I’m actually most concerned about the brain regarding ECM aging because there will definitely be a time where growing a full fresh body and getting your head or brain transplanted to it will be possible.

            “There is only one way to close this argument: We will demonstrate rejuvenation of ECM in our next study.”

            I am glad to hear you are confident about that. I really hope you’re right and that you will measure some markers of ECM aging to prove such a rejuvenation. I think it would be most important to demonstrate ECM rejuvenation in tissues that are not continuously dividing in adulthood. I’m not so optimistic on that however. I’m expecting partial ECM rejuvenation in the ECM around cells that are continuously dividing throughout life like around epithelial cells. I’m expecting almost no ECM rejuvenation in tissues that almost completely do not divide at all in adulthood, like the brain.

            “Then you mentioned to Kunal that if the cells are repaired it won’t improve DNA repair. Where do the enzymes and proteins that are part of the DNA repair machinery come from? They come from cell’s DNA. And when cells are rejuvenated it will result in improvement of DNA repair.”

            That I agree with. I’m just pointing out that resetting DNA repair to youthful level is still not going to result in perfect DNA repair because it is never perfect even in youth. Identical twins don’t even have the exact same DNA when they are born and the DNA in one of your cells isn’t the same as in all the other ones. The error accumulation is very small and hardly significant and not a great problem for aging.

            “I can easily get exasperated by your long, long posts here and give up like the others but in my busy schedule I do take out the time to respond because I believe that you do have a passion for this field.”

            I have great passion for life-extension and have been kind of obsessed with it since late 2003. I’m only continuing to comment because I don’t think aging is programmed (although programming has a huge influence on it) and I think people are putting too much faith into reprogramming being a solution to everything and that this can cause problems down the road. I think reprogramming will solve a lot of things but I think there will be a lot of problems left to solve that will be more difficult to solve than reprogramming cells in vivo. But if all goes well the reprogramming treatments will be one of the things that buy us enough time to solve the rest of the problems. So I really hope you and Harold get very successful and prove me wrong on my pessimistic view of programming as a solution. If you do then everyone wins. If you don’t and I’m right then we better hope we have enough time to fix the rest of the problems. I’d rather risk being proven wrong and have a solution to aging soon than risk being proven right and see other problems being tackled too late to solve aging in time for lots of people including possibly me.

          • I just feel like I’m fed up reading hundreds, even thousands of theoretical papers on aging over the last 8 years, and even more fed up reading arguments to and fro on the internet about which approach is best. I am guilty of doing the same myself, via my many defences of the telomere theory of aging. At the end of the day testing is King and we will then ‘backfil’ in the theoretical or mechanistic underpinning for why what we have found to work, works. In my own humble way I now test many biomarkers on myself and share what I find, positive or negative. I don’t expect to fix everything about my aging body on my own, but I expect that we won’t need a particularly ‘hi-tech’, big pharma led treatment to make significant gains in healthspan and even lifespan. This might seem crazy, but I have solved numerous issues like terrible hay fever, an injured knee, etc., when all doctors had failed me, through my own research and experimentation. I applaud Akshay and Harold for putting themselves on the line with their blood fraction treatment. I hope it works in humans, but even if it does not, it will have been worth the effort.

      • “yes, if we were to recreate the molecular environment present in the young”

        Yes but we haven’t been able to do that, not even in cell culture, and there are no good reasons to think that we can do that with cellular rejuvenation. The cellular rejuvenation experiments show rejuvenation of cells in a major way and that’s great for the cells but we can’t forget the rest. We must not forget that our body isn’t made of just cells. It’s made of cells and a bunch of other stuff the cells are embedded in, much of this last is the extracellular matrix. If you think of your body as a city the cells are a bit like the houses in the city and the extracellular matrix is everything else, like the gardens, side walks, roads, electricity system, sewer system and all the infrastructure. Cellular rejuvenation applied in a body is a bit like fixing all the houses in a city. It’s great and will make the city livable for longer, but you have to fix all the other parts of the city eventually too you can’t just focus on the houses and ignore the rest, otherwise the city will keep on deteriorating. I hope this analogy helped.

        • Let us complete the analogy,the houses in the city are the cells, they have the machinery, the code to completely overhaul, the city’s infrastructure, similarly the cells in the body have the code to rebuild the EcM, the lens etc, the problem is the body is acting on a portion of code which is self destructive, that program has to be overcome.

          • Let us complete the analogy,the houses in the city are the cells, they have the machinery, the code to completely overhaul, the city’s infrastructure, similarly the cells in the body have the code to rebuild the EcM, the lens etc, the problem is the body is acting on a portion of code which is self destructive, that program has to be overcome.

            Problem is the cells don’t have the code to fix the ECM. I have challenged people to prove me wrong but no one has been able to do so. The gene for a repair machinery to repair the lens does not exist. The gene for a repair mechanism to repair glucosepane cross-links does not exist. I could go on and on here, there are so many problems that no repair mechanisms exist for. Repairing the body requires very different instructions as creating it in the first place. Think of the recipe for a cake. You can use that recipe to bake a cake but if you drop the cake on the floor the recipe to bake the cake isn’t going to work to fix a cake that has already been baked and is damaged. You would have no choice but to start from scratch and bake a new cake or find some really advanced methods (that are not found in the original recipe) to fix the damaged cake.

        • the cells in the young have the code to fix the ECM by eliminating excess waste products and regenerating new ECM. The body has instructions that eliminates/excretes hard to reverse damage and replace it with the new. In the young the elimination/excretion and the regeneration process is efficient, which degrades as we age.

          • The cells of the body do not have the code to fix the ECM damage even in youth. The damage accumulates in youth. And the regeneration process in youth is not fully efficient, just more efficient than in adulthood.

  17. Look at this study!! Looks Like Sinclair is right on aging by loss of differentiation>>>

    Published: 02 December 2020
    Reprogramming to recover youthful epigenetic information and restore vision
    Yuancheng Lu, Benedikt Brommer, […]David A. Sinclair
    Nature volume 588, pages124–129(2020)
    Abstract
    Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1,2,3. Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity5,6,7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by DNA methylation—that can be accessed to improve tissue function and promote regeneration in vivo.

    • I don’t want to put words in Sinclair’s mouth, I will give him the benefit of doubt here because my memory may be wrong on what he said in his interviews when asked, but I think that even though he is a proponent of programmed aging he still has admitted that cellular programming will not fix everything. In any case this study shows that cellular reprogramming can have major rejuvenation benefits on cells there is no doubt about that. It does not show that this kind of rejuvenation fixed the extracellular matrix surrounding those cells. It most certainly did not. Why? Because much of the damages to that matrix are not under programmed control. I will be more impressed when someone shows me a study that shows that cellular reprogramming can reverse glycation of the extracellular matrix or fix other stochastic extracellular matrix damages that keep being ignored by proponents of programmed aging.

      • Sinclair is aproponent of antagonsitc pleiotropy…
        And how did we get this extracellular matrix in the first place…did it just appear as a gift from God?

        • “Sinclair is aproponent of antagonsitc pleiotropy…”

          Being a proponent of antagonistic pleitropy doesn’t equate to being a proponent of programmed aging. It just means you think evolution influences aging, not necessarily that it is the ultimate cause. I certainly think antagonistic pleitropy has a large influence on aging in some animals in particular but that does not mean I think it’s the fundamental cause of it.

          “And how did we get this extracellular matrix in the first place…did it just appear as a gift from God?”

          That’s the wrong question to ask. I know the answer you want to hear is we got it from the programming, the programmed development, which is true. However it’s irrelevant where you got it from. What matters is that it is subjected to stochastic damages that the body is not equipped with the machinery to fix. What machinery under genetic control fixes cross-links in the lens crystallin of the eyes? There is no such mechanism which is why damage continues to accumulate there. And because there is no such machinery in the body no amount of tweaking your gene expression is going to fix it. You can’t tweak something that doesn’t exist.

          • you wrote “Being a proponent of antagonistic pleitropy doesn’t equate to being a proponent of programmed aging.”

            You just don’t get it….

            I was pointing out that Sinclair is only half right…you think we all don’t know what antagonistic pleiotropy is?? this isn’t aging 101

          • you ask.. What machinery under genetic control fixes cross-links in the lens crystallin of the eyes?

            I admit I hjaven’t studied this question..I do not have time to look under every little rock…but simple logic suggests you have to be wrong on this…
            If eye repair is impossible then all animals would have their eyes malfunctioning at about the same time…yet the greenland shark has perfect eyes for 500 years….galapagos tortoises 200 years…and for some reason mice eyes go bad after 2 years.. pretty imprecise stochastic processes wouldn’t you say?

          • How can you be so sure, that once a molecular environment present in the young recreated, the damage you are mentioning will not get resolved

        • “You just don’t get it….

          I was pointing out that Sinclair is only half right…you think we all don’t know what antagonistic pleiotropy is?? this isn’t aging 101”

          Good job at evading my questions and resorting to insults. I wasn’t implying that you don’t know what antagnoistic pleitropy is, of course not. Anyway this isn’t about Sinclair so lets get back to the question you evaded. Here it is again: What machinery under genetic control fixes cross-links in the lens crystallin of the eyes?

          • counter question
            What machinery under genetic control prevents cross-links in the lens crystallin of the eyes in childhood and instead increases the size of the lens.

          • “counter question
            What machinery under genetic control prevents cross-links in the lens crystallin of the eyes in childhood and instead increases the size of the lens.”

            There is a machinery to increase the size of the lens but none to prevent cross-link formation. The cross-links do accumulate in childhood. Just like I explained above in my example of bicycle tire wearing out from the first minute you start riding your bike even though the wearing will be far too small to cause noticeable problems until much later, the lens crystallin will start accumulating cross-links not only in childhood but even before you are born. The damage that has accumulated at such young ages is just far too small to cause noticeable problems. But it’s still accumulating unfortunately and eventually the accumulation will be great enough to cause problems.

        • “I admit I hjaven’t studied this question..I do not have time to look under every little rock…but simple logic suggests you have to be wrong on this…
          If eye repair is impossible then all animals would have their eyes malfunctioning at about the same time…yet the greenland shark has perfect eyes for 500 years….galapagos tortoises 200 years…and for some reason mice eyes go bad after 2 years.. pretty imprecise stochastic processes wouldn’t you say?”

          No this makes perfect sense without the need for repair mechanisms to explain it. The eyes can be designed to withstand aging damage up to a certain age without it being equipped with any repair mechanisms. As long as the eyes of humans are created in a way that they can withstand close to 100 years of age-related damage before becoming so damaged that loss of eyesight occurs then no repair is needed as long as the person manages to function well and pass its genes on and raise successful off springs. All animals would not have eyes malfunctioning at the same time because different evolutionary pressures would have caused them to evolve eyes that differ in how long they can remain functional in the absence of any repair. Evolution didn’t select for mice having eyes that lasted 200 years because there was no need to, they don’t live nearly that long. Their lenses last long enough to not require any repair for them to live their normal life span in a healthy way but if you would want to tweak their gene expression to make them last for 200 years then you most likely couldn’t. It’s too late. The eyes of the adult mice are already developed and the eyes of the turtles will have a different composition than those of the mice even from birth resulting from a different developmental program. The lenses of the mice which were developed to last only long enough for mice cannot be changed to similar to those of the turtle. They are already equipped with a mouse lens with a finite “expiration” and no major mechanisms of repair.

          Note another major difference that gives sharks and turtoises an advantage in terms of accumulation of stochastic damage to their eyes is that turtoises have a very slow metabolism and sharks live underwater at much lower temperatures than mammals and lower temperatures will slow down most chemical reactions that cause stochastic damages. This is another reason why eyes of animals should malfunction at different times.

  18. To anyone that believes in aging being caused by programming (rather than merely being influenced by programming) here is a great and very important paper I suggest reading: http://pmid.us/32540391

    This paper gives examples of various stochastic damages that accumulate with aging with many of them occurring in places where they are not subject to any repair at all even in youth. Therefore many of those damages represent damages that will not be directly fixed by reprogramming or rejuvenation of cells. To expect them to be fixed by rejuvenating your cells is a bit like expecting your garden to be fixed by simply fixing your house.

    Now here is a challenge for people that believe aging is fundamentally programmed. Please give evidence or very good reasoning for a mechanisms by which these damages will be fixed in a human being by mere cellular rejuvenation. Lets take cross-linking of the extracellular matrix of the skin as an example. Cross-links accumulate in collagen and elastin fibers of the extracellular matrix with age and this is a stochastic process that occurs also in vitro in a cell free media where there is no cellular programming to influence it or cause it. Please provide evidence or well supported explanations for how fixing the cells by cellular rejuvenation will fix the cross-links in this extracellular matrix that surrounds those cells. Another example of extracellular matrix damage is lens crystallin cross-linking. It is not contained within cells so it will not be automatically fixed merely by rejuvenating cells. If aging were programmed all you had to do would be to turn back the programming and these things would get fixed. But again there is no mechanism by which this could happen given that this damage is outside of the cells and is not directly influenced by cellular rejuvenation.

    The reason I ask the above questions is that so far I have not seen any proponent of programmed aging theories give evidence or good answers to questions like this. The response is usually evading the question or pointing at the longevity of some completely different animal that does not have to deal with the same problems to the same degree as humans and claim (with wishful thinking) that cellular rejuvenation will just “somehow” fix this problem all the while totally ignoring that any programmed machinery to fix many of these problems just does not exist in the first place. You cannot reprogram a repair mechanism to youthful levels if that repair mechanism doesn’t exist in the first place.

    • Apparently you do not know about the mouse studies whereby altering their immune systems- mice with holes punched through their ears that are normally permanent regrew the holes with perfectly new tissue..Much like a salmander can regorw a leg when cut off.

      • “Apparently you do not know about the mouse studies whereby altering their immune systems- mice with holes punched through their ears that are normally permanent regrew the holes with perfectly new tissue..Much like a salmander can regorw a leg when cut off.”

        That is not relevant here unless cutting off limbs and tissues and growing them back is your rejuvenation plan, then I say good luck. Show me research where a mouse with some kind of programming gradually takes its extracellular matrix and replaces it with a young one or repairs the damage in the old extracellular matrix.

      • Btw Jeff you evaded my main question just like I said proponents of programmed aging theories usually do when confronted with examples of things programming won’t fix. I repeat the question. Please provide evidence or well supported explanations for how fixing the cells by cellular rejuvenation will fix the cross-links in this extracellular matrix that surrounds those cells.

        Note regeneration of limbs doesn’t apply to my question. In case of limb regeneration you aren’t tweaking cells embedded in an already established and aging extracellular matrix which is what you are doing when applying reprogramming therapies to a human body in vivo. Instead you are developing completely new tissue from scratch which will come with development of new and fairly fresh extracellular matrix. When you apply reprogramming factors to animals in vivo the extracellular matrix does not get removed and replaced with a fresh one (if you have evidence that it does please show me, I have not found such evidence) so this scenario doesn’t apply to my question.

        • Hello Olafur,

          We have had this discussion some times ago, but I haven’t been convinced by your arguments. My own research seems to point to ECM turnover to be continuous throughout life, no matter how slow ( I remember something like 15years turnover for ECM).

          One exception is indeed the eyes lens, as this study tells us: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001529

          Quoting the study conclusions: “Such a life-long permanence of human tissue has hitherto only been described for dental enamel. In confront to dental enamel it must be held in mind that the eye lens is a soft structure, subjected to almost continuous deformation, due to lens accommodation, yet its most important constituent, the lens crystalline, is never subject to turnover or remodelling once formed”

          This implies that only eye lens and teeth are permanent, and everything else get eventually replaced.

          Could you give me some sources pointing to ECM been permanent and never replaced?

          Regarding DNA damages, I am not really worried about that. Yes, it can’t be fixed and the individual cell level, however at the organism level, cells which real DNA damage can (and are) eliminated if the mutation is detrimental. So you end up with genetic drift, and growing mosaicism in the body as different stem cells propagates differents mutations. But I don’t see why this would causes issues before a real long time as passed (maybe).

          What other damages do you see not fixed by cellular reprogramming tech?

          • “Hello Olafur,

            We have had this discussion some times ago, but I haven’t been convinced by your arguments. My own research seems to point to ECM turnover to be continuous throughout life, no matter how slow ( I remember something like 15years turnover for ECM).”

            Hi Raphael,

            Your 15 year number appears to be the number for collagen turnover. It matches with the half-life of collagen in the skin which has found to be around 15 years. In the same study it was found to be about 117 years in cartilage. http://pmid.us/10976109 Also if you check the full text you will see that glycation damage was accumulating in the collagen linearly even in the early twenties and before that which supports the notion that cellular rejuvenation to a young age still won’t stop damage accumulation in the ECM since the turnover even in peak health in your early twenties is still very slow. The turnover of the ECM is probably very different in different tissues and in some it might be negligible. Also collagen is just one component of the ECM. Other components may be degraded or replaced slower or faster or not at all. Elastin may have a half-life of 74 years, at least in the lungs. http://pmid.us/2022748 That is pretty darn slow. Cellular reprogramming may cause some slight positive effects here but in no way do I expect it to rejuvenate the ECM to a much younger state. Note that the turnover of the ECM is already pretty darn slow in young adulthood and there is likely a good reason for that. For one too much turnover might cause instability in the rigid structure of the fully developed body. In addition it might increase the risk of cancer but ECM degradation is one of the things cancer cells increase to metastasize and spread throughout the body.

            “Could you give me some sources pointing to ECM been permanent and never replaced?”

            That’s a great question. On top of my head I don’t recall some other ECM compartments where turnover is almost absolutely certain to be non existent. On the other hand I don’t remember seeing examples of tissues where cross-links or isoaspartyl residues do not continue to progressively accumulate with age indicating that any turnover is far too slow to fully replace the ECM.

            “Regarding DNA damages, I am not really worried about that. Yes, it can’t be fixed and the individual cell level, however at the organism level, cells which real DNA damage can (and are) eliminated if the mutation is detrimental. So you end up with genetic drift, and growing mosaicism in the body as different stem cells propagates differents mutations. But I don’t see why this would causes issues before a real long time as passed (maybe).”

            I agree with you here. I too am not particularly worried about DNA damage for the reasons you mentioned at least not until after several more urgent problems will be fixed.

            “What other damages do you see not fixed by cellular reprogramming tech?”

            Great question. There is a lot of stuff. Some main examples are accumulation of various types of long lived proteins, spontaneous damage to proteins, cross-link formation, nuclear pore complex damage, extracellular aggregate accumulation, extracellular matrix stiffening. I don’t mean to discount the possibility that some of these will be improved somewhat if only indirectly and slightly by cellular rejuvenation therapies, but doubt any of these would be fixed in a major way by such therapies.

          • Thanks a lot Olafur, it makes sense. I appreciate the calm and detailed answer.

            By the way, I tend toward the “programed aging ” camp but I don’t see it incompatible with your position. I just don’t think labels help much here, like in a lot of positions.

          • I wish to than everyone on their input and comments. The only nonsense comment was mine, but it’s wishful thinking that our DNA instructions included something new and beautiful like an ugly caterpillar metamorphosis into a beautiful immortal Butterfly instead of a long suffering, aging death.

          • You have a valid point Olafur, but then again, nothing within the human body lives in complete isolation.

            Take cancer cells as an example. Even if you deprive the body from all macronutrients, cancer cells still thrive. How? They simply change their metabolism and obtain their fuel from amino acids in the ECM.

            As for collagen turnover rate, aging seems to be a powerful factor. We know for certain that collagen turnover in young people happens at a much higher rate than in mature skin. Certainly it must be determined by the epigenetic age of the cells.

            But for crosslinks in the ECM we still have a lot to learn, I agree.

    • I noticed that you have posted thirty (30) times. That amounts to one third (1/3) of all comments of this blog. And you argue about one thing: That reprogramming cannot cure all problems. One or two comments would be sufficient to make your point. The rest is “noise”.
      But to respond to the substance of your argument: “So What” if reprogramming cannot fix all damage? There is no law in physics that will not allow fixing damage using other methods. The entropy that you refer to in one of your comments above is not a problem, as it is valid only for “closed systems”.
      So, let’s take advantage of what will soon be available (senolytics, the elixir, etc). For sure, soon there will be even more tools available. While the ” bowhead whale” has the upper hand in longevity today, humans are sure to surpass it. Maybe we don’t know how to take care of AGE’s YET. But there is no physics law that says that it is impossible.

      • “I noticed that you have posted thirty (30) times. That amounts to one third (1/3) of all comments of this blog. And you argue about one thing: That reprogramming cannot cure all problems. One or two comments would be sufficient to make your point. The rest is “noise”.”

        Sure that’s a lot of posts but I am not simply making a point that reprogramming cannot cure all problems. I am engaging in discussions to help point out things people are missing about the causes of aging and when different people keep bringing up various different reasons for why they think aging is programmed each of those reasons require different explanations to point out the misconceptions that are causing those beliefs. If I were to just make one comment to explain all the reasons it would have to be a short article where I cover a lot of the misconceptions about aging. If you read my comments you will see I do use logic and give useful explanations and examples rather than just repeating that I don’t think aging is programmed. Some of the people I have responded to have also given useful responses back which is how we engage in reasonable discussions on the topic that people can think about and learn from.

        “But to respond to the substance of your argument: “So What” if reprogramming cannot fix all damage? There is no law in physics that will not allow fixing damage using other methods. The entropy that you refer to in one of your comments above is not a problem, as it is valid only for “closed systems”.
        So, let’s take advantage of what will soon be available (senolytics, the elixir, etc). For sure, soon there will be even more tools available. While the ” bowhead whale” has the upper hand in longevity today, humans are sure to surpass it. Maybe we don’t know how to take care of AGE’s YET. But there is no physics law that says that it is impossible.”

        I agree that there is no physical law that makes it impossible to fix the rest of the damage using other methods and I sure encourage using all methods to do what we can about it now. Regarding your “so what” statement. Well I think it is very important to have a clear picture on what causes aging so we can prioritize what to work on. We may not have the luxury of just starting somewhere and fixing the rest of the problems later. Many people will run out of time that way.

        On this subject, extracellular matrix (ECM) aging is very much ignored by many scientists in the field, specially those that believe in programmed aging, and I don’t think that is something we should just ignore and fix later after we have advanced reprogramming treatments in particular since ECM aging is in many ways very difficult to fix and we haven’t really seen any progress in that area for a long time and I don’t see anything very effective on the horizon in that department. Cellular reprogramming is I think closer to be within reach given the remarkable progress we have made in that area in the past decade. Because of this I think the whole field would benefit from putting more focus on starting to solve ECM aging also in particular since so few scientists are looking into methods to do so.

        Another reason to focus more on the ECM is because the ECM influences the programming of the cells that reside in it so it’s going to be harder to rejuvenate cells that are living in the damaged ECM of an old person. Ironically rejuvenating the ECM will likely become important in order to gain benefit from the cellular rejuvenation therapies that the programmed aging proponents think will solve pretty much everything. FYI here is a study demonstrating how a young ECM can reprogram cells to a youthful state. http://pmid.us/21108727 Turns out that if we fixed and rejuvenated the ECM the cellular rejuvenation might to a small extent take care of itself. How is that for a change! Are any programmed theory proponents paying more attention to the importance of fixing the ECM now?

        • I apologize to all for posting again..but all this talk of slow to low turnover of this and that stimulates me to release a little secret I leanred from my many many years of high dose vitamin d3 therapy resrearch/ experimentation…
          High dose vitamin d3 supercharges yoiur tissue remodeling system so that life long accumulated injuries all of the sudden start to heal….D3 is not a vitamin but actuially a hormone that controls 2700+ genes that affect your tissue remodeling system and immune syustem ..Who knows what tissues and proteins and repair systems it would affect..You can go to JeffTbowles.com and use the high dose vitamin d3 1,000+ case studies search engine and read a bout all sorts of amazng stories like people’s eyesight improving to the point where their doctors think they have gotten Lasik surgery when all they had done was taken high dose d3 for a few months. There is also the case of a woman in Austria who was taking high dose D3 for her endometriosis and it was working , she wrote me back a few monthns later and said I forgot to tell you my huisband has been blind in one eye for several years the doctros say it is permanent..She went on to say that he decided to take high dose d3 along with her>> not sure maybe 30,000 or 60,000 IUs per day…She said after about 6 weeks he woke up and said to her ..”You’re not going to believe this…I am looking at you with my blind eye”. the doctors said it was a freak of natrure and had nothing to do with the D3…HAHA his original problem was some sort of damage to his optic nerve from a sinus infection…So my point is all this talk of slow turnover/unrepaired accumlated damage mentioned by Olafur is probably bad information based on sampling people that are by definition vitamin d3 deficient (people whose ancestors have turned white due to living in a land of weak sun) with very slow tissue remodeling systems.. I bet most of Olafur’s facts are wrong… I’d like to see if high dose D3 somehow leads to repair of the lens and the ECM at a rapid rate.. (And when Is say high dose..it is just high dose as defined by the powers that be ..which is really a lie…20,000 IUs sounds like a lot of d3 doctors used to tell you to never take more than 400 ius a day…Well it turns out that if a light skinned person sunbathes for 1/2 hour in Finland in the summer they can make 20,000 IUs of D3 in their skin….

          • “I apologize to all for posting again..but all this talk of slow to low turnover of this and that stimulates me to release a little secret I leanred from my many many years of high dose vitamin d3 therapy resrearch/ experimentation…”

            I gave references above for this slow turnover in my response to Raphael above. If you missed them here they are. The first one shows that the half-life of collagen in the skin and cartilage is 15 and 117 years respectively. http://pmid.us/10976109 If you look at the tables in that study you see that the accumulation of isoaspartyl residues starts even in young adulthood which is good proof that turning back the gene expression to that age won’t be enough to stop it. The second study shows that the half-life of elastin in the lungs is a whooping 74 years! http://pmid.us/2022748 This is evidence. All you offer is some hope and weak hypotheses. Where is your evidence of the turnover being very fast or at least fast enough at any age to stop or reverse accumulation of extracellular matrix damage? I would love to see such evidence but unfortunately it likely doesn’t exist. If it does then some of you must be able to provide it.

            “She said after about 6 weeks he woke up and said to her ..”You’re not going to believe this…I am looking at you with my blind eye”. the doctors said it was a freak of natrure and had nothing to do with the D3…HAHA his original problem was some sort of damage to his optic nerve from a sinus infection…So my point is all this talk of slow turnover/unrepaired accumlated damage mentioned by Olafur is probably bad information”

            That’s a very interesting case report but sorry your logic clearly doesn’t make sense here. I’m going to ignore the fact that anecdotal reports like that are weak evidence and instead give you the benefit of doubt and just think about what was reasonably going on here *if* vitamin D was the cause of her benefits. You mentioned that the original problem of this person was damage to the optic nerve. Well the optic nerve is a cell! We already know from the David Sinclair experiments that cellular reprogramming of the optic nerve can fix blindness in animals where the blindness is a result of optic nerve damage and that makes sense given what we know about reprogramming. Reprogramming a cell can in many ways fix that cell. So the logical conclusion here is that somehow that person’s optic nerve got regenerated partially, sufficiently enough to regain some sight. Now we both know vitamin D3 acts as a hormone and influences gene expression of cells so it is theoretically possible that it somehow fixed the gene expression of the optic nerve in a way that allowed it to regenerate. This is a theory that I agree being possible because it makes logical sense based on how the body works. However we do not have any good evidence or reason to think the person’s eyesight was improved by some kind of extracellular matrix regeneration such as fixing of the damaged lens or vitreus of the eye and we absolutely do not have any evidence or a reasonable hypothesis for how vitamin D would be able to have such effects since it doesn’t matter if it can influence the gene expression of the optic nerve cells if the optic nerve cells have no capacity to fix the extracellular parts of the eyes no matter how its genes are tweaked. So again your hypotheses hold no water here and what you say is wishful thinking not science. Again I invite you to provide good reasoning or evidence for how cellular reprogramming would fix the extracellular compartment of the eyes, not just the optic nerve.

            “based on sampling people that are by definition vitamin d3 deficient (people whose ancestors have turned white due to living in a land of weak sun) with very slow tissue remodeling systems.. I bet most of Olafur’s facts are wrong… I’d like to see if high dose D3 somehow leads to repair of the lens and the ECM at a rapid rate”

            That wouldn’t be a wise bet to make when you have given no good reasons or evidence for how tweaking the genes of a cells in or surrounding the eyes (by whatever means, including with vitamin D) would be able to somehow magically fix the extracellular matrix there. I say magically because it’s wishful thinking if you have no reasonable explanation or evidence for how it would happen.

            “(And when Is say high dose..it is just high dose as defined by the powers that be ..which is really a lie…20,000 IUs sounds like a lot of d3 doctors used to tell you to never take more than 400 ius a day…Well it turns out that if a light skinned person sunbathes for 1/2 hour in Finland in the summer they can make 20,000 IUs of D3 in their skin….”

            Yes an ultra high dose of vitamin D might have caused some effects on the optic nerve cells perhaps resulting in major benefits that are not seen with more moderate doses. That is plausible so I don’t disagree with that being a possible explanation here. However once again I state, it’s not likely to fix the extracellular matrix because a higher dose is not going to make a machine fix something if the machine to fix it doesn’t exist in the first place. If you want to convince someone of that actually happening first you have to give good evidence or reasoning for how cellular rejuvenation would fix the extracellular compartment, then you can talk about some interventions that do so by influencing cells. Otherwise you are acting like a person that would tell someone to pour more gas on their bicycle to go faster on the bicycle while totally ignoring the fact that the bicycle has no engine in the first place. Again I am waiting for evidence or explanations for cellular rejuvenation fixing the extracellular matrix to a major extent and so far you have provided none. In the meantime I think most of us can agree that perhaps ultra high doses of vitamin D might in some rare instances have some cellular rejuvenation effects on damaged optic nerves. I see no holes in that hypothesis.

        • Hi Olafur,

          I posted on the ECM study a few months ago.

          One thing that I think people have missed in the studies in connecting old and young rats blood supplies is that they are also connecting the animal’s ECMs together in the process.

          From the ECM study we should have seen a de-aging effect in the old animal from just that alone.

          It should be easy enough to check how much of an effect the young ECM has on the de-aging process of the older animal.

          Connect the rats ECMs only and check for cell de-aging at various distances from the connect point in the older rat.

          I am not saying that the blood doesn’t have anti-aging effects, just that there might be 2 anti-aging inputs in the experiment throwing off the results.

          • Olafur,

            I’d like to go one step further.

            Organ transplants from young to older individuals; again ECM from young is connected to the older person.

            From what I understand, the young organ ages to match the older person’s age, also the older person appears to de-age slightly.

            Again the ECMs are connected.

        • The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. Its expression appears to decline during aging

          • The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. Its expression appears to decline during aging

            I am aware of the existence of the PIMT enzyme but it is an intracellular enzyme. I am not aware of any evidence that it is exported from cells in significant quantities where it would be needed to help repair the ECM:

  19. Regarding your “speculation for statistics geeks”. As I understand it, you are proposing a model where the distribution of methylation levels at a given age is independently gaussian at each of the chosen CpG sites. Is this sketch correct? If so, is there strong reason to believe that either of these assumptions (independence, normality) holds well enough for this to be a useful model?

  20. What a coincidence…we were talking about eyes and up pops another study related to David Sinclair’s new study of eyes>>>>
    I think the flood gates are opening up for these yamanka factor rejuvenation studies….buckle up here they come (and I wasn’t researching eyes…but Oct4
    just saw Sinclairs video he does not use the myc-c factor as it has a cancer risk adn is apprently not needed for some tissues..>>>

    Cell Stem Cell
    . 2021 Jan 7;28(1):5-7. doi: 10.1016/j.stem.2020.12.006.
    Unlocking Tissue Regenerative Potential by Epigenetic Reprogramming
    Pradeep Reddy 1, Sebastian Memczak 1, Juan Carlos Izpisua Belmonte 2
    Affiliations expand
    PMID: 33417872 DOI: 10.1016/j.stem.2020.12.006
    Abstract
    The regeneration potential of axons projecting from retinal ganglion cells (RGCs) is lost shortly after birth. In Nature, Lu et al. (2020) demonstrate that epigenetic reprogramming of RGCs by overexpression of Oct4, Sox2, and Klf4 leads to axon regeneration and restoration of vision in a glaucoma model and aged mice.

    Copyright © 2020 Elsevier Inc. All rights reserv

    • I have seen this study. It’s an important research and sure offers exciting opportunities in the future. While very effective for the intended purpose here, unfortunately as expected the therapy only demonstrates regeneration of the cells (the retinal ganglion cells). While that is great and important for future rejuvenation therapies this kind of rejuvenation therapy does not rejuvenate the extracellular matrix of the eyes. I’m still waiting for anyone to show me good evidence or reasoning for cellular reprogramming being a possible means to rejuvenate the extracellular matrix in vivo.

      • I think Sinclair’s approach worked because he effectively de-differentiated cells so that they could heal the damage he did – ordinarily these type of cells no longer exist in the nerve. It is probably also true thar the cells that made the lens are no longer present. We should also be aware that the division between cell and ECM is not as black and white as often made out. ECM structure interacts with cells via actin fibres within the cell, and this is partly what decides what type of cell it is. Part of what makes a stem cell different is it’s small size and less complex interior structure. Making cells smaller and simpler is what frees them from the suppressive effect of the (aged) ECM. In this way we can see that cellular reprogramming and any future rejuvenation of the ECM are two sides of the same coin.

        • “I think Sinclair’s approach worked because he effectively de-differentiated cells so that they could heal the damage he did – ordinarily these type of cells no longer exist in the nerve. It is probably also true thar the cells that made the lens are no longer present. We should also be aware that the division between cell and ECM is not as black and white as often made out. ECM structure interacts with cells via actin fibres within the cell, and this is partly what decides what type of cell it is. Part of what makes a stem cell different is it’s small size and less complex interior structure. Making cells smaller and simpler is what frees them from the suppressive effect of the (aged) ECM. In this way we can see that cellular reprogramming and any future rejuvenation of the ECM are two sides of the same coin.”

          These are great points you’re making here Mark! The ECM surely interacts with cells and vise versa. That is one reason it is often more difficult to rejuvenate cells in vivo than in vitro. In cell culture you can regularly add fresh media so the cells are always surrounded by fresh media which signals they are in a young environment which in turn can help them reprogram to a younger state. In the body of an old adult the same kind of cells would be surrounded by an old damaged and stiff ECM and the cells will sense that to some degree and we know that an old ECM makes it harder for cells in it to get reprogrammed/rejuvenated. The ECM therefore can be an ally or an enemy when it comes to cellular rejuvenation. For this reason I think cellular reprogramming in vivo is going to be harder in older people than younger people, which is ironic because the old people are the ones needing it more.

          • Olafur,
            Your argument against comparing the conserved similarities between trees and humans does not explain why almost all of the trees have a much much shorter lifespan whereas very few live in full bloom of youth for thousands of years.
            Secondly Prof Richard Morimoto has given evidence of a change occurring just after puberty when there is no chance of stochastic damage accumulation:
            https://www.cell.com/fulltext/S1097-2765(15)00499-2
            This repressive mark on Heat Shock Response transcription dropping its initiation against stress by 60% to 80% just after puberty can only be an outcome of programmed intervention. Morimoto himself uses the word and says this fall in protein folding efficiency so early after puberty is conserved across species.
            Tony Wyss-Coray in this paper in Nature Medicine titled Undulating Changes in Human Plasma Proteome Profiles Across Lifespan tells us that they observed waves of proteome changes cresting at 34, 60 and 78 in 4,263 humans of different age. Such temporal coincidence can not occur in all participants by stochastic events.
            Regarding ECM it is not in isolation and it is wrong to assume that Elixir rejuvenation will not rejuvenate ECM. There is constant crosstalk between cells, ECM and plasma components:
            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767504/
            You will find Mina Bissell’s TED talk fascinating where she describes how a healthy cell in an old ECM turned cancerous and this cancerous cell in a young ECM turned normal again.

          • ‘The body obviously evolved to be able to develop into a healthy young functioning adult but it never evolved to resist entropy indefinitely’
            Why should the body waste time in reversing damage, when it can easily eliminate the damage and generate new. The multicellular body evolved to resist entropy by generating new and eliminating waste, which goes haywire during aging.

          • “Why should the body waste time in reversing damage, when it can easily eliminate the damage and generate new.”

            Many kinds of damage in the body can’t be eliminated or renewed by any type of cellular reprogramming. If you claim otherwise you are going to need to provide some strong evidence for that. A good example would be pointing me towards a study that shows that extracellular glucosepane cross-links surrounding cells can be fixed by reprogramming those cells. Also some parts of tissues do not regenerate at all even in a one year old baby, then there is no good reason to think that they would regenerate when you turn back the clock of an adult to even such a young age.

          • extracellular glucosepane accumulates as we age, studies done point out that extracellular glucosepane accumulation accelerates after age 60 till 90 and beyond, i.e accumulation is multiple times in the 30 year period from 60 till 90 than from the 30 year period fro age 30 till 60. the question is why is it so.
            does proteolytic digestibility tackle extracellular glucosepane, which degrades as we age, can proteolytic digestibility be improved with anti aging intervention such as young blood plasma, effectively improving ECm turnover. i am afraid no study has been done on this.

          • https://www.mdpi.com/1422-0067/18/5/984/htm
            ‘The Proteolytic System
            While stable AGEs accumulate over time on proteins with a long half-life such as collagen of the skin, the AGE burden in organs that have higher protein turnover is shifted to a certain extent away from the modified protein to the proteolysis machinery. In this regard proteolysis is the only universal AGE detoxification mechanism. AGE modified proteins are more resistant to digestion by the proteasomal—as well as the lysosomal proteolytic system [127]. This does not necessarily result in accumulation of AGE-modified proteins as long as the proteolytic system is able to adapt the digestive capacity.’

          • https://www.sciencedirect.com/science/article/pii/S0925443918303296#bb0155
            ‘Anti-glycation pathways generally only operate on intermediates of glycation. Once generated, excessive AGEs accumulate and eventually become insoluble causing intense changes in the subcellular metabolism. However, there are intracellular degradative mechanisms that help clear these toxic adducts. Both the ubiquitin-proteasome system (UPS) and autophagy have been reported to contribute to the removal of AGEs (Fig. 2) [[28], [29], [30], [31]]. They may operate autonomously or cooperatively. At present, there is little information about the molecular processes and factors involved in the targeting of AGEs to these degradative routes’

        • “https://www.sciencedirect.com/science/article/pii/S0925443918303296#bb0155
          ‘Anti-glycation pathways generally only operate on intermediates of glycation. Once generated, excessive AGEs accumulate and eventually become insoluble causing intense changes in the subcellular metabolism. However, there are intracellular degradative mechanisms that help clear these toxic adducts. Both the ubiquitin-proteasome system (UPS) and autophagy have been reported to contribute to the removal of AGEs (Fig. 2) [[28], [29], [30], [31]]. They may operate autonomously or cooperatively. At present, there is little information about the molecular processes and factors involved in the targeting of AGEs to these degradative routes’”

          Nice to see you looking up some references kumal. Thanks for that.
          Regarding the degradative mechanisms mentioned above, note that these degradative mechanism are intracellular. Cells do have pretty good capacity to clear damage inside of them including removing AGEs however these degradative pathways aren’t found in the extracellular matrix. To fix similar damages in the ECM the cells would need to somehow take damaged molecules from the ECM and transport them into cells which is not something they do to any significant degree.

          • “Well here is a case where a woman grew brand new ECM….
            check out this youtube video about a woan who grew her severed fingertip back
            https://youtu.be/MZdS0tDyS0w
            now that is some real good ECM repair!..grow some brand new ECM”

            Although impressive that’s creating a new ECM not fixing an old one. Those are two very different things. A regrowth of a fingertip is an example of programmed development not programmed aging. She didn’t fix the old fingertip she grew a new one. Regrowth of limbs and organs is great and will be very useful, I’m all for it, but we must also fix the ECM in those organs that cannot be regrown like the brain.

      • Average age of new born baby is 3.5 kg, and the average of an adult is 63 kgs, 95% percent of the body is not present at birth and the body acquires this 95% mass in approx 18 to 20 yrs.
        Therefore everything can be regenerated

          • “Everything can be generated. But that doesn’t prove that it can be REgenerated, it’s not the same thing.”

            Thanks Raphael. Your answer is spot on. Those are indeed very different things. The body obviously evolved to be able to develop into a healthy young functioning adult but it never evolved to resist entropy indefinitely to be able to stay in a perfect state of young and healthy body indefinitely. Saying the program for that exists in humans (or any similar animals) is therefore a huge stretch and requires a lot of proof to be taken as a serious possibility.

    • one thing should be noticed for this study is that eye are immune-privileged. i am not sure this partial OKSM reprogramming method will work on non immune-privileged organ without cancer risk or not.

  21. Josh:
    I urge caution in use of the term “methylization signal.” Under the general theory of relativity, a signal cannot travel at a speed that exceeds the speed of light in a vacuum. This has the consequence that one cannot receive a signal from the future.
    In an attempt at exercising control over human aging, the control system must receive information from the future in regard to the outcome of events of the future given the outcomes of events of the present. This information cannot be carried by a signal. Thus, this information cannot be carried by a methylization signal. The term “methylization data” would be a suitable replacement for the term “methylization data” for some purposes.
    Terry Oldberg

  22. I may suggest “loss of bivalent chromatin” is a better indicator than “loss of global DNA methylation” for biological aging measurement. it’s from my observation on 3 things:
    1. cancer shows abnormal hypermethylation on bivalent genes comparing to embryogenesis. there are several papers on this topic. the following is just 2 of them:
    https://www.biorxiv.org/content/10.1101/2020.12.02.406751v1
    https://www.nature.com/articles/srep37393
    2. ischemic preconditioning is an effective way to save lives for harmful ischemic injuries. scientists found ischemic-tolerant epigenetics(go through prolonged ischemic injury after short ischemic preconditioning) is similar with hibernation pattern. as we know, mammals with hibernation will live much longer than no-hibernation. these hibernation animals live longer than our humans as well. so i can say ischemic preconditioning should have anti-aging capability.
    however, scientists found both of ischemic-tolerance and ischemic preconditioned are global DNA hypomethylation.
    3. no matter aging or cancer, keeping cell identity is very critical. H3K27me and PRC2 play important role to maintain cell identity.

    currently i am trying to figure out the root cause for “loss of bivalent chromatin” from the complex relationship between bivalent chromatin, PRC2, 2-OGDDs like Jmjc-KDM, TET, oxygen, glycolysis and TCA cycle. then we will get a systematic solution, not just focus on cellular or ECM rejuvenation.
    for example, loss bivalent chromatin could abnormally activate glycolysis pathway and disregulate glycolysis, then too much methylglyoxal (MG) will be produced. then too much AGEs and finally abnormal ECM. abnormal ECM further hurt cell and this becomes vicious feedback loop. samely, loss bivalent chromatin could initiate aberrant cellular pathway, then transmit to ECM by cytokines/chemokines etc. a vicious cycle will be formed too.

    if we put embryogenesis, cancer, regeneration like axolotl/zebrafish into the above complex relationship, i am sure we can get something.

  23. Hi Josh,

    I think it is more important how one feels AND it is perceived by the others than any clock. Though it would be interesting to correlate the clock with how fit is a man (woman) in the daily life. Is there any study regarding this ?

  24. Hi Olafur,

    Apparently you know a thing or two about the advanced glycation end products. 🙂
    Do you know about any ways to moderate the damage caused by AGEs in the extracellular matrix knowing that reversing that damage is currently not possible.
    Reducing blood glucose seems to be a nobrainer but is there anything to do against AGEs beyond this?

  25. Critics of programmed aging support the idea that development is programmed and after development ends, the body is exposed to natural degradation, which is not programmed. If that is the case age span of an individual in a species should be random after the development program ends and follow random probability distribution. In humans if there is consensus that the development program ends at age 25, age span in humans should display a random distribution after age 25.

    • “Critics of programmed aging support the idea that development is programmed and after development ends, the body is exposed to natural degradation, which is not programmed.”

      No they don’t support that idea, not in my case at least. The body is always exposed to degradation, both before and after development. It is just better at handling and defending against the degradation early in life. Programming also doesn’t stop after development. There always exists some programming to defend against degradation but it is limited in what it can do.

      • ‘Programming also doesn’t stop after development. There always exists some programming to defend against degradation but it is limited in what it can do’

        But that is precisely what programmed aging is all about, the rate of decline of the renewal and repair factors specific to a particular species.

    • Yeah ..trying to look at aging and saying it s programmed can leave room for argument by those who have not really taken the deep dive and looked into it with the proper perspective. To those who argue aging is not programmed I tell them try someting simpler that has the same effect as aging from an evolutonary persepctive>> the end of your spreading your genes ..

      Expain how menopause is not programmed first, and when you can do that then come back and tell us how aging is not programmed. HAHA good luck

Leave a Reply to Akshay Atomic Bliss Cancel reply

Your email address will not be published. Required fields are marked *