What to Look For in a Biological Clock

In this article, I’m reporting on 

  • new proteomic clock from Adiv Johnson and the Stanford lab of Benoit Lehalier
  • new methylation clock developed with “deep learning” algorithms by an international group from Hong Kong 
  • the advanced methylation clock developed by Morgan Levine, Len Guarente, and Elysium Health

Prelude

Aging clocks = algorithms that compute biological age from a set of measurable markers. Why are they interesting to us? And what makes one better than another?

The human lifespan is too long for us to do experiments with anti-aging interventions and then evaluate the results based on whether our subjects live longer. The usefulness of an aging clock is that it allows us to quickly evaluate the effects on aging of an intervention, so we can learn from the experiment and move on to try a variant, or something different.

Many researchers are skeptical about using clock algorithms to evaluate anti-aging interventions. I think they are right to be asking deep questions; I also think that in the end the epigenetic clocks in particular will be vindicated for this application.

It may seem obvious that we want the clock to tell us something about biological aging at the root level. We are entranced by the sophisticated statistical techniques that bioinformaticists use to derive a clock based on hundreds of different omic factors. But all that has to start with a judgment about what’s worth looking at.

Ponder this: The biostatisticians who create these clocks are optimizing them to predict chronological age with higher and higher correlation coefficient r. But if they achieve a perfect score of r=1.00, the clock becomes useless. It cannot be used to tell a 60-year-old with the metabolism of a 70-year-old from another 60-year-old with the metabolism of a 50-year-old, because both will register 60 years on this “perfect” clock.

It’s time to back up and ask what we think aging is and where it comes from, then optimize a clock based on the answer. As different people have different answers, we will have different clocks. And we can’t objectively distinguish which is better. It depends on whose theory we believe.

Straw man: AI trained to impute age from facial photos now has an accuracy of about 3½ years, in the same ballpark with methylation clocks. If we used these algorithms to evaluate anti-aging interventions, we would conclude that the best treatments we have are facelifts and hair dye.

Brass tacks: People with different positions about the root cause of aging all agree that (a) aging manifests as damage, and (b) methylation and demethylation of DNA take place under the body’s tight and explicit site-by-site regulation.

But what is the relationship between the methylation and the damage? There are three possible answers.

  1. (from the “programmed” school) Aging is programmed via epigenetics. The body downregulates repair mechanisms as we get older, while upregulating apoptosis and inflammation to such an extent that they are causes of significant damage.
  2. (from the “damage” school) The body accumulates damage as we get older. The body tries to rescue itself from the damage by upregulating repair and renewal pathways in response to the damage.
  3. (also from the “damage” school) Part of the damage the body suffers is dysregulation of methylation. Methylation changes with age are stochastic. Methylation becomes more random with age.

My belief is that (1), (2), and (3) are all occurring, but that (1) predominates over (2). The “damage” school of aging would contend that (1) is excluded, and there are only (2) and (3).

How can these three types of changes contribute to a clock? 

(3) makes a crummy clock, because, by definition, it’s full of noise and varies widely from person to person and from cell to cell. There is no dispute that a substantial portion (~50%) of age-related changes in DNA methylation are stochastic. But these changes are not useful and, in fact, most of the algorithms used to construct methylation clocks tend to exclude type (3) changes. I won’t say anything more about stochastic changes in methylation, but I’ll acknowledge that there is more to be said and refer you to this article if you’re interested in methylation entropy.

If you are from the “damage” school, you don’t believe in (1), so this leaves only type (2). If changes in methylation are the body trying to rescue itself, then any intervention that makes the body’s methylation “younger” is actually dialing down protection repair. You expect that reducing methylation age will actually hasten aging and shorten life expectancy. You have every reason to distrust a clinical trial or lab experiment that uses methylation age as criterion for success.

White cell count is used as a reliable indication of cancer. As cancer progresses, white cell count increases. The higher a person’s white cell count, the closer he is to death. So let’s build a “cancer clock” based on white blood count, and let’s use it to evaluate anti-cancer interventions. The best intervention is a chemical agent that kills the most white blood cells. It reliably sets back the “cancer clock” to zero and beyond. But we’re puzzled when we find that people who get this intervention die rapidly, even though the cancer clock predicted that they were completely cured. The problem is that white blood cells are a response to cancer, not its cause.

If you are from the “programmed” school, you think that (1) predominates, and that a clock can be designed to prefer type (1) changes to (2) and (3). Then methylation clocks measure something akin to the source of aging, and we can expect that if an intervention reduces methylation age, it is increasing life expectancy.

The fact that methylation clocks trained on chronological age alone (with no input concerning mortality or disease state) turn out to be better predictors of life expectancy than age alone is a powerful validation of methylation technology. But only if you believe (for other reasons) that methylation is an upstream cause of aging. You could expect this from either type (1) or type (2) methylation changes.

I believe that aging is an epigenetic life program, and that methylation is one of several epigenetic mechanisms by which it is implemented. That’s why I have faith in methylation clock technology.

Conversely, people who believe that the root cause of aging is accumulated damage are right to discount evidence from epigenetic clocks as it pertains to the efficacy of particular treatments. As in the cancer example above, treatments that create a younger methylation age can actually be damaging.

The basis for my belief that aging is an epigenetic program is the subject of my two books, and was summarized several years ago in this blog. I first wrote about methylation as a cause of aging in this space in 2013. For here and now, I’ll just add that we have direct evidence for changes of type (1). Inflammatory cytokines are up-regulated with age. Apoptosis is upregulated with age. Antioxidants are downregulated with age. DNA repair enzymes and autophagy enzymes and protein-folding chaperones are all down-regulated with age. All these are changes in gene expression, presumably under epigenetic control.

Which is more basic, the proteome or the methylome?

For reasons I have elaborated often in the past, I adopt a perspective on aging as an epigenetic program. I think of methylation clocks as close to the source, because methylation is a dispersed epigenetic signal. But the proteome is, by definition, the collection of all signals transmitted in blood plasma, including all age signals and transcription factors that help to program epigenetics cell-by-cell. The proteome is generated by transcription of the DNA body-wide, which transcription is controlled by methylation among other epigenetic mechanisms. So one might argue from this that the methylome is further upstream than the proteome. On the other hand, methylation is just one among many epigenetic mechanisms, and the proteome is the net result of all of them. On this basis, I would lean toward a proteomic clock as being a more reliable surrogate for age in clinical experiments, even better than methylation clocks. It is a historic fact, however, that methylation clocks have a 6-year headstart. Methylation testing is entering the mainstream, with a dozen labs offering individual readings of methylation age, priced to attract end-users.

Let’s see if proteomic clocks can catch up. The new technology is based on SOMAscan assays, and so far is marketed to research labs, not individuals or doctors, and it is priced accordingly. The only company providing lab services is SOMAlogic.com of Boulder, CO. SOMAscan is an aptamer-based proteomics assay capable of measuring 1,305 human protein analytes in serum, plasma, and other biological matrices with high sensitivity and specificity.” [ref] As I understand it, they have a microscope slide with 1305 tiny dots, each containing a different aptamer attached to a fluorescent dye. An aptamer is like an engineered antibody, optimized by humans to mate to a particular protein. Thus 1305 different proteins can be measured by applying a sample (in our case, blood plasma) to the slide, chemically processing the slide to remove aptamers that have not found their targets, then photographing the slide and analyzing the readout from the fluorescent dye.

Aptamers are synthetic molecules that can be raised against any kind of target, including toxic or non immunogenic ones. They bind their target with affinity similar or higher than antibodies. They are 10 fold smaller than antibodies and can be chemically-modified at will in a defined and precise way. [NOVAPTech company website]

Curiously, aptamers are not usually proteins but oligonucleotides, cousins of RNA, simply because the chemical engineers who design and optimize these structures have had good success with the RNA backbone. The SOMA in SOMAlogic stands for “Slow Off-rate Modified Aptamers”, meaning that the aptamers have been modified to make them stick tight to their target and resist dissociating.

An internal proteome-methylome clock?

It’s possible that there is a central clock that tells the body “act your age”. I have cited evidence that there is such a clock in the hypothalamus, and that it signals the whole body via secretions [20152017].

Another possibility is a dispersed clock. The body’s cells manufacture proteins based on their epigenetic state, the proteins are dispersed in the blood, some of these are received by other cells and affect the epigenetic state of those cells. This is a feedback loop with a whole-body reach, and it is a good candidate for a clock mechanism in its own right.

I’m interested in the logic and the mathematics of such a clock in the abstract. Any feedback loop can be a time-keeping mechanism. Such a mechanism is
_____Epigenetics ⇒ Protein secretion ⇒ Transcription factors ⇒ Epigenetics
This is difficult to document experimentally, but it is an attractive hypothesis because it would explain how the body’s age can be coordinated system-wide without a single central authority, which would be subject to evolutionary hijacking, and might be too easily affected by individual metabolism, environment, etc. But the body’s aging clock must be both robust and homeostatic. If it is thrown off by small events, it must return to the appropriate age.  So my question—maybe there are readers who would like to explore this with me—is whether it is logically possible to have a timekeeping mechanism that is both homeostatic and progressive, without an external reference by which it can be reset.

Last year, Lehalier and a Stanford-based research group jumpstarted the push toward a methylomic aging clock with this publication [my write-up here]. The same group has a follow-up, published a few weeks ago. The new work steps beyond biologically agnostic statistics to incorporate information about known functions of the proteins that they identified last year. The importance of this is twofold: It suggests targets for anti-aging interventions. And it supports the creation of a clock composed of upstream signals that have been verified to have an effect on aging. I argued in the long Prelude above that this is exactly what we want to know in order to have confidence in an algorithmic clock as surrogate to evaluate anti-aging interventions.

They work with a database I had not known about before: the Human Ageing Genomic Resources Database.  HAGR indexes genes related to aging and summarizes studies that document their functions. Some highlights of the proteins they identified:

  • Inflammatory pathways are right up there in importance. No surprise here. But if you can use inflammatory epigenetic changes to make an aging clock, you have a solid beginning.
  • Sex hormones that change with age turn out to be even more prominent in their list. The first several involve FSH and LH. These are hormones connected with women’s ovarian cycles; but after menopause, when they are not needed, their prominence shoots up, and not just once-a-month, but always on. Men, too, show increases in LH and FSH with age, though they are more subtle. I first became aware of LH and FSH as bad actors from the writings of Jeff Bowles more than 20 years ago.
  • “GDF15 It is a protein belonging to the transforming growth factor beta superfamily. Under normal conditions, GDF-15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as such as liverkidneyheart and lung.” [Wikipedia]  “GDF15 deserves a story of its own. The authors identify it as the single most useful protein for their clock, increasing monotonically across the age span. It is described sketchily in Wikipedia as having a role in both inflammation and apoptosis, and it has been identified as a powerful indicator of heart disease. My guess is that it is mostly Type 1, but that it also plays a role in repair. GDF15 is too central a player to be purely an agent of self-destruction.” [from my blog last year]
  • Insulin is a known modulator of aging (through caloric restriction and diabetes).
  • Superoxide Dismutase (SOD2) is a ubiquitous antioxidant that decreases with age, leaving the body open to ROS damage.
  • Motilin is a digestive hormone. Go figure. Until we understand more, my recommendation would be to leave this one out of the aging clock algorithm.
  • Sclerostin is a hormone for bone growth. It may be related to osteoporosis, and well worth inclusion. 
  • RET and PTN are called “proto-oncogenes” and are important for development, but associated with cancer later in life.

Which proteins are most relevant?

The Horvath clocks have been created using “supervised” optimization, which involves human intelligence that oversees the application of sophisticated algorithms. But what happens if you automate the “supervised” part? On the one hand, you must expect mistakes and missed opportunities that you wouldn’t have with human supervision. On the other hand, once you have a machine learning algorithm, you can apply it over and over to different subsets of the data, produce hundreds of different clocks, and choose those that perform best. That’s what Johnson and co-authors have done in the current paper. They describe creating 1565 different clocks based on different subsets of a universe of 529 proteins. In my opinion, their most important work combines biochemical knowledge with statistical algorithms. The work using statistical algorithms alone are much less interesting, for reasons detailed in the Prelude above.

Summary

This new offering from Lehalier and Johnson is a great step forward in that

  • proteins in the blood are a broader picture of epigenetics than methylation alone
  • specific proteins are linked to specific interventions that are reliably connected to aging in the right direction. Crucially, the clock is designed to have type (1) epigenetic changes (from the Prelude above) and to exclude type (2)

Next steps

  • to calibrate the clock not with calendar age but with future mortality. This would require historic blood samples, and it is the basis of the Levine/Horvath PhenoAge clock.
  • to optimize the clock separately for different age ranges or, equivalently, to use non-linear fitting techniques in constructing the clock algorithm
  • to commercialize the Aptomer technology, so that it is available more widely and more cheaply

Elysium Index

Elysium is a New York company advised by Leonard Guarente of MIT and Morgan Levine (formerly Horvath’s student, now at Yale). They have an advanced methylation clock available to the public, which they claim is more accurate than any so far. Other clocks are based on a few hundred CpG sites that change most reliably with age, but the Index clock uses 150,000 separate sites (!) which, they claim, offers more stability. The Horvath clocks can be overwhelmed by a single CpG site that is measured badly. (I have personal experienc with this.) Elysium claims that variations from one day to the next or one lab slide to the next tend to average out over such a large number of contributions. On the other hand, as a statistician, I have to wonder about deriving 150,000 coefficients from a much smaller number of inividuals. The problem is called overfitting, and the risk is that the function doesn’t work well outide the limited data set from which it was derived.

In connection with the DataBETA project, I have been talking to Tina Hu-Seliger, who is part of the Elysium team that developed Index. I am impressed that they have done some homework that other labs have not done. They compare the same subject in different slides. They store samples and freeze them and compare results to fresh samples. They compare different clocks using saliva and blood.

I wish I could say more but Elysium Index is proprietary. There is a lot I have not been told, and there is more that I know that I have been asked not to reveal. I don’t like this. I wish that all aging research could be open sourced so that researchers could learn from one another’s work.

Two other related papers

DeepMAge is a new methylation clock, published just this month, based on more sophisticated AI algorithms instead of the standard 20th-century statistics used by Horvath and others thus far. Galkin and his (mostly Hong Kong, mostly InSilico) team are able to get impressive accuracy in tracking chronological age. This technology has forensic applications, in which evidence of someone’s calendar age is relevant, independent of senescence.  And the technology may someday be the basis for more accurate predictions of individual life expectancy. But, as I have argued above, a good clock for evaluating anti-aging measures must look at more than statistics. Correlation is not the same as causation, and only detailed reference to the biochemistry can give confidence that we have found causation.

Biohorology is a review paper from some of this same InSilico team together with some prominent academics, describing the latest crop of aging clocks. The ms is long and detailed, yet it never addresses the core issue that I raise in the Prelude above, about the need to distinguish upstream causes of aging from downstream responses to damage.

The beginning of the ms contains a gratuitous and outdated dismissal of programmed aging theories.

“Firstly, programmed aging contains an implicit contradiction with observations, since it requires group selection for elderly elimination to be stronger than individual selection for increased lifespan.”

Personally, I bristle at reading statements like this. which ignore an important message of my own work and, more broadly, ignore the broadened understanding of evolution that has emerged over the last four decades.

“Secondly, in order for the mechanism to come into place, natural populations should contain a significant fraction of old individuals, which is not observed either (Williams, 1957).” 

This statement was the basis not just of Williams’s 1957 theory, but more explicitly of the Medawar theory 5 years earlier. Neither of these eminent scientists could have known that their conjecture about the absence of senescence in the wild would be thoroughly disproven by field studies in the 1990s, The definitive recent work on this subject is [Jones, 2014].

Take-home message

For the purpose of evaluating anti-aging treatments, the ideal biological clock should be created with these two techniques:

  • It should be trained on historic samples where mortality data is available, rather than current samples where all we know is chronological age, and
  • Components should be chosen “by hand” to assure all are upstream causes of aging rather than downstream responses to damage. (Type 1 from analysis above.)

102 thoughts on “What to Look For in a Biological Clock

    • We are deceived by modern science and this does not give us the opportunity to correctly cognize the world around us. Everyone is given what he is tuned for. My knowledge gave good health and rejuvenation, and I do not need knowledge of modern science, which takes me away from what I have achieved now.

          • ICD (diagtor.com.ua) is obtained by the method of information and energy activation malic acid stabilized by YaS in the form of a powder, which differs from the food additive of malic acid E-296 in that it has one property – it suppresses all viruses, bacteria, fungi, activates plant growth … Administration of YaKS solution to animals allows to stop aging and start the process of rejuvenation. The use of YAKS together with honey allows a person to stop aging and start the rejuvenation process. For the experiment, we can present YAK. Send your request to ErmakovP@i.ua.

  1. Well we don’t get mentioned anymore and that’s fine, we expect third-party validation in the next few months, but our raw data was examined by bioRxiv before they would put out Steve Horvath and my preprint, so what I’m trying to say is that whether or not they’ve been put up to peer-review, our results were real. For the ‘proteome’ we used two inflammatory factors (and we will do sex hormones at some time) Il-6 and TNF as well as reparative transcription factor Nrf2. Also, physiological tests, such as grip strength and maze solving, altogether more than 30 assays related (more than you would think) to aging. All were consistent with each other. So, for example, in rat aging, as with aging humans, blood levels of HDL cholesterol decrease with age while LDL cholesterol levels increase with age. This is often considered the result of lack of exercise or some other changes in lifestyle – but we can set these levels back to youthful by injecting our young plasma fraction. Therefore that plasma fraction contains whatever is required to set the levels of HDL and LDL cholesterol back to normal. Ditto with the inflammatory cytokines I mentioned – our ‘plasma fraction’ returns the levels of these cytokines to youthful levels, though there is a whole field of study implicating latent infections, genomic viruses sprouting from our DNA as the cause of the chronic inflammation due to aging, yet simply providing our plasma fraction, returns levels to youthful ones. So you can say that the chronic inflammation due to aging is due to lack of this plasma fraction. And finally, the DNAm age was reduced in half. So it would seem that the mechanism by which our plasma fraction works is by resetting the cellular age-phenotype to the equivalent of a young adult – and everything else follows from that. BTW SOD is not a universal antioxidant – but very specifically turns the superoxide radical anion (increasingly formed in aging cells as high energy electrons pass along the Electron Transport Chain (ETC)), and turning this highly energetic molecule into the less energetic hydrogen peroxide – which is required by the cell (otherwise it dies of reductive stress, [which actually depends on oxidative stress for its killing effects]). Also, the proteome is not the only part of the genome responsible for aging (there are families of miRNAs like Let-7). Josh, you mention down-regulation of some proteins and upregulation of others, Lastly, your misgivings about tracking chronological age I believe are appropriate – what we believe is that what we track is biological age which is different, it is more like tracking what stage of your life you’re at (e.g. ‘late-middle-age’) which tells you about your rate of aging and your expected duration of life. Unlike chronological time, biological time is reversible and can be slowed down or speeded up, and better their either, can be reset. We have to find out to what extent.

    • Thanks for the technical corrections, Harold.
      All the readers of this page and I are cheering for your success, and we’ll gobble up any information you can provide about your progress. Independent replication will be an important stepping stone.
      – Josh

      • Thanks Josh, in January I’m going down to California to make Elixir myself, as we can’t get any of our people from India over. I’d hoped by this time someone would have taken over lab tech work – but I’ve got to drive 1,000 miles (and meet Akshay who’ll help (so much as a financier can – in Akshay’s case a great deal). But there is no choice.

      • It seems clear that there is a trade off at the subcellular level between energy production and repair. For example upregulation of nrf2 takes NADH that could otherwise be used to pump protons across the mitochondrial inner membrane to create the charge gradient needed to make ATP. Similarly the NAD+ produced by the ETC could be fed back to the Krebs cycle to make more NADH or it could be used to catalyse a number of important reparative reactions, like in the one carbon cycle to make mitochondrial proteins for the complexes of the ETC.

        But we also know for the various rejuvenations achieved via parabiosis, tgf-b suppression, blood dilution, plasma fractions (elixir), that this basic mismatch between energy and repair, specific to each species, must set in motion a much larger cascade of age related dysfunction. And it is this larger cascade that is being reversed by the various successful treatments, probably without having any effect on the basic species rate of aging, which will continue from the lower reset point.

        Does this mean we may solve the problem before we even understand the full complexity of the problem?

        • Hi Mark, I agree with you that oxidative stress is a cause of aging, but there are others. What you don’t realize (and I didn’t for years) is that understanding cell energetics is not the solution, and will never lead to a solution because it makes the assumption that cells age. This is simply not true; cell’s do not age, they take on the age-phenotype the body gives them.

          • This is what is so hard to accept for most aging scientists. What I think you are saying Harold, is that Hayflick was essentialy wrong. In the right culture (or serum) conditions cells are immortal- and that we might need to reverse the long held adage that we age because our cells age.

          • The control of the body and the very existence of an animal is conditioned by its Soul. The animal soul is a structure of a magnetic field and has an information volume of about a billion bytes. The soul controls the body through the creation of certain electrical signals that propagate along the nerves throughout the body. Control signals of the Soul determine the structure of DNA and genes.

          • I agree with HK and Mark, but Ermakov fills in what is lacking in just saying that cells theoretically could be immortal (true). In our current created state (fallen world) they are limited in that enterprise regardless of their potential. I can’t speak to the electromagnetic explanation that Ermakov gives, but it certainly is a different dimension that our souls are in tune with that “informs” us in different ways, let’s say. Our purpose in this life is to train this created soul to be virtuous like the uncreated soul (God). In the appropriate dimension (the eternal existence of God where love abounds) God grants immortality with Him.

            I join you all in our quest for improved health but death in this world is a requisite for many reasons, so my only worry is making self preservation an idol. Don’t do it.

    • Dear Harold L. Katcher Thanks for the encouraging information. It would be a big breakthrough in gerontology if your test subjects maintain the achieved level of “the DNAm age was reduced in half” for a long time.

      • So far we only have hints, during our first treatment, after about 60 days – equivalent to about five human years, levels of inflammatory cytokines started to rise, and at 90 days (~8-9 years) levels of inflammatory cytokines rose to about halfway to those of the old control. However, after the second treatment, which actually brought levels of inflammatory cytokines to lower levels than our old controls, and after sixty days following the second treatment, there was no significant rise in the levels of inflammatory cytokines in the treated group, even though the young controls seemed to rise – you can check it out yourself. My hope is that aging stopped, but that’s very unlikely, my guess is that after all pro-aging substances were purged from the blood (by the passage of time, and the lack of manufacturing new such) then aging would proceed normally, you’d be back in your 20s and would start aging normally, however, there doesn’t seem (so far) to be anything to prevent additional rejuvenations.

        • Hi, Harold, I have a few questions:
          I have a few questions:
          1) In view of the fact that blood supply to cartilage is limited, do you think that the elixir injections will repair damaged catilage? If not so, would a local patch or injection to the joints repair cartilage damage?
          2) Similarly, would the injections have an effect on bones?
          3) Do you expect that the elixir will have an effect on autoimmune dideases such as Reumatoid Arthritis?
          It is possible that you might not have concrete answers to these questions yet. Even so, I would be very interested to see your “educated guess” on these.

    • Hi Harold, Anxiously awaiting your product.

      “For the ‘proteome’ we used two inflammatory factors (and we will do sex hormones at some time) Il-6 and TNF as well as reparative transcription factor Nrf2.”

      I don’t understand what you mean here. Do you feed/inject compounds to activate Il-6,TNF and Nrf2?

  2. A voice of reason in the wilderness! I have made the same arguments in online forums until my fingers ache. The most common response is non-response.

    If you define aging as the increase of mortality with time, then you obviously have to base your clock on that! I should note that the aging.io clock, trained to chronological age, says that I am 46. I’m 79. The Phenotype clock, based on SOME mortality parameters, says I am 77, but my actual chronological age is a heavily weighted factor. If I lie and say my age is 46, it says I’m 46. Obviously, neither of these clocks is helpful to me other than perhaps indicating whether a therapeutic action moves things in the right direction, but I’m not certain that they are accurate enough for even that.

    I am not learned enough to critique an analysis designed to separate proteomic cause from effect, but I wish there were more of them. Perhaps you can help. Treating effects rather than causes seems less useful if not pointless. Right now, I am inclined to look towards epigenetic measurements as aging indicators but I know that histone modifications are probably even more important than DNA methylation, and I am unaware of any clocks based on them.

    I have searched and searched this (your) article and have yet to find anything on which to disagree. My greatest compliments!

  3. Josh:
    Thanks as always for the excellent summary of an important facet of recent aging research.. For the future, I advise more precise use of statistics-related terms, including the term “AI” in the sentence ” AI trained to impute age from facial photos now has an accuracy of about 3½ years.” In the revised terminology, the item trained would be called a “model” or “theory.”

    The Horvath “clock” is the result of training a model through the use of regression analysis but regression analysis is not the only available method for training a model nor is it without fault. Its fault is to fail to solve the philosophical problem that is called the “problem of induction.” The problem is of how, in a logically justifiable manner, to select the inferences that are made by the model. This method was solved in 1963 by the late Ronald Arlie Christensen, then a PhD candidate in the theoretical physics program of the University of California, Berkeley. Christensen solved this problem by selecting the inferences through the information theoretic optimization that he called “entropy minimax.” Circa 1980 he documented his work in the seven volume series that he called the “Entropy minmax source book.” This solution to the problem of induction has the property of existence and uniqueness, supporting the conclusion that it solves the problem of induction.

    Were entropy minimax to be used in the creation of epigenetic models this would not result in the existence of Horvath’s clock. Ideally it would result in the existence of highly informative models that were predictive of selected outcomes of events. In the creation of these models, information theoretically optimal patterns would be discovered, the names of which would evolve the language of epigenetic research in new and more fruitful directions.

  4. Josh, Concerning possibility (1) among your mentioned possibilities 1, 2 and 3, I agree, hypothetically at least, on decreasing damage repair in the old (as well as upregulation of apoptosis and inflammation). But, why is it that you allways dismiss the another obvious possible cause of (programmed) aging (inside possibility (1) ): that the body “purposedly” upregulates the rate of damage generation itself from within. Precisely there is ample evidence that the “Rate of Mitochondrial ROS GENERATION” is strongly related to Aging Rate BOTH Among and Withing a simple species. I have found this during decades of lab. Experimentation and so have found many other well known research groups. In co trast, evidence favoring the other mechanisms within (1) is not so complete, especially so, and most importantly, concerning longevity-Interspecies comparisons.

    • I think there’s no question that you’re correct and a basis of hypothesis 1, programmed aging. However, studies show that aging can be slowed down or sped up by respectively, by limiting the number of damages (for example in C. elegans) by adding N-acetyl-cysteine to the media – or sped up by adding ROS generators, or cells lacking the FOXO transcription factor that mediates repair. (And yet if ‘normalized’ for maximum lifespan length, all survival curves, sped up or slowed down by all conditions superimpose exactly on each other. Fontana (Harvard says that means there is a loss of what he calls ‘resilience’ (or ‘organ reserve, or ‘vitality’) and that loss determines the probability of death. The literature shows us that organs start aging, in the same manner, but beginning at different times, and if we look more closely we can see that there are a few hundred age-dependent proteins – and a few of them are vital to energy generation, DNA repair and chromatin remodeling as well as the writers and erasers of the constantly changing chromatin and other epigenetic ‘codes’. And of course inflammation produces oxidative conditions that further deplete the (exogenously determined) stores of protective and reparative enzymes, NADPH, glutathione, NAD+ (used by the sirtuin deacetylases, so important in epigenetic changes) etc. And if you look at survival curves and particularly the rate of aging, which is d (log t)/dt, you can see it go up exponentially with age; as though aging conditions accelerated aging, as you’d expect they would once one piece unravels, it all starts coming apart faster.

  5. Continuing my comment from a few min. ago, I forgot to add that:

    An implication of my point is that your old way of dividing us, aging researchers, into “programmed school” and “damage school” is not correct, at least in some cases like mine, and can lead to confusion. My case is such one because working most of my life on the relationship between mitochondriial ROS production and Aging Rate I will fall, according to your dicotomic definitions into BOTH the “damage school”and the “programmed school”, because after so many decades of work I continue to beleive that each species Actively controls and sets its basal level (Rate) of mitochondrial ROS generation, which then contributes to establish its Rate of aging (and thus its longevity). Aging Rate being controled (in part) by mitROSp Rate (which makes sense: Rate 1 causally leads to Rate2)..

    • I believe that’s part of it, but I think ROS overgeneration is one of the controllers of the speed of the ‘aging clock’ and I agree that it is set cell non-autonomously, as they say, by the body. And the interaction with the immune system contributes to this. We were able to study normal untreated rats for almost eight months, a substantial part of their lives, and we saw the rate of inflammatory cytokines go up steadily at about the same rate in young and old rats. Seems to me this steady rise in inflammatory cytokines in a natural part of the aging program, and it too will determine the aging rate. I think the rate of inflammation rises way more than the increasing presence of senescent cells can explain (though our ‘plasma fraction’ appears to remove them as well) but by their nature, senescent cells should show an exponential increase with age, (since a senescent cell can transform neighboring cells to senescence, the number arising is a constant function of those present hence exponential increase), rather than the steady increase of inflammation shown by our control animals. But as senescent cells increase in such a manner they’d have their most significant effect at old age. So that’s a built-in aging accelerator designed to finish the job.

      • Only slightly off topic if you consider the use of aging clocks to measure therapeutic efficacy:

        Vince Giuliano says that a “younging” therapy in humans will take years to show up in measurable terms including DNA methylation. I note, however, that your mice regained youthful grip strength essentially immediately after treatment. Akshay informs me that rats have to be sacrificed for tissue DNA methylation measurements, so until larger animal studies we cannot determine what is happening epigenetically. What thinkest you is happening?

        Which brings me to a question I can find no answers to: what are the relative times for a therapy to eventuate between species? A lot of folks seem to assume that it is proportional to the relative life expectancies. I would maintain that it makes more sense to assume it proportional to metabolic rate, a much, much smaller number for rat/human comparisons. What sayest thee?

        • Just a question to Jeff Bowles:

          It is well known (it is basic physiology) that LH and FSH production fron the pititary are strongly subjected to negative feedback from circulating estrogens and androgens. Since these two decrease in the old, these decreases can be responsible (at least in part) for the increases in LH and FSH in the old due to existance of less feedback inhibition to the hypothalamus.

          It is then possible that the increases in LH and FSH in old age are simple final consequences of aging of sexual organs without any role as causes of aging?

          Is there clear mechanistic evidence that high LH and FSH, by themselves, directly “cause” damage or aging? And, if your answer were yes , what are these deleterious effects of LH and FSH at molecular/cellular/tissue level?

          • Hello

            When I wrote my paper in 1998 it was not known that there were LH receptors in cells all over the body..the general consensus was that they were limited to the sex organs a number of years it was later discovered that LH receptors were found all over the body. Including the brain. My paper also predicted LH woudl be found to cause or contribute to Alzheiemr’s neurodegeneration..this was confirmed bythe NIH in a 2005 paper search gonadotropipns and neurodegeneration and you will find it… How does LH and FSH cause aging…good qurestion I didn’t follow the trail all the way down to the atomic interaction level…I just have a big picture idea of how it works..Basically my understanding is that Higher levels of LH bind to LH receptors and trigger apoptosis ..This is exactly what LH does to the developing follicle that contains the egg…the LH eats away at the egg follicle tissue which release the egg..I believe it triggers COX-2 to intiate the apoptosis..A big clue for me about Alzheimers and LH being associated was that ibuprofen users were found to be protected from Alzhiemers somewhat…Ibuprofen is a Cox-2 inhibitor. You can also look at the big picture puzzle piece of Werner’s syndrome..I believe the unique-to-Werner’s syndrome rapid aging symptoms (that are not shared with progeria) are the ones that are triggered by the LH rise…and all of them involve the wasting (atrophy) of tissues or cancers (my paper suggets that cancers are just failed attempts at apoptosis as apoptosis starts off using the mirtosis machinery to begine the process) …you could call it little old ladyism…Interstingly Werner’s syndrome does not kick in until pouberty when there is that big rise in LH and FSH that kicks in. You make the connection betwenn testosterone and estrogen decline allowing FSH and LH levels to skyrocket….Actually in men there is no huge decline in testosterone on average and actually estgrogen continues to increase with progesterone past age 50 in men even while FSH and LH are beginning their large increases..In men it is an ultimate drop in progesteone around age 60 or so that really corresponds to big jumps in LH and FSH…Several studies I read noted that LH and FSh synthesized by the pituitary in the absence of testoseteone and estrogen are much LARGER and Much more bioactive and have longer half lives than LH and FSh synthesized in the presence of these molecuels Makes you think doesn’t it…FSH is a whole other story and I beleive it corrpsonds to the aging symptoms seen in progeria kids and does noty include cancer or apoptosis but is more geared towards calcifications and growing little follciles in your veins and arteries…however one symptom does not fit well as progeria kids suffer from dysplatic osteporsis which seems like some sort of tissue atrophy…While Werner’s syndrome victims suffer from peripheral osteoprosis..So some how FSH is involved with one form of osteoporsis which is the one little piece of my theory that needs more work..FSH increases do not caude cancers or tissue atrophy in general..Interstingly progeria kids are sharp as a track to the day they die and NEVER get cancer… while Werner’s syndrome victims almost always suffer from neurodegeneration symptoms and almost always get many cancers..

        • 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. It is plausible that the effect of growth factors on an old body will be fairly instantaneous.

          • Thanks for your response. I had hoped that Dr. Kathcher would weigh in, but… alas! Speaking of the growth phase, I once had someone argue that growth to adulthood was NOT a program, as I was arguing, but “development”. I guess I’m just too dense to tell the difference!

          • If for a moment suppose we assume there is no aging program rather there is a repair program which has been selected, aging is a consequence of the maturity phase coming to an end and age span left after maturity is purely dependent on repair mechanisms, enhanced by exercise, diet, yoga etc. but without the growth factors, aging span cannot be indefinitely extended. For an organism growth,maturity and aging are a continuum and it can be the repair program depends on the rate of decline of the growth factors, and therefore enhancing youthful factors will maybe reverse age or enhance repair.

        • I don’t have the ‘think’ about it Wayne – Steve Horvath’s epigenetic clocks show that the age of the cells at their most intimate level (DNA methylation) are reset to young cells – everything follows from that, but as you not it takes time for some functions to rejuvenate. However, grip strength which acts specifically on muscle cells, and so occurs at the lowest (cellular) level of rejuvenation and doesn’t take time, and even inflammation starts to go down within a few days, again, it occurs at the cellular level and doesn’t take much time. However, when something needs to occur at higher levels of the hierarchy, like maze solving (which requires changes at the systemic levels) that takes more time.

          • Thank you Dr. Katcher. I noted the rapid drop in inflammation and surmised that neuromuscular inflammation might be involved. Vince has indicated in his blog that he plans to publish a video interview with you, and I am looking forward to it. Much Regard, Wayne

  6. Thank you Josh for your insightful post! I am not sure if it is me but the link to your “own work” in the paragraph “Personally, I bristle at reading …” seems not to open.

  7. Josh, differing from your asserption, I know well that there is ample evidence, already from decades ago, that (total tissue) Antioxidants do NOT show a clear pattern of change with aging in mammals, since increases, decrases, and lack of changes have been reported multitude of times by expert scientists.

    My only point (possible exception) is “Mitochondrial ” antioxidants. These have never been directly studied, neither among species nor in many other important models (like CR or age). Perhaps if that were done, at least part of the past apparent contradictions could be resolved…. As far as I know Daniel Munroe also thinks that way, and has published in Aging Cell some (couple of papers), although indirect, evidence in favor of a role for “Mitochondrial” antioxidants in Aging rate determination.

    Anyone who could do those experiments…that would be most important. I tried it, but “logistic” problems avoided me to finally obtain an answer to that. I hope someone else tries. If not, that possible most relevant mechanism will be unknown “forever”….

  8. Josh writes…”Sex hormones that change with age turn out to be even more prominent in their list. The first several involve FSH and LH. These are hormones connected with women’s ovarian cycles; but after menopause, when they are not needed, their prominence shoots up, and not just once-a-month, but always on. Men, too, show increases in LH and FSH with age, though they are more subtle. I first became aware of LH and FSH as bad actors from the writings of Jeff Bowles more than 20 years ago.”
    Thanks for the shout out….
    A sligth correction the changes in men’s LH and FSH are not more subtle…they are just as extreme if you look at it as changes in percent increase from baseline….Yes, men’s FSH and LH levels are much lower than women’s over a lifetime…but the percentgage changes after age 50 are extreme in both sexes…going up hundred to even 1,000 pdercent in BOTH sexes.

    You might want to some day add “I first became aware of DNA methylation/ epigentics being involved with controlling aging from the writings of Jeff Bowles more than 20 years ago.” HAHA
    Anyway the neat thing about the LH and FSH increase causing aging in both men and women after age 50 (also hCG increases about 500% as well in BOTH SEXES) So Harold you might need to find a way to shut the FSH and LH related proteins down….Anyway the neat thing is In children what causes puberty to start?? the rise in testosterone or estrogen?? NO the first major hormone changes are large increases in LH and FSH which causes the body to grow and develop….only later do the testosterone or estrogen increases kick in. And in kids who are approaching puberty too fast (precocious puberty) what do the docs give them?? Lupron…what does ti do? It suppresses LH and FSH to about 0. So what do LH and FSH teach us? That LH and FSH drive development growth and puberty ( a highly organzied program) and they also drive aging (another program!!). It seems development and aging are part of the same process the advancement of a life /death program…

      • Hi Bill

        you should email me at jeffsbandn@gmail.com and I will send you a free pdf copy of my book 16 Fascinating Covid-19 and Spanish Flu Mysteris Solved…Which was banned by Amazon!!! I send otu free pdf fiels to all who want it…it si a great book the health guru Bill Sardi called it”Exquisite” and said he was jealous…
        Turns out the activated form of VitaminD3 calcifediol at a d3 equivalent dose of 100,000 IUs up front then 50,000 IUS every other day…. calcefidiol is more active and 5x strogner than d3 so the doses needed are 20,000 and 10,000 to replicat ethe SPanish study where ICU admissions were reduiced by 96%!!! the contrll group of admitted patietns n=26 who got no calcifediol had 13 ICU admissions and 2 deaths..the califediol group n=50 had NO deaths and only 1 ICU admission!! it’s at the end of my book…anyway if you take D3 it takes your body a few days to convert it first to califediol then finally to the avctive form of d3 calcitriol…Trump was taking this protocll along with his other things…at 50,000 every other day

        • Hi Jeff:

          I enjoyed reading your PDF book regarding the Spanish Flu and Covid 19.

          Regarding Vitamin D3, all the pieces you presented regarding D3, in your book, fall neatly into place and make perfect sense.

          • Thanks Heather…

            you might also want to browse around my Wwbsite JeffTbowles.com it has lots of intersting blog posts 60+ and a high dose vitamn d3 1,000+ case stuidies search engine . You can look over 1,000+ self reported case studies of people who have tried to cure a disease or condition with high dose d3..

      • Yeah that might be right..it seems to me the primary purpse of the FSH andLH rise is to shut down female reproduction via inducing the menopause….and then ..the hormones seem to be determined to slowly shut off a man’s ability to reproduce starting after age 50…and the side effects of this seem to be aging and eventual death in both sexes kind of as an unintended side effect because once you are not reproducing I figure evolution really does not care what happens to you…..But if you can survive this hormonal onslaught my prior thinking awas that eventually the telomere shortening would get you at age 120…but Im not sure about that anymore now that we know more about how telomeres really work and can be lengthened at will by the genome..WHat limits us to 120 years?? Still a good question

  9. Regarding Elixer treatment, what’s incorrect about this statement?
    An 8-day rat treatment period ≈ 258 human days, and 258 / 7 ≈ 37 weeks.
    Would a human expect results by 37 weeks?

    • Depends, it might take 37 weeks or more for some aspects of ‘youthening’ to become obvious, it might even take years for others, but who really cares if you are growing younger every day? For change at the epigenomic/cellular level to travel up the biological hierarchy from cells to organ systems seems to take time, but the process can be repeated indefinitely (so far as we know) so by the second rejuvenation you’re already starting at ‘young’. (That would be every eight to ten years I believe.)

      • Are you basing relative therapeutic time on life expectancy? This seems to be a common assumption, but I can find no evidence. Why wouldn’t relative metabolic rates be a better factor?

      • Hello Dr Katcher. Could you please tell me if the sex hormones have influence on aging since delayed Menopause results in a much longer lifespan? I am trying to understand if it’s better for dogs to spay at an old age when all the hormones did their jobs or to leave intact? I am very, very interested in this dimension and would be amazingly happy if you could answer.

  10. Maximum lifespan can also be calculated from CpG density at promoter sites.
    First Adam T McLain and Christopher Faulk demonstrated that, in mammals, CpG density at around 1000 conserved gene promoters correlates with lifespan.

    Then, last year, Benjamin Mayne at al. derived a clock for all vertebrates and estimated the max. lifespan of humans at 38 years, which is not accurate but tellingly it is the estimated lifespan of our closest relative the chimpanzee. The correlation is not as strong as the existing DNAm clocks but I think it can potentially be very informative in comparative biology studies. Other interesting results are an estimated max lifespan of 268 years for Bowhead whales.

    It would appear that one way, perhaps the main way?, in which genetic max. lifespan is modulated is by simply increasing CpG sites at promoters.

    More recently, on his online talk for the “Aging Research and Drug Discovery meeting ” on Youtube, Steve Horvath commented that the levels of methylation on ONE single cytosine site strongly correlates with max. lifespan. I imagine this is likely downstream of something that on average results in less (in this case) methylation at that particular site for longer lived species. One wonders, would reverting the meth. state of that particular site have a significant effect? Probably not so simple. I haven’t found this published so I imagine it is some preliminary result.

    I think that these findings may point us in the way in which the clock functions, or at least it may explain why it can vary so much between closely related species.

    • You meant ELOVL2 (elongation of very-long-chain fatty acids-like 2) gene which encodes a transmembrane enzyme involved in elongation of long-chain polyunsaturated fatty acids? The Elovl2 CpG site may have an evolutionarily conserved role in regulating the onset of age-associated physiological changes in mammals. The age-dependent decrease of ELOVL2 expression may result in the decrease of the utilization of DHA and other polyunsaturated fatty acids, and this decrease may cause degenerative changes of the aged tissue. See: https://doi.org/10.1177/1535370220947015

      • Given that we only get polyunsaturates from the diet, and I doubt they are essential- then why would a gene that lengthens them be so important? I’d guess it must have other purposes?

  11. If Jeff is right about LH and FSH, wouldn’t it be prudent to take testosterone as a man, starting at age 50? And I’m not talking supraphysiologic levels, like all of these physique or bodybuilder types, but rather replacement to make sure you are around 700-1000. I was considering it anyway. I do not love the idea of being on an injection for a long time (or forever) or messing up the HPG axis, but I am checking testosterone levels just to see how much my workout regiments can’t overcome the aging process and T production.

    Anyone have more thoughts on this? Quality is more important to me than quantity, anyway. I don’t really give a poop, especially as a very healthy person, if I live beyond 90.

  12. It seems to me that a counter aging measure that produces immediate and dramatic results is available now. This also seems to be the opinions of the Conboy’s. It’s something of a brute force approach, but has already proven to be safe and replicates the benefits of multiple animal studies.

    The Wyss-Coray article referenced below, and the seed of this current post by Josh, indicates that: 75.84% (361) of all proteins associated with aging (529 total targeted proteins) increased expression with age while only 24.16% (115) are associated with a decreased expression. If three times as many age associated components of the proteome increase (75%) as aging progresses and (25%) decrease, It would be a reasonable conclusion that a protocol incorporating a 50% dilution of all plasma proteins, (Conboy article also below,) would result in a net positive impact on aging.

    An all or nothing approach is very unlikely to be optimal, but since the increasing proteins that correlate with aging exists in a ratio of 3 to 1 to the decreasing proteins, the approach of diminishing all proteins would have the net effect of diminishing the increasing proteins in a weighted manor that is three times more impactful than on the decreasing fraction.

    This may provide some insights into the mechanism that positively correlates from the Conboy mouse study were: “Specifically, we performed a “neutral” blood exchange (NBE) by replacing the platelet-rich-plasma (PRP), fraction with physiological saline, supplemented with 5% purified commercial (fraction V) albumin. Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenate effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice…”

    The Wyss-Coray observation combined with the TPE data from four human subjects also reported in the Conboy paper, adds emphasis to the conclusion of the Conboy’s that an effective intervention to ameliorate the detrimental effects of aging is available to older individuals now and should move forward immediately.

    “This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.”

    Data mining of human plasma proteins generates a multitude
    of highly predictive aging clocks that reflect different aspects
    of aging

    Benoit Lehallier1,2,3 | Maxim N. Shokhirev4 | Tony Wyss-Coray1,2,3,5 |
    Adiv A. Johnson6

    Abstract: We previously identified 529 proteins that had been reported by multiple different studies to change their expression level with age in human plasma. In the present study, we measured the q-value and age coefficient of these proteins in a plasma proteomic dataset derived from 4263 individuals. A bioinformatics enrichment analysis of proteins that significantly trend toward increased expression with age strongly implicated diverse inflammatory processes. A literature search revealed that at least 64 of these 529 proteins are capable of regulating life span in an animal model. Nine of these proteins (AKT2, GDF11, GDF15, GHR, NAMPT, PAPPA, PLAU, PTEN, and SHC1) significantly extend life span when manipulated in mice or fish. By performing machine-learning modeling in a plasma proteomic dataset derived from 3301 individuals, we discover an ultra-predictive aging clock comprised of 491 protein entries. The Pearson correlation for this clock was 0.98 in the learning set and 0.96 in the test set while the median absolute error was 1.84 years in the learning set and 2.44 years in the test set. Using this clock, we demonstrate that aerobic-exercised trained individuals have a younger predicted age than physically sedentary subjects. By testing clocks associated with 1565 different Reactome pathways, we also show that proteins associated with signal transduction or the immune system are especially capable of predicting human age. We additionally generate a multitude of age predictors that reflect different aspects of aging. For example, a clock comprised of proteins that regulate life span in animal models accurately predicts age.

    Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288913/

    Melod Mehdipour1, Colin Skinner1,*, Nathan Wong1,*, Michael Lieb1,*, Chao Liu1, Jessy Etienne1, Cameron Kato1, Dobri Kiprov2, Michael J. Conboy1, Irina M. Conboy1

    We replaced half of the plasma in mice with saline containing 5% albumin (terming it a “neutral” age blood exchange, NBE) thus diluting the plasma factors and replenishing the albumin that would be diminished if only saline was used.

    Abstract: Our data demonstrate that a single NBE suffices to meet or exceed the
    rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity. Comparative proteomic analysis on serum from NBE, and from a similar human clinical procedure of therapeutic plasma exchange (TPE), revealed a molecular re-setting of the systemic signaling milieu, interestingly, elevating the levels of some proteins, which broadly coordinate tissue maintenance and repair and promote immune responses. Moreover, a single TPE yielded functional blood rejuvenation, abrogating the typical old serum inhibition of progenitor cell proliferation. Ectopically added albumin does not seem to be the sole determinant of such rejuvenation, and levels of albumin do not decrease with age nor are increased by NBE/TPE. A model of action (supported by a large body of published data) is that significant dilution of autoregulatory proteins that crosstalk to multiple signaling pathways (with their own feedback loops) would, through changes in gene expression, have long-lasting molecular and functional effects that are consistent with our observations. This work improves our understanding of the systemic paradigms of multi-tissue rejuvenation and suggest a novel and immediate use of the FDA approved TPE for improving the health and resilience of older people.

    • Congratulations Josh. Let the 2021 be the year to finally found out the thing which will grow us younger. My number 1 hope is on Dr Harold Lawrence Katcher. Merry Christmas.

  13. Modern methods of influencing the human body are not rejuvenation, but an improvement in the state of tissues through chemical and physical exposure. Such influence gives little result and does not concern the control programs of the Soul. Real rejuvenation is a rearrangement of the control programs in the Soul and a return to the chosen age. Further, from the selected age, there is a restructuring of the biological body and further aging from this new point of reference. For example, the body from the age of 75 goes to the age of 20. The Soul constantly contains control programs concerning all control points of the state of the organism from birth to death.

    • So, let’s see you transform yourself into a 20-year-old. And what is this ‘soul’ you talk of – where’s your proof? Churches always talk about the soul – the ‘immortal soul’ – where there is no proof? Jesus never believed in an immortal soul, he believed in resurrection in a perfect body in a “New Heaven and a New Earth.’, so where is the ‘authority’ for a ‘soul’? The Church apparently found this idea of resurrection ridiculous, and so used Plato and later Aristotle’s definition of a soul (Aristotle’s multipart description of the ‘soul’ describes the nervous system and endocrine systems.) Having people believe in a soul, heaven and hell gave the Church complete control over people’s lives, “Don’t obey and you will be tortured for all of eternity. The medieval Church developed its own brutal tortures – I guess helping Satan really give it to non-believers.

      • I absolutely agree, Doc. When people believe in immortal souls and heaven, they do not live life to the fullest, do not help each other, kill, do not respect with the hope of next life. Or they are totally controlled by a church and inadequately irrational and incorrect intangible assets. That should change if not today, as soon as possible.

        • I am still uncertain as to Ermakov’s theories or speculations, but Leo you are sadly and wildly incorrect in saying

          “When people believe in immortal souls and heaven, they do not live life to the fullest, do not help each other, kill, do not respect with the hope of next life.”

          Everything about us is created, though we can live eternally with God (emphasis on with). That is and has always been the orthodox teaching. Mostly, the opposite of your statement is true. If people don’t believe there is anything but darwinism and ultimate death, there is no reason to not live like animals. So I am confused with your conflicting statements here, as we have examples of such far more than without religious belief – though of course that can be dangerous depending on its nature.

          HK, there are many bad explanations of God and only 1 is orthodox, that’s the point. Just like many bad explanations are present in science and your goal is to keep seeking to find the best. Correct? God Bless

          • I am not sure. I see everything but opposite to kindness and support here. We must respect every minute, every human, every animal because we may die tomorrow, due to some factors. I see that. Congrats to you if you see contrasting things in this dimension.

          • When people believe in an immortal soul, a trick most religions use to enslave people, they know that their life on Earth is at best of very limited duration, so they know as well that their afterlife (because that’s what it means to have an immortal soul or it doesn’t mean anything) will be infinitely long as compared to their lives so they do what people in the know (they tell them) say will get them a better deal in the afterlife. There are ‘Christians’ who can’t wait for the world to end, and Muslims to do their best to ensure it. Life is improving life, life’s purpose is life. Soon, biological immortality will be a thing, I promise. Okay, maybe only to double or triple your lifespan, but that will be only a start once we really nail down the principles. Jesus did not believe in an immortal soul, once you were dead and you had no soul that went anywhere. He believed in the resurrection with a New Heaven and a New Earth. He believed God would bring back all people in perfect bodies, but those not worthy of living with him and recognize and feel guilty for their sins would be burned up as seeds thrown into a hot furnace, and the rest in their ‘perfect’ bodies- and that’s what we’re beginning – man immortal in the heavens may refer to our conquest of the Galaxy. Man has a glorious future or he can love death and destruction and have no future at all. If he believes in an immortal soul, he appears to prefer death and destruction, because what does Earth matter compared to Heaven?

          • My goal is to find an explanation that works, and truthfully, crazy as it sounds it’s my ‘mission’ to do so. I found the explanation only after doing the work, though I had ideas, (many wrong). I’ve spent my life guided by a supernatural force, but since to produce real results, I can’t suppose it’s Satan, the Father of lies. Results and the tangible truth.

        • You aren’t understanding where I am coming from nor the orthodox teachings. Are there bad teachings out there? Yes absolutely. That’s the point, as I stated earlier – divisions and error must be present so that the proper teachings are approved and understood/followed, and there is therefore harmony and balance for those that follow the truth which will also be evident. It is the same in science.

          You have inverted the teachings of the gospel, which is dangerous since you understand a portion of the teachings but are in error about others (the most dangerous combination). We can continue but only if you desire. I don’t think you have any bad axe to grind and I believe you are faithful in trying to help others and figure things out, but your sources regarding truth and what the Church truly teaches (I think you rightly understand the franco roman church is in error) are lacking majorly. A hint might be my name, if you didn’t notice it. Our Holy Fathers wrote treatise that were called (in one instance) “against the Hellenists.”

          My best to everyone as always, happy new year and blessings in difficult times.

      • Dear scientists.
        I have an exceptional opportunity to receive information from the information field of the Universe. Therefore, what I am writing is the answers to my questions from this field. Errors in answers can be for various reasons, with a long clarification of a question, the number of errors decreases. Now we have received information about the structure of space, the structure of man, treatment of diseases and a lot of other information.
        The Soul is located in the right hemisphere of the brain, the Soul has the structure of the information field. The soul controls the whole body. The Creator lays the program for the Soul. The Creator places the Soul in a giving birth child on the 66th day from conception, and after that the embryo is a human. The state of the human body is divided from birth to death into 100 states of information bodies (IT). Birth is IT # 1, the end of improving the body is IT # 16, the end of the old age IT # 100. The Soul has a counter of the division of nerve cells. Cells can divide up to 100 times. The main moments of fate are written in the soul. During rejuvenation, the Creator turns on the control program in the Soul to return the biological body to position IT # 16, which is approximately 20 years of age. The accumulated deformations of the body during rejuvenation are preserved. Both aging and rejuvenation are characterized by the fact that the proportions between the number of tissue cells and the state of the cells change.
        The religion was introduced for people by representatives of Shambhala – an energy civilization who have a base on Earth in an energy field form. People will never own all the information in the cosmos.
        Respectfully yours, Ermakov

  14. It seems that some aspects of a proteomic clock could be measurements of diet via accumulation of advanced glycation end products. From https://www.mdpi.com/2076-3921/9/11/1062/htm

    “Although AGEs are irreversible adducts and cross-links in our tissues, these can be removed through different proteolytic capacities:
    The ubiquitin proteasome system – Ubiquitin is a protein that when conjugated to a protein substrate can facilitate degradation of that substrate by the proteasome. Obsolete or damaged proteins are tagged with ubiquitin and these ubiquitinated substrates are degraded by the proteasome. Operates mainly on soluble substrates.
    Autophagy – Can operate on insoluble substrates, including organelles such as mitochondria. Autophagy requires macromolecular assemblies and organelles to identify, sequester, and eventually degrade substrates via the lysosome.

    Unfortunately, the function of both proteolytic pathways declines with extensive glycative stress and upon aging in many tissues, resulting in intracellular accumulation of protein aggregates (also glycated conjugates) and dysfunctional organelles. This thwarts strategies to lower AGEs accumulation by boosting proteolytic capacities.”

  15. It can be there is an optimum level of methylation density at maturity of the organism, and the decline of the growth/repair factors perturb the methylation density at a steady rate, influenced by exercise,diet etc. Therefore introducing growth factors in the aging body can restore optimum levels of methylation density, showing up as reduction in epigenetic age.

    • This is why I wonder about maintenance levels of testosterone, for example, at age 40-50 or so. Did you have any other replacement growth factors in mind?

      I wonder what the epigenetic ages would be for men with TRT regimens as opposed to similar control experiment/aged men.

      • I don’t think testosterone is involved in the growth phase of the organism, rather it is involved in the maturity phase. we should be considering growth factors in the pre puberty phase which are attenuated due to the onset of puberty and then undergo a steady decline, which can lead to the perturbation of optimum methylation density. optimum methylation density at peak youth is optimum genomic expression, which gradually deteriorates, I would suppose due to the steady decline of growth factors.

  16. I am disappointed that nobody has responded to my question/assertion about relative therapy times. After all, if a therapy obtains optimal efficacy in a given time in mice, we would need to have a good idea of how long to wait for the same results in humans. Relative life expectancy? Relative metabolic rates? Some other parameter?

  17. I would like to suggest that the best aging clock would include both DNA methylation and histone modifications. I am constantly reminded of what happens to H3K27me3 in C. elegans upon reproductive maturity – a phenomenon that certainly seems to be causative.

  18. Do you all think that by 2025 we will have enough knowledge to at least guess, or try, particular plasmapheresis protocols along with mild supplementation with T or growth factors that will show promise?

    When would be the earliest you would try these protocols in the expectation that the cellular milieu (or Ermakov’s “soul”) might be aided in longevity or quality of life?

    • No, Palamas, that’s not how aging works, it’s not a defect it’s a programmed progressive process, a continuation of development with the body doing more to kill itself with advancing years, progressive life-states where each succeeding life-stage has a higher mortality (there are rare exceptions). Cellular aging externally controlled (cell non-autonomous), and none of those remedies that slow ‘cell aging’ (basically all antiaging medicines) can significantly extend anything but old age, rejuvenation is the only path, returning your body to early adulthood (or earlier?) and pretty much keeping it that way. Sure but if you want Bible, Abraham bemoaned the fact that he was an old man at 130 years of life, while his father was a young man at the same age, so maybe live in youthful conditon for as long as Methusalah.
      Let me just add that the early Church once Rome took it over could deal with ‘resurrection’ so they used Plato as an Authority that there was an immortal soul. What kind of authority is that, Plato knew hardly anything despite his great mind. The way the world works cannot be revealed by deep thinking, science is needed. Later Aristotle became the Church’s ‘authority’ (People south of the equator walked on their heads) – and his ‘soul’ is very much a description of the nervous and endocrine system; he though only the part capable of logic was immortal. Again, would you take Aristotle as an expert in physics? No, he was mostly totally wrong, then why would you take him as an authority on the after-life? Why?

      • The entire Bible speaks about the soul/spirit living on after physical death. At the resurrection when Jesus returns then soul and body are reunited to either eternal life with God on a renewed earth or to eternal damnation. Aging began when mankind fell in paradise and no one lived past 1000 years. After the global flood only 8 persons carried the genes forward and thereafter lifespan dwindled to what it is today. Death is still an enemy even for Christians and so we highly value life, even unborn human life. So we support efforts to mitigate the effects of a sin-filled world and the diseases of aging. Your mission of immortality in this existing world won’t and can’t happen but the science discussed on this blog is interesting nonetheless. Happy new year to all.

        • Yes, this is correct and true. Thanks Rick. In any case, Christ defeated death and his new body is a prefiguration of our transfiguration if we live in Him – he alone defeated death because he lived in accordance with life and obedience to God His Father. So, if we do as he commanded us, and his commandment is eternal life, we will live in such a manner. Notice that his actions, deeds, thoughts and virtues were all beautiful and eternal – that’s what He is. As a result, no follower of His could ever say that loving death and destruction is the path of a Christian, as you state.

          I state these things to clarify the truth about the only man who trampled down death by his own death. How could the author of Life be a victim of corruption? Thus, he was raised for all, and us with him, if we love Him and keep his commandments (repentance is one of them!). Self preservation is not one of those commandments – thought I as a physician will help others in their sufferings just as God did. Love to all.

        • Where? The Hebrew Nashuma translated as ‘soul’ means ‘breathe’. Jews didn’t, don’t believe in an immortal soul but in a resurrection, a belief that started about 200 years before Jesus. The ‘immortal soul’ came from Greek philosophers and is believed by most major religions on the planet. It is an ancient belief, but it has no evidence than the contents of the after-life vary from culture to culture. Jesus did not believe in an immortal soul but in resurrection – did you ever hear (by repute) say “I am the Resurrection and the Life?” Since there is not subjective time between death and resurrection, no time has passed for the deceased between death and resurrection (“Tomorrow you will sit…”) and everyone will be resurrected. Those bound for destruction will regret their lives and feel remorse for their sins and only they be burnt as chaff tossed into a furnance, not everlasting Hell, just oblivion. The good would live forever with perfect bodies in the heavens. Not my words, but my objective as well.

        • I’m curious as to why death would be anything but a joyous event to Christians who are about to enter a better world?

  19. This anti-aging interventions can only have temporary effects. The organism will “adapt” in time to such interventions and the antiging effects will fade.
    This is the fate of all interventions to an organism. There are only 2 possibilities: the organism will be destroyed by the intervention or the organism will adapt and the effect of intervention will fade away in time

    • This effect will fade in time because the organism will learn to evade the signals that reset its epigenetic clock? I don’t think so, but we will find out, as, with the help of Didier Corneille, we have started a study wherein we will keep giving rats elixir at regular intervals, or according to some criterion, like levels of proinflammatory enzymes, or grip strength, so long as they live. There may be a limit to the number of times rejuvenations can take place, or there may not. No one can say at this point, but we believe we can reset the epigenetic clock and the body will never learn to evade this trick – but we’ll see.

      • Harold doesn’t yet believe that all men must die. I am trying to inform him that it is not the first death that is as significant as the second one. Mercy to all.

      • Floretin has spoken before of his belief that aging cannot be reversed until certain toxins like heavy metals are removed from the body. Cadmium for example is troubling – kind of like taking out metal fillings from your teeth – is it best to leave them be, or extract them with the danger of contaminating other tissues? We can hope that a youthful body will have sufficient detox ability to overcome build up of heavy metals, for a few centuries at least.

        • Truthfully how long of a life can a (wo)man endure? My sister asked if she would still have to work if she regained her youth, of course, I replied. She wasn’t so happy about that extension. My hope is that with long lives we will begin to treat the Earth as the treasure she is and at the same time go out and conquer the galaxy. We may be the only life, and only those with very long lives are suitable for the decade and century-long journeys and those who wait for their return.

          • Harod! I don’t think those who live a long time and remain young will have to worry about working more than a decade or two…Haven’t you heard about the miracle of compound interest?

          • ” My sister asked if she would still have to work if she regained her youth, of course, I replied.”

            This depends on investments.

            SP500 index doubles in value approximately every 7 years.

            A 3% annual withdrawal rate, means it is extremely unlikely to run out, and the value of your assets will increase dramatically over time.

            At 1% annual withdrawal it is practically impossible to run out of money, unless global economy permanently collapses and civilization comes to an end.

            A really wealthy person makes more from their investments in a month than the average working person makes in a lifetime from their work.

            Compound interest really is one of the wonders of the world.

        • Heavy metal accumulation would be highly problematic to long lived apex predators like whales. Yet these manage to live for centuries without problem. Do they have additional mechanisms to deal with this?

          There are also other organisms like certain sharks that again last for centuries.

  20. https://dash.harvard.edu/bitstream/handle/1/37365788/LU-DISSERTATION-2020.pdf?sequence=1&isAllowed=y

    Yuancheng Lu’s PhD thesis. He is Sinclair’s student who published the latest OSK driven rejuvenation study. I like the thesis very much. Gives a nice concise explanation about the mechanism of aging (digital information in DNA versus analog information in epigenetics) also a nice history of the recent rejuvenation advances from Belmonte’s 2016 paper.

    • I like elements of this idea but it clearly isn’t all right. For example, epigenetic dysregulation as a result of (past) DNA damage should be random, but it ain’t. Secondly, the additional methylation is posited to occur at or near sites of repair, but this doesn’t match the findings of their more recent work. So part of the puzzle. But certainly not the whole picture.

      • I think their idea is that epigenetic maintenance factors are recruited to sites of double strand breaks thus causing slow erosion of of epigenetic information at sites where it is highly needed

  21. During the growth phase, the epigenetic clock is shown to advance at a very rapid pace. But during the intervention in an aged individual by OSK factors/young blood plasma which can be considered as growth factors, the epigenetic clock is shown to reverse rather than advance. That can be an indication that there is an optimal level of cpg density at peak maturity/youth.

  22. According to ISD (diagtor.com.ua), the human soul lives for many trillions of years. On Earth, the Soul lives from 5 to 12 cycles and leaves its biological body every time after death. After staying on Earth, a person lives in his alien civilization in accordance with his destiny forever. The fate of everyone is different and the civilizations where a person will live will be different in their development. On Earth, with rejuvenation, a person will live as long as it is written in fate. In order to prolong life, it is necessary to implement another doctrine – the doctrine of life extension. Rejuvenation and life extension depend only on the Creator.
    Please note that the lifetime on Earth depends on the structure of the consumed water. When consuming ordinary old water, a person does not live for more than 100 years; when consuming water with 44 molecules in a cluster, a person lives no more than 122 years; when consuming water with 33 molecules in a cluster, a person does not live for more than 182 years. The structure of water is one of the main reasons for the accelerated death of a living organism.
    Experiments are now being carried out with stabilized MAS malic acid, which is energized using the ISD technology. The first results show that when the grains are wetted with MAS, the growth of grain and their yield is significantly accelerated. The idea is that MAS suppresses all infection and stimulates grain growth and increases its energy output.

  23. I will tell only part of the truth. The Soul is immortal, but some Souls are destroyed by the Creator for sins. Jesus was a man of the Earth and after leaving the Earth he left for his extraterrestrial civilization of a high level of development. Twenty years ago, I met a man of extraordinarily high ability who was suggested by one of the alien civilizations to become the new resurrected Jesus. He refused, since before that he had traveled all over space for 20 years and was preparing for life, after leaving Earth, in his most advanced alien civilization, which followed the instructions of the Creator. Man will never see the Creator. The information is given to expand the knowledge of the world.

  24. We know as much as the Creator wants to give us information. We miss the opportunity to know the world through the information systems of the Creator, the Universe, God, Earth, Shambhala … Our knowledge through trial and error gives very little information. Unfortunately, many are not admitted to the top-level source of information. Reasoning at the level of trial and error does not allow us to know the higher laws and regulations of the structure of our world. Of the field structures, the information field occupies the highest level, which can direct the actions of the magnetic field, then the magnetic field can control the actions of the electric field. From this it follows that the correct thought and spoken by those who are admitted to control, governs energy fields and matter. When we change genes, we disrupt the natural course of control – from thought to matter. The Creator punishes for such actions. Most medicine goes exactly this wrong way. It will be a long time before scientists begin to understand the erroneousness of their actions in the field of genetics, but they will cause a lot of problems during this time.

    • That’s not true. We could not imagine that but one day David Sinclair told us about the molecule called NAD. Today we are able to super easily buy it’s boosters. Then we figured out Ca AKG, which significantly extended the lifespan of rats and kept them amazingly healthy during their healthspan. It’s very rational to think tomorrow, day after tomorrow or after several month Dr Katcher will tell us about the miraculous molecule which will not only slow but actually reverse the aging process. I used to study a Kabbalah and was under the same “regulations” and thoughts. That’s wrong. Do not think the creator sits somewhere in the sky and thinks what to tell us, please.

  25. Information from the Creator. The human soul is created in the cosmic place of creation of human souls. After that, the Soul is placed on planets with biological life. We live on Earth from 5 to 12 cycles. In between, the Human Soul undergoes additional training in the afterlife. God is teaching. After a person ends his life cycles, a person’s Soul is transferred to a certain alien civilization, where the person’s soul lives endlessly or is destroyed by the Creator for its sins. The purpose of man’s stay on Earth is to learn the caution of life. For training, a person on Earth is given diseases, various events, the opportunity to partially cognize the world. To accelerate education on Earth, representatives of the alien civilization Shambhala created Bibles. It will never be calm on Earth, thus human learning is accelerated.

  26. I think it will be useful and interesting for you to know the following. Of all the elements, only hydrogen has memory; the hydrogen atom has an information field structure that has 2.3 kilobytes of memory. This is similar to a person who has a Soul that controls all processes. The hydrogen atom is a part of organic molecules and the structure of these compounds is created by the command of God and the Creator through the hydrogen atom. The hydrogen information field perceives commands through the information field and transmits this impact through energy fields – a magnetic field and an electric field. Thus, the whole variety of molecular organic compounds is created.

  27. Don’t be so quick to discount motilin signalling as an important finding from the Stanford group. Ghrelin gets implicated in aging related things all the time, and it’s closely related.

Leave a Reply

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