I have promoted the idea that aging is programmed and that the program is epigenetic. Hence epigenetic age is fundamental. But what is it that imprints epigenetic age on the chromosomes and keeps it updated? Is the “methylation clock” responding to a higher authority, a separate clock which coordinates epigenetic age throughout the body? Do epigenetic clocks in different tissues talk to each other? Such questions are important not just for theoretical understanding, but also because they have two practical consequences. (1) Can we rejuvenate the body with system-wide signaling, or do we have to de-age cell-by-cell? (2) Can we be confident that if we set back the body’s methylation age the person will feel younger and live longer?
I have been reading and thinking about these questions for several weeks, and I can report no clear answers.
Is aging a cell-by-cell deterioration, or is it orchestrated at the level of the whole body and managed through signal molecules in the blood? If pressed, I think everyone would have to admit there is some of each, and differences within the community of aging biologists are about the relative importance of the former vs the latter.
One thing I think we ought to be able to agree on is that the system level, including signal molecules in the blood, makes a vastly more accessible target for anti-aging interventions. Repairing the body cell-by-cell is a daunting proposition; whereas modifying levels of signal molecules in the blood is a piece of cake, once we identify those molecules and determine their optimal youthful levels. The words “low-hanging fruit” come to mind, as well as “Pascal’s wager”.
If there are multiple, independent aging clocks, it is probable that the one that registers the oldest age is the one that can kill us, independent of the others. To make the big leaps in life extension that we are looking for, we probably will need to reset all the clocks. How much do the cell-level and system-level clocks talk to each other? How much progress can we expect to make by working at the (more accessible) system level without addressing the (more challenging) cell-level aging?
|Why is the preponderance of research devoted to aging at the cellular level? A small part of the explanation comes from scientific inertia; aging was understood in terms of increased cellular entropy for many years, whereas the paradigm of central control remained in a Russian backwater until publication of the Stanford parabiosis experiments in 2005. A larger part of the explanation has been the infusion of venture capital into aging research in the last decade. You can’t patent hormones and you can’t make money from rebalancing blood levels of the body’s native signal molecules. I believe that the profit motive has deeply corrupted aging research, as it corrupted medical research through the previous century.|
I am passionate about these issues, but I leave them aside to talk about questions of fundamental interest: Differential gene expression—epigenetics, and methylation in particular— seem able to change the body’s age state. It seems clear that gene expression is the primary way in which the age state of the body is transmitted and coordinated system-wide. But is gene expression the end of the line, the ultimate upstream aging clock? Or is there a “higher authority” that keeps track of time and programs the body’s methylation, etc accordingly? Does the epigenetic state of the body constitute an autonomous time-keeping mechanism, or is there a time-keeping reference clock, perhaps in the hypothalamus, which dictates the body’s age through secretions, and distant cells respond to these secretions by adjusting their methylation patterns?
And, if the answer is that methylation constitutes an independent clock, does that clock advance cell-by-cell independently, or does gene expression at the cell level export proteins that coordinate methylation age across the body?
I don’t have answers, but several experiments bear on these questions, and offer a nuanced outlook.
The practical question
We need measures of biological age in order to efficiently tell us when we are on the right track with an anti-aging intervention. Methylation clocks are presently the best technology we have for measuring biological age. So, can we be confident that if an intervention sets back the methylation clock that the intervention really is making a person (or animal) younger?
Reasons to think yes:
- Methylation clocks track chronological age better than any other biomarker
- Some of the difference between methylation age and chronological age is meaningful. It correlates with mortality. In other words, each of the major methylation clocks is a better predictor of life expectancy than chronological age. Remarkably, this is true even for the clock algorithms that were trained only on chronological age.
- There are theoretical reasons for believing that epigenetics is the primary driver of aging, so that methylation changes may actually be close to the causal nexus of biological age. (This conclusion is especially cogent for theorists like me who believe that aging is an evolutionary program; however, there are also prominent scientists in the field who reject programmed aging but embrace epigenetics as a primary driver of aging.)
Two things that could go wrong:
- There could be a higher authority, a centralized clock that sets up the methylation state. If this is the case, then setting back the body’s methylation age may be temporary, and the methylation state will revert to the age programmed by a central clock. (Cavadas and Cai have adduced evidence that aging signals are transmitted from the hypothalamus.)
- In the worst case, methylation changes with age could be an adaptive response when the body senses the accumulation of damage. In other words, the body changes its gene expression when damaged because it is working overtime to repair that damage. In this case, resetting methylation state to a younger age just makes the body less able to cope with the consequences of aging and actually shortens lifespan.
Evidence from parabiosis
In parabiosis, a young mouse is surgically joined to an older mouse of the same genotype. Tissues of the old mouse respond by becoming functionally younger. Since this 19th-century finding was brought to the modern scientific community, the search has been on for chemical factors in the blood that either promote aging or promote youth. [read more].
The parabiosis phenomenon and related findings in rejuvenation through blood plasma transfusions has led to a paradigm that says aging is coordinated throughout the body by signals in the blood. To the extent that single cells age, this is happening under central control, and the process can even be reversed if the cell is exposed to the right signals.
Evidence from bone marrow transplants
Bone marrow transplants are the most powerful available treatment for leukemia, and are also applied for some rarer diseases. The bone marrow comes with the epigenetic age of the donor, and thus the (white) blood cells subsequently generated by the transplanted bone marrow also carry age information. Several different studies [ref, ref, ref, ref] have found consistently that the white blood cells (and presumably the bone marrow from whence they came) retain the age signature of the donor. The donor may be younger or older than the patient. In either case, the methylation age of the patient’s white blood cells—post-op and for years afterward—remains keyed to the donor and does not correlate significantly with the patient’s age.
The lesson of parabiosis experiments was supposed to be that cell aging is not cell-autonomous, but rather a response to signals in the blood that instruct the cells what age to be. Young somatic cells could be aged rapidly in an old blood plasma environment, and — more impressively — old somatic cells could be made younger in a young environment.
Now we have a series of bone marrow transplant studies where the methylation age of the donor is the determining factor, not the patient into which the marrow was transplanted. Bone marrow contains the stem cells from which blood cells grow. Blood cells turn over every few months and they represent an accessible tissue sample which reflects the age state of the bone marrow in approximately real time.
“We found that the DNAm age of the reconstituted blood was not influenced by the recipient’s age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder.” Soraas et al (2019)
This seems on its face to contradict our paradigm from parabiosis that says cell age is not cell-autonomous, but is programmed by the environment. How can we interpret the two results together? Some possibilities…
- Maybe only differentiated somatic cells are susceptible to age programming by plasma proteins, and not stem cells.
- Maybe these stem cells are providing the biochemical environment in the plasma. Maybe the stem cells and the white blood cells that they generate are the agents that secrete the plasma proteins responsible for sending age signals.
- Please think creatively about other possibilities.
Another result from these bone marrow studies
Consistently, the blood cells get older after transplant, whether they are transplanted from young-to-old or from old-to-young. This says two things. First, the point of comparison is the donor age, i.e., the age of the cells pre-transplant, and not the age of the patient who is associated with the systemic environment. Second, the cells seem to age rapidly after transplant, as measured by the methylation age. From there, the age of the cells may (in some studies) revert slowly to their original age trajectory over a period of several years.
Why the rapid methylation aging? It seems like a good guess that the rapid aging initially comes from high rates of reproduction in these transplanted cells that are generating a whole new source of much-needed blood. Could this be a link between telomeres and methylation age (which previously were found to be inversely correlated? Or is there another mechanism by which stem cells keep track of the number of times they have divided asymmetrically?
Am I the only one asking these questions?
Already a decade ago I was thinking about the question How Does the Body Know How Old It Is? Questions about time-keeping mechanisms and coordination of age information through the body go hand-in-hand with conceptions of aging as a programmed phenomenon, and perhaps the prejudice against programmed aging helps to explain the fact that few aging researchers are thinking in this way. A welcome exception is this article by Argentine gerontologists, which I was delighted to discover just yesterday. Lehmann et al: Hierarchical Model for the Control of Epigenetic Aging.
Although there is evidence suggesting that the cellular epigenetic clock possesses an intrinsic ticking rate [ref, ref, ref] multiple observations at organismal level in humans and other mammals lead to the inference that in vivo, the ticking rate of the clock in tissues is synchronized by a master pacemaker.
Lehmann cites as prima facie evidence for this
For a given chronological age, it was found that in DNA samples taken from whole blood, peripheral blood mononuclear cells, buccal epithelium, colon, adipose, liver, lung, saliva, and uterine cervix, Horvath’s algorithm read essentially the same epigenetic age, the only exceptions being some brain regions and very few other organs.
In addition, she cites Katcher’s success in rejuvenating rats (and their diverse organs) using only a set of intravenous signals. The article goes on to propose a model in which there are four time-keepers in the body, coordinated by signals in the circulatory systems. The four are:
- Light-sensing and neural processing
- Neuroendocrine signaling (esp the suprachiasmatic Nucleus of the Hypothalamus)
- The Immune system, including thymic involution
Curiously, she does not include the replication counter implicit in telomere shortening, which Fossel, Blasco and other luminaries have adduced as the primary source of aging. I also would add that the hypothalamus is the best candidate we have, not just for one aging clock among several, but as a central, coordinating organ.
Fig. 1. Proposed organismal regulatory network in mammals. The diagram includes the autonomic nervous system (ANS, acting via neurotransmitters), the neuroendocrine system (NES, acting via blood-borne hormones), the immune system (acting via blood-borne cytokines and thymic hormones), the circadian clocks (acting via blood-borne hormones and neurotransmitters) and a putative pathway connecting the neuroendocrine network to the DNAm clock in organs and cells. All networks act on peripheral organs. Inset- Bidirectional interactions among all networks including (in red) the hypothetical DNAm network.
In addition to Lehmann, there is a 2021 review by Raj and Horvath, speculation from the horse’s mouth. They note that all the Horvath clocks are based on small differences in % of cells methylated at a given site (conventionally notated as β).
Increase in epigenetic age is contributed by changes of methylation profiles in a very small percent of cells in a population.
One way to interpret this fact (my speculation, not R&H) is that immune sensitivity, (anti-) oxidation, and inflammation are all under tight homeostasis in the body, because these are sensitive functions, balanced on a knife edge between insufficient protection and self-destruction. It is easy to tip the balance over toward self-destruction with small changes in the set point for a few signal molecules in blood plasma.
Another way to interpret this (again, my speculation) is that it is only a handful of cells at the tail end of the distribution that go over an edge into a state where they cause all the damage of aging. This hypothesis is consonant with the story about short telomeres, cell senescence, SASP, and the powerful benefit of senolytics. However, a big hole in the narrative is that it requires a set of CpG’s that would be capable of precipitously tipping the cell over into a toxic state. We know that critically short telomeres can do this, but there is no study yet of methylation-induced cell senescence. R&H speculate about such a mechanism connected with PCR=Polychrome Repressive Complex.
Raj and Horvath also stress the continuity between epigenetic changes that begin in utero, associated with development, and the changes that lead to senescence late in life. Blagosklonny as well has emphasized this point.
“Collectively, these five features of DNA methylation allow one to summarize with some degree of certainty that epigenetic ageing is a measure of change of epigenetic heterogeneity, contributed by a relatively small percentage of cells, seemingly in line with developmental processes that are conserved across species and begins very soon after conception. This seemingly inescapable deduction provides us with a reference point against which models and hypotheses can be measured.”
If I may carry the logic of these two experts one step further, I would emphasize the role that methylation has in determining what hormones and enzymes are secreted into the blood. Therein lies the possibility that intracell methylation clocks are coordinating, both with other cells and with other clocks, via signal molecules in blood plasma.
Other provocative findings that we might hope to integrate into a theory of aging
The methylomes of naked mole rats age at a normal rate, but the phenotypes of the rats themselves show no signs of age [ref]. Males and females age epigenetically in somewhat different ways [ref]. Methyl donor molecules in the diet can lead to a younger methylome, with benefits both for hyper- and hyomethylated regions (validated for MTHFR snps only) [ref]. When human fibroblasts are reprogrammed (with RNA) to turn them into neurons, they remember their Horvath age even after forgetting their identity [ref]. BMI is associated with accelerated methylation aging [ref]. Mice challenged with a high-fat diet can be brought back to normal weight with a normal diet, but accelerated methylation aging persists [ref]. Cessation of smoking decreases Hannum and Horvath DNAmAge [href]. The methylation shadow cast by years of smoking is a better predictor of subsequent morbidity and mortality than the smoking history itself [ref]. Methylation image of telomere length is a better prediction of age and mortality than is telomere length itself [ref]. Pregnancy increases Hannum Age, DNAmAge, and PhenoAge [ref].
(Apologies to Rafil Kroll-Zaiti)
Katcher has been conducting a longevity trial for rats treated with E5 (background story here). Partial results suggest that treated rats are living statistically longer than untreated, but not as much as you would expect if the greatly reduced methylation age indicated full rejuvenation. The results are preliminary, and I will publish a full analysis in this space as soon as I can get the detailed dataset.
The finding, if validated, suggests that multiple clocks in the body are not completely synchronized, and the “fastest clock wins”, meaning that it kills the animal no matter what the other clocks may say.
I am disappointed as you are in not being able to provide fundamental answers, but I hope that (together with Lehmann, Goya, Raj, and Horvath) we have provided a framework and a set of questions that can guide fundamental research. Very few other researchers are addressing these questions, and the answers will be crucial both for devising effective interventions and also for measuring the effectiveness of interventions that we already have.
Why can’t it just be as simple as compounded mutations from replication that increases over time until the effects of the mutations are so great systems stop functioning properly?
It “can” be, but it isn’t. The experiment has been done in many forms. Somatic mutations do happen, but not in quantities that contribute meaningfully to senescence.
I have even tried to tell physicians, who are woefully unaware of many things these days due to capture/system problems/laziness or social pressures (just look at the covid debacle, incidentally this is meaningful also to my post) this very point. If you have a working immune system, it will identify “cancer”/mutated cells for example, and induce them to apoptosis or clear them. The idea that you are “unlucky” to die from a mutation that just randomly happens and goes berzerk is nonsense but is typical of human thinking, which wants to attribute simple answers to things and simultaneously doesn’t want to be accountable for the result with other behaviors that might have contributed to it. For this reason, you’ll see very high mortality related to the covid experiments/injections, because it clearly hurts your body on a systemic level as well as weakens your immune system. More later, as this post by Mr. Mitteldorf was phenomenal. Well done, Josh.
Oddly enough there is a masters thesis that confirmed IL-10 as being causative of senescence.
This is through inhibiting NF kB and reducing the citrate carrier so the histone is not acetylated.
I have a theory backed up with many facts that provides a simple explanaiotn to at least part of Josh’s questions…what is the master upstream regulator of DNA methylation?
If I am correct it is quite simple…it all boils down to free radicals and antioxidants.
My 1998 paper predicted that antioxidants woudl catalyze the methylation of DNA (5mC) by altering the activity of DNA methyltransferases.- this has been proven to be true. I also predicted that free radicals would also catalyze the demethylation of DNA (5mC) by altering activity of DNA Methyltransferases,, again proven true. So basically this model can explain how the 12 genes found by Horvath that get demethylated with age – they are influenced by the Redox stage of the cell and the organism…As we age antioxidant hormones like melatonin Dhea pregnenolone progesterone all decline dramatically and free radical hormones’ like LH and FSH increase dramatically , we also start to accumulate iron which causes the cellular environment to become free radicalized even more. So the DNA methyltransferases that used to work to put methyl groups on, now take methyl groups off. This system also allows for reversibility of aging (DNA methylation) in that during caloric restriction all the free radial hormones’ are suppressed and the antioxidant hormones increase dramatically. It also explains the general global hypomethylation seen in DNA 5mc with age.
Now we get to the neat stuff… Horvath found 36 genes that get turned off with aging by being hyper methylated with age! All the 36 genes were found to be development related genes involved with maintaining a cell’s differentiation status..ie making sure a skin cell does not turn into anything else. These 36 genes make transcription factors which bind to DNA and shut down various genes in a cell that are not needed for that cell type.
Ok so thes genes are a real puzzle and I had not imagined them when I wrote my 1998 paper – they work in total reverse of everything else…these genes GAIN methylation with age as opposed to the entire genome and the 12 Horvath aging genes that lose methylation with age! What’s going on here? Well we have these backwards acting DNA methyltransferases called TET enzymes…In the presence of the antioxidant AKG (alpha keto glutarate) a major actor in the mitochondrial Krebs/citric acid cycle which makes our energy, the TET enzymes keep their associated genes DEMETHYLATED…This was crazy to me and completely contrary to my predictions in my 1998 paper- I never imagined these could exist..but they do…So like wise you could say in the presence of free radicals that TET enzymes either do not work or maybe even actively methylate the DNA of their associated genes.. In either case..when free radicals like LH and FSH replace antioxidants like AKG, the TET enzymes quit working and the 36 anti aging genes get turned off. It has also been found that TET enzymes work even better when you add the anti oxaind t Vitamn C to the mix….So does AKG control aging? Yes I think it does for the 36 genes. AKG drops dramatically with age, it goes up dramatically during caloric restriction.And recently a company Ponce De Leon Inc found that giving Ca-AKG to older human subjects reversed their DNA methylation age by 8 yerarfs over 7 months….So if my theory is correct. (which it is) .the upstream (loose) regulators of DNA methylation are both hormones, and free radical/antioxidant biochemicals/ chemicals/minerals/metals.
Jeff, I encourage you to write up your ideas in a coherent and organized format and submit a ms for peer review. Undoubtedly some of what you say will survive this process, and some of it will fall by the wayside, and we’ll all be wiser for the process.
My posts aren’t for the lazy
Oh and I have given up on publishing for science journals….if anyone wants to take a little trip through aging science and theory that ends with a pretty good understanding of how it all works…take some time and look over my blog post on aging….link below it’s long. but it is mostly updates about 30 of them…..but when you are done I expect most of you will be satisfactorily surprised and filled with that AHAA feeling… it explains it all from progeria to Werner’s syndrome to hormone changes to AKG to aging reversal with Yamanaka factors to DNA methylation to free radicals to antioxidants here is the link>>>>
keep in mind my 1998 paper on aging predicted that aging was controlled by DNA methylation and epigenetics (the first paper ever to do so) about 14 years before Rando of Stanford even started looking into it..Josh had read about it in my paper in 2000 or so but his biochem skills were weak at that time so he didnt understand it…….so it took him until about 2015? I think to write a paper about it….saying “Hey aging is controlled by DNA methylati0n and epigenetics” Had he spent a little more effort trying to understand my paper it would not have taken him 16 years to figure out what I was saying..HAHAHA..Don’t be lazy!
I was trying to get Josh to work his way through my blog post but it was like pulling teeth! I suspect he has still not read the whole thing
Regarding the all female rats lifespan study mentioned in the Bulletin we had a lower response in taming chronic inflammation versus what we saw in the all male study that preceded. I mention this because it would be interesting to see results of a lifespan study where the higher response is maintained throughout the study. If the preceding study showed 3.6 times higher response would the same be seen in life extension?
Josh’s idea that aging is programmed and controlled by epigenetic changes is fundamental to understanding aging. Everything else that has been promoted for the past 100 years under the rubric of “biology of aging” and “evolutionary theory” which claims that evolution has no role in aging has been all poppycock.
30 years ago Josh was a lone voice in the wilderness. Now the evidence supporting what Josh has always proclaims is becoming undeniable.
Let’s take a look at this from a practical viewpoint since we’re both practicing physicians.
So, Patient A has been on rapamycin and “ feels” younger.
Shorter recovery time after exercise.
Better endurance and sleep.
Fewer aches and pains.
He’s 60 and tells you that he feels like he did at 40 and people are telling him that he even looks younger.
So you check his epigenetic age and unfortunately it comes back at 60.
How much would you trust it since it contradicts everything he’s telling you?
Should he keep taking it? Stop it?
On the flip side let’s say it comes back at 40, just like he feels.
Does this mean that it’s accurate? Is he actually 20 years younger?
Can you trust it or is it just another piece of information?
These are difficult questions in real life situations.
Pragmatically and given what we know *today* I would tell Patient A to continue taking Rapamycin. Their look and feeling definitely are biological indicators of youthfulness, and perhaps the methylation clocks don’t tell the whole story. However, it also could be that their lifespan is still exactly what it was, and we have just improved their healthspan.
I believe this article is specifically looking for a cohesive story for increasing lifespan, not just healthspan. This means that interventions that “cover up” aging (address the symptoms) aren’t what we are searching for here (even though it is super useful to look for those things as well!).
Healthspan can’t really be divorced from lifespan. All of the very old patients that I’ve seen have been able to delay age related diseases until very late in life.
It’s very difficult to get to 100 in poor health and conversely great health often translates to longer life.
From our perspective, we want to know if various interventions are actually having a longevity effect or are they essentially useless. My point is that the test better correlate with how I actually feel on the intervention or I’m ignoring the test. If the test tells me I’m 25 years younger then I sure as hell better look and feel 25 years younger.
I’m an MD too, Paul, and while you’re technically right that an interesting overlap exists between what you say (healthspan/lilfespan) it’s particularly rate limiting. That is, there are plenty of people that live to historically “old ages” (80, let’s say) now that are in very poor health. 100? I agree, they likely have other things going on that made them healthier and they also kept it up. That’s almost an insignificant cohort to talk about though, since the N is so low.
My feeling is that a proof for Josh, while never being allowed due to political considerations, is that if you study the races, you’ll clearly see that what Josh is getting at is true. Have you seen Bo Jackson lately? There are certain universals in the world, and especially races that have tendency for r over k strategy of reproduction will also show you that it is programmed (since they mature earlier) that they will not have the longevity. Remember (just like in women, though this is different), earlier maturation = lower ceiling. Eurasians evolved to have the characteristics we all know they have due to a different type of evolutionary strategy. Compared to sub saharan africans, for example, they will thus be advanced less in body/physical ways but that also tends to give, for a multiplicity of reasons, greater longevity as well. I’ll just leave that topic there for now, but it’s one of the most obvious yet funny enough taboo topics in science out there.
My grandfather died at 88 and he had really bad health for decades, including obesity and open-heart surgery at 74. My three living grandfathers are all around 90, and my two grandmothers have been obese, sedentary and in terrible shape at least since I was born three decades ago.
Thanks, Alan. This tribute means a great deal to me coming from you.
It’s true that some luminaries in the field have been vocal advocates of programmed aging. Cynthia Kenyon, Valter Longo, Rafa de Cabo, Dale Bredesen. George Church and Caleb Finch have privately confided in me that they know aging is programmed, but they won’t take a public stand. Meanwhile, I’m mystified that two of the people who have discovered fundamental evidence supporting programmed aging are openly and publicly hostile to the idea — Len Hayflick and Morgan Levine.
For me, personally, it has been tremendously gratifying to see an idea that I articulated in the mid 1990s gradually edge toward the mainstream. I no longer have any doubt that it is correct, and acceptance is just a matter of time. But why should it take so long? Why is there so much inertia in the scientific community? In 1900, Max Planck tried to tell the physics community that everything in nature comes in quantized packages, E = h nu, and it took 30 years before they realized he was right.
Part of thinking creatively is looking at all evidence, as best as we know it.
Why aren’t we born old? Apparently, we start out old, and age is reset at gastrolation stage in embryonics. One could surmise that aging restarts then. After all, cell death is a part of embryo development. This is a wasteful use of resources, yet it has a purpose. I suspect that the initial methylation reset turns on a aging timer, which is used by embyonic development as part of the shaping and maturing of the embryo. A necessary and required part generating the next generation of sexually reproducing adults. Note that there are still parts to be deleted of the physiology all the way up to adulthood. (Neural pruning, immune system development, tissue growth, thymus regression, ect.) Is this long term cascade triggered by the initial de-methylation in the early embryonic stage, and the reset follows as a series of triggered aging acts? Think of it as a string of firecrackers, each stage triggering the next stage, (some in series and some parallel), and on and on until you reach the dead organism stage.
Could this be interrupted? Yes, possibly, rolled back? That depends, we don’t know. Some aspect obviously can, but how much does that slow the continuing process? Shrug.
But there are rare sports in humans that may hold clues. First, there are a very few (maybe 1 to 2 a year – worldwide) cases of abnormal aging of young children. They grow old and die (of old ages and its related diseases) before they are 20. What s going on in their blood? Would something like E5 have any effect, ever if fleeting, for such a person?
On the other hand, there are babies that don’t seem to develop much, and grow at a vastly slower rate. They, too, don’t live that long, usually dead by 30, and suffering from all sorts of birth defects. What would their methylation rates look like? What might be missing in their blood proteins?
Just some out-of-the-box thinking.
I fully embrace the idea that the epigenetic changes we call “aging” are continuous with those we call “development”, but I hesitate to interpret this as “aging begins in the womb”.
I encourage you to look at the unique and original work of Michael Levin to understand how bodies are shaped during development.
Josh, how should we interpret the findings of the field of Developmental Origins of Health and Disease tracing virtually every adult disorder to the prenatal stage? This is sometimes explained as “scarring” which might indicate traumatic injuries rather than aging. On the other hand infants are sometimes found to be born with epigenetic and telomeric indicators of being already in a course of accelerated biological aging….or both might be true
To clarify, DOHaD doesn’t say all disorders start prenatally, only raises the risk, and disorders can certainly have causes at any point later in life
This is a field I’m unfamiliar with.
DOHaD is simply the name given to all the research stimulated by the “thrifty phenotype” proposal of Hales & Barker (1992). Type 2 (non-insulin-dependent) diabetes mellitus: The thrifty phenotype hypothesis. Diabetologia, 35(7), 595–601.
Hypothesis: low nutrient levels in womb signal fetus that external environment is likely to also be nutrient-poor, leading the fetus to reduce its birth weight and tune its energy-relevant systems to extract as much energy as possible from whatever food is available. But if calories turn out to be readily available, this phenotype tends to poorly manage energy balance and suffer from metabolic and cardiovascular disorders later in life. Early evidence was claimed based on people born during the Dutch famine of World War II.
There’s now an international DOHaD Society and many national ones!
You’ve actually probably seen and even cited quite a few “DOHaD” articles because epigenetic clocks and telomeres are VERY commonly used, by being on prenatal and childhood stages they can be considered as “DOHaD” although not using that term in the text
Josh this is a great validation from someone like Dr. Alan Green who actually has done something about aging in so many patients versus many famous scientists who have more press interviews then interventions.
It would seem to me that any clocking mechanism theories would need to be applicable to growth and development. Surely, we don’t suddenly switch control and clocking mechanisms when we become adults. The developing fetus knows what needs to be created and when – I suspect before a hypothalamus even exists.
When an aging theory also explains development, I’ll really sit up and take notice.
Hello there Wayne….
Here is something you might take notice of….there are two hormones that they call reproduction hormones but they are actually development/reproduction/ and aging hormones they control all 3 functions the most well know of these are luteinizing hormone and the other is follicle stimulating hormone. If you loo k at the level of these hormones in a developing fetus, you will see they are very highi as he fetus develops into and infant…they then subside a bit and then increase a gain to drive the development of the infant into a prepubescent child. At around age 10 or 11 there is another surge which then drives the development program to cause the child to enter puberty and develop into a sexually mature adult. The FSH and LH in women then dramatically cycle on a monthly basis from her teenage years to menopause, controlling the function of reproduction. Finalyl around age 50 in both men and women, LH and FSh surge to dramatically new heights increasing 500 to 1000% which then drives the development program to cause aging and death. A picture is worth 1,000 words just go to google and search lifetime LH FSH levels then search images you should see some interesting graphs/charts…
And what drives/controls these changes?
that’s a good question we might gain some insight by figuring out what causes the surge of testosterone and estrogen during puberty
probably methylation hahaha a chicken and egg problem
What causes overweight individuals to hit puberty earlier. Do hormones drive development or does development drives hormones.
Good question I do remember seeing a study once where they noted that fat on the buttocks tends to cause excess estrogen generation in women while fat on the abdomen causes excess cortisol to be produced….
Then there are revolutionary considerations. If a girl is fat..evolution figures food is in abundance and it is ok to have children no danger of starvation of the chiild and the mother…when food is scarce best to postpone reproduction….if women get too skinny they stop menstruating and cannot get pregnant..
More hormone triva when people are starving their melatonin levels go way up…And you can use melatonin as birth control they did it in europe 75mg a night and the women could not get pregnant
It’s all quite up in the air with many factors to consider, such as phthalates, which are considered endocrine disrupters and proposed as a factor in the secular trend towards both obesity and early menarche…..yet this recent LONGITUDINAL study suggests delayed menarche in some circumstances:
Associations between Prenatal Exposure to Phthalates and Timing of Menarche and Growth and Adiposity into Adulthood: A Twenty-Years Birth Cohort Study
“Weak positive associations between some of the high molecular weight phthalate metabolites and height z-score were detected during childhood. While still within the normal range, age at menarche was slightly delayed in girls with higher prenatal exposure to the higher molecular weight phthalate metabolites. We derived some associations between prenatal phthalate exposure with early growth patterns and age at menarche.”
If and it’s a big one, aging is a continuation of the development program, you would then have your answer that meets your criteria. It is a thesis that has been put forward many times. TBD Michael
Early stage development, from a zygote to a mass of stem cells to a fetus, is indeed wonderful and mysterious. Michael Levin is addressing one aspect of this problem. But as you say, there must be a timekeeping mechanism in these cells, as well as an environment-sensing mechanism. My guess is that this is an even more difficult problem than aging.
My guess is that it is the same problem.
Maybe you’re right.
It occurs to me that perhaps the time keeper is simply molecular chemistry. Without getting into the metaphysics of time, it takes a finite amount of it to transcribe some DNA, get it into the cytoplasm, make a protein or interact in some manner, send more transcription information to the nucleus, etc. What happens next must depend on what else is happening. The rules cannot be that different from a computer program (if this, then this).
My current, subject to change, opinion is that both the “aging is damage” and “aging is programmed” folks are correct. Aging is the programmed loss of repair.
I am with the idea of molecular chemistry. As the senescent burden increases more cells become senescent and the level of cytosolic citrate (which varies from cell to cell anyway) is reduced.
Hence we have a reinforcing system of aging which underpins the Gompertz formula.
Methylation patterns arrive from the level of acetylation and the implied energy level of the cell (the average concentration of cytosolic citrate)
Yes, but I think Josh’s point would be that at all the stages, you could theoretically have repaired until the programming says (this was essentially predetermined, thus “programmed”) no, it’s time. I think the conundrum we really have is small buffer zone of time where this is essentially the case but with the same person living 1000 different lives (humor me) the date of death would differ between many months or around a year. That’s probably why people suggest that doing the “right things” (quality is more important if you do age) is smart, rather than it making you actually live longer. If people totally abuse themselves, it seems that they can overwhelm the normal “programming” which is why people get sidetracked and distracted since those are not really the people that we are concerned about regarding doing smart things to increase health/lifespan.
FYI there is another timekeeper besides the telomeres …way back in the 1980’s or 1990’s a scientist by the name of Al Mazin found that total amount of DNA methylation in a cell’s genome was just as accurate a predictor of the Hayflick limit as the length of the telomeres.
Well this little fact might be useful for your thinking about development and methylation/aging..
When an ovum is fertilized the entire genome is demethylated and then fully remethylated again… As the egg divides into cells and cells divide into more cells the amount of DNA methylation in the nucleii decreases dramatically on each division…..but after awhile the demethylation slows down to a more stable rate over the life time of the individual
With the multiplicity of functions performed by mTOR is becomes a good candidate for this function Josh.
 mTOR signaling regulates central and peripheral circadian clock function
Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN).
Our finding that mTOR regulates clock function in multiple peripheral cell/tissue models (U2OS, MMH-D3, 3T3-L1, and the liver) suggested a ubiquitous modifier role and raised the possibility that mTOR also regulates the central SCN clock function. Leveraging the mTOR inhibitors, we show that treatment of Per2Luc SCN explants with rapamycin significantly lengthened the period length (Fig 5A). Similar to the inhibitory effect of rapamycin, PP242 also caused similar period lengthening effect in SCN explants and markedly decreased the amplitude (Fig 5B). Prompted by these observations, we asked whether genetic perturbation of mTor can alter the SCN clock. To this end, we show that SCN explants of mTorheterozygous mTorflx/–;Per2Luc mice have significantly longer period lengths and lower amplitudes, compared to mTorflx/flx;Per2Luc controls (Fig 5C). Taken together, our data suggest that mTOR functions not only in peripheral clock models but also in the central SCN clock.
Michael, I am sure you will be interested then in our first comparative work on mTOIR ever done: Mota-Martorell et al. “Gene expression and regulatory factors of the mechanistic
target of rapamycin (mTOR) complex 1 predict mammalian longevity”. GeroscienceGeroScience (2020) 42:1157–1173.https://doi.org/10.1007/s11357-020-00210-3
If you do not have access, ask it from me (email@example.com)
A possible aging timer?
I wonder what place you see for mitochondria, targeted in many aging theories? I only have rudimentary understanding of them, but read Nick Lane’s (2006) Power, Sex, Suicide: Mitochondria and the Meaning of Life. Here’s how I tried to summarize it:
Lane (2006) proposed a universal theory of aging across eukaryotes based on the inevitable increase in mitochondria dysfunction over time. He argued that the once-favored view that ROS causes senescence by damaging numerous cell components must be wrong, given pervasive research failures to extend lifespan with antioxidants. He suggested that the responsible electrons, leaking from mitochondrial respiration chains, are so reactive as to be highly unlikely to make it out of a mitochondrion, but instead have their effect locally by causing mutations in the small number of mitochondrial genes (mtDNA), at much higher rates than for genes in the cell nucleus. Within individuals, there is much diversity across mitochondria lineages and constant culling, in part through damage detection mechanisms that induce mitophagy (degradation and recycling of damaged mitochondria) which, if affecting a high enough proportion of mitochondria, induces their cells to also self-destruct through apoptosis. Over time, the proportion of mitochondria with mtDNA damage inevitably reaches levels that reduce respiratory efficiency and also degrade tissue functioning due to increased rates of cell apoptosis and senescence. Species-specific paces of aging are related to metabolic rates because faster metabolisms leak reactive electrons at faster rates than slower metabolisms. According to Lane (2006, 2011), this inherent constraint is a universal cause of aging for eukaryotes, having been present since their origin from “immortal” prokaryotes and subsequent evolution into multicellularity. The great diversity of eukaryotes stems from the potential to scale up mitochondria numbers as needed to power different cell types that are far larger than prokaryotes, which are limited in size due to lack of scalable energy generators such as mitochondria and chloroplasts. While the longer lifespans of birds and bats compared to similarly sized land mammals is commonly explained as their ability to fly away from extrinsic mortality threats, Lane (2006) traced it instead to their having more mitochondria with greater density of respiration chains to meet flight’s increased need for aerobic capacity. This enables longer lifespans through greater reserve capacity and more efficient mitochondrial quality control. Lane (2011) stressed that central to quality control is ensuring a sufficient functional match between mtDNA and genomic DNA, the lack of which can induce mitoptosis potentially leading to cellular apoptosis with long-term negative health impacts.
I later listened to an audiobook version released in 2019 that I figured would provide insightful updates, but in the intro he said he saw no reason in all the research since 2006 to change his views. Other authors have described mitochondria as being central to aging through apparently being at the center of within-cell and across-cell responses to stress.
P.S. The Lane (2011) reference is: Mitonuclear match: Optimizing fitness and fertility over generations drives ageing within generations. Bioessays, 33(11), 860-869.
What is interesting about mitochondrial control of aging is that the mitochondria rely on the Krebs/citric acid cycle to generate energy. Among the may substrates and chemicals involved in the whole reaction are NAD+ and AKG both of which decline dramatically with age and drive the aging process. Possibly the Krebs/citric acid cycle is the original primordial aging system that controls subsequently evolved aging systems.
I wrote a three-part review of Nick Lane’s work seven years ago (one, two, three). He is an original thinker who combines a detailed knowledge of biochemistry with the courage to address the biggest questions in an integrated way.
Personally, I haven’t been able to put together a story of aging based on mitochondria. On the positive side, mitochondria are the assassins of the cell during apoptosis. But on the negative side, they have lifetimes much shorter than the lifetime of organisms or even cells, and their reproduction and purging seems to be organized at a level that takes orders from the cytoplasm. I don’t see them as autonomous.
According to informational space diagnostics of ICD, the main drawback of modern theories of aging is that they are based on the analysis of the biological components of the body. ICD on many examples established that a person consists of a biological body, a mental body, an etheric body and a Soul. The soul consists of a set of a huge number of control programs. In the Consciousness and Subconsciousness of the Soul there are 7 Centers of control programs that determine all the information of a person. Human cells are a link in the execution of commands of control programs. The information network in the biological body is a nervous system that transmits information between the Soul and all other human cells. As long as scientists do not recognize the Soul as the main information component of a person, there will be no sense from any far-fetched reasoning. The sooner this happens, the sooner there will be some achievements in the assessment of old age and the process of rejuvenation. The structure of DNA and genes is determined by the control programs in the Soul.
What would you consider your definition of aging at that juncture? Is it the total dissertation provided here or is there a distilled version? I ask because mine now appears a little overly simplistic? Thanks, Michael
Great article, Josh. It’s moving to read this amazing article, and to remember that some months ago, because of the accident, we almost lost the opportunity to count with your invaluable contribution in our fight for life, which is what, deep down, the efforts to understand aging and implement an eventual human rejuvenation technology mean. You bring to the public sphere a very important scientific discussion, and your role in that has been unique.
Hi, Nick – Yes, I’m back on my feet, bicycling and swimming as I always did, going up and down stairs still with difficulty I didn’t used to have, and hiking in the woods somewhat more slowly and with less surefooted confidence than I used to have. No running at all at this point.
I am grateful for the doctors who re-assembled my pelvis and pieced my legs back together. I’m even more grateful for this body that continues to grow stronger and more flexible 11 months after my bicycle was slammed by a truck. And I notice that in some important ways my life is better than it was before my date with destiny. I am more confident and daring, less haunted by depression, happily reunited with my girlfriend, and I carry a sense of mission in my work that was tenuous before.
It’s great to hear that, Josh. Your case in an example to show that our fight for life with science isn’t in vain, as your recovery was only allowed by the scientific advances achieved in the last centuries, so it proves that we are in the right track — now we only need to advance more, and mastering the aging process to save even more lives.
Next thing I know, I’m looking at the sky
My bicycle in pieces far away
Flesh torn, the blood is streaming from my thigh
Atypically, my mind begins to pray.
Forgotten are all thoughts of speeding truck
No pain, no anxious worry in my head
No trace of irony, I praise my luck:
“Now I can know what it’s like to be dead”
No sooner does this thought articulate,
I think of “miles to go before I sleep”
As sure as life itself, it is my fate
To climb along this path, however steep
The coming times will offer difficult
New challenges, occasions to exult.
Beautiful poem! So I suppose we can call you biologist/poet? In that case, I accept to be called journalist/football player, since as soon as rejuvenation comes, I will re-start my football player career and participate in a football World Cup. After all, it’s for enjoying life — the arts, sports and other pleasant activities — that we are doing this, right? And who knows what abilities we could develop or dedicate ourselves if we had more time?
The energy status of the cell which is affected by the citrate carrier drives acetylation and methylation of the histone. The key cytokine for his IMO is Interleukin-10 which is part of SASP.
This is how you get patches of baldness and senescence etc as the cytokine travels most easily to the nearest cells.
Bone marrow transplants:
“The methylation age of the patient’s white blood cells—post-op and for years afterward—remains keyed to the donor.”
What about the epigenetic age of other tissues in these patients? If other tissues also show a (somewhat) younger age (when the donor was younger), it could mean the younger white blood cells rejuvenated the other tissues.
Yes – this is an experiment that hasn’t been done, and it would provide an important insight. (I think the reason it hasn’t been done is that we have historic blood samples from marrow transplant patients in the past, but we don’t have biopsies of other organs.)
So many more useful experiments to be done. We are just exploring the tip of a new continent. So much more to be learned. Just a couple:
What happens to net lifespan (in rats) of giveing E5 to a young rat, on a continuing basis? What effect on health and reproduction?
What happens (once again in a rat) with a age mismatched bone marrow transplant when given E5? Some tissues show de-methylation and some don’t? Or all show de-methylation?
So much more to learn. . .
I am experimenting with the rejuvenation of my body and three other people with the help of the IDO informational rejuvenation doctrine. The experiment lasted 5.5 years and will continue for almost a year before it ends. With the help of informational space diagnostics of the ICD, I determine the relevant parameters of the state of the body. This information will be of interest to you.
To date, 5.5 years of the experiment (before the experiment, my age was 70 years old, and now 75.5 years old). The biological age of nerve cells and their DNA for all physiological systems, except for skin, hair and teeth, is 20 years. The biological age of all other body cells and their DNA is 20 years. The biological age of the nerve cells of the skin, hair and teeth and their DNA is 75 years. According to the rejuvenation plan, all cells and DNA will decrease to the biological age of 16 years by the end of rejuvenation. The end age of rejuvenation at 16 years is ordered in the information doctrine of rejuvenation. The rejuvenation program is located in the program center of the Self of my Soul and is controlled only by the Creator, but taking into account my request. All human information is in the Soul and this is the main position of the human structure. A person consists of a biological body, a mental (magnetic) body, an ethereal (electrical) body and a Soul, which is the structure of the information field. A very limited number of people have access to the information field. This is information from the Creator.
Is ‘epidemic age’ a freudian typo (second row)?
Thank you — fixed. It wasn’t an autocorrect error, so I have to blame my subconscious, as you suggest.
Recent parabiosis papers show that individual cell types including the blood stem cells respond to young plasma. if all the cell types in the body respond to young plasma, then aging is activated right from the beginning of development in my opinion. The differentiated cells have an intrinsic methylation aging clock. As development progresses the mass of differentiated cells increase vis a vis stem cells, which then collectively influence the plasma and the plasma holds the epigenetic age of the organism. It is the ratio of stem cells vs the differentiated cells which decides the aging rate.
Perhaps the thymus limited the E5 test lifespan
This could be the case.
A good way to test this would be to use the E5 therapy and the Thymus Regrowth therapy with HGH , DHEA and metformin in the same experiment.
I have been wondering about this same subject for a long time.
I am convinced that aging is programmed into us as species selection as many in this community now believe.
It is clear to me there is more to the story then just the epigenome.
Originally I thought even if the epigenetic changes are down stream, if you do an intervention and measure your epigenome then you know that intervention has worked, unfortunately with the E5 experiment it is evident that there is more to the story as they did reverse their epigentic age which made them more youthful (this is great) but this did not translate into the cessation of aging as I had hoped for.
I was hopeful that all we needed to do was use an intervention to change our epigenome back to a more youthful time and be perpetually young again alas this is not the case.
We probably need to study the super long lived species the ones that have negligeble sensense and see what the difference is.
If we could crack the code of negligeble sensense I think that would be a great step forward.
With each new breakthrough we get closer and closer to the holy grail of perpetual life.
Thanks for the deeply insightful post, Josh, it made me do a lot of thinking and some research that led to a few thoughts/questions. I also invite everyone else to answer them. Bear in mind that I’m not a biologist at all, so may well be saying complete nonsense.
First, a couple of questions related to Katcher’s experiment:
1) Was the epigenetic age of the treated rats measured recently? If so how far was it from their chronological age?
2) Do we know what treated rats die from? Even naked mole rats die in captivity despite the fact that they don’t seem to age significantly. Are we sure that the 3 treated rats that have died died because of aging?
3) Do we know anything about E5’s impact on the rats’ thymuses?
Now, to some findings and the questions that they inspired.
1) Thymic involution seems to be caused by a massive, continuous decrease in expression of just one gene, FOXN1 probably caused by hypermethylation.
As far as I understood from the Raj & Horvath paper you cite, epiginetic aging arises from only a small subset of cells (most probably stem cells). How do hugely impactful epigenetic changes that only concern single genes in somatic cells fit into the picture? Could these be the real drivers of aging?
2) It was recently found that there is no transcriptomic change in the skin of naked mole rats with age.
How can this be given that NMR undergo epigenetic aging? Do other elements of their epigenome perhaps protect their cells from the effects in methylation pattern changes? There seems to be evidence that their epigenome is resistant https://www.cell.com/stem-cell-reports/pdfExtended/S2213-6711(17)30433-2
Or is it because epigenetic clock-measured changes only relate to a small subset of cells?
3) NMR seem to have little impairment in T cell generation despite thymic involution.
Could this be why they do not age? Then, it would seem that if one clock (assumming T cell depletion is a clock) Or could the putative T-cell depletion clock be a more important clock than the epigenetic one? Could the potential master clock reset the epigenetic clock if it sensed that the T-cell-based one shows a lower age but not vice versa?
This is an important piece of the puzzle. The thymus does “decay” from at least neonatal period on to death. Furthermore, this seems to be driven by epigentic methylation of the FOXN1 DNA in the relevant thymus cells. The paper points out the skin cells (which are continually produced throughout the life span) does not show the heavy methylation of the thymus tissue.
What this may mean:
E5 de-methylates DNA to a certain extent. It does not totally de-methylate, as it does not cause the embryonic tetromas a complete de-methylation would cause. The E5 level of de-methylation may be adequate for rejuvinating many tissues, as seem in the experiments to date, but it may not be adequate for some tissues, such as the thymus. Such tissues probably lead to organism death over time, as each tissue fails.
Consider the 115 year “barrier”. The few who reach that age all tend to die around that age. We don’t know why; clinicians speak of non-specific immune system failure. The same thing may be happening with the E5 test, ageing is pushed out, then the animals seem to just die. (Yes, this is guesswork until the autopsies are performed, I can easily be changes with more data.) I do not say that only the thymus has this situation, there may be other tissues with similar limits. A 40year old’s thymus may not e any more “effective” than an 80 year old’s. (A 10 year old’s may be a totally different issue.)
Can this be solved? Shrug. We will see.
Perhaps that’s why BHT was so successful.
Denham Harman in
1968 published a study showing that BHT fed over a lifetime to mice produced a 45% increase in life span.
Harman, D (1972). “A biologic clock: the mitochondria?”. JOURNAL OF THE AMERICAN GERIATRICS SOCIETY 20 (4): 145-147. PMID 5016631.
BHT increases ESR transferrin and ceruloplasmin signals in the blood. Also significant BHT-induced changes in the plasma concentrations of ACTH, 11-OHCS, TSH and T3 hormones:
NIH recently found that
BHT increases ROS in mitochondria. Amazing because it was expected to do the opposite.
Dear Tom Blalock,
I reviewed the subject in Biological Reviews Biol. Rev. (2004), 79, pp. 235–251. f Cambridge Philosophical Society 235 DOI: 10.1017/S1464793103006213
In table 2 I summarized all the experiments feeding antioxidants to rats and mice up to that date which I could find. Look at table 2. It is evident from the Table that there is no increase in MAXIMUM longevity feeding up to 14 different natural or artificial low molecular weight CYTOSOLIC! antioxidants or their combinations in 2-4 given simultaneously for the whole life of the animals. For BHT Clapp et al J. Gerontol. (1979) found 22% increase in MEAN lsp with no change in MAXIMUM lsp (the one that matters for aging), and Harman J. Gerontol. (1968) found 31% increase in MEAN and again mo change in MAXIMUM lsp.
Afterwards, using transgenics overexpressing CYTOSOLIC antioxidant enzymes no increase in maximum lsp was ever observed as predicted by us one decade before (our most highly censored paper: 4 journals, 4 years: finally published after 2 years thinking about it in Perez-Campo et al, J. Comp. Physiol. (1998), initially written in 1994 for the Hawaii Conference on ROS and aging to which I was invited by the organizers (Lester Packer, Richard Cutler, and Akitani Mori-local organizer) a Review of data from all the 5 labs. that had measured antioxidants total cell in different species including us (27 correlations of TOTAL TISSUE antioxidants vs. species longevity, of which 21 were significantly negative correlations with longevity, 6 resulted in no significance, and not a single case of positive correlation with longevity).
But LOOK OUT! IN THE ONLY EXPERIMENT EVER PERFORMED IN HISTORY OF SCIENCE IN WHICH when catalase was overexpressed INSIDE MITOCHONDRIA: mouse MAXIMUM longevity did SIGNIFICANTLY increase [Schriner et al…George Martin….Peter Rabinovitch Science (2005)] whereas, in the same paper, when catalase was overexpressed in the peroxisomes or the nuclei of mice, maximum longevity did not increase!
After all this and a couple of dirty OR flawed papers by Rochelle Buffenstein in Naked mole rats using almost only highly unspecific unreliable techniques 8LIKE KITS OR TBARS…) in naked mole rates (AND unknown if THEY USED queens or workers, MOST LIKELY THE SHORTER LIVED WORKERS because it would be most difficult to have 8 or much more queens pooled to sample initial homogenates..) curiously published paired together in the same number of Aging Cell by the then Editor in Chief madame Cuervo, MFRTA was discarded as wrong in USA, an absolutely wrong decision on my opinion….It is simply impossible that mitochondria are not involved in aging among other resons in this comment, because mitochondria are 50% of cells by metabolism…
But the time passed and:
Now we know that INSIDE MITOCHONDRIA:
(1) MitROS PRODUCTION IS SMALLER in long- than in short-lived animal species
(2) MitDNA BASE EXCISION REPAIR (BER) IS HIGHER (first time seen! in the nucleus it is lower in long-lived species ! see Vilhelm Group Stuart et al papers in 2010 and 2011) ; and
(3) MOST LIKELY (WE HAVE VARIOUS DIRECT AND INDIRECT EVIDENCES ABOUT IT ALREADY) MITOCHONDRIAL ANTIOXIDANTS ARE ALSO HIGHER;..the 3 .. IN LONG-LIVED SPECIES COMPARED TO SHORT-LIVED ONES. (mtDNA oxidative damage, not nuclear DNA is less oxidatively damaged in long-lived species, Herrero and Barja, FASEB J. 2000) .
Those three factors work together to decrease mitochondrial oxidative stress in long-lived animals. And the differences quantitatively we find fit well: 2,5 fole less mitROSp in long lived, 1,4 fold more active mitBER in long-lived, and 1,4fold more? mitochondrial antioxidants in long-lived species makes: 2,5 x 1,4 x 1,4 = around 5 fold increase for species with a difference in longevity of 13 fold (from mouse to horse). % fold higher longevity, if someones does this triple experiment would be the largest increase in longevity ever seen: 5 fold compared to the best increase in longevity ever obtained in well done experiments in mammals until now after one century of research: CR 1,4 fold increase “only”, most curiously just the same as single gene mutant long-lived mice :1,4 fold increase in maximum longevity.
This makes sense to me (5 fold not 13 fold) since other aging affectors apart from mitochondria contribute to determine the final longevity: autophagy, apoptosis, Double Bond Index (DBI) of membrane fatty acids, proteostasis? part of inflammaging (since part of it at least is secondary due to presence of mtDNA fragments cut by mitROS through DSBs not only in all chromosome arms inserted near genes, but also inside circulating blood to loosely helping to control whole organism aging since they are part of the DAMPS, like wt mtDNA, causing inflammaging. (for almost all this please see Barja Towards a Unified Theory of Aging Exper. Gerontol. 2019).
June 28, 3:38 am
I forgot to say that if you do not have access to any of the papers cited in my comment from 1 min ago, please do not hesitate in asking it from me at firstname.lastname@example.org
I have always wondered with NMR experiments to what extent they encounter the hypoxia that they encounter in their natural environment. HIF is generally a healthy transcription factor.
Maybe one of the ways to find the Master Timekeeper would be to find all the body processes, cells, etc that are dependent or connected to the SAME gland, organ, body function,,blood marrow, blood signals or nervous system by direct or indirect
connection. This SAME _____?? could be the Master Timekeeper.
Obviously this would be a daunting task but maybe biologists of the human body have ways to do this?
Josh, thanks for your excellent post on methylation and aging clocks.
At the end of your post, just before the “Conclusions” you state: ” ….suggests that multiple clocks in the body are not completely synchronized, and the “fastest clock wins”, meaning that it kills the animal no matter what the other clocks may say.”.
But if this were true, then the non-PA argument against a single master clock would be valid, because INDIVIDUAL selection would eliminate such “fastest clock”, because it would strongly decrease the fitness of the individual.
In fact the escape to this problem by PA proponents has allways been that there are more than one intermediate level msster clocks. This is analogois to my postulation of various intermediate hierarchical level Master genes instead of a sungle MASTER GENE inside the cell nuclus Aging Program (Barjs, Biogerontology,2008, 2019), to avoid this classucal problem of individual selecton eliminatin a SINGLE master clock in the body and a sungle Master gene in the Cell Nuclear Aging Program.
Multiple Mastter clocks or genes could be a way out of this neo-Dsrwinistic classic criticism on PA. What do you think og this relevant problem?
I have an annual Portulaca Oleracea in the pot (still 2 out of 3, the third flowered and produced seed bags before I noticed early in spring) growing the second season. I just cut the shoots before they start flowering. It’s just one of the many examples of species that naturally die long before they could have lived long after. So the master program is the main obstacle to longer living for now. Methylation is the result of this program (which is controlling dropping level of AKG, epithalon, GHK-Cu and unknown number of other still unknown factors, which in turn manifest as methylation aging), not the driving factor, but it may be useful indicator of this program and maybe just maybe interventions on it. But beyond this there are factors of pure deterioration, like AGEs and lipofuscin and other factors that the body don’t know how to fix. Both programmed aging and demage repair (after controlling master program they will be more evident) must be mastered before radical life extension will take place.
Hi there-YES the flowering and “going to seed” of annual plants is an excellent example of what is controlling at least one aspect of aging (I believe there are 2 major aging systems 1. sex/reproduction related (seen at an accelerated rate in humans in Werner’s Syndrome which kicks in at puberty) 2. somatic (seen at an accelerated rate in the rapid aging disease of progeria which kicks in at infancy) I have not researched this but I would suspect that the hormones that cause the annual plant to develop from a seed into a plant and then to flower and then die are all the same hormones- the development/reproduction/aging hormones (at least that’s seems to be how it works in humans with LH and FSH). So if plants are aging in the same manner as humans, different levels of the same hormones cause different stages of development reproduction and death. If you pinch off the flowers of an annual plant before they make seeds the plant can live a much longer and healthier. In fact in the American Colonies tobacco growers were required by law to remove any and all buds to prevent flowering of tobacco that was to be sold for consumption. Similarly if you castrate a pacific salmon it can live 7 years+ instead of rapidly dying at age 3. Reports of Korean Eunuchs (serving in the ancient king’s court) suggest castration may allow males to live 15 years longer on average than intact males . I expect in flowering plants, that the flowers and seeds themselves are cranking out much higher levels of the development/reproduction/aging hormones. And if changes in DNA methylation are the ultimate cause of aging and death- then we may have identified the upstream regulators as hormones.
>”flowers and seeds themselves are cranking out much higher levels of the development/reproduction/aging hormones”
Or the production of seeds are using up resources that cannot be replenished.
I wonder if the dwindling sex drive in aging males is a kind of self preservation
to not burn up much needed resources and prolong homeostasis.
HAHA that’s kind of a version of Kirkwood’s disposable soma theory that so much resources and effort go into reproduction that the soma (body is an afterthought) and can be disposed of….maybe it’s a path and reproduction strategy that the plant choose in its evolutionary path.. but that sure is a huge sacrifice of your genetic contribution to the gene pool as compared to being able to continue to reproduce every year which we know is possible when you look at the existence of annuals. I suspect that there is some sort of evolutionary advantage that the plant dying has and that is why its death is programmed. For example in the case of bamboo trees they live a long time but trees of the same species all around the world flower drop seed and all die at the same time- and it is always a large prime number of years. (usually between 40 and 80 years) sometimes as high as 130 ish..this seems to be a predator avoidance strategy so that a predator can’t easily time the flowering to feed off of the seeds of flowering bamboo tree. This is similar to the reproduction/life cycle strategy of the cicada which hatches abd comes out of the groupnd every 17 years to have a mass mating orgy and ehn lay eggs and die and then wait another 167 years to be reborn…17 is a prime number…
Here are all the prime numbers up to 200….. I am sure that all bamboo species will have ages at which they flower as one of these prime numbers.>>>>
2, 3, 5, 7, 11, 13, 17, 19, 23, 29, 31, 37, 41, 43, 47, 53, 59, 61, 67, 71, 73, 79, 83, 89, 97,101, 103, 107, 109, 113, 127, 131, 137, 139, 149, 151, 157, 163, 167, 173, 179, 181, 191, 193, 197, 199
I also believe there is some sort of evolutionary advantage for Pacific Salmon to rapidly age and die right after mating and laying their eggs. The massive amount of salmon carcasses laying around provide a superabundance of food for predators and scavengers that they won’t spend much time eating the salmon eggs on the river’s bottom.
Pacific Salmon are killed by a huge surge of LH and FSH right before and during spawning upt o 15,000% Similar to but much higher than humans’ 500 to 1000% increase in LH and FSH around age 50.
Likewise, bamboo flowering and death are also controlled by hormones.
So the bottom line is I suspect the disposable soma theory as being the reason annual plants die as they produce seeds is likely not the correct answer. I think it confers some sort of evolutionary advantage toward the survival of the seeds. Either it fertilizes the ground where the seeds will drop, or possible a dead plant looks un appetizing to a potential seed predator. kind of like a possum playing dead to avoid being eaten.!
I suspect many present interventions to prolong health and life, like calorie restriction, stalling development and reproduction, are merely hurdles we throw into the path of an evolutionary program that is running from birth over organism growth, possible reproduction and offspring protection to death.
Abstinence from reproduction may add some years to life, as we see in monks living in monasteries but finally they also meet their end.
The immune system follows a regulating principle were single cells are seen expendable for the greater good of the whole organism as millions of cells are driven into apoptosis or are killed off each day.
Maybe the seeds of our early progenitors carried a program where the greater good was an increase in the survival probability of all the brothers and sisters in the seeds, when the generation had a limited life span.
It would need different approaches wether aging is just biophysical decay, accumulation of unhealthy metabolites, progressing methylation of genes, stem cell depletion etc, or a basic program which constantly regulates in the background with the final target of organism death.
In that case we would have to constantly intervene against a master program, wether we clear senescent cells or supplement decreasing biosynthesis of enzymes like NAD.
Regarding plants I found an interesting paper from 2008 where the blocking of two proteins changes the phenotype of an annual plant into a longer living one of a perennial shrub. “Flowering-time genes modulate meristem determinacy and growth form in Arabidopsis thaliana” (doi:10.1038/ng.253).
Sadly for humans we do not know of an alternative longer living form to transform into like a flowering plant can transform into a woody plant.
Good points Marty and your post reminded me I forgot to add some finishing touches on my prior post….
As far as semelparous aging organisms that have one big burst of reproduction and then die I suspect that aging and death has a different purpose than what is seen in much longer living gradually aging animals. Even though aging is driven by the same processes in both types or organisms -increases in development/reproduction/aging hormones. In the animals / plants that die in a burst of reproduction, I suspect that the evolutionary purpose is to protect their offspring from predators…like seed predators’ in bamboo…there are just so many seeds at an unexpected time that the predators cannot eat them all. The Pacific Salmon ‘s carcasses might feed potential egg predators’ until they cant eat anymore in an effort to protect their eggs. So in these semelparous animals it seems that aging exists to provide protection from immediate and imminent predation of the offspring.
In more gradually aging animals that engage in iteroparous reproduction..aging in my theory also protects against predation but not immediate or imminent predation. In my world, aging in long lived animals preserves gene pool diversity by preventing anyone individual rom contributing too much to the gene pool. Diversity protects the group from encounters with novel predation by giving the group the diversity to allow it to evolve a defense to the novel predation quickly enough to avoid being eaten to extinction…
No one other point I wanted to expand on was the idea that in humans and mammals there are two major aging systems sexual and passive (somatic)
Sexually related aging would be the most recent to have evolved along with sex . I believe the 12 genes that Horvath discovered become hypomethylated with age control the sexual aging system, and when these 12 genes are activated by aging they pump out proteins and such that are actively trying to kill the organism- just like what you see in the animals that rapidly die during a burst of reproduction like the Pacific salmon killed in 3 days by massive (15,000%+) increases in the development/reproduction/aging hormones LH and FSH…
The there are the 36 genes that Horvath discovered that become methylated with aging and they quit producing proteins and transcription factors that are used for maintaining cellular identity. So as we age this aging system causes all our cells to lose information and forget what kind of cells they are and to start spitting out inflammatory substances etc.. This is a more passive aging system and it probably evolved before the sexual aging system from an ancient form of reproduction that is still used , at times , by the modern day jellyfish, where in certain circumstances in order to reproduce the ancient organism (or modern jellyfish) would simply (DE)reprogram ALL its cells to lose their identity and become single cell embryo spores that are dispersed into the environment…Billions of potential new identical individuals from one parent. Evolution has harnessed this ancient reproduction system to kill us by making us younger in an unhealthy way that kills us!
And finally you can see an acceleration of the active-sexual aging program in the rapid aging disease of Werner’s Syndrome which kicks in at puberty, and then you can see an acceleration of the passive somatic information loss aging system in the rapid aging disease of progeria which afflicts children beginning in their infancy. If you want a bunch of infrmation about this and 30 various updates about aging including Horvath’s and Katcher’s discoveries please check out my blog post on aging at>>> https://jefftbowles.com/aging-is-programmed/
title>>> NEW STUDY DISPROVES ALL MAINSTREAM THEORIES OF AGING-AND REVEALS THE NEW: PROGRAMMED LOSS OF CELLULAR DIFFERENTIATION THEORY OF AGING
Regarding disposable soma, has anybody noticed the apparent course reversal of its developer, Thomas KIRKWOOD, probably the most prominent opponent of programmed aging? See:
Omholt, S. W., & Kirkwood, T. B. (2021). Aging as a consequence of selection to reduce the environmental risk of dying. Proceedings of the National Academy of Sciences, 118(22), Article e2102088118.
In this article, Omholt and Kirkwood essentially abandon the central tenet of disposable soma, namely early-late life energetic trade-offs across growth, maintenance, and reproduction. But they provide barely any explanation and absolutely no historical context. Their aim here seems to be to save disposable soma by restating it: “In essence, the disposable soma theory proposes that natural selection should favor allocation to somatic maintenance only as much as is necessary to keep the organism in good functional condition for as long as it has a reasonable chance still to be alive, subject to the prevailing level of risk.” (p. 1)
Instead of trade-offs, they proposed that “natural selection might drive the establishment of a genetic program that leads to reduced allocation to somatic maintenance from an initial state where there is no such reduction” (p. 6). Although energy thus saved might be invested elsewhere, trade-offs “will not involve somatic maintenance as such” (p. 7). Rather, the adaptive purpose of just-enough-energy-allocation-to-maintenance would be to reduce mortality risk, with their prime example being reduced need for energy-seeking activities (e.g., foraging, hunting) and hence fewer contacts with abiotic and biotic sources of mortality. They also suggested that increased energy storage might be programmed to reduce mortality risk by providing backup for surviving environmental challenges, mobilizing the immune system, or detoxifying contaminants.
This seems far from some “universal physiological principle” explaining aging, as they promised in the introduction!
Farewell disposable soma! For me the black swan is the largemouth buffalo fish which increases both fecundity and repair with age.
when I see a spec ies witha long lifespan and especially with increasing fertility I immediately look for some sort of excellent defense to predation…
Isolation is a great one as you can see by the long lives of cave animals and mountain top and desert plants…so maybe these long living fish live in in deep waters in very isolated lakes. Deep dwelling sea fish like the orange Roughy, and Rockfish also have very long lifespans 120 years+
HAHAHAHA indeed! The formal modeling that Kirkwood used to support disposable soma and “disprove” programmed aging was also based on bad assumptions, including:
(1) virtually no animals in the wild survive to old age — but now his new model predicts “the ubiquitous presence of senescent individuals in a highly diverse group of natural animal populations” (p. 1)
(2) aging starts at around reproductive maturity — but there have long been observations of accelerated biological aging in immature rodents and children, even at birth
The largemouth buffalo inhabit shallow lakes. Humans are the major predators of the larger (older) specimens. Surely, there must be countless species of animals with minimal predation which age just like we do.
This fish, growing larger, becoming more resistant to disease, and producing more fertile offspring every year, must have evaded all the evolution-based theories of aging of which I am familiar. Perhaps I really don’t need to die at age 78 to preserve the species after all!
HAHA well we actually age very slowly based on our body size as a result of us having a good defense to predation- intelligence…I f we aged like other animals on the body size life span continuum we probably would die of old age around 25 years old. So if you want to see what I am talking about look at the body size life span continuum charts>>>>>the animals with exceptionally long life spans way OFF the line have excellent defenses to predation which include isolation, flight (myotis bat size of a mouse lives 43 years vs 2 for the mouse) , intelligence (humans 120 vs 25) , full body armor (tortoises 130 years, arctic clams 600 years, lobsters 250+ years) link>>>
The issue with evolution is not so much that longevity poat reproduction is selected against, but not aelected for. Makeham as part of Gompertz-Makeham is normally relevant as well
HAHAHA my head is spinning..Kirkwood’s latest sounds more like a word and idea salad!
@Wayne, the Bigmouth Buffalo fish has no telomere shortening, therefore it doesn’t age.
Jeff is probably right that with no predation and a stable, pleasant environment evolution selects for a longer life rather than the breed
-quick, die-young, fast life strategy that plagues most mammal species.
Jeff, what causes the “huge surge of LH and FSH right before and during spawning upt o 15,000% Similar to but much higher than humans’ 500 to 1000% increase in LH and FSH around age 50. ” ?
It seems very important to investigate.
Are the driving changes localized or global/systemic ?
If the changes, at some stage, are local to some part (organ/tissue/gland), maybe removing that part can eliminate that LH/FSH surge and allow much longer lifespan?
Well if they castrate the Salomon they don’t get the LH and FSH surge and can live up to 10 years instead of 3… so are the gonads producing the LH and FSH?? Or are they prroducing GnRH which causes the pituitary to release its LH and FSH…Im not sure would have to research it-why don’t you look into it?
This is a testable hypothesis with today’s technology. There are drugs used in treating late stage prostate cancer that act as “chemical” castration. They block the creation of both LH and FSH. What ose would be needed for only partially blocking LH/FSH is unknown, but testable in animal models.
Did I miss it but you did not seem to discuss the recent experiment treating mice with doses of Yamanaka factors that seemingly reduced affects of aging without deleterious side effects. Altos labs with $B in funding and an impressive array of participants (including Yamanaka and Horvath) seems to be pursuing this avenue.
Hi Edmund I think that was a few posts ago
Dear Edmund O Kelly,
I saw experiment in mice by perhaps the most famous Spanish biology researcher Juan Carlos Izpizsua (Nature paper?) previously at UDSA now working at China. They treated mice with Yamanaka factors but the curves published stop at middle age! so they do not demonstrate anything concerning life span extension. And they used short-lived strains as controls. All too badly designed for gerontology standards.
It seems that the clock that coordinates development must be present just after conception.
If that clock ticks based on days it seems that an experiment on mice subjected to longer light/dark cycles might show up in epigenetic age or longer lives.
Totally plausible. Day/light cycles determine sleeping and eating cycles, which determine transcription and various internal cellular reactions that drive epigenetic changes.
New study demonstrating that in extreme longevity, hypothalamic function is intact.
Suggests a relationship between the two.
Alternatively it is not a clock, but a gradual failure of cell processes through a lack of acetylation of the histone which drives the rest including methylation.
John, bravo! I was wondering when someone would point out that histone modification may be even more controlling than DNA methylation. I know that some correlation between DNA methylation and histone modification has been suggested, but I am unaware of any study that shows that histone modifications are controlling. Could you provide a reference?
I wrote this section “Chromatin as a substrate for epigenetic regulation of cellular aging” as part of a review on social forces and aging (references also added below):
Nearly all of the above-described research focused on DNA methylation, which is relatively easy to measure and done most often using leukocytes, which might not be representative of other tissues. As stressed by Cao-Lei, et al. (2017), the complexity of epigenetics means we have as yet little understanding of how different epigenetic mechanisms might interact to regulate gene expression. Chromatin is highly relevant because its component histones can be epigenetically “marked” through methylation, acetylation, phosphorylation, or ubiquitination, leading to changes in expression of associated genes (Cao-Lei, et al., 2017; Szyf, 2009; Tikhodeyev, 2018). Aging has been associated with transcriptional deterioration as a result of impaired chromatin functioning, with increasing mitochondrial dysfunction considered a likely cause (Perez-Gomez, et al., 2020).
Changes in the 3-D structure of chromatin can also modulate gene expression, which like DNA methylation also involves CpG sites. As explained by Lee, et al. (2021), the chromatin architecture of each cell type is optimized for precise gene expression. However, this architecture is liable to disorganization over time which “has long been speculated to be the primary culprit behind age-associated physiological deterioration” due to its association with normal aging, cellular senescence, and premature aging diseases (p. 1). Their research suggests critical differences between genes with versus those without high frequencies of CpG dinucleotides, called CpG islands, in their promoter regions. In mammals, about 60% of genes have CpG islands and are generally expressed throughout the body, while about 40% do not and tend to be expressed only in specific tissues. Evidence suggests that genes without CpG islands are much more liable to be misexpressed, leading to “age-related physiological deterioration, notably for increased secretion of inflammatory mediators” (p. 1). This proposal is supported by a relatively rare example of primate research on chromatin epigenetics, in which female rhesus monkey social status was experimentally manipulated. Falls from higher to lower social status, as well as low initial social status, were found to be associated with lower chromatin accessibility and hence reduced expression of certain immune cell genes, which might help explain why low status is associated with high inflammation (Snyder-Mackler, et al., 2019).
Cao-Lei, L., De Rooij, S. R., King, S., Matthews, S. G., Metz, G. A. S., Roseboom, T. J., & Szyf, M. (2017). Prenatal stress and epigenetics. Neuroscience & Biobehavioral Reviews, 117, 198-210.
Lee, J. Y., Davis, I., Youth, E. H., Kim, J., Churchill, G., Godwin, J., … & Beck, S. (2021). Misexpression of genes lacking CpG islands drives degenerative changes during aging. Science Advances, 7(51), Article eabj9111.
Perez-Gomez, A., Buxbaum, J. N., & Petrascheck, M. (2020). The aging transcriptome: Read between the lines. Current Opinion in Neurobiology, 63, 170-175.
Snyder-Mackler, N., Sanz, J., Kohn, J. N., Voyles, T., Pique-Regi, R., Wilson, M. E., … & Tung, J. (2019). Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques. Proceedings of the National Academy of Sciences, 116(4), 1219-1228.
Szyf, M. (2009). Epigenetics, DNA methylation, and chromatin modifying drugs. Annual Review of Pharmacology and Toxicology, 49, 243–263.
Tikhodeyev, O. N. (2018). The mechanisms of epigenetic inheritance: How diverse are they? Biological Reviews, 93(4), 1987-2005.
There are quite a few references for the crosstalk between acetylation and methylation eg
However, IMO acetylation has to be the first step.
The reference appears to me to be talking about crosstalk between histone modifications. An admittedly quick read by my 81-year-old grey cells found no mention of CpG methylation. I am thus still without a good explanation of the relationships of DNA methylation and other epigenetic mechanisms.
It is obvious that epigenetics includes not only DNA methylation, but also histone modifications of many kinds plus changes in the structure of chromatin (that is very well established). This is true independently of the fact that only CpG methylation clocks have been investigated up to date. There is an obvious need of studying also the other two main types of epigenetics acting on histones and chromatin structure (both are surely extremely important for aging and control and cross-talk with the gens of the nuclear aging program)
Methylation is just one of many epigenetic mechanisms. It’s a historic accident that methylation is the easiest measurement to make, and the breakthrough in clocks came with methylation clocks. Maybe the future of aging clocks is in proteomics, where (1) we integrate the effects of all epigenetic mechanisms and (2) we have a more direct way of knowing the phenotypic effects of the data points.
The question is whether methylation changes are the primary cauar of age based deterioratiob or an effect of something else. My view is that that are consequential to failures of differentiauon primarily as a result of a shortage of nuckear acetyl-coa. Its is this failure of differwntiaion that causes most aging phenotype problems (unsurprisingly). Evrn consider diabetes where pancreatic cells get a liking for absorbing fat.
The acceleration of methylation age parallels the shortening of telomeres that accompanies HSC implantation and expansion into peripheral blood cell types.
Whereas in the case of telomeres the mechanistic cause is obvious, for methylation changes are likely reflecting shortfalls in the available material for the remethylation (then demethylation) process that comes after the creation of the daughter strand in DNA replication. Hence why additional telomerase can make this appear worse, as it permits more divisions.
It may be that differential strand methylation is actually what drives asymmetrical as opposed to symmetrical division. But further ‘error’ is likely just reflective of further cellular division and/or DNA repair, which also requires the methylation machinery.
All this suggests to me that methylation is reflecting the balance of cellular turnover and DNA repair and the ability of the methylation machinery to keep up and is not itself the driver of aging. Therefore judging the success or failure of anti aging efforts by this measure is likely to lead to disappointment.
In 2014, a DNAm “clock” was developed that used only THREE CpG sites with a purported error of less than 5 years. In 2019, CRISPR technology was used to change the methylation state of CpG sites related to the Oct4 gene which resulted in a changed expression of said gene. Unfortunately, other epigenetic changes were not measured. Nonetheless, it would seem that the intervention would not have directly changed other epigenetic factors (histone modification, chromatin remodeling, post-translational alterations, etc.) except downstream as an effect of the changed gene expression. An in vivo experiment changing just the 3 sites of the 2014 clock might yield some interesting results. Meanwhile, DNAm now seems more causal than I previously thought.
Notwithstanding the above, to unravel all the interactions of changes in thousands of gene expressions in order to fully understand the development/aging process seems well beyond current capabilities. Finding regenerative treatments would seem more likely to occur by intelligent trial and error. Analysis of the mechanisms of action of treatments that seem to work such as revealed by the ITP could point to more potent interventions. When the makeup of E5 is revealed, a lot more of the mechanisms of aging might become known.
I find it incredible that such a long discussion of the development/aging process has not once mentioned Vince Giuliano and his pinpointing of H3K27me3 as a major participant. The fact that this trimethylation occurs within 4 hours of the onset of egg laying in nematodes and turns off a great number of cellular repair mechanisms would seem to strongly support the programmed theory of aging at the expense of the it’s all just damage folks.
In any event, I am beginning to wonder if the word “clock” shouldn’t be changed to “stage” or something to reflect that aging, like development, is a series of states that occur in a predetermined order (the plan or program). This is not to say that stochastic damage does not occur, only that it is the programmed ability to deal with it that is important. Consider the largemouth buffalo fish whose fecundity and repair ability both increase with age.
Here’s a fascinating study showing the transformation of old human skin into young skin after being transplanted onto a young mouse.
They were able to isolate the protein responsible to vascular endothelial growth factor, or VEGF-A. This supports their theory of angiogenesis and anti aging.
One issue here is that VEGF is associated with cancer , and more specifically, metastatic cancer. In fact, inhibition of VEGF is one of the primary anti cancer mechanisms of rapamycin. Is this, like with telomeres, going to be one of those trade off debates?
That is a very interesting study, and relevant here as VEGF-A is identified as a systemic factor leading to organ (in this case skin) rejuvenation. Of course as the resident telomere champion I must point out that VEGF-A benefits to angiogenesis require telomerase activity, see: Telomerase Mediates Vascular Endothelial Growth Factor
dependent Responsiveness in a Rat Model of Hind Limb Ischemia
Maybe other proteins are involved, too.
Skin cells that express a high level of COL17A1,divide symmetrically, outcompete and eliminate stressed clones that express low levels of COL17A1, which divide asymmetrically.
Hemidesmosome component collagen XVII, or ( COL17A1) has also been shown to encourage replication of healthy skin and discourage replication of old damaged skin.
To maintain healthy levels of COL17A1 in skin? Researchers found two potential chemicals that might help: apocynin and something called “Y27632.”
Collagen 17, is a specific type of collagen protein that is critical for rooting the stem cell to the basement membrane.
That is basically a stem cell competition argument. Symmetrically dividing clones will come to predominate over asymmetrically dividing ones. Y27632 is a ROCK inhibitor, so it is preventing full differentiation, i.e. keeping precursor cells as precursor cells. It would of course be a fine balance as if all stem cells divided only symmetrically we’d all be dead.
Jeff Bowles points out that truncated proteins are known to cause various rapid aging pathologies. Most proteins are assembled from multiple mRNA’s via “splicing factors” which become damaged with aging. Professor Lorna Harries at University of Exeter Medical school has shown resveratrol totally restores splicing factors to a youthful state in old cell cultures. Hypothetically repeated doses of resveratrol can do the same for aging humans..
Hi Richard! you are focusing on the final push for the end solution of aging! I am working with Lorna (via email chats) right now to finish the whole puzzle. It turns out that as we age Steve Horvath has found that one gene gets turned on called LARP1 which has an RNA binding domain which is very rare. It likely improperly truncates the ATM protein RNA to make the mutated ATM protein which causes ataxia telangiectasia. Normal ATM protein controls RNA spicing all over the genome. When the protein is in the mutant form it screws up RNA from all sorts of genes including the lamin A protein that is truncated in progeria it also looks like it truncates the normal WRN RNA in normal aging -this WRN protein is mutated in Werner’s syndrome- (based on a study I found) -inhibiting ATM protein rescues both progeria and Werner’s cells- but i believe the researchers did not realize they were inhibiting mutated ATM protein caused by improper aging-related RNA truncations not normal ATM…..it also attacks the mitochondria to cause mutations… So if aging is programmed why not just attack DNA instead of RNA? Because I have come up with the first hallmark of programmed aging- all aging has to be reversible so you can run the program backwards and get embryonic stem cells from adult cells (what harold is doing to a limited extent). If you damaged the DNA that would screw everything up! that s why thiws part of the aging program only attacks RNA transcripts!
because it is totally reversible and does not damage the DNA. Lorna also has found 2 other genes are doing the same thing FOXO1 and ETV6 she says these are more powerful than ATM in causing splicing errors and these are downstream from AKT and ERK I found both ATM and AKT control production of Lamin A which is mutated (truncated) in progeria and during normal aging. She has written a HUGE paper on this>>> FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence
and it only has 3 citations! One of them form her! Nobody knows how far ahead she is! It is kind of funny! She is way ahead of her time and in my book on aging I am working on I might describe her as aging science after Horvath!
Could you provide the source for the paper? I should like to read it.
Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence https://bmcmolcellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7
Thank you for the paper link.
Professor Lorna Harries publications: https://medicine.exeter.ac.uk/people/profile/index.php?web_id=Lorna_Harries