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Josh Mitteldorf: Methylation Clocks and True Biological Age

josh mitteldorf aging methilation clocks methylation clocks

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#1 Engadin

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Posted 19 October 2019 - 10:24 AM


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S O U R C E :    Josh Mitteldorf _Aging Matters blog

 

 

 

Data-BETA-logo-768x738.jpg

 

 

 

The good news is that the DataBETA project has found a home.  After several months of seeking a university partner, I am thrilled to be working with Moshe Szyf’s lab at McGill School of Medicine.  DataBETA is a broad survey of things people do to try to extend life expectancy, combined with evaluation of these strategies (and their interactions!) using the latest epigenetic clocks.  Szyf was a true pioneer of epigenetic science, back in an era when epigenetics was not yet on any of our radar screens. No one has more experience extracting information from methylation data.

 

DataBETA is just the kind of study that is newly possible, now that methylation clocks have come of age. Studies of anti-aging interventions had been impractical in the past, because as long as the study depends on people dying of old age, it is going to take decades and cost $ tens of millions. Using methylation clocks to evaluate biological age shortcuts that process, potentially slashing the time by a factor of 10 and the cost by a factor of 100.  But it depends critically on the assumption that the methylation clocks remain true predictors of disease and death when unnatural interventions are imposed. Is methylation an indicator, a passive marker of age? Or do changing methylation patterns cause aging?

 

 

Two types of methylation changes with age

 

Everyone agrees that methylation changes with age are the most accurate measure we have, by far, of a person’s chronological age—and beyond this, the GrimAge clock and PhenoAge clock are actually better indications of a person’s life expectancy and future morbidity than his chronological age.

 

Everyone agrees that methylation is a program under the body’s control. Epigenetic signals control gene expression, and gene expression is central to every aspect of the body’s metabolism, every stage of life history. Sure, there is a loss of focus in methylation patterns with age, sometimes called “epigenetic drift”.  But there is also clearly directed change, and it is on the directed changes that methylation clocks are based.

 

But there are two interpretations of what this means. (1) There is the theory that aging is fundamentally an epigenetic program. Senescence and death proceed on an evolutionarily-determined time schedule, just as growth and development unfold via epigenetic programming at an earlier stage in life. Several prominent articles were written even before the first Horvath clock proposing this ideas [refref], and I have been a proponent of this view from early on [ref]. If you think this way, then methylation changes are a root cause of aging, and restoring the body to a younger epigenetic state is likely to make the body younger.

 

(2) The other view, based on an evolutionary paradigm of purely individual selection, denies that programmed self-destruciton is a biological possibility. Since there is a program in late-life epigenetic changes, it must be a response and not a cause of aging. Aging is damage to the body at the molecular and cellular level. In response to this threat, the body is ramping up its repair and defense mechanisms, and this accounts for consistency of the methylation clock. In this view, setting back the methylation pattern to a younger state would be counter-productive. To do so is to shut off the body’s repair mechanisms and to shorten life expectancy.

 

So, if you believe (1) then setting back the bodys methylation clock leads to longer life, but if you believe (2) then setting back the bodys methylation clock leads to shorter life.

 

I think there is good reason to support the first interpretation (1). Epigenetics is fundamentally about gene expression. If you drill down to specific changes in gene expression with age, you find that glutathione, CoQ10=ubiquinone, SOD and other antioxidant defenses are actually dialed down in late life when we need them more. You find that inflammatory cytokines like NFκB are ramped up, worsening the chronic inflammation that is our prominent enemy with age.  You find that protective hormones like pregnenolone are shut off, while damaging hormones like LH and FSH are sky high in women when, past menopause, they have no use for them. There is a method in this madness, and the method appears to be self-destruction.

 

Until this year, I have been very comfortable with this argument, and comfortable promoting the DataBETA study, which is founded in the premise that setting back the methylation clock is our best indicator of enhanced life expectancy. The thing that made me start to question was the story of Lu and Horvath’s GrimAge clock, which I blogged about back in March. 

 

The GrimAge clock is the best predictor of mortality and morbidity currently available, and it was built not directly on a purely statistical analysis of direct associations with m&m, but based on indirect associations with such things as inflammatory markers and smoking history. (This is a really interesting story, and I suggest you go back and read the March entry if you have not already. The story has been told in this way nowhere else.)

 

(Please be patient, I’m getting to the point.) Years of smoking leave an imprint on the body’s methylation patterns, and this imprint (but not the smoking history itself) is part of the GrimAge clock. I asked myself, How does smoking shorten life expectancy? I have always assumed that smoking damages the lungs, damages the arteries, damages the body’s chemistry. Smoking shortens lifespan not through instructions imprinted in the epigenetic program, but quite directly through damaging the body’s tissues. Therefore, the epigenetic shadow of smoker-years that contributes to the GrimAge clock is not likely to be programmed aging of type (1), but rather programmed protection, type (2).

 

For me, this realization marked a crisis. I have begun to worry that setting back the methylation clock does not always contribute positively to life expectancy. The canonical example is that if we erased the body’s protective response to the damage incurred by smoking, we would not expect the smoker to live longer.

 

 

 

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F O R   T H E   R E S T   O F   T H E   S T U D Y   &   I N T E R E S T I N G   C O M M E N T S ,   P L E A S E    V I S I T   T H E   S O U R C E .

 

 

 

 

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#2 Turnbuckle

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Posted 19 October 2019 - 11:27 AM

Mitteldorf: For me, this realization marked a crisis. I have begun to worry that setting back the methylation clock does not always contribute positively to life expectancy. The canonical example is that if we erased the body’s protective response to the damage incurred by smoking, we would not expect the smoker to live longer.

 

 

You can't set back the methylation clock by giving up smoking any more than you can mend a broken glass by being careful not to drop it again. You have to throw it out and buy a new glass. And it's the same with the body. Epigenetic age can only be reversed by throwing out epigenetically old cells and replacing them with epigenetically young cells derived from stem cells (whether natural or induced). The body does this self-renewal for decades before its stem cell pools get depleted, after which aging proceeds very rapidly.



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#3 Rocket

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Posted 20 October 2019 - 12:49 AM

You can't set back the methylation clock by giving up smoking any more than you can mend a broken glass by being careful not to drop it again. You have to throw it out and buy a new glass. And it's the same with the body. Epigenetic age can only be reversed by throwing out epigenetically old cells and replacing them with epigenetically young cells derived from stem cells (whether natural or induced). The body does this self-renewal for decades before its stem cell pools get depleted, after which aging proceeds very rapidly.


But not all cells in the body are replaced. So that can't be cause of aging for the cells that are not replaced. If all cells are replaced eventually you end up with a new body, periodically. This isn't the case. Its part of it, yes. But the cause of aging? Can't be. Glycation. Cellular waste. ELLPs. Gene expression. Mitochondria failure.Too much to list. There are many causes of aging, some known, some yet to be discovered.

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#4 Turnbuckle

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Posted 20 October 2019 - 01:37 AM

But not all cells in the body are replaced. So that can't be cause of aging for the cells that are not replaced. If all cells are replaced eventually you end up with a new body, periodically. This isn't the case. Its part of it, yes. But the cause of aging? Can't be. Glycation. Cellular waste. ELLPs. Gene expression. Mitochondria failure.Too much to list. There are many causes of aging, some known, some yet to be discovered.

 

 

All cells but brain cells are replaced, and even some brain cells. But you don't have to have aging of all organs to age the organism, nor do they have to age at the same rate.


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#5 Rocket

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Posted 21 October 2019 - 12:46 AM

So why do cells themselves age? Why do they accumulate waste products when they are replaced? I observe that aging acellerates once the body stops growing new tissues at which point, a few years later (roughly 10) the body becomes catabolic very early in your 30s.
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#6 Turnbuckle

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Posted 21 October 2019 - 10:33 AM

So why do cells themselves age? Why do they accumulate waste products when they are replaced? I observe that aging acellerates once the body stops growing new tissues at which point, a few years later (roughly 10) the body becomes catabolic very early in your 30s.

 

Cells age genetically, epigenetically, and telomerically. Genetic aging is due to mutations of the genome that occur mostly from chemical or radiation exposure. Cells have very good error correction mechanisms so such mutations don't happen very often. Telomeric aging is actually a protective device, a sell by date. It protects against cancer and keeps cells from getting too epigenetically screwed up. Without it, cells would essentially be immortal, though they would still age epigenetically and genetically. Epigenetic aging is where the action is. The 200 cell types of the body are distinguished by their epigenetic coding. This is like sheet music that tells the cells what proteins to make. Screw that up and a liver cell is no longer a very good liver cell as it's making the wrong balance of proteins. And once screwed up, it can't be fixed. You have to get rid of the cell and replace it with a new cell with de novo epigenetic coding. A few animals can erase epigenetic programing of somatic cells and reprogram them, but mammals can't do this. We have to kill epigenetically old cells (apoptosis) and replace them with new cells derived from stem cells.

 

There is one animal that is thought to be immortal, and it achieves this epigenetically. Turritopsis dohrnii is a jellyfish that can revert to an earlier stage and grow old again, then revert again, and can do this endlessly. It does this Benjamin Button number by epigenetic reprogramming of somatic cells.


Edited by Turnbuckle, 21 October 2019 - 10:46 AM.

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#7 Rocket

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Posted 22 October 2019 - 12:23 AM

So replenish stem cells in all tissues, you suggest, will considerably slow aging?

Because I hypothesize anabolism slows aging by growing new young tissue, when I stopped CRON 6 years ago and decided relatively late in life to take up body building and put my body into a state of anabolism I felt really fantastic for the initial couple of years. My entire body grew, including all of my bones. I went through 2 or 3 wedding bands because my finger bones even grew. Now at steady state for a few years I feel mortal again. My body grew so much that its physically impossible to reach my weight from 6 years ago without looking like a big skeleton. Just an anecdotal n=1 experience.

How do we turn on the mechanisms to replenish stem cells in all of the body tissues? And might that not increase risks for all forms of (knock on wood) cancers since we are producing more cells again as in youth? And why in your writings do you say that c60 can deplete stem cells? There's too much to read. And might not hgh be of value here?

Do you think people like Liz Parrish doomed herself by turning on telomerase?

Edited by Rocket, 22 October 2019 - 12:24 AM.

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#8 Turnbuckle

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Posted 22 October 2019 - 09:38 AM

So replenish stem cells in all tissues, you suggest, will considerably slow aging?

Because I hypothesize anabolism slows aging by growing new young tissue, when I stopped CRON 6 years ago and decided relatively late in life to take up body building and put my body into a state of anabolism I felt really fantastic for the initial couple of years. My entire body grew, including all of my bones. I went through 2 or 3 wedding bands because my finger bones even grew. Now at steady state for a few years I feel mortal again. My body grew so much that its physically impossible to reach my weight from 6 years ago without looking like a big skeleton. Just an anecdotal n=1 experience.

How do we turn on the mechanisms to replenish stem cells in all of the body tissues? And might that not increase risks for all forms of (knock on wood) cancers since we are producing more cells again as in youth? And why in your writings do you say that c60 can deplete stem cells? There's too much to read. And might not hgh be of value here?

Do you think people like Liz Parrish doomed herself by turning on telomerase?

 

 

When you reach geriatric age, huge numbers of cells are reaching their Hayflick limits even as stem cell pools are drying up. Demand for replacement cells is going up while supply is going down. The rate of aging thus ramps up dramatically. The solution is to refill stem cell pools. This does not increase the potential for cancer, as those new cells are still limited by their telomeres, just as they were when you were younger.

 

Stem cells are controlled by two mitochondrial switches--mito morphology and membrane potential (or equivalently, ATP output). SC mitochondria are loaded up with UCP2 pores that short circuit ATP synthase and keep SCs quiescent. In my SC protocol, mito fusion biases stem cells to self-renewal (proliferation vs differentiation), while a UCP2 blocker (C60) increases membrane potential and ATP output. Stem cells wake up and divide into new stem cells, increasing the pools.

 

Using C60 without mito fusion will result in asymmetric division and eventual depletion. It's robbing Peter to pay Paul, as the saying goes. Working out produces a state of health due to the activation of stem cells, but also uses them up. My hypothesis is that methionine restriction does the opposite -- it reduces unnecessary stem cell activity now (since methionine is a primary SC nutrient), thus conserving SCs for later use when they become more important. If you can refill SC pools, however, then you are no longer bound by the usual restrictions. You can work out and build muscle and eat what you like.

 

I don't think you necessarily doom yourself by using telomerase supplements. As long as you stop, cells will again begin to age telomerically, but they will reach an older epigenetic age before they reach their Hayflick limits. I've seen this effect myself. 


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#9 dlewis1453

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Posted 22 October 2019 - 02:28 PM

What do you think is responsible for the partial rejuvenation of old mice that occurs in parabiosis experiments?  In these experiments, the old mice are partially rejuvenated, while the young mice age quickly. 

 

The researchers in the parabiosis field, along with Josh Mitteldorf and some others, believe there are rejuvenating peptides in the plasma of the young mice and inflammatory peptides in the plasma of the old mice. If this is the case, it will be interesting to discover how these peptides interact with our stem cell populations. Some studies that isolate these peptides and their effects have already been released. 

 

On the other hand, perhaps part of the effect of parabiosis can be explained by the old mouse piggybacking off the stem cell populations of the young mouse, and the young mouse being damaged by inflammation secreted by the senescent cells of the old mouse. 



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#10 dlewis1453

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Posted 22 October 2019 - 02:32 PM


Because I hypothesize anabolism slows aging by growing new young tissue, when I stopped CRON 6 years ago and decided relatively late in life to take up body building and put my body into a state of anabolism I felt really fantastic for the initial couple of years. My entire body grew, including all of my bones. I went through 2 or 3 wedding bands because my finger bones even grew. Now at steady state for a few years I feel mortal again. My body grew so much that its physically impossible to reach my weight from 6 years ago without looking like a big skeleton. Just an anecdotal n=1 experience.
 

 

Hi Rocket, what is "CRON"? 

 

Interesting bone growth results. I'm guessing that growth was enhanced by growth hormone and steroids. Any other interesting results? Such as a mini height boost? Or acromelagy? 



#11 aribadabar

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Posted 22 October 2019 - 10:20 PM

what is "CRON"? 

 

Caloric Restriction with Optimal Nutrition 


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#12 dlewis1453

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Posted 24 October 2019 - 03:26 PM

I found the following paragraph in this paper (https://www.ncbi.nlm...les/PMC5635645/) , and thought it was interesting and relevant to the discussion here:  

 

 "Discordance in DNA methylation profiles between MZ twins can be used to discriminate between age-related changes of DNA methylation that represent a cumulative result of stochastic errors and those that are a part of the hypothetical epigenetic program of aging [24]. Methylation levels of total lymphocyte DNA were found to be practically identical between MZ twins in 65% pairs and significantly different in 35% pairs. Identical DNA methylation levels were usually observed in young pairs, whereas aged pairs had most different ones. Thus, the DNA methylation difference between MZ twins gradually increases with age. An analysis of differentially methylated genome loci in most epigenetically discordant twin pairs showed that 43% of them are located in Alu family repeat sequences, 9% are in repeat sequences of other families (LINE, MER, MIR), 34% are in unidentified transcribed sequences, and 13% are in known unique genes. Generally, nearly identical methylation patterns were characteristic of young twin pairs that lived together for the most part of their life and had similar life styles, whereas most discordant methylation patterns were characteristic of older twin pairs that lived separately and had different life styles. Thus, large phenotypic discordance in MZ twin pairs may be caused by accumulated epigenetic differences. These differences could be due to both the effects of external and internal factors (smoking, physical activity, dietary preferences, etc.) and stochastic methylation errors (epigenetic drift) accompanying aging. Methylation errors probably occur much more often compared with mutations, since the fidelity of DNA methylation is by far lower compared with DNA replication and repair [6]."







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