• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

Josh Mitteldorf: Methylation Clocks and True Biological Age

data beta aging methilation clocks josh mitteldorf

  • Please log in to reply
4 replies to this topic
⌛⇒ MITOMOUSE has been fully funded!

#1 Engadin

  • Guest
  • 114 posts
  • 260
  • Location:Madrid
  • NO

Posted 19 October 2019 - 10:19 AM


.

 

 

 

 

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.

 

 

 

.../...

 

 

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 .

 

 

 

 

.


  • Informative x 1

#2 Nate-2004

  • Guest
  • 2,304 posts
  • 317
  • Location:Philadelphia
  • NO

Posted 22 October 2019 - 01:50 PM

Just when we think we have answers we don't. But think about it, if certain measures are taken as interventions, Fahy's study for example, and we see a two year reversal in epigenetic aging, perhaps this was the body's response to improved condition because the expression normally seen was no longer needed. So either way, we would see a reversal in epigenetic clock either as an effect, or as a cause. If it's an effect then it's just a biomarker to be measured, if it's a cause of aging reversal, then it's a target. So I disagree that point 2 means shortened lifespan, I say it means you're on track. Point 2 means interventions were successful.


Edited by Nate-2004, 22 October 2019 - 01:51 PM.


Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#3 to age or not to age

  • Guest
  • 151 posts
  • 91
  • Location:NY

Posted 22 October 2019 - 02:15 PM

Sinclair Interview Excerpts

YouTube

https://youtu.be/uA9z8K5snOk

 

I am posting 7 minutes of excerpts from my July interview with David Sinclair where in he posit his theory of what causes aging.

​One note regarding Mitteldorf: he does some good reporting but he is overly invested in his theory that aging is tightly 

programmed.  Sinclair pretty much busts his theory in these excerpts.  Mitteldorf, who I have met a couple of times,

took down this video from his comments because it conflicts with his theory. Sinclair states that aging looks like a program

but it's not. Sinclair is the real thing.


Edited by to age or not to age, 22 October 2019 - 02:18 PM.

  • unsure x 1
  • Enjoying the show x 1
  • Disagree x 1

sponsored ad

  • Advert
Advertisements help to support the work of this non-profit organisation. [] To go ad-free join as a Member.

#4 Nate-2004

  • Guest
  • 2,304 posts
  • 317
  • Location:Philadelphia
  • NO

Posted 22 October 2019 - 05:17 PM

I trust Mitteldorf more than Sinclair, one is significantly more invested financially in the outcome and at least Mitteldorf is entertaining the possibility of being wrong above. I am not so sure he's right in his assessment that this means a reversal of methylation shortens lifespan if he's wrong about programmed aging. I personally think aging is merely damage and a product of late acting genes not selected out due to the environmental conditions requiring earlier reproduction years from our ancestors. This is also the view of RIchard Dawkins, who wrote the Selfish Gene, something Mitteldorf vehemently disagrees with.


Edited by Nate-2004, 22 October 2019 - 05:18 PM.

  • Agree x 1

sponsored ad

  • Advert
Advertisements help to support the work of this non-profit organisation. [] To go ad-free join as a Member.

#5 kurt9

  • Guest
  • 118 posts
  • 0

Posted 23 October 2019 - 04:29 PM

I've read Sinclair's latest book and have read Mitteldorf's book as well. Mittledorf's book is good at ruling out traditional theories of aging, especially the conventional genomic DNA damage theories. However, one problem I have with Mittledorf is that he has a near religious obsession with the concept of group selection. I believe it is this obsession with group selection that is the root of bias Mitteldorf has against the selfish gene theory. The problem with group selection is that there is no plausible molecular biological mechanism underlying it. Most proponents of group selection therefor resort to various kinds of oogoo boogoo to promote. Mitteldorf, to his credit, does not do this. Sinclair, on the other hand, has a financial stake in his ideas being correct and that should alway be taken into account when evaluating his ideas. In any case, only rigorous experiment will set the record straight. Personally, I am skeptical of "programmed" aging theories for the simple reason I do not believe our genes evolved to kill us.


  • Disagree x 1
  • Agree x 1





Also tagged with one or more of these keywords: data beta, aging, methilation clocks, josh mitteldorf

2 user(s) are reading this topic

0 members, 2 guests, 0 anonymous users