Few Evident Relationships Between Accelerated Epigenetic Aging and Cancer

Epigenetic clocks are produced by identifying characteristic shifts in epigenetic marks with age, the decorations on the genome that control gene expression. It remains unclear as to the exact relationship between specific epigenetic marks and the underlying damage and dysfunction of aging, and so it remains unknown as to how comprehensively epigenetic clocks reflect the processes of aging: do all of the processes of aging contribute, or only some of them? If the latter, it will be hard to use epigenetic clocks to assess the quality of potential rejuvenation therapies. Removing that uncertainty will require a great deal of further work.

When epigenetic age is higher than chronological age, this is referred to as accelerated epigenetic age. It is thought to reflect a greater burden of the underlying cell and tissue damage that causes aging, but of course the uncertainty remains as to whether this is a full versus selective representation of the state of health for any given epigenetic clock - any given combination of epigenetic marks, in other words. Are there aspects of aging that contribute little to epigenetic age?

With that in mind, researchers here note that a first pass at analysis of cancer incidence and accelerated epigenetic age found little in the way of firm correlations. This is interesting, as (a) cancer risk is very robustly age-associated, (b) the risk of a number of other age-related conditions does correlate to accelerated epigenetic age, and (c) recent work suggests that incidence of serious mutational damage causes epigenetic change, so one might expect a greater pace of mutational damage to lead to both more cancer and more epigenetic aging.

Cancer: The aging epigenome

Age is a prominent risk factor for most types of cancer. Cancer risk increases with age, in part, because genetic mutations that arise from DNA replication errors and exposure to environmental carcinogens accumulate as we get older. Aging also alters the epigenome, the chemical marks spread across DNA that help switch genes on or off by altering how the genome is packaged. For instance, the addition of a methyl group to DNA can play a role in compressing the nearby DNA sequence so it can no longer be accessed by the cell's machinery. Epigenetic modifications, including DNA methylation, have also been shown to contribute to the development of cancer. However, the potential impact of age-related epigenetic changes on cancer development has not been fully characterized.

It has been hypothesized that people whose epigenetic age is greater than their age in years - a phenomenon known as accelerated aging - may be at higher risk of age-related diseases, including cancer. However, previous studies linking accelerated epigenetic aging and cancer have produced mixed results. Now a team has taken a different approach. Instead of associating a person's risk of cancer with epigenetic clock estimates, they correlated it against genetic variations that are known to influence these algorithms.

The results did not show many clear relationships between the epigenetic aging clocks and risk for the various types of cancer studied. The most promising finding was an association between the GrimAge clock and colorectal cancer. The GrimAge clock was not designed to predict age alone, but also reflects the effects of smoking and other mortality-related epigenetic features. Thus, the interpretation of this association is not straightforward, as this clock may capture the effects of environmental or lifestyle factors on the epigenome. One caution is that epigenetic clocks have largely been developed based on how aging affects DNA methylation in blood cells. Much less is known regarding aging and epigenetics in other tissue types, including those prone to cancer.


@Reason. Maybe a better approach would be to measure epigenetic damage rather than using epigenetic methylation?

I think that is what they managed to do in this paper: "High throughput single-cell multi-omics platform to jointly capture genotype and chromatin accessibility; charting the differentiation of clonal outgrowths". From the Landau lab

But I'm not entirely sure that's what they were doing.

Posted by: Matt at May 12th, 2022 1:38 PM

Hi there! Just a 2 cents.

''Are there aspects of aging that contribute little to epigenetic age?''

A few posts behind you posted, there was one study that showed that fly epigenetic partial reprogramming and senescence reduction made the fly live longer; but, the important point from the study was that it was only epigenetic reprogramming that increased its maximum lifespan; not senescence reduction/senolytic...and that doing both was better/stronger, than one of the two alone..

This is very important, senescence reduction did not make maximum lifespan increase...
it only improved its health (health threshold maintenance); by having health maintained (enough); the fly coud age longer - but it would not reach the maximum lifespan possible --- that, would need partial epigenetic reprogramming (via Yamanaka epifactors);

Therefore, senescene reduction/senolytic removal of senescence cells (p16 cells) will reduce the inflammation burden of age caused by them (SASP); SASP if removed, it will reduce inflammation/inflammasome...I think it's rather SAHF that can really accelerate chromatin foci and will precipitate chromatin disassembly and accelerate its demythelation...but, it's possible that SAHF is not That consequential...what is More consequential is the demethylation and loss of order structure of chromosome (decompaction, decondensation, uncoiling, histone loss); it's been shown - when chromosome are unpacked and loosen...aging accelerates 1:1 to them...
or nearly, 1:1...this demonstrates that aging - is truly - a chromosomal problem ..brought about the damage (DNA DSBs/SSBs -Double Strand Breaks/Single S..) which causes epigenetic drifting and this will lead to chromosomal rearrangement (peaks and valleys); and thus, the epiprogram will continue its course -- Aging You (older epi 'age signature'). This is why senescence reduction could not extend life to maximum; senescence = healthspan/avg lifespan; epigenetic = maximumspan/longevity; the fact that the fly could not continue on - live Above the maximum lifespan; demonstrates that DNA damages are the Largest Other problem (besides telomere shrinking, accumulating dysfunctional proteins and residues clogging lysosomes); DNA damage is directly into chromosome/telomere territory, nuclear DNA/nucleus...but also mitochondrial DNA (albeit, less important); it's clear now, that mitochondrial ROS caused substantial damages to telomeres farther...but the more important point, is not so much the ROS damage to DNA from mitos...it's the loosening of chromosomal integrity...I would bet it...if they messed up the fly's chromos...the fly would die almost immediately; there have been many studies that showed that fly life reduced dramatically if there was Any touching of chromosomes...this concords Progeria and Werney Syndrome/Down 21...fast aging where the chromosome can't 'assemble' correctly (Either because of mutant Lamin or in Werney faulty Excision DNA Repair/Helicase); DNA damage Repair is Why we can live so long; since DNA lesions/breaks cause DSBs and DSBs cause epigenetic clock acceleration; but since, partial epireprogramming could not make the fly live longer above its MLSP;...then, damage is consequential...and senescence is Less consequential - it is Consequential to you health; more so..than you longevity/maximum specie longevity; that's clearly, the epidomain/DNA damage.

Just a 2c.

PS: partial reprogramming could make us (by the Fly's longevity reaching its maximum possible); we could reach 120...but that's not enough/is problematic because it's not what people had hoped...living to 120..is Great...but it ends there. Plus, the fly did not have cancer..that's a good sign (of course, that is because they respected teh Window Limit of 6-7 days of Yamanaka exposure...not above that or else teratoma formation; to reduce the epigenetic age yet not erase the signature neither (become stem cell - 0 age/back to undifferentiated state - which that is deadly; has been shown - mice Fully Reprogrammed - die...only partial is feasable to not erase Completely the cell signature)); but, there is still the but...DNA damage...the fly did not live above MLSP; and they said it was better to combine senescence reduction + epireprogramming;
it made more benefit -- the fly was healthier - for longer AND reached the maximum...
while Only epigenetic reprogramming meant the fly was less healthy...and Could die...of health complication - But - was rejuvenated epiclock...thus, it means that epigenetic reversal is not so much about the health but the Possibility of reaching longer life/the maximum of the specie; and that health is entwined with longevity - but not Entierly...they can be disconnected too; I would wager that an Unhealthy fly..could Live to its Maximum..but it would struggle and it would be a life of misery and sickness..But it Would reach the maximum lifespan potential; but it Chances...of that happening would be Cut by the ^possibility of dying of 'health complication/disease' -----Unrelated to Reaching the Maximum *Longevity*.
This is exacctly the old .: ''why do young people die...should they not live long? they are young...why do they do die prematurely of some disease...what if they did not have that disease...would they reach 120 year old???...''
The answer is almost int he question...if you become sick you can accelerate the process of health threshold loss..and this may accelerate the aging process - in my case, Atherosclerosis...i saw..that it could Dramatically make someone 'gray' 'overnight'...because you lose the capacity to maintain your health; thus, you could experience an epigenetic acceleration; but, the disease might not necessarily mean that you have 'aged on the epi - clock'; rather, you are experiencing dysfunction of an organ - not Necessarily Aged - in the body; if an organ - young or old - stops working; it stops working; this can disconnect the health and aging of an organ; and it is Why a young person could die young - Even If by the epigenetic clock they Are Younger...
and it concords withe the fly...that lives longer when senescence is reduced...but it does not reach the maximum...it Needs epigenetic reversal; and epigenetic reversal Itself - Alone - can make that fly reach the maximum; but the fly - will Struggle (if Only epireprogramming); because it will have a higher senescence burden - than if it did Senolytics and reducing SASP inflammation burden....On Top of the/combined with Epigenetic Reversal..
We have a few things to fix -- DNA damage + epigenetic age + SASP + telomere shrinking + residues + mitoDNA/mitocopy loss + chromosome/histone loss/demethylation of methylome/epidrifting..
Now if we can fix these, then yes, we will be able to go above the MLSP;
but the fly study (and the other one in old mouse) confirmed that partial epigenetic reprogramming, will sadly, not make any human live above MLSP (120) on its own.
Neither will any senolytics therapies - they only affect health...and will not make you reach 120; rather it will Enable you to reach 120; but maintaing you health..until then; but if there is Discrepancy in epiclock and your Chronologic Age is Higher than your EpiAge...it won'T happen.
this leaves us with the big one - DNA damage/DSBs/SSBs.

Posted by: CANanonymity at May 13th, 2022 2:18 AM

PPS: ''Chronologic Age is Higher than your EpiAge''...my bad/typo... I meant the reverse..
* ''EpiAge is Higher than your Chronological Age''
(is when biological aging is greatly advanced/accelerated; when you chronological age is much Higher than your epiage...you are actually biologically much younger because you are chronologically very old (in years time/real time) - but in your body; your epiclock is very low - that is what allows to reach MLSP; is having the lowest epiclock possible and the highest chrono age).

Posted by: CANanonymity at May 13th, 2022 2:30 AM

Methylation also disinhibits transcription of carcinogenic viral retrotransposons.

Posted by: mert erogul at May 19th, 2022 9:28 PM
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