Cycles of DNA Damage and Repair as a Cause of Age-Related Epigenetic Drift

Researchers have recently proposed that the normal operation of DNA repair contributes to the epigenetic change that is observed to occur with age. This is an interesting concept, and we'll see how it progresses in the years ahead, particularly as therapies based on alteration of epigenetic markers emerge as an area of active medical research and development.

Epigenetic decorations to DNA are a part of the complex regulatory system controlling the amounts and timing of protein production carried out by a cell. Cells react to changing circumstances with changes to epigenetic markers such as DNA methylation. Some of the alterations in cells and tissues that take place with advancing age, such as rising levels of molecular damage, are very similar between individuals, and thus weighted combinations of the status of specific epigenetic markers can be used to measure age. But most epigenetic change is highly variable and highly individual, dependent on the circumstances that each cell finds itself in, communications with surrounding cells, the overall environment, diet, state of health, and so forth.

At the present time is far from clear as to why exactly most epigenetic changes occur; building the full map and understanding of epigenetic adjustments in response to circumstances will likely still be a going concern decades from now. Even those epigenetic markers used to build biomarkers of aging are not yet firmly connected to specific underlying causes, though work is proceeding towards that end. This uncertainty gives rise to academic and popular debate over where epigenetic change sits in the tangled web of cause and consequence in aging. Programmed aging theorists hold that epigenetic changes are a cause of aging, and reversing them is therefore rejuvenation. Aspects of this view are being voiced more loudly these days, now that certain entities with deep pockets and well-oiled hype machinery are putting venture funding into the development of clinical therapies based on reprogramming cells to have youthful epigenetic patterns.

It would be very surprising to find that epigenetic change is at the roots of aging. The most telling arguments against this are the numerous contributions to aging based on the accumulation of metabolic waste that our biochemistry cannot break down, even in youth. No approach to restoring youthful epigenetic patterns can address that. Epigenetic change can certainly be a proximate cause to all sorts of disarray in aging, however. Reprogramming cells has been shown to restore mitochondrial function, and the general malaise in mitochondria that takes place in all cells in aging tissue can be traced back through failing fission, failing mitophagy, to gene expression levels of specific proteins. Force a cell to produce those proteins at a youthful level, and mitochondria will function once again.

Yet how great a gain can be produced while ignoring the underlying causes? If the history of medicine teaches us anything, it is that efforts to treat age-related disease without addressing its causes have been a miserable failure. Will it really be that much better to take one or two steps closer to the cause, while still not addressing it? That is an important question, and one we are going to see tested in practice, sadly. Enthusiasm and funding for taking those one to two steps is far greater than that for addressing the known root causes of aging.

In this broader context, the work noted here is quite interesting, proposing that the normal ongoing processes of DNA damage and repair taking place in every cell can, over time, produce at least some of the epigenetic changes of aging. They use artificially raised levels of DNA damage and repair to produce accelerated epigenetic change in mice that is at least similar to that of aging.

DNA Damage Leads to Epigenetic Alterations

Despite it long having been the consensus that DNA damage and the resulting epigenetic changes are drivers of aging, some recent studies have questioned the importance of mutations in aging. For example, the number of mutations present in aged yeast cells is fairly low, and some genetically engineered strains of mice with high levels of free radicals or mutation rates do not appear to age prematurely, nor do they have shorter lifespans than their wild-type counterparts.

This appears to suggest that mutational load may not have such a strong influence on aging as was once thought, and the researchers of this new study consider further evidence suggesting the same. They also suggest that epigenetic alterations are perhaps the most important driver of aging and that, far from being random in nature, these changes are predictable and reproducible.

Researchers suggest that DNA double-strand breaks (DSBs) are a possible reason for epigenetic changes and show that there are clues to be found in yeast. In yeast cells, DSBs trigger a DNA damage signal that summons epigenetic regulators and takes them away from gene promoters to the site of the DSB on the DNA, where they then facilitate the repair of the break. The researchers suggest that after these repairs, the regulators responsible for repairing the DSBs return to their original locations on the genome, thus turning off the DNA damage signal, but this does not always happen.

The researchers suggest that with each successive cycle of DNA damage response and repair, the epigenetic landscape begins to change and regulators gradually become displaced, reaching a point where the DNA damage response remains active, leaving cells in a chronic state of stress. This stressed state then causes them to become dysfunctional and ultimately alters their cellular identity.

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

There are numerous hallmarks of aging in mammals, but no unifying cause has been identified. In budding yeast, aging is associated with a loss of epigenetic information that occurs in response to genome instability, particularly DNA double-strand breaks (DSBs). Mammals also undergo predictable epigenetic changes with age, including alterations to DNA methylation patterns that serve as epigenetic "age" clocks, but what drives these changes is not known. Using a transgenic mouse system called "ICE" (for inducible changes to the epigenome), we show that a tissue's response to non-mutagenic DSBs reorganizes the epigenome and accelerates physiological, cognitive, and molecular changes normally seen in older mice, including advancement of the epigenetic clock. These findings implicate DSB-induced epigenetic drift as a conserved cause of aging from yeast to mammals.

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Sinclair Interview Excerpts
YouTube
https://youtu.be/uA9z8K5snOk

Here are 7 minutes of excerpts from my July interview with David Sinclair (From "To Age Or Not To Age - Transforming the Human Condition") where in he explains his theory of what causes aging.

Posted by: Robert Kane Pappas at October 15th, 2019 3:24 PM

One further note, I ask Sinclair if he anticipates attacks along the lines of Reason's questions.
I am creating a series with a number of the scientists.

Posted by: Robert Kane Pappas at October 15th, 2019 3:27 PM

It would be interesting if someone would combine partial reprogramming with senescent cell removal in a mouse model to check if the lifespan extension effects of each stack.

Posted by: jimofoz at October 15th, 2019 4:04 PM

@Reason - I think you are being a bit too dismissive of this being a legitamate cause of damage with aging. Yes it was in vitro in cells that have artificially high rates of DNA damage, but it does seem plausible. I guess further experiments will settle things.

An interesting experiment could be to use CRISPRi to "turn off" the area of DNA that gets "stuck on" with repeated DNA damage and see if that reduces inflammation rather than full "4 day partial epigenetic reprogramming".

It does offer an alternative explanation for the life extension effects in mice of reprogramming other than just "putting damaged cells back to work" (or both could be in effect).

Even if it does turn out to be a class of damage outside of the SENS 7 classes, there is already a solution for it entering clincial trials soon.

Posted by: jimofoz at October 16th, 2019 7:11 AM

@Robert Kane The finding that you can regrow crushed nerves in a mice is very interesting, I think there is something to reprogramming and Reason is overly pessimistic, on the other hand in your video Sinclair touched cancer, and cancer is clearly a genetic disease, as fare as I know nobody every found a cancer without a mutation in the described oncogenes like RAS, BRAF ect or tumors suppressor genes like P53, STK11 ect. so I don't see how epigentic reprogramming could solve mutations in the nuclear DNA that occur over time. Reason brings up other hallmarks that reprogramming can't solve, at least not in an obvious way, of course you can always hand wave to a rejuvenated immune system that can do magical things, but still, a lot of kids die of cancer.

Posted by: Tom at October 16th, 2019 7:29 AM

Senescence induced by curcumin was DNA damage-independent and resulted from influencing many signaling pathways: ""We observed characteristic senescence markers but the number of DNA damage foci DECREASED". This statement is in no way consistent with the idea of accumulation of DNA double-strand breaks as a primary Cause of Mammalian Aging. See: Curcumin induces senescence of primary human cells building the vasculature in a DNA damage and ATM-independent manner. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315775/

Posted by: Dmitry Dzhagarov at October 16th, 2019 10:25 AM

Written this before but....Just to shine some extra light on this question / discussion as it gets a but confused at times

There is a bit of difference between "cellular reprogramming" and "whole organism reprogramming"

The former, per the technologies of AgeX, Turn, Salk, many others, etc., are tools for in essence "cleaning up a cell" - epigenetic modifications, organelle remodeling, telomere "re"-longation, etc.

These are all variants from the original 1952 cloning experiments by Robert Briggs and Thomas J. King, modified by Gurdon, Jaenisch, Yamanaka, and many others etc. into the current day - and they are all pretty good, from one angle or another, in making a cell "younger / rejuvenated "

The latter, organism rejuvenation via reprogramming, is NOT the same thing - it is a bit of a more complicated set of events, but can be summed up as such:

Organisms (such as amphibians, planarians, echinoderms, hydrozoans, etc.) that have the ability to "turn back biological time", to regenerate / repair / rejuvenate most (or all) of their bodies, possess two inherent capabilities that they use in synergy: 1) The ability to re-establish the "embryogenic" potential of their cells / genomes / gene regulatory networks (per inherent cellular reprogramming dynamics - like above),

AND, of equal (if not greater), importance,

2) ...the ability to re-establish the "morphodynamic" architecture of their tissues / organs / limbs / body segments

The latter involves many other things beyond cell reprogramming - ECM histolysis and remodeling, activation of components of the innate immune response, membrane potential changes, morphogenetic gradient formation, and a long additional list of other stuff that I won't take up space with here

But the point is, it is in the context of the regenerative micro-environments that RESULT from this reprogrammed cellular flexibility that we see the really neat stuff happening - not just in these "lower" non-human species, but also in mammalian embryos - this is why you can "dump" all sorts of "junk" into a mammalian embryos (normal somatic tissues, cancer cells, viruses, etc.) and it all gets organized out

Here are some links to nice reviews on the general theme of regenerative micro-environments and their ability to "organize in / out" stuff they don't need, and well as modify the diseased phenotype. As a subset of this re-organization theme, here are also papers on the topics of revertant mosaicism (primarily seen in tissues with an active regenerative niche) and cellular competition (seen in both development and the maintenance of tissue fitness)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706275/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735296/pdf/v040p00721.pdf?fbclid=IwAR2KU3-lOXwUfW-7J8ImXwoTyuDkbwUi6QW__kyLuuNQotPgSlYwHgtTydI

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763810/pdf/TSWJ-2010-10-742904.pdf?fbclid=IwAR12BmgpftnZleWh73VmLRagy8deNc1_xn0LV1BKrRthSgsAZ3zWP9Srv_w

http://jcb.rupress.org/content/200/6/689.full

The seminal work on embryos and teratocarcinoma was done by Mintz et al in Philadelphia in the 1970s:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC433040/

Similar dynamics also occur in the plant kingdom:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC335936/

The point is that for whole organism human rejuvenation using such tools, especially for complex tissues and organs, we will need to go well beyond just "throwing in" some reprogramming factors and walking away - that is far from how the process works in nature

But there is tremendous potential with these tools if used correctly in the right bio-dynamic context

Posted by: Ira S. Pastor at October 16th, 2019 11:00 AM

What is your explanation for the various pro and anti aging effects of curcumin, Dmitry?

Posted by: Mark at October 17th, 2019 9:06 AM

Dear Mark, this remains to be seen. The authors of the article do not give an answer to this question. But an interesting pattern exists: the reprogramming of somatic cells into iPSCs, as a rule, is accompanied by the simultaneous rapid aging of neighboring cells. In addition, these aged cells by their secretions contribute to the reprogramming (and therefore rejuvenation) of the future iPSC cells. Perhaps we observe a similar phenomenon in the case of curcumin described above, when authors observed "characteristic senescence markers but the number of DNA damage foci DECREASED". https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315775/

Posted by: Dmitry Dzhagarov at October 19th, 2019 10:25 AM

Perhaps Dmitry, but I still think I'll steer clear of curcumin for now. Thanks.

Posted by: Mark at October 20th, 2019 2:45 AM

@ Ira S. Pastor.
Thank you for re-emphasizing here the distinction bewteen "cellular reprogramming" and "whole organism reprogramming". I very likely have overlooked it and wonder if you can point to other materials you have written along the same lines. Thank you.

Posted by: albedo at October 20th, 2019 11:17 AM

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