A Discussion of Epigenetic Reprogramming and Rejuvenation

Cell reprogramming can be achieved by gene therapies that express pluripotency genes - some or all of the Yamanaka factors. It is akin to the process that takes place in the early stages of embryonic development, and which removes the mitochondrial dysfunction and epigenetic alterations found in old tissues. Although germline cells are already very well protected, this extra step is necessary in order for children to be born physiologically young.

Cell reprogramming has largely been used to produce induced pluripotent stem cells, an important tool in the field of regenerative medicine and tissue engineering. In recent years, however, researchers have started to deploy cell reprogramming gene therapies in animal studies, finding the potential to achieve reversal of at least some markers of aging. Mitochondrial function and epigenetic regulation of gene expression are the targets of greatest interest, and this is giving new energy to the minority faction in the research community who think of aging as an evolved epigenetic program.

To my eyes, epigenetic change looks like a downstream outcome of deeper processes of aging, such as repeated cycles of DNA damage and repair, perhaps. Raised blood pressure is also a downstream consequence, but reduced mortality in older people can be achieved via forced control of blood pressure, implemented without addressing the underlying causes. Will reversal of epigenetic change prove to be a better version of blood pressure control, so to speak? A greater possible gain for health, while still leaving the underlying causes of aging to produce other harms? That remains to be seen.

There are clearly issues that cannot be solved by success in the application of reprogramming to reverse age-related epigenetic alterations. Many forms of harmful metabolic waste (persistent cross-links, lipofuscin components, and the like) cannot be broken down effectively even in youthful cells and tissues. Nuclear DNA damage and somatic mosaicism cannot be erased by rejuvenating cells. Cancerous and senescent cells should be destroyed, not rejuvenated. And so forth.

Aging and rejuvenation - a modular epigenome model

Gerontology is perhaps the biological discipline that has given rise to the largest number and variety of theories even before the development of modern science. Most theories aimed not only at elucidating the mechanism of aging but also at providing effective interventions to slow aging down. In the late 1950s the focus of research attention moved to DNA as the likely driver of aging either by expressing a program of aging or by being the target of endogenous and external insults that accumulated damage on the molecule during the lifetime of an organism. Up to this stage, aging was considered as an essentially irreversible process. However, with the discovery of cell reprogramming, early in this century, a view began to emerge that considers aging as a reversible epigenetic process.

The hypothesis proposing the epigenome as the driver of aging was significantly strengthened by the converging discovery that DNA methylation at specific CpG sites could be used as a highly accurate biomarker of age defined by the Horvath clock. The strong correlation between the dynamics of DNA methylation profiles and the rate of biological aging leads to the idea that the epigenetic clock may in fact be the pacemaker of aging or at least a component of it. And it is at this point where epigenetic rejuvenation comes into play as a strategy to reveal to what extent biological age can be set back by making the clock tick backwards.

The few initial results already documented seem to suggest that when the clock is forced to tick backwards in vivo, it is only able to drag the phenotype to a partially rejuvenated condition. Nevertheless, it would be premature to draw firm conclusions from the scanty experimental results so far documented. What seems to be clear is that epigenetic rejuvenation by cyclic partial reprogramming or alternative non-reprogramming strategies holds the key to both understanding the mechanism by which the epigenome drives the aging process and arresting or even reversing organismal aging.

Comments

Or it could well be that epigentic drift is the 8th deadly SENS that needs to be fixed like everything else.

Posted by: Tom at March 6th, 2021 7:55 AM

In my opinion, a comprehensive senolytic clearing of essentially all senescent cells should precede any attempt at rejuvenation by epigenetic reprogramming to a more youthful epigenome profile. As stated in the article "senescent cells should be destroyed, not rejuvenated" and there are ways of achieving that, e.g., by the Oisin plasmid technique.

Posted by: John G Cramer at March 6th, 2021 11:45 AM

@John G Cramer: Since Goya's paper specifically refers to Harold Katcher's & co's "elixir" (more recently referred to as "E5"), it should be noted that epigenetic rejuvenation by E5 (and also by the Conboy's plasma dilution therapy) was accompanied by restoration of many biomarkers to youthful levels, including elimination of senescent cells. In my eyes that's actually why these therapies are so remarkable - they provide complete systemic rejuvenation, presumably including the immune system components responsible for clearing senescent cells. This would render senolytics obsolete before they are deployed! Given the long history of parabiosis that inspired this work, it's amazing to me that these therapies weren't discovered years, even decades ago.

Posted by: Nick Westgate at March 7th, 2021 5:45 PM

these processes are associated, alphaketoglutarate is one of identified components that naturally makes epigenetic rejuvenation, but with age it's productions drops considerably (combined with TGFbeta it causes organism wide fibrosis) but it's production control mechanism is unknown. Senolytics so far don't regulate it back up. Do E5 discoverers fallen on on this mechanism?

Posted by: SilverSeeker at March 9th, 2021 8:36 AM

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