Advocating for the Reprogramming of Cells as a Path to Treat Aging

A fair number of researchers consider cellular reprogramming to be a promising path forward for the treatment of aging. Some of these think that epigenetic change is an important cause of of aging, while others see the epigenetic changes characteristic of aging as a downstream consequence of underlying processes of damage, but consider reprogramming to be a potentially useful point of intervention regardless. Reprogramming as a basis for therapy entails at least partially pushing cells towards pluripotency, in the same manner as the production of induced pluripotent stem cells, but not so far down this path that they lose their differentiated identity and ability to function. As a side-effect, the epigenetic patterns of gene expression are reset to a more youthful configuration. Mitochondrial function improves, cell function improves. This cannot repair DNA damage, and will likely also struggle with some of the other issues of aging, such as the accumulation of waste products in long-lived cells. It does, however, appear to produce benefits in animal models, in early exploratory studies.

Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal somatic cells, which age and die. In this review, we describe the germline as clock-free and somatic cells as clock-bound and discuss aging with respect to three DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks.

The initiation of the DNA methylation aging clock, the telomeric clock, and perhaps other clocks at the beginning of development suggests an intimate relationship between development and aging. Indeed, the adaptation of developmental clock rate to environmental pressure could account for the wide variation in lifespan observed between species. For example, humans and naked mole-rats exhibit neoteny, where slowing the rate of development correlates with an extension of lifespan. The application of germline strategies in somatic stem cells has resulted in the remarkable regenerative capacity of lower life forms that are capable of indefinite lifespans, such as sponges, planarians, and hydra. This regenerative capacity has become increasingly restricted as more complex life forms evolved, being confined prior to the embryonic to fetal transition period in mammals. However, retention of extensive capacity for regeneration is observed in lower vertebrates, including fishes, amphibians, and reptiles, which also exhibit remarkable phenotypic plasticity in their capacity for metamorphosis and in certain cases of remarkable reversals of developmental stage and sexual development.

Finally, reprogramming using germline factors can uncover a similar but latent phenotypic plasticity in mammals by reverting both the developmental state and cellular age. Indeed, both natural phenotypic plasticity in the blue wrasse and partial reprogramming involve the repression of DNA methyl transferases and induction of demethylases which, by a yet-to-be-determined mechanism, may enable the DNA methylation clock to tick backward. The discovery that partial reprogramming can reverse the aging clock without permanent alteration of cellular identity has led to initial studies that demonstrate the potential to reverse organismic aging. Although there are many challenges ahead, our current understanding of cellular clocks and our ability to reprogram them using germline factors opens the door to many promising therapeutic approaches to slowing down, preventing, or reversing aging itself and thus treating the many age-related diseases that burden society. Indeed, if these approaches can be made practical and scalable, we may find ourselves in a future in which we have no time to age.



Gerostate Alpha now on Wefunder.

Posted by: Gekki at May 3rd, 2021 6:58 AM

Related to your last sentences, Reason: Was it ever investigated, if cellular reprogramming can reverse cellular damages (you mentioned improved mitochondrial function. Do you have a source?) How about telomere attrition, protein aggregates, AGEs etc? And could reprogramming reverse cellular senescence? Propably not, since it is an irreversible process, or?
Do you know if the tissue function during aging decreases becauses of dysfunctional cells or because of increased cell death or because of accumulation of senescent cells? Which is the dominating force? Or are all playing a role?
(I am asking, because I think all these questions play a role in considering reprogramming as a therapy)

Posted by: Arthur at May 8th, 2021 1:24 AM

I agree that epigenetic reprogramming seems to be a very promising approach to the treating of aging. However, It is my view that first one should clear as many senescent cells as possible and then do epigenetic reprogramming on the cells that remain. This will, at least to some extent, avoid the problem of reprogramming cells that have sustained DNA damage.

Posted by: John G Cramer at May 9th, 2021 8:03 PM
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