Towards Many Efforts to Produce Rejuvenation Therapies Based on Cellular Reprogramming

There is enthusiasm in the research community for in vivo cellular reprogramming as a path to treat aging. Reprogramming somatic cells to pluripotency recaptures some of the processes that take place in the developing embryo, and has been shown to restore youthful patterns of gene expression, leading to improved mitochondrial function. Reprogramming can't do much for DNA damage or forms of persistent molecular waste in long-lived cells, but forms of reprogramming may be able to improve tissue function to a sizable enough degree to be worth the effort. Early results in mice are promising. There is a long way to go in order to produce systems of reprogramming that are safe enough and sophisticated enough to be used systemically, however, rather than in comparatively small and isolated areas of the body, such as the retina.

As we age, we become increasingly vulnerable to age-related diseases. The progressive aging of the population makes this issue one of, if not the, major current scientific concern in the field of medicine. Aging is an intricate process that increases the likelihood of cancer, cardiovascular disorders, diabetes, atherosclerosis, neurodegeneration, and age-related macular degeneration. The regenerative capacity of cells and tissues diminishes over time and they thus become vulnerable to age-related malfunctions that can precipitate death.

Developing prophylactic strategies to increase the duration of healthy life and promote healthy aging is challenging, as the mechanisms causing aging are poorly understood, even if great progress has been made from studying naturally occurring or accelerated-aging phenomena. We now know that aging inculcates many changes, or 'hallmarks': genomic instability, telomere shortening, epigenetic alterations, loss of proteostasis, cellular senescence, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, and stem cell compromise and exhaustion. These various hallmarks of aging are all active fields of molecular mechanistic study with much promise but relatively few tangible results have been translated into therapy.

Perhaps the most effective strategies so far have been those that focus on the removal of senescent cells with 'senolytic' drugs. In some ways, however, we feel this is too focused on the symptoms of aging whereas perhaps the most promising strategy for the future would be to focus on the causes of aging and its corollary, the rejuvenative capacity of stem cells.

Simply expressing four transcription factors, OCT4, SOX2, KLF4 and c-MYC (OSKM), converts somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming occurs through a global remodeling of the epigenetic landscape that ultimately reverts the cell to a pluripotent embryonic-like state, with properties similar to embryonic stem cells (ESCs). This cellular reprogramming allows us to imagine cell therapies that restore organ and tissue function. Indeed, by reprogramming a somatic cell, from a donor into iPSCs, these cells can then be modified or corrected before redifferentiation, to produce 'rejuvenated' cells, tissues or organs, for replacement in the same donor or an immune-compatible person.

In recent years, emerging results have led to new ideas demonstrating that the mechanics of cellular reprogramming can be used to reduce the deleterious effects of aging and to delay these effects by increasing regenerative capacity, either at the cellular or the whole-organism level.



An aged immune system drives senescence and ageing of solid organs

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5,6,7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8,9,10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.

Posted by: Robert Read at May 13th, 2021 7:53 AM

Reason said: "Reprogramming can't do much for DNA damage or forms of persistent molecular waste in long-lived cells ..." True but perhaps misleading. The strategy should be to clear senescent cells, i.e., those with DNA damage and accumulated waste, BEFORE undertaking epigenetic reprogramming. There are existing techniques for doing both.

Posted by: John G Cramer at May 13th, 2021 11:34 AM

I think that senolytics should not be used as monotherapy, but in combination with methods of replacing the loss of old cells by increasing the number of younger progenitor cells. Attempts to carry out replacement therapy by transplantation of mesenchymal stem cells are, as a rule, not very successful due to the observed mass death of cells after transplantation, caused by a hostile environment. A better approach would be to activate the filling of the "released space" by stimulating endogenous replacement mechanisms. But in the adult body, such a replacementis usually are fibrous scar tissue cells, instead of functional tissue. –°hronic fibrotic diseases account for more than 45% of all deaths.
"Reversible immortalization" technique called Conditionally Reprogrammed Cells (CRC) culture method allows in vitro propagation of adult cell culture WITHOUT ANY GENETIC MANIPULATIONS. I suggested to use for this technology the combination of ROCK inhibitors (Y-27632, Fasudil, Thiazovivin, maybe statins?) and 5-LOX inhibitors (zileuton, baicalein, berberine, curcumin, caffeic acid or CASIN). It is unlikely that such a combination of drugs that obviously should stimulate proliferation of progenitor cells, will promote oncogenesis, since ROCK inhibitors and 5-LOX inhibitors are commonly used to prevent it. Such a simplification of the technology of conditionally reprogrammed cells opens up the possibility of transferring this technology from a test tube to the body, affecting cell proliferation in situ.
By placing a combination of ROCK inhibitor and 5-LOX inhibitor in microspheres from a lactic and glycolic acid copolymer (PLGA) for controlled prolonged release, it should be possible to initiate the formation of CRC cells in situ directly in an animal. The powder from such microspheres can be used to treat diseases of various organs (lungs, liver, heart, eyes, skeletal muscles) leading to dystrophy or fibrosis, as well as to combat a number of age-relatedand oncological diseases. More details in:

Posted by: Dmitry Dzhagarov at May 15th, 2021 6:23 AM

People that live to 110 have better DNA damage repair mechanisms. I liked the idea of giving our mitochondria the ability to produce NAD+.

Posted by: Tj Green at May 16th, 2021 2:15 AM
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