Advocating for Epigenetic Reprogramming as a Potential Rejuvenation Therapy

Partial epigenetic reprogramming emerges from the intersection of understanding how cells behave in cancerous tissue and during embryonic development. In the developing embryo there is a point at which adult germline cells convert themselves into embryonic stem cells, discarding forms of damage and dysfunction characteristic of adult cells and restoring a youthful pattern of the epigenetic markers attached to the genome that control its shape in the cell nucleus and thus gene expression. Some of the genes involved are known to also operate in cancers, in which replication and reprogramming runs wild, but which use many of the same mechanisms as the embyro.

Given exploratory work to date, it seems possible to pick apart the regulatory systems controlling (a) change of cell type via dedifferentiation, and (b) restoration of youthful epigenetic markers. That second item is highly desirable. If researchers could reset the epigenetics of aged cells, they would become more youthful. Given enough cells reset in this way, tissues and organs would become more youthful in function. Some forms of age-related molecular damage can't be repaired in this way, such as persistent metabolic waste or nuclear DNA damage, but evidence from studies of epigenetic reprogramming in aged mice suggest that there are sizable gains that can be achieved via this approach, provided that cancerous transformation of cells can be kept at bay.

One might argue that given the existence of Altos Labs ($3 billion), Retro Biosciences ($180M), and at least another $100M in investment in various epigenetic reprogramming ventures, there is little need to advocate for epigenetic reprogramming as a road to rejuvenation. That road will be traveled in the years ahead regardless of the thoughts that any of the rest of us might have on the matter. The funding is there, a great many researchers are working on the challenges involved, the big questions will be answered, initial therapies will be cautiously deployed in small parts of the body such as the eye, and whether or not expression of reprogramming factors throughout much of the body, via small molecules or gene therapy, is viable as a basis for rejuvenation therapies will be much more clear a few years from now.

Epigenetic Reprogramming as a Key to Reverse Ageing and Increase Longevity

The pursuit for the fountain of youth has long been a fascination amongst scientists and humanity. Ageing is broadly characterized by a cellular decline with increased susceptibility to age-related diseases, being intimately associated with epigenetic modifications. Recently, reprogramming-induced rejuvenation strategies have begun to greatly alter longevity research not only to tackle age-related defects but also to possibly reverse the cellular ageing process. Hence, in this review, we highlight the major epigenetic changes during ageing and the state-of-art of the current emerging epigenetic reprogramming strategies leveraging on transcription factors. Notably, partial reprogramming enables the resetting of the ageing clock without erasing cellular identity. Promising chemical-based rejuvenation strategies harnessing small molecules, including DNA methyltransferase and histone deacetylase inhibitors are also discussed.

Moreover, in parallel to longevity interventions, the foundations of epigenetic clocks for accurate ageing assessment and evaluation of reprogramming approaches are briefly presented. Going further, with such scientific breakthroughs, we are witnessing a rise in the longevity biotech industry aiming to extend the health span and ideally achieve human rejuvenation one day. In this context, we overview the main scenarios proposed for the future of the socio-economic and ethical challenges associated with such an emerging field. Ultimately, this review aims to inspire future research on interventions that promote healthy ageing for all.

Numerous intriguing questions remain unanswered. (1) What are the specific molecular mechanisms behind epigenetic dysfunction that contribute to the ageing process and how do these correlate with the different hallmarks of ageing? (2) To what extent can the current in vitro aged animal models be translatable to the human ageing process in its entirety? Will emerging humanized in vitro 3D models such as organoids accelerate longevity research? (3) Realistically, how far are we from reprogramming-induced epigenetic rejuvenation interventions in human clinical trials? Will these rejuvenate organs and even the entire human body? Could these prevent and eradicate ageing-related diseases safely? (4) In the future, could epigenetic reprogramming be a routine medical procedure to reverse the biological age and extend human healthspan? Would these interventions be effective in both young and elderly individuals? How far could we go? (5) How reliable could epigenetic clocks be in research and clinical settings for developing and prescribing novel healthspan-prolonging interventions? (6) Will legislative and policy frameworks be able to keep pace with the scientific breakthroughs in the young science of anti-ageing treatments? How will bioethicists, society, and medical professionals perceive these emerging findings?


I for one am really happy how much funding has been put into this field in last 5 years. Somethings gotta stick soon.

Besides reading Reasons blog, I see many other articles regularly on potential means to slow down if not repair the ageing process.

Posted by: Robert at February 6th, 2024 3:43 PM

I think senolytics could do at least as much. Which is why it is crazy that no one is putting hundreds of millions to billions into a CAR-T senolhtic.

On the other hand, why aren't there hundreds of millions to billions going into cholesterol breakdown and removal?

Posted by: jimofoz at February 7th, 2024 7:41 AM

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Posted by: Rob at February 8th, 2024 6:30 PM

@ Rob, I wonder how many years, if at all, this makes it into available treatment for the average person?

Posted by: Robert at February 8th, 2024 11:19 PM
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