Cell reprogramming as a basis for the treatment of aging involves inducing the expression of Yamanaka factors for a short period of time, ideally resulting in a shift in cell epigenetic state to a more youthful configuration without disruption of cell function or the creation of potentially harmful pluripotent stem cells. While early efforts focused on gene therapy technologies, there is a branch of research focused on small molecules that might achieve sufficient Yamanaka factor expression to be interesting. A number of combinations of small molecules have been explored, and the one assessed in mice here has been called the 2c cocktail by other authors. While small molecules have the advantage of effective delivery to the whole body, a goal that remains impossible for adult gene therapies, side-effects remain a sizable concern for the known small molecule reprogramming agents.
Targeting partial cellular reprogramming pathways through specific small molecule combinations holds promise for lifespan extension in model organisms. Chemical cocktails like RepSox and tranylcypromine (TCP) may induce beneficial age-related changes without the risks of full reprogramming. Female C3H mice were divided into two age groups: "old" (16-20 months) and "senior" (10-13 months). They received intraperitoneal injections of RepSox (5 mg/kg) and TCP (3 mg/kg) or DMSO (control) every 72 h for 30 days.
In the "old" group, treated mice showed enhanced neurological status, fur and skeletal health, and increased cortical angiogenesis, though with some adverse histological changes in the liver and brain. In the "senior" group, treated mice displayed a plateau in mortality after month seven, while deaths continued in controls. Although overall survival was not significantly different, maximum lifespan significantly increased in treated mice. Histological findings revealed localized adaptive changes rather than major toxic effects. These results suggest that the combination of RepSox and TCP exerts protective effects on aging phenotypes and may potentially slow systemic aging processes in C3H mice.
Link: https://doi.org/10.1002/brb3.70573
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