Aging is the major risk factor for most human chronic diseases. During development, cellular reprogramming initiates the formation of zygotic and primordial germ cells, accompanied by significant chromatin reorganization. This process generates totipotent and pluripotent cells that are free from age-related molecular defects, illustrating that both cell identity and age can be reversed. This alteration of cell identity has been successfully replicated in vitro through various methods, including somatic cell nuclear transfer (SCNT), the forced expression of transcription factors (OSKM), and, more recently, treatment with small molecules (7c). While several groups have shown that in vivo partial reprogramming via transient application of OSKM can rejuvenate molecular hallmarks of aging, restore tissue function, and extend lifespan in mice, inefficient gene delivery and risk of oncogenesis hinders clinical development. Considering both the rejuvenating effects of OSKM partial reprogramming and the ability of small molecule cocktails to induce pluripotency, I propose the use of chemical-induced partial reprogramming for the amelioration of aging phenotypes.
In this thesis, I demonstrated that partial reprogramming using a defined cocktail of small molecules (7c) can improve key drivers of aging including genomic instability and epigenetic alterations in vitro. In addition, I identified an optimized combination of two reprogramming molecules (2c) capable of inducing additional improvements of aging phenotypes including cellular senescence and oxidative stress.
Importantly, application of this reduced cocktail in C. elegans induced multiparameter amelioration of markers of aging, stress-resistance, and healthspan, and was able to significantly extend lifespan in vivo. Taken together, these data demonstrate the improvement of key drivers of aging and lifespan extension via chemical-induced partial reprogramming, opening a path towards future translational applications.