(422d) Reprogramming Skeletal Muscle Rejuvenation.

Aging is associated with the presence of senescent cells within tissues that impairs organ function and physiological integrity. Senescent cells are characterized by biomarkers that conceptualize the underlying mechanisms of aging. Here we show that expression of an embryonic transcription factor, NANOG, in senescent cells ameliorated several hallmarks of cellular senescence i.e. epigenetic marks, DNA damage response, autophagy, and cellular energetics. NANOG is an embryonic transcription factor that maintains the self-renewal and stemness in embryonic stem cells and iPSCs while it is not expressed in most of the cells after completion of development. Ectopic expression of NANOG in the senescent progenitors of skeletal muscle (myoblasts) reprogramed the senescent cells to reactivate AMP-activated protein kinase (AMPK) and upregulate autophagy. The increased autophagy flux removed the misfolded proteins and dysfunctional mitochondria from the senescent cells and conferred them a superior respiration and energetics. NANOG expression also strengthened the DNA repair pathways and heterochromatin marks to restore genomic stability in senescent cells. In vivo expression of NANOG in the TA muscle reinstated the pool of juvenile myogenic progenitors in a mouse model of premature aging.