Abstract
The decline of tissue regenerative potential with agecorrelates with impaired stem cell function. However,limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system,we identify cell death by mitotic catastrophe as acause of impaired stem cell proliferative expansionin aged animals. The mitotic cell death is caused bya deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibitionof Mdm2 expression through Hey transcription factors during normal muscle regeneration and thatthis pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion ofaged MuSCs in vivo. Altogether, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and isdysregulated during aging, contributing to the agerelated decline in muscle regenerative potential.

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Liu L, Charville GW, Cheung TH, Yoo B, Santos PJ, Schroeder M and Rando TA.
Impaired Notch Signaling Leads to a Decrease in p53 Activity and Mitotic Catastrophe in Aged Muscle Stem Cells
Cell Stem Cell. 2018; 23(4):544-556.e4.