摘要Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia,and increases the risk of many aging-related metabolic diseases.Here,we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging.A higher transcppoonalfluctuation was observed in myonuclei relative to other interstitial cell types,indicating a higher susceptibility of skeletal muscle fiber to aging.We found a downregulation of FOXO3 in aged primate skeletal muscle,and identi-fied FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis.Through the establishment of a complementary experimental pipeline basedon a human pluripotent stem cell-derived myotube model,we revealed that silence of FOXO3 acceler-ates human myotube senescence,whereas genetic activation of endogenous FOXO3 alleviates human myotube aging.Altogether,based on a combination of monkey skeletal muscle and human myotube aging research models,we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging,providing a comprehensive resource for the development of clini-cal diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.