Mitophagy Deficiency Drives Skeletal Muscle Aging: Translational Evidence for Urolithin A and Spermidine in Reversing Primary Sarcopenia

Primary sarcopenia is an age-associated degenerative disorder marked by progressive loss of skeletal muscle mass, strength, and function, representing a major driver of frailty and morbidity after midlife. Convergent evidence from human muscle biopsies, aged rodents, Drosophila, and myogenic cell models identifies mitochondrial dysfunction as the proximal cause of this decline, with impaired mitophagy emerging as the central mechanistic failure. Aging muscle exhibits reduced mitochondrial content, compromised oxidative phosphorylation, dysregulated dynamics favoring excessive fission, and accumulation of oxidized, depolarized mitochondria. These defects closely associate with a collapse in mitophagy flux, characterized by coordinated downregulation of PINK1–PARKIN signaling, receptor-mediated pathways (BNIP3, NIX, FUNDC1), autophagosome formation, and lysosomal clearance, resulting in defective mitochondrial turnover and bioenergetic insufficiency. Genetic or pharmacological restoration of mitophagy reverses these phenotypes, preserving muscle mass, respiratory capacity, and functional performance while extending lifespan in multiple model organisms. Notably, the natural compounds urolithin A and spermidine consistently activate mitophagy, improve mitochondrial quality control, and enhance muscle strength and endurance in aged animals and sedentary middle-aged humans. Collectively, these data position age-related mitophagy suppression as the pivotal driver of skeletal muscle aging and define mitochondrial quality control as a tractable, mechanistic therapeutic target to delay or reverse primary sarcopenia.