Lysosomal Competence in Skeletal Muscle Aging: Autophagic Flux, Measurement Gaps, and Human Translation

Age-related deterioration of skeletal muscle contributes to loss of mobility, frailty, and disability. Altered autophagy-lysosome competence has been proposed as a mechanism linking impaired proteostasis, mitochondrial damage, inflammation, and regenerative failure to sarcopenia. Chronological muscle aging and clinically defined sarcopenia overlap, but evidence from healthy aging, frailty, disuse, cachexia, obesity, or chronic disease cannot be treated as interchangeable. This narrative review examines how lysosomal acidification, degradative capacity, biogenesis, and turnover influences autophagic flux in aging muscle and evaluates the strength of evidence across experimental models and human studies. Genetic and pharmacological studies show that severe disruption of autophagy or specific lysosomal functions can cause myofiber damage, mitochondrial impairment, defective regeneration, and weakness. However, direct evidence that lysosomal acidification, fusion, hydrolase activity, membrane integrity, recycling, cargo degradation, or completed autophagic flux is impaired in aging human muscle remains limited. Much of the human literature relies on static abundance of LC3-II, SQSTM1/p62, lysosomal proteins, or transcriptional signatures, which cannot distinguish increased autophagosome formation from impaired degradation. We therefore separate causal experimental evidence from human associations and focus on V-ATPase, TMEM175, LAMP proteins, TFEB/TFE3, lysophagy, and crosstalk with mitophagy and the ubiquitin-proteasome system. Exercise improves clinically relevant outcomes in older adults, but mediation through completed autophagic flux has not been established. Recent trials of metformin and once-weekly sirolimus did not improve prespecified functional outcomes in the tested populations and regimens, whereas urolithin A produced endpoint-specific signals while missing key primary outcomes.