Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older Adults.

Autophagy is widely proposed to decline with age; however, direct evidence across human cell types remains limited. Moreover, it is unclear whether age-associated changes in autophagy-gene transcription are accompanied by corresponding changes in autophagic activity, and whether autophagic activity relates to physiological function during aging. We performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort. Autophagy-related gene expression increased with age in primary dermal fibroblasts and, to a lesser extent, in induced neurons (iNs). However, autophagy flux was cell type- and sex-specific and uncoupled from transcriptional remodeling. Autophagy flux decreased in male fibroblasts, remained stable in female fibroblasts, and increased in female iNs with age. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became increasingly heterogeneous with age and trended higher in older individuals, independent of sex. Associations between autophagy flux and physiological function varied across the adult lifespan; however, in adults aged > 70 years, higher autophagy flux was associated with reduced physical function. In a pilot intervention study, PBMC autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function, suggesting that autophagic activity in PBMCs is responsive to physiological intervention in late life. Together, these findings show that autophagy is remodeled in a cell type-, sex- and physiological function-dependent manner during aging, challenge the view that autophagy uniformly declines with age, and suggest that elevated autophagy flux in older adults may reflect compensatory responses to age-associated stress rather than enhanced autophagic capacity.