Nat Aging. 2025 Feb 05.
Rabia R Khawaja,
Adrián Martín-Segura,
Olaya Santiago-Fernández,
Rebecca Sereda,
Kristen Lindenau,
Mericka McCabe,
Adrián Macho-González,
Maryam Jafari,
Aurora Scrivo,
Raquel Gomez-Sintes,
Bhakti Chavda,
Ana Rosa Saez-Ibanez,
Inmaculada Tasset,
Esperanza Arias,
Xianhong Xie,
Mimi Kim,
Susmita Kaushik,
Ana Maria Cuervo.
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.