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.
This project represent the first characterization of CMA activity along aging in different tissues, accounting for cell type variability and specificity. The CMA aging atlas is comprised by scRNA and inmunofluorescence data. The scRNA data was obtained upon analysis of the well documented repository on aging at the sigle cell level known as Tabula Muris Senis.
Raw code can be found at Khawaja et al 2024-GitHub repository.
This image represent the level of CMA activity in different cell types at single cell level. It is a UMAP representation based on cell type markers. The color code represents CMA activity calculated from immunofluorescence images cuantification.