Why Senescent Cells Build Up: Declining Macrophage Autophagy Blocks Their Clearance

A new explanation has emerged for why senescent cells are not removed and build up in tissues with age. Researchers at Albert Einstein College of Medicine in the United States published in Nature Aging mouse and cell study results showing that a decline in chaperone-mediated autophagy (CMA) interferes with immune clearance of senescent cells.

Both senescent cells and clearing cells are affected

CMA is an intracellular cleanup system that picks out damaged proteins and sends them to lysosomes for breakdown, and its activity falls with age. The researchers found that when cells lacking CMA enter senescence, they take on the features of old senescent cells, and substances these cells secrete promote senescence in neighboring cells while also suppressing CMA in macrophages, reducing their ability to engulf senescent cells. Mice with CMA blocked in macrophages accumulated more senescent cells, and the finishing stage of wound healing was delayed.

Conversely, when CMA was activated with a drug, the burden of senescent cells in old mice fell, and in a pulmonary fibrosis model, disease severity was lower. This is significant in suggesting an approach that restores the immune system's cleanup ability rather than killing senescent cells directly.

These are results from mice and cultured cells, and it has not been confirmed whether the same mechanism works in people or whether activating CMA is safe in the long term.