Nature agingOct 5, 2026

Reduced cell cleanup by support proteins in aging weakens immune cell removal of old cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 7, 2026

Abstract

A decline in chaperone-mediated autophagy (CMA) is associated with increased accumulation of senescent cells.

CMA-deficient cells undergo senescence, adopting characteristics similar to aged senescent cells.
The secretions from these senescent cells promote further senescence in neighboring cells.
CMA deficiency in macrophages reduces their ability to clear senescent cells.
Blocking CMA in macrophages leads to increased senescent cell presence in mice and slows the resolution of senescence during wound healing.
Activating CMA pharmacologically reduces the number of senescent cells in aged mice and lessens severity in a pulmonary fibrosis model.

Simplified

Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.