Autophagy mediates the mitotic senescence transition

TLDR

Senescence is a dynamic stress response driven by multiple effector mechanisms that shape its phenotype. The study identifies autophagy as a novel effector mechanism of senescence. Autophagy is activated during senescence, correlating with PI3K–mTOR negative feedback, and its upregulation—e.g., via ULK3 overexpression—induces senescence while inhibition delays senescence‑associated secretion, indicating that autophagy‑mediated protein turnover drives the senescence phenotype.

Abstract

As a stress response, senescence is a dynamic process involving multiple effector mechanisms whose combination determines the phenotypic quality. Here we identify autophagy as a new effector mechanism of senescence. Autophagy is activated during senescence and its activation is correlated with negative feedback in the PI3K–mammalian target of rapamycin (mTOR) pathway. A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype.