A novel mechanism of autophagic degradation in cellular senescence

The National Institute on Aging awarded $237,270 to The General Hospital Corporation, doing business as Massachusetts General Hospital, on August 20, 2026, under the Aging Research program (CFDA 93.866) to investigate a novel mechanism of autophagic degradation in cellular senescence.

The research will examine how autophagy—a cellular self-digestion process—functions in senescent cells and how covalent conjugation of ATG8 family proteins to autophagy substrates facilitates protein degradation specifically in senescence rather than in quiescence or starvation. The project comprises two aims: investigating the mechanisms of covalent conjugation in senescence and examining the role of a covalently conjugated demethylase identified through proteomics in regulating senescence. The investigator plans to engage in training and career development activities to advance their career progression. The research may provide insights into age-related diseases and potential therapeutic interventions for senescence-associated conditions.

Work is performed in Boston, Massachusetts, with performance ending March 24, 2029.

Abstract

Cellular senescence is characterized by stable cell cycle arrest and pro-inflammatory responses, contributing to both aging and disease. Autophagy is a self-digestion process, which maintains cellular homeostasis and is upregulated in senescence. The specific roles of autophagy in senescence remain poorly understood. The degradation of autophagy substrates requires ATG8 family proteins, which bind to substrates via protein-protein interactions. My preliminary data suggest that a specific ATG8 family protein can covalently conjugate to autophagy substrates in senescent cells, which facilitates protein autophagic degradation. Furthermore, this covalent conjugation-mediated autophagic degradation occurs specifically in senescence, and not in quiescence or starvation. I performed unbiased proteomic identification of covalently conjugated autophagy adaptor proteins in senescence, revealing numerous targets, including a demethylase. I plan to test the central hypothesis that covalent conjugation to autophagy adaptors represents a novel mechanism for degrading autophagy substrates in senescence, and propose that targeting this mechanism holds promise in intervening senescence-associated diseases. Specifically, in aim 1, i propose to investigate the mechanisms of covalent conjugation in senescence, examining the key differences underlying senescence and starvation. In aim 2, i propose to investigate the covalently conjugated demethylase identified from proteomics, focusing on its role in regulating key aspects of senescence. I further plan to actively engage in a variety of training and career development opportunities to facilitate my career progression. Overall, this project investigates a novel mechanism of substrate recognition by autophagy, and will shed new light on the biology of senescence. These findings could provide new insights into age-related diseases and potential therapeutic strategies for targeting senescent cells. The planned career and training activities will prepare me to become a future independent investigator.