Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

摘要

Cellular senescence,a persistent state of cell cycle arrest,accumulates in aged organisms,contributes to tissue dysfunction,and drives age-related phenotypes.The clearance of senescent cells is expected to decrease chronic,low-grade inflammation and improve tissue repair capacity,thus attenuating the decline of physical function in aged organisms.However,selective and effective clearance of senescent cells of different cell types has proven challenging.Herein,we developed a prodrug strategy to design a new compound based on the increased activity of lysosomalβ-galactosidase (β-gal),a primary characteristic of senescent cells.Our prodrug SSK1 is specifically activated by β-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types.In aged mice,our compound effectively cleared senescent cells in different tissues,decreased the senescence-and age-associated gene signatures,attenuated low-grade local and systemic inflammation,and restored physical function.Our results demonstrate that lysosomalβ-gal can be effectively leveraged to selectively eliminate senescent cells,providing a novel strategy to develop anti-aging interventions.