Photoactivatable senolysis with single-cell resolution delays aging

Strategies that can selectively eliminate senescent cells (SnCs), namely senolytics, have been shown to promote healthy lifespan. However, it is challenging to achieve precise, broad-spectrum and tractable senolysis. Here, we integrate multiple technologies that combine the enzyme substrate of senescence-associated beta-galactosidase (SA-beta-gal) with fluorescence tag for the precise tracking of SnCs, construction of a bioorthogonal receptor triggered by SA-beta-gal to target and anchor SnCs with single-cell resolution and incorporation of a selenium atom to generate singlet oxygen and achieve precise senolysis through controllable photodynamic therapy (PDT). We generate KSL0608-Se, a photosensitive senolytic prodrug, which is selectively activated by SA-beta-gal. In naturally-aged mice, KSL0608-Se-mediated PDT prevented upregulation of age-related SnCs markers and senescence-associated secretory phenotype factors. This treatment also countered age-induced losses in liver and renal function and inhibited the age-associated physical dysfunction in mice. We therefore provide a strategy to monitor and selectively eliminate SnCs to regulate aging. Shi, Liu, Gao et al. present a strategy to monitor and selectively eliminate senescent cells in mice during aging through controllable photodynamic therapy, which inhibited the age-related functional decline.

Automated summary

This study presents a strategy to monitor and selectively eliminate senescent cells in mice during aging through controllable photodynamic therapy, which inhibited the age-related functional decline.