Photoactivatable senolysis with single-cell resolution delays aging

• Published in: Nature aging Vol. 3; no. 3; pp. 297 - 312
• Main Authors: Shi, Donglei, Liu, Wenwen, Gao, Ying, Li, Xinming, Huang, Yunyuan, Li, Xiaokang, James, Tony D, Guo, Yuan, Li, Jian
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-03-2023
• Subjects: Aging; Animals; Cellular Senescence - physiology; Longevity; Mice; Photodynamic therapy; Senescence
• ISSN: 2662-8465; 2662-8465
• DOI: 10.1038/s43587-023-00360-x

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 β-galactosidase (SA-β-gal) with fluorescence tag for the precise tracking of SnCs, construction of a bioorthogonal receptor triggered by SA-β-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-β-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.