Photoactivatable senolysis with single-cell resolution delays aging

Donglei Shi, Wenwen Liu, Ying Gao, Xinming Li, Yunyuan Huang, Xiaokang Li, Tony James, Yuan Guo, Jian Li

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Abstract

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.
Original languageEnglish
JournalNature Aging
Early online date2 Feb 2023
DOIs
Publication statusE-pub ahead of print - 2 Feb 2023

Bibliographical note

Funding Information:
We gratefully appreciate the financial support from the National Natural Science Foundation of China (grants 22037002 to J.L. and Y. Guo, 32121005 to J.L., 21977082 to Y. Guo and 22007032 to Xinming Li), the Natural Science Basic Research Program of Shaanxi (grant 2020JC-38 to Y. Guo), the Innovation Program of Shanghai Municipal Education Commission (grant 2021-01-07-00-02-E00104 to J.L.), the Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism (grant 2021 Sci & Tech 03-28 to J.L.), the Innovative Research Team of High-level Local Universities in Shanghai (grant SHSMU-ZDCX20212702 to J.L.) and the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204 to J.L.). T.D.J. wishes to thank the Royal Society for a Wolfson Research Merit Award and the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University for support (Grant 2020ZD01 to T.D.J.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Data availability
All data during the current study are available within the paper and its Supplementary Information or from the corresponding author upon reasonable request.

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