Volume 30, No 7, Jul 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 7, July 2020: 574-589   |  Open Access

ORIGINAL ARTICLES

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

Yusheng Cai^1,† , Huanhuan Zhou^1,2,† , Yinhua Zhu^3,4,† , Qi Sun¹ , Yin Ji¹ , Anqi Xue¹ , Yuting Wang¹ , Wenhan Chen¹ , Xiaojie Yu¹ , Longteng Wang⁵ , Han Chen⁴ , Cheng Li⁶ , Tuoping Luo^3,4,* , Hongkui Deng^1,2,*

¹The MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, and School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Peking University, Beijing 100191, China;
²State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology & Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China;
³Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China;
⁴Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China;
⁵School of Life Sciences, Joint Graduate Program of Peking-Tsinghua-NIBS, Peking University, Beijing 100871, China ;
⁶School of Life Sciences, Center for Bioinformatics, Center for Statistical Science, Peking University, Beijing 100871, China
^†These authors contributed equally
Correspondence: Tuoping Luo(tuopingluo@pku.edu.cn)Hongkui Deng(hongkui_deng@pku.edu.cn)

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 lysosomal β-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 lysosomal β-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.

https://doi.org/10.1038/s41422-020-0314-9

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