Elimination of senescent cells by \u03b2-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

Yusheng Cai,Yinhua Zhu,Yin Ji,Huanhuan Zhou,Longteng Wang,Cheng Li,Tuoping Luo,Wenhan Chen,Han Chen,Xiaojie Yu,Anqi Xue,Yuting Wang,Hongkui Deng,Qi Sun

doi:10.1038/s41422-020-0314-9

Yusheng Cai, Yinhua Zhu + Show 12 more

Open Access

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

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Abstract

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.

Highlights

Aging is the predominant risk for physiological degeneration, increased chronic morbidities, and age-specific mortality.[1,2] One major hallmark of aging is the chronic accumulation of cellular senescence, a permanent state of cell-cycle arrest in response to various damaging stimuli.[3,4] Cellular senescence impairs the ability of tissue regeneration and drives chronic low-grade inflammation, which exacerbates the aging process.[5,6] Importantly, transplantation of senescent cells into young mice was sufficient to drive agerelated pathology and cause persistent physical dysfunction.[7]
Gemcitabine has been reported to be transported into cells via molecular transporters for nucleosides given its hydrophilicity,[24,25] SSK1 was modified with acetyl group and β-gal-responsive moiety suggesting its hydrophobicity (Fig. 1b)
Nucleoside transporter inhibitor was unable to block the killing effect of SSK1 indicating that SSK1 entered the senescent cells independent of transporter (Supplementary information, Fig. S1e)

Summary

Introduction

Aging is the predominant risk for physiological degeneration, increased chronic morbidities, and age-specific mortality.[1,2] One major hallmark of aging is the chronic accumulation of cellular senescence, a permanent state of cell-cycle arrest in response to various damaging stimuli.[3,4] Cellular senescence impairs the ability of tissue regeneration and drives chronic low-grade inflammation, which exacerbates the aging process.[5,6] Importantly, transplantation of senescent cells into young mice was sufficient to drive agerelated pathology and cause persistent physical dysfunction.[7] In contrast, deletion of senescent cells by a genetic approach attenuated age-related deterioration and extended the healthspan in aged mice.[8,9] These studies demonstrated that senescence is one of the major drivers of aging and that clearing senescent cells is a promising approach to treat age-related diseases and improve physical function.[6,10]

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