Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types

Chandani Limbad,Ryosuke Doi,Julia Mcgirr,Serban Ciotlos,Kevin Perez,Zachary S Clayton,Radha Daya,Douglas R Seals,Judith Campisi,Simon Melov

doi:10.1016/j.isci.2022.103848

Abstract

SummaryCellular senescence is a driver of many age-related pathologies. There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells. We utilized single-cell RNA sequencing to identify CRYAB as a robust senescence-induced gene and potential target for senolysis. Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic. We then validated 25HC as a senolytic in mouse and human cells in culture and in vivo in mouse skeletal muscle. Thus, 25HC represents a potential class of senolytics, which may be useful in combating diseases or physiologies in which cellular senescence is a key driver.

Highlights

Cellular senescence causes proliferative cells to undergo an essentially permanent cell-cycle arrest upon encountering stressful stimuli such as genotoxic chemotherapy, radiation, or telomere shortening (Bernadotte et al, 2016; Demaria et al, 2017; Limbad et al, 2020)
There is an active search for pharmaceuticals termed senolytics that can mitigate or remove senescent cells in vivo by targeting genes that promote the survival of senescent cells
Using chemical inhibitor screening for CRYAB disruption, we identified 25-hydroxycholesterol (25HC), an endogenous metabolite of cholesterol biosynthesis, as a potent senolytic

Summary

Introduction

Cellular senescence causes proliferative cells to undergo an essentially permanent cell-cycle arrest upon encountering stressful stimuli such as genotoxic chemotherapy, radiation, or telomere shortening (Bernadotte et al, 2016; Demaria et al, 2017; Limbad et al, 2020). There is an active search for drugs that can kill senescent cells (senolytics) (van Deursen, 2019). This class of drugs improves health span in multiple contexts of aging, and has potential to mitigate many age related diseases (Chang et al, 2016; Fuhrmann-Stroissnigg et al, 2017; Kim and Kim, 2019; Kirkland and Tchkonia, 2017; Wissler Gerdes et al, 2020; Xu et al, 2018). The potential benefits of ABT as a senolytic were studied after skeletal muscle injury (Chiche et al, 2017), but no benefits were reported in aging skeletal muscle

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