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

ABSTRACT: Cellular 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.

SUBMITTER: Limbad C

PROVIDER: S-EPMC8851282 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Limbad Chandani C Doi Ryosuke R McGirr Julia J Ciotlos Serban S Perez Kevin K Clayton Zachary S ZS Daya Radha R Seals Douglas R DR Campisi Judith J Melov Simon S

iScience 20220202 2

Cellular 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 <i>in vivo</i> 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 met ...[more]

PMID: 35198901

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Project description: Not available

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