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

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

doi:10.1016/j.isci.2022.103848

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

Journal Article · Tue Feb 01 23:00:00 EST 2022 · iScience

DOI:https://doi.org/10.1016/j.isci.2022.103848· OSTI ID:2470722

Limbad, Chandani ^[1]; ^[1]; McGirr, Julia ^[1]; ^[1]; Perez, Kevin ^[1]; ^[2]; Daya, Radha ^[1]; Seals, Douglas R. ^[2]; Campisi, Judith ^[3]; ^[1]

Buck Institute for Research on Aging, Novato, CA (United States)
University of Colorado, Boulder, CO (United States)
Buck Institute for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2470722

Journal Information:: iScience, Journal Name: iScience Journal Issue: 2 Vol. 25; ISSN 2589-0042

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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