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

Autor: Limbad C; Buck Institute for Research on Aging, Novato, CA, USA., Doi R; Buck Institute for Research on Aging, Novato, CA, USA., McGirr J; Buck Institute for Research on Aging, Novato, CA, USA., Ciotlos S; Buck Institute for Research on Aging, Novato, CA, USA., Perez K; Buck Institute for Research on Aging, Novato, CA, USA., Clayton ZS; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Daya R; Buck Institute for Research on Aging, Novato, CA, USA., Seals DR; Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA., Campisi J; Buck Institute for Research on Aging, Novato, CA, USA.; Lawrence Berkeley National Laboratory, Berkeley, CA, USA., Melov S; Buck Institute for Research on Aging, Novato, CA, USA.
Jazyk: angličtina
Zdroj: IScience [iScience] 2022 Feb 02; Vol. 25 (2), pp. 103848. Date of Electronic Publication: 2022 Feb 02 (Print Publication: 2022).
DOI: 10.1016/j.isci.2022.103848
Abstrakt: 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.
Competing Interests: The authors declare no conflicts of interest in this work.
(© 2022 The Author(s).)
Databáze: MEDLINE
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