Senescence is a stable form of growth arrest. Senescent cells accumulate during aging, contributing to a litany of age-associated pathologies. Pharmacologic targeting of senescent cells – so-called “senolytics”– have been shown to ameliorate multiple aging phenotypes in mice; however, there are only few known senolytic drugs and they have limited clinical potential. Using a genomewide CRISPR/Cas9 screen in a pool of differentiated mouse embryonic stem cells induced to senescence, we report additional senolytic targets that lead to the selective killing of senescent cells. We identified a total of 13 “top hits”, which we validated in vitro using shRNAs in independent human cell lines. Our highest-ranking candidates include novel hits PARN and AATF whose depletion was most effective at inducing senescent whilst sparing health cells. Both of these genes have been reported to be regulated by the MK2 kinase, and pharmacological suppression of this pathway also lead to the selective killing of senescent cells in vitro. Taken together, this study identifies PARN and AATF genes as novel, promising therapeutic strategies for senolysis and provides a large number of genetic vulnerabilities of senescent cells that can be pursued in downstream studies.
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