Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9-based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24-/- mice that exhibit a premature aging phenotype. CRISPR-Cas9-based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.
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