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Here, we observed that aging is associated with a decline in protein phosphatase 2A (PP2A) activity in the brains of zebrafish and mice. Moreover, drugs activating PP2A reversed age\u2010related behavioral changes. We developed a transgenic zebrafish model to decrease PP2A activity in the brain through knockout of the <jats:italic>ppp2r2c<\/jats:italic> gene encoding a regulatory subunit of PP2A. Mutant fish exhibited the behavioral phenotype observed in old animals and premature accumulation of neural cells positive for markers of cellular senescence, including senescence\u2010associated \u03b2\u2010galactosidase, elevated levels <jats:italic>cdkn2a\/b<\/jats:italic>, <jats:italic>cdkn1a<\/jats:italic>, senescence\u2010associated secretory phenotype gene expression, and an increased level of DNA damage signaling. The behavioral and cell senescence phenotypes were reversed in mutant fish through treatment with the senolytic ABT263 or diverse PP2A activators as well as through <jats:italic>cdkn1a<\/jats:italic> or <jats:italic>tp53<\/jats:italic> gene ablation. Senomorphic function of PP2A activators was demonstrated in mouse primary neural cells with downregulated <jats:italic>Ppp2r2c<\/jats:italic>. We conclude that PP2A reduction leads to neural cell senescence thereby contributing to age\u2010related behavioral changes and that PP2A activators have senotherapeutic properties against deleterious behavioral effects of brain aging.<\/jats:p>","DOI":"10.1111\/acel.13780","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T08:17:04Z","timestamp":1673857024000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Protein phosphatase <scp>2A<\/scp> activators reverse age\u2010related behavioral changes by targeting neural cell senescence"],"prefix":"10.1111","volume":"22","author":[{"given":"Jun","family":"Xing","sequence":"first","affiliation":[{"name":"Geriatric Department, Geriatric Medical Center, Shanghai Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"International Laboratory in Cancer, Aging and Hematology Shanghai Jiao Tong 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