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Motor independence is strongly associated with the quality of life of elderly people, yet the regulators for motor aging have not been systematically explored. Here, we designed a fast and efficient genome-wide screening assay in\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    and identified 34 consistent genes as potential regulators of motor aging. Among the top hits, we found VPS-34, the class III phosphatidylinositol 3-kinase that phosphorylates phosphatidylinositol (PI) to phosphatidylinositol 3-phosphate (PI(3)P), regulates motor function in aged but not young worms. It primarily functions in aged motor neurons by inhibiting PI(3)P-PI-PI(4)P conversion to reduce neurotransmission at the neuromuscular junction (NMJ). Genetic and pharmacological inhibition of VPS-34 improve neurotransmission and muscle integrity, ameliorating motor aging in both worms and mice. Thus, our genome-wide screening revealed an evolutionarily conserved, actionable target to delay motor aging and prolong health span.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3002165","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T13:22:55Z","timestamp":1689081775000},"page":"e3002165","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Partial inhibition of class III PI3K VPS-34 ameliorates motor aging and prolongs health span"],"prefix":"10.1371","volume":"21","author":[{"given":"Zhongliang","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamei","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaru","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangce","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengsong","family":"Gou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangbang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6041-4454","authenticated-orcid":true,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"issue":"8","key":"pbio.3002165.ref001","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.tcb.2016.05.002","article-title":"Does Longer Lifespan Mean Longer Healthspan?","volume":"26","author":"M Hansen","year":"2016","journal-title":"Trends Cell Biol"},{"issue":"10033","key":"pbio.3002165.ref002","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1016\/S0140-6736(15)00516-4","article-title":"The World report on ageing and health: a policy framework for healthy ageing","volume":"387","author":"JR Beard","year":"2016","journal-title":"Lancet"},{"issue":"3","key":"pbio.3002165.ref003","doi-asserted-by":"crossref","first-page":"E277","DOI":"10.1073\/pnas.1412192112","article-title":"Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants","volume":"112","author":"A Bansal","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7797","key":"pbio.3002165.ref004","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41586-020-2037-y","article-title":"Two conserved epigenetic regulators prevent healthy ageing","volume":"579","author":"J Yuan","year":"2020","journal-title":"Nature"},{"issue":"1","key":"pbio.3002165.ref005","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/mus.1215","article-title":"Aging of the human neuromuscular system","volume":"25","author":"AA Vandervoort","year":"2002","journal-title":"Muscle Nerve"},{"issue":"7","key":"pbio.3002165.ref006","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/BF02982704","article-title":"Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives","volume":"12","author":"Y Rolland","year":"2008","journal-title":"J Nutr Health Aging"},{"issue":"1\u20132","key":"pbio.3002165.ref007","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0531-5565(78)90027-X","article-title":"Age dependent changes in the behavior of Caenorhabditis elegans on attraction to Escherichia coli","volume":"13","author":"R. 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