{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:55:31Z","timestamp":1790574931862,"version":"4.1.0"},"reference-count":29,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P01AG062413"],"award-info":[{"award-number":["P01AG062413"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG068182"],"award-info":[{"award-number":["R01AG068182"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG086085"],"award-info":[{"award-number":["R01AG086085"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG068048"],"award-info":[{"award-number":["R01AG068048"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG82708"],"award-info":[{"award-number":["R01AG82708"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UG3\/UH3CA268103"],"award-info":[{"award-number":["UG3\/UH3CA268103"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG087387"],"award-info":[{"award-number":["R01AG087387"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37AG13925"],"award-info":[{"award-number":["R37AG13925"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R33AG061456"],"award-info":[{"award-number":["R33AG061456"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001642","name":"Glenn Foundation for Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001642","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016997","name":"Noaber Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100032810","name":"Robert and Arlene Kogod Center on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100032810","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Genotoxic stress induced by cancer therapies is increasingly recognized as a driver of accelerated aging in long\u2010term cancer survivors, yet the mechanisms responsible for the emergence of age\u2010related dysfunction months to years after treatment remain poorly understood. Here, we use sublethal whole\u2010body irradiation as a model of systemic genotoxic stress to test whether senescent cells contribute to the progression of post\u2010therapy age\u2010related dysfunction and whether the benefits of senescent cell clearance depend on the timing of intervention. Using the\n                    <jats:italic>INK\u2010ATTAC<\/jats:italic>\n                    mouse model, we selectively eliminated p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    \u2010positive cells either early (1\u2009month) or later (4\u2009months) after irradiation. Early clearance had no effect on lifespan or functional outcomes. In contrast, delayed clearance markedly reduced frailty, improved neuromuscular and cognitive function, restored blood\u2013brain barrier integrity, improved hepatic metabolic dysfunction, and increased median survival, with the survival benefit being most evident in female mice. Mechanistically, irradiation induced an early p21\n                    <jats:sup>Cip1<\/jats:sup>\n                    \u2010associated stress response and later accumulation of p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    \u2010positive cells in the brain and liver, which was associated with inflammation and tissue dysfunction. Clearance of p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    \u2010positive cells at the later stage attenuated these changes. Together, these findings identify p16\n                    <jats:sup>Ink4a<\/jats:sup>\n                    \u2010positive cells as key drivers of the radiation\u2010induced accelerated aging\u2010like state that emerges progressively after genotoxic stress. They also show that the efficacy of senescence\u2010targeted interventions depends on when treatment is initiated, with implications for improving long\u2010term outcomes in cancer survivors.\n                  <\/jats:p>","DOI":"10.1111\/acel.70693","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T03:40:29Z","timestamp":1787802029000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Timing\u2010Dependent Clearance of p16\u2010Positive Cells Mitigates Radiation\u2010Induced Accelerated Aging"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8058-5453","authenticated-orcid":false,"given":"Karla","family":"Valdivieso","sequence":"first","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Weigand","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3795-1649","authenticated-orcid":false,"given":"Daniela G.","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"},{"name":"Faculty of Pharmacy University of Coimbra  Coimbra Portugal"},{"name":"Center for Neuroscience and Cell Biology (CNC\u2010UC) and Center for Innovation in Biomedicine and Biotechnology (CIBB) University of Coimbra  Coimbra Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Pirius","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8789-4585","authenticated-orcid":false,"given":"Helene","family":"Martini","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivangi","family":"Oberai","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology and Experimental Therapeutics Graduate Program Mayo Clinic Graduate School of Biomedical Sciences  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Inman","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3876-3156","authenticated-orcid":false,"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Cellular and Integrative Physiology UT Health San Antonio  San Antonio Texas USA"},{"name":"The Sam and Ann Barshop Institute for Longevity and Aging Studies UT Health San Antonio  San Antonio Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"von Zglinicki","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2936-4372","authenticated-orcid":false,"given":"Sundeep","family":"Khosla","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2002-0418","authenticated-orcid":false,"given":"Nathan","family":"LeBrasseur","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8765-1890","authenticated-orcid":false,"given":"Jo\u00e3o F.","family":"Passos","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4623-7145","authenticated-orcid":false,"given":"Tamara","family":"Tchkonia","sequence":"additional","affiliation":[{"name":"Center for Advanced Gerotherapeutics, Department of Medicine Cedars\u2010Sinai Health Sciences University  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1676-4905","authenticated-orcid":false,"given":"James L.","family":"Kirkland","sequence":"additional","affiliation":[{"name":"Center for Advanced Gerotherapeutics, Department of Medicine Cedars\u2010Sinai Health Sciences University  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4486-0857","authenticated-orcid":false,"given":"Diana","family":"Jurk","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering Mayo Clinic  Rochester Minnesota USA"},{"name":"Robert and Arlene Kogod Center on Aging Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2013.51.1055"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.02.031"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature16932"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10600"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13602"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4010"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44321\u2010026\u201000400\u20100"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159\u20108290.Cd\u201016\u20100241"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75492"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2466"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1708"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2017.76.4696"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474\u20109726.2012.00795.x"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2017.76.7467"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2013.52.2268"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14270"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15691"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.12.008"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12971"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050110"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djab064"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1909"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/2041\u20109414\u20102\u20107"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010026\u201001101\u20106"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44318\u2010025\u201000601\u20102"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/sageke.2003.33.pe24"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3420"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glt136"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0092-9"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70693","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70693","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70693","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:07:50Z","timestamp":1790572070000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70693"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":29,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/acel.70693"],"URL":"https:\/\/doi.org\/10.1111\/acel.70693","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"assertion":[{"value":"2026-03-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70693"}}