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However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms.<\/jats:p>","DOI":"10.1038\/s43587-025-01022-w","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T10:02:25Z","timestamp":1764064945000},"page":"108-126","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness"],"prefix":"10.1038","volume":"6","author":[{"given":"Onur","family":"Eskiocak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Gewolb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6874-5285","authenticated-orcid":false,"given":"Vyom","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4262-2363","authenticated-orcid":false,"given":"James A.","family":"Rouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saria","family":"Chowdhury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erdogan O.","family":"Akyildiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Fern\u00e1ndez-Maestre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob A.","family":"Boyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aveline","family":"Filliol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander S.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0055-2548","authenticated-orcid":false,"given":"Raditya","family":"Utama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangran","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0008-151X","authenticated-orcid":false,"given":"Carolina","family":"Castro-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuella","family":"Nnuji-John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlie","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Flowers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Habel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8268-2903","authenticated-orcid":false,"given":"Paul B.","family":"Romesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7884-1905","authenticated-orcid":false,"given":"Ross L.","family":"Levine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott W.","family":"Lowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9031-8025","authenticated-orcid":false,"given":"Michel","family":"Sadelain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4730-4012","authenticated-orcid":false,"given":"Semir","family":"Beyaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7654-6216","authenticated-orcid":false,"given":"Corina","family":"Amor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"1022_CR1","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.stem.2011.10.004","volume":"9","author":"B Biteau","year":"2011","unstructured":"Biteau, B., Hochmuth, C. 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He also offers uncompensated professional services and activities for 10x Genomics, XRad Therapeutics and the HPV Alliance and Anal Cancer Foundation non-profit organizations. R.L.L. is on the Supervisory board of Qiagen (compensation\/equity), a co-founder\/board member at Ajax (equity), a board member of the Mark Foundation for Cancer Research and is a scientific advisor to Mission Bio, Kurome, Syndax, Scorpion, Zentalis, Jubilant, Auron, Prelude and C4 Therapeutics; for each of these entities, he receives equity\/compensation. He has received research support from the Cure Breast Cancer Foundation (with IP rights), Calico, Zentalis and Ajax, and has consulted\/provided professional services for ECOG-ACRIN, Genome Canada, Goldman Sachs and Astra Zeneca. S.B. received research funding from Caper Labs, Elstar Therapeutics and Revitope Oncology for research unrelated to this study. S.W.L. is a founder and member of the scientific advisory board of Blueprint Medicines, Mirimus, ORIC Pharmaceuticals, Senescea and Faeth Therapeutics; is on the scientific advisory board of PMV Pharmaceuticals; and is a consultant for Fate Therapeutics. S.B. is an advisor for Caper Labs. S.B. and C.A. are listed as inventors on a patent application related to the regenerative effects of senolytic CAR T cells (63\/510,997). S.L., M.S. and C.A. are listed as the inventor of several patent applications (62\/800,188; 63\/174,277; 63\/209,941; 63\/209,940; 63\/209,915; 63\/209,924; 17\/426,728; 3,128,368; 20748891.7; 2020216486) related to senolytic CAR T cells. M.S. is also listed on other unrelated patents concerning CAR T technology. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}