biostudies-literatureUnknown6(1)Eskiocak OIntestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. 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 microbiomNature aging108-126https://www.ebi.ac.uk/biostudies/studies/S-EPMC12823409biostudies-literatureAnti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness.PMC12823409Boyer JAHabel JUtama RAnderson ALevine RLChowdhury SBeyaz SSadelain MLowe SWAmor CRomesser PBFernandez-Maestre ICastro-Hernandez CChung CRouse JAHarris ASFlowers SGuo GEskiocak ONnuji-John EShah VAkyildiz EOFilliol AGewolb JfalseAnti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness.Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. 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 microbiom2026-01-01T00:00:00Z2026 Jan2026-06-06T17:58:48.605Z2026-06-04T03:10:14.662ZS-EPMC128234094129125810.1038/s43587-025-01022-w