biostudies-literatureAmor CNIA NIH HHSNCI NIH HHSNIH HHS336-349https://www.ebi.ac.uk/biostudies/studies/S-EPMC10950785biostudies-literatureUnknown4(3)Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.Nature agingProphylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.PMC10950785R01 AG082800P30 CA008748R01 CA190092U01 CA224013DP5 OD033055R01 AG065396P30 CA045508U01 AG077925R01 CA188134S10 OD028632U01 CA210240R35 CA197594R01 CA229699Boyer JAHo YJGraham CMezzadra RLevine RLChowdhury SSadelain MWereski MGAmor CLowe SWTuveson DAFernandez-Maestre IFeucht JJones LWNadella SNnuji-John ECarrasco SEBarthet VJAHinterleitner CfalseProphylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals. We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.2024-01-01T00:00:00Z2024 Mar2024-11-15T04:14:53.73Z2024-11-15T04:14:53.73ZS-EPMC109507853826770610.1038/s43587-023-00560-5