This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) T cells in targeting and eliminating stress-induced senescent cells in vitro. Cellular senescence, characterized by permanent cell cycle arrest and the senescence-associated secretory phenotype (SASP), contributes to age-related tissue decline. Immunotherapy, particularly CAR-T cell therapy, is emerging as a promising approach to selectively eliminate senescent cells. The study focuses on the NKG2D receptor, which binds to ligands (NKG2DLs) upregulated in senescent cells, offering a target for CAR-T cells. Using mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, the researchers demonstrate that NKG2DLs are elevated in response to genotoxic and oxidative stress. NKG2D-CAR T cells exhibited potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. The findings provide the first evidence of NKG2D-CAR T cells' ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The research paves the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases.This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) T cells in targeting and eliminating stress-induced senescent cells in vitro. Cellular senescence, characterized by permanent cell cycle arrest and the senescence-associated secretory phenotype (SASP), contributes to age-related tissue decline. Immunotherapy, particularly CAR-T cell therapy, is emerging as a promising approach to selectively eliminate senescent cells. The study focuses on the NKG2D receptor, which binds to ligands (NKG2DLs) upregulated in senescent cells, offering a target for CAR-T cells. Using mouse embryonic fibroblasts (MEFs) and astrocytes (AST) as senescence models, the researchers demonstrate that NKG2DLs are elevated in response to genotoxic and oxidative stress. NKG2D-CAR T cells exhibited potent cytotoxicity against these senescent cells, with minimal effects on non-senescent cells, suggesting their potential as targeted senolytics. The findings provide the first evidence of NKG2D-CAR T cells' ability to target senescent brain cells, offering a novel approach to manage senescence-associated diseases. The research paves the way for future investigations into the therapeutic applicability of NKG2D-targeting CAR-T cells in naturally aged organisms and models of aging-associated brain diseases.