ABT263, a BCL-2 and BCL-xL inhibitor, selectively kills senescent cells (SCs) in mice, rejuvenating aged hematopoietic stem cells (HSCs) and muscle stem cells (MuSCs). The study shows that ABT263 effectively clears SCs in both sublethally irradiated and normally aged mice, reducing age-related disorders and improving the function of aged HSCs and MuSCs. ABT263 induces apoptosis in SCs by targeting anti-apoptotic proteins, leading to the clearance of senescent cells and the rejuvenation of tissue stem cells. This process is mediated by the reduction of senescence-associated secretory phenotype (SASP) factors and the restoration of stem cell function. The results suggest that senolytic drugs like ABT263 could be used to mitigate radiation-induced aging and extend healthspan. However, ABT263 has some toxic side effects, such as transient thrombocytopenia and neutropenia, which may limit its use in anti-aging therapies. The study highlights the potential of senolytic drugs as a new class of radiation mitigators and anti-aging agents.ABT263, a BCL-2 and BCL-xL inhibitor, selectively kills senescent cells (SCs) in mice, rejuvenating aged hematopoietic stem cells (HSCs) and muscle stem cells (MuSCs). The study shows that ABT263 effectively clears SCs in both sublethally irradiated and normally aged mice, reducing age-related disorders and improving the function of aged HSCs and MuSCs. ABT263 induces apoptosis in SCs by targeting anti-apoptotic proteins, leading to the clearance of senescent cells and the rejuvenation of tissue stem cells. This process is mediated by the reduction of senescence-associated secretory phenotype (SASP) factors and the restoration of stem cell function. The results suggest that senolytic drugs like ABT263 could be used to mitigate radiation-induced aging and extend healthspan. However, ABT263 has some toxic side effects, such as transient thrombocytopenia and neutropenia, which may limit its use in anti-aging therapies. The study highlights the potential of senolytic drugs as a new class of radiation mitigators and anti-aging agents.