Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI)1–6. Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders7, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a ‘senolytic’ pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type– and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
Previous efforts to identify small molecules that selectively kill SCs have yielded only two nonspecific and cell type–selective senolytic drugs8. To identify senolytic drugs that are more specific and have broader-spectrum activity, we took a targeted approach by individually titrating the cytotoxicity of a handful of small molecules that participate in pathways predicted to be important for the viability of SCs or for the maintenance of their phenotype (Supplementary Tables 1 and 2). We studied the effects of these compounds on human WI-38 fibroblasts, because this cell line has been extensively used to study replicative and stress-induced premature senescence in culture9,10. After incubation with the compounds, we assessed the survival of WI-38 cells that either were non-senescent or that had been induced to senesce by treatment with ionizing radiation (IR), replicative exhaustion or oncogenic Ras expression. Using this approach, we identified ABT263 as a potent senolytic drug that selectively, potently and rapidly kills SCs, regardless of how they were induced ( and Supplementary Fig. 1). In addition, ABT263 treatment was cytotoxic against SCs in a cell type– and species-independent manner: senescent human fibroblasts (IMR-90), human renal epithelial cells (RECs) and mouse embryo fibroblasts (MEFs) were more sensitive to ABT263 treatment than were their non-senescent counterparts ().
Collectively, our results show that ABT263 is a potent and broad-spectrum senolytic drug, with potential activity as a mitigator of radiation injury, particularly with respect to the late effects of IR that are associated with increases in SC abundance, such as IR-induced long-term bone marrow injury. However, ABT263 has some toxic side effects35; in particular, transient thrombocytopenia and neutropenia are the common toxicities associated with ABT263 treatment in patients. Adverse drug effects are hurdles for anti-aging therapies that require long treatment intervals5,36. Therefore, it remains to be determined whether ABT263 treatment can be used to delay aging or age-related diseases in normally aged experimental animals or in humans. https://www.nature.com/articles/nm.4010