The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Small molecule drugs that selectively kill senescent cells could significantly improve quality of life and reduce the burden of age-related chronic diseases. This study identifies a new class of drugs called senolytics that selectively eliminate senescent cells. Transcript analysis revealed increased expression of prosurvival networks in senescent cells, consistent with their resistance to apoptosis. Using siRNA to silence key nodes of this network, including ephrins, PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, senescent cells were selectively killed. Drugs targeting these factors, such as dasatinib and quercetin, were effective in eliminating senescent cells in vitro and in vivo. In vivo, the combination of dasatinib and quercetin reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid mice. In old mice, cardiac function and carotid vascular reactivity improved after treatment. Following irradiation of one limb, a single dose of the combination led to improved exercise capacity for at least 7 months. Periodic drug administration extended healthspan in progeroid mice, delaying age-related symptoms and pathology. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics in alleviating symptoms of frailty and extending healthspan. Key words: dasatinib; dependence receptors; ephrins; p21; PI3K delta; plasminogen-activated inhibitor; quercetin.The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Small molecule drugs that selectively kill senescent cells could significantly improve quality of life and reduce the burden of age-related chronic diseases. This study identifies a new class of drugs called senolytics that selectively eliminate senescent cells. Transcript analysis revealed increased expression of prosurvival networks in senescent cells, consistent with their resistance to apoptosis. Using siRNA to silence key nodes of this network, including ephrins, PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, senescent cells were selectively killed. Drugs targeting these factors, such as dasatinib and quercetin, were effective in eliminating senescent cells in vitro and in vivo. In vivo, the combination of dasatinib and quercetin reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid mice. In old mice, cardiac function and carotid vascular reactivity improved after treatment. Following irradiation of one limb, a single dose of the combination led to improved exercise capacity for at least 7 months. Periodic drug administration extended healthspan in progeroid mice, delaying age-related symptoms and pathology. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics in alleviating symptoms of frailty and extending healthspan. Key words: dasatinib; dependence receptors; ephrins; p21; PI3K delta; plasminogen-activated inhibitor; quercetin.