Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.
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DOI：
10.1038/nm.4010
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发表时间：
2016-01
期刊：
影响因子：
82.9
通讯作者：
Zhou D
中科院分区：
文献类型：
--
作者：
Chang J;Wang Y;Shao L;Laberge RM;Demaria M;Campisi J;Janakiraman K;Sharpless NE;Ding S;Feng W;Luo Y;Wang X;Aykin-Burns N;Krager K;Ponnappan U;Hauer-Jensen M;Meng A;Zhou D
衰老细胞（SC）随着年龄的增长和遗传毒性应激（如全身照射（TBI））后积累。使用转基因方法清除早老性小鼠模型中的SC延迟了几种年龄相关疾病，表明SC在某些年龄相关的病理学中起致病作用。因此，一种可以选择性杀死干细胞的“衰老清除”药剂有望恢复组织干细胞的活力并延长健康寿命。为了测试这个想法，我们筛选了一系列化合物，并将ABT 263（抗凋亡蛋白BCL-2和BCL-xL的特异性抑制剂）鉴定为有效的衰老清除药物。我们表明，ABT 263选择性地杀死SC在培养中的细胞类型和物种的独立方式，通过诱导凋亡。向亚致死剂量照射或正常老化的小鼠口服施用ABT 263有效地耗尽了SC，包括衰老的骨髓造血干细胞（HSC）和衰老的肌肉干细胞（MuSC）。值得注意的是，这种消耗减轻了TBI诱导的造血系统的过早老化，并使正常老化小鼠中的老化HSC和MuSC恢复活力。我们的研究结果表明，选择性清除SC的药理学试剂是有益的，部分通过其年轻化的老化组织干细胞。因此，衰老清除药物可能代表一类新的辐射缓解剂和抗衰老剂。
Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, 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.