The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.
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DOI：
10.1111/acel.12344
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发表时间：
2015-08
期刊：
影响因子：
7.8
通讯作者：
Kirkland JL
中科院分区：
文献类型：
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作者：
Zhu Y;Tchkonia T;Pirtskhalava T;Gower AC;Ding H;Giorgadze N;Palmer AK;Ikeno Y;Hubbard GB;Lenburg M;O'Hara SP;LaRusso NF;Miller JD;Roos CM;Verzosa GC;LeBrasseur NK;Wren JD;Farr JN;Khosla S;Stout MB;McGowan SJ;Fuhrmann-Stroissnigg H;Gurkar AU;Zhao J;Colangelo D;Dorronsoro A;Ling YY;Barghouthy AS;Navarro DC;Sano T;Robbins PD;Niedernhofer LJ;Kirkland JL
通过使用转基因自杀基因杀死衰老细胞来增强小鼠的健康寿命。使用小分子实现同样的目标将对生活质量和与年龄相关的慢性疾病的负担产生巨大影响。在这里，我们描述了一种新的药物，称为senolytics，选择性地杀死衰老细胞的识别和验证的基本原理。通过转录分析，我们发现衰老细胞中促生存网络的表达增加，与它们对凋亡的既定抗性一致。使用siRNA沉默该网络的关键节点的表达，包括肝配蛋白（EFNB 1或3）、PI 3 K δ、p21、BCL-xL或纤溶酶原激活抑制剂-2，杀死衰老细胞，但不杀死增殖或静止的分化细胞。针对这些相同因素的药物选择性地杀死衰老细胞。达沙替尼消除衰老的人脂肪祖细胞，而槲皮素对衰老的人内皮细胞和小鼠BM-MSC更有效。达沙替尼和槲皮素的组合在消除衰老的MEFs中是有效的。在体内，这种组合减少了按时间顺序老化，辐射暴露和早衰Ercc 1 −/Δ小鼠的衰老细胞负担。在老年小鼠中，单次给药后5天，心脏功能和颈动脉血管反应性得到改善。在小鼠的一个肢体照射后，单剂量导致药物治疗后至少7个月的运动能力改善。定期给药延长了Ercc 1 −/Δ小鼠的健康寿命，延缓了与年龄相关的症状和病理学、骨质疏松症和椎间盘蛋白聚糖的丢失。这些结果证明了选择性消融衰老细胞的可行性以及衰老缓解剂用于缓解虚弱症状和延长健康寿命的功效。
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.