Identification of HSP90 inhibitors as a novel class of senolytics.
Identification of HSP90 inhibitors as a novel class of senolytics.
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DOI：
10.1038/s41467-017-00314-z
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发表时间：
2017-09-04
影响因子：
16.6
通讯作者：
Robbins PD
中科院分区：
文献类型：
--
作者：
Fuhrmann-Stroissnigg H;Ling YY;Zhao J;McGowan SJ;Zhu Y;Brooks RW;Grassi D;Gregg SQ;Stripay JL;Dorronsoro A;Corbo L;Tang P;Bukata C;Ring N;Giacca M;Li X;Tchkonia T;Kirkland JL;Niedernhofer LJ;Robbins PD
衰老是许多慢性退行性疾病和癌症的主要危险因素。各种组织中衰老细胞负荷的增加是衰老和年龄相关疾病的主要原因。最近，一类称为senolytics的新药被证明可以延长健康寿命，减少脆弱性并改善多种衰老小鼠模型中的干细胞功能。为了鉴定新的和更优化的衰老药物和组合，我们建立了衰老相关的β-半乳糖苷酶测定作为筛选平台，以快速鉴定特异性影响衰老细胞的药物。我们使用了DNA修复能力降低的原代Ercc 1 −/−小鼠胚胎成纤维细胞，如果在大气氧气中生长，它们会迅速衰老。该平台用于筛选调节自噬的化合物的小文库，鉴定出HSP 90伴侣蛋白家族的两种抑制剂在小鼠和人细胞中具有显著的衰老清除活性。用HSP 90抑制剂17-DMAG治疗Ercc 1 −/Ercc 1小鼠（人类早衰综合征的小鼠模型）延长了健康寿命，延迟了几种与年龄相关的症状的发作，并降低了p16 INK 4a的表达。这些结果表明，我们的筛选平台的效用，以确定衰老剂以及确定HSP 90抑制剂作为一个有前途的新一类的衰老清除药物。衰老细胞的积累被认为有助于组织功能的年龄相关性下降。在这里，作者在体外筛选中将HSP 90抑制剂鉴定为一类新的衰老清除化合物，并表明HSP 90抑制剂的施用减少了早衰小鼠中与年龄相关的症状。
Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 −/− murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 −/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs. The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.
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影响因子：
7.8
作者：
Harrison DE;Strong R;Allison DB;Ames BN;Astle CM;Atamna H;Fernandez E;Flurkey K;Javors MA;Nadon NL;Nelson JF;Pletcher S;Simpkins JW;Smith D;Wilkinson JE;Miller RA
通讯作者：
Miller RA
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
11.1
作者：
Korolchuk VI;Miwa S;Carroll B;von Zglinicki T
通讯作者：
von Zglinicki T
DOI：
10.3402/pba.v1i0.7219
发表时间：
2011-01-01
期刊：
PATHOBIOLOGY OF AGING AND AGE-RELATED DISEASES
影响因子：
--
作者：
Dolle, Martijn E. T.;Kuiper, Raoul V.;van Steeg, Harry
通讯作者：
van Steeg, Harry
影响因子：
16.6
作者：
Jurk, Diana;Wilson, Caroline;Passos, Joao F.;Oakley, Fiona;Correia-Melo, Clara;Greaves, Laura;Saretzki, Gabriele;Fox, Chris;Lawless, Conor;Anderson, Rhys;Hewitt, Graeme;Pender, Sylvia L. F.;Fullard, Nicola;Nelson, Glyn;Mann, Jelena;van de Sluis, Bart;Mann, Derek A.;von Zglinicki, Thomas
通讯作者：
von Zglinicki, Thomas