Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan.
Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan.
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DOI：
10.1038/nature09873
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发表时间：
2011-04-14
期刊：
影响因子：
64.8
通讯作者：
Lithgow, Gordon J.
中科院分区：
文献类型：
--
作者：
Alavez, Silvestre;Vantipalli, Maithili C.;Zucker, David J. S.;Klang, Ida M.;Lithgow, Gordon J.
遗传研究表明，蛋白质稳态是后生动物长寿的主要因素。蛋白质稳态的崩溃导致蛋白质错误折叠级联和不溶性蛋白原纤维和聚集体的积累，如淀粉样蛋白。一组小分子，传统上在组织病理学中用于染色组织中的淀粉样蛋白，在体外和细胞培养中结合蛋白原纤维并减缓聚集。我们提出用这些化合物治疗动物可以促进体内蛋白质稳态并延长寿命。在这里，我们表明，成年秀丽隐杆线虫暴露于淀粉样蛋白结合染料硫黄素T （ThT）导致寿命大大延长，并减缓衰老。ThT还抑制突变亚稳态蛋白的病理特征和人类β-淀粉样蛋白相关毒性。ThT的这些有益作用依赖于蛋白质稳态网络调节剂热休克因子1 （HSF-1）、抗逆性和长寿转录因子SKN-1、分子伴侣、自噬和蛋白体功能。我们的研究结果表明，蛋白质稳态网络的药理维持对衰老速度有深远的影响，促进了针对衰老和年龄相关疾病的新型治疗干预措施的发展。
Genetic studies indicate that protein homeostasis is a major contributor to metazoan longevity. Collapse of protein homeostasis results in protein misfolding cascades and the accumulation of insoluble protein fibrils and aggregates, such as amyloids. A group of small molecules, traditionally used in histopathology to stain amyloid in tissues, bind protein fibrils and slow aggregation in vitro and in cell culture. We proposed that treating animals with such compounds would promote protein homeostasis in vivo and increase longevity. Here we show that exposure of adult Caenorhabditis elegans to the amyloid-binding dye Thioflavin T (ThT) resulted in a profoundly extended lifespan and slowed ageing. ThT also suppressed pathological features of mutant metastable proteins and human β-amyloid-associated toxicity. These beneficial effects of ThT depend on the protein homeostasis network regulator heat shock factor 1 (HSF-1), the stress resistance and longevity transcription factor SKN-1, molecular chaperones, autophagy and proteosomal functions. Our results demonstrate that pharmacological maintenance of the protein homeostatic network has a profound impact on ageing rates, prompting the development of novel therapeutic interventions against ageing and age-related diseases.
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影响因子：
7.8
作者：
Walker, GA;Lithgow, GJ
通讯作者：
Lithgow, GJ
DOI：
10.1073/pnas.95.22.13091
发表时间：
1998-10-27
影响因子：
11.1
作者：
Lakowski, B;Hekimi, S
通讯作者：
Hekimi, S
影响因子：
4.5
作者：
Chen D;Thomas EL;Kapahi P
通讯作者：
Kapahi P
影响因子：
4.8
作者：
Mccoll, Gawain;Roberts, Blaine R.;Bush, Ashley I.
通讯作者：
Bush, Ashley I.
影响因子：
56.9
作者：
Cohen, Ehud;Bieschke, Jan;Dillin, Andrew
通讯作者：
Dillin, Andrew