Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity.
Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity.
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DOI：
10.1038/nature14021
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发表时间：
2015-03-05
期刊：
影响因子：
64.8
通讯作者：
Blackwell, T. Keith
中科院分区：
文献类型：
--
作者：
Ewald, Collin Y.;Landis, Jess N.;Abate, Jess Porter;Murphy, Coleen T.;Blackwell, T. Keith
延缓衰老的干预措施调动了保护和修复细胞成分的机制，但目前尚不清楚这些干预措施如何减缓细胞外基质的功能下降，细胞外基质在衰老过程中也会受损。减少胰岛素/IGF-1信号传导（rIIS）延长了整个进化谱的寿命，在幼年C。秀丽隐杆线虫还允许转录因子DAF-16/FOXO诱导发育为dauer，这是一种能够承受恶劣条件的滞育（补充讨论）。有人认为，rIIS延迟C。在成年期，rIIS通过激活与dauer相关的过程而衰老，但一些rIIS条件赋予了强大的寿命延长，而不伴随任何dauer样特征。在这里，我们展示了rIIS可以提升C。线虫通过一个与dauer途径在遗传上不同的程序来延长寿命，并且需要Nrf（NF-E2相关因子）直系同源物SKN-1与NRF-16平行作用。SKN-1被IIS抑制，并与寿命有广泛的关系，但即使是轻微的dauer相关过程的活性也会导致rIIS寿命延长。当IIS在不诱导dauer性状的条件下降低时，SKN-1最显著地增加胶原蛋白和其他细胞外基质（ECM）基因的表达。不同的遗传、营养和药物促长寿干预延缓了胶原蛋白表达的年龄相关性下降。这些胶原蛋白介导成年ECM重塑，并且需要通过不涉及dauer性状的干预来延迟衰老。通过遗传学描绘一个不依赖于子代的rIIS衰老途径，我们的研究结果表明，IIS控制着C。elegans成年，并可能有助于阐明的过程中普遍重要的长寿。胶原蛋白产生在不同抗衰老干预中的重要性意味着ECM重塑是长寿保证的基本特征，并且促进ECM年轻化的药物可能具有全身益处。
Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced Insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile C. elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions (Supplementary Discussion). It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through an program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) ortholog SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix (ECM) genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood ECM remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that ECM remodelling is a generally essential signature of longevity assurance, and that agents promoting ECM youthfulness may have systemic benefit.
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