1] Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA [2] Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02215, USA.
Department of Molecular Biology, Lewis-Sigler Institute for Integrative Genomics, Princeton University, 148 Carl Icahn Laboratory, Washington Road, Princeton, New Jersey 08544, USA.
Nature. 2015 Mar 5;519(7541):97-101. doi: 10.1038/nature14021. Epub 2014 Dec 15.
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 Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. 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 a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue 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 genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix 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 extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.
干预衰老会激活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，因为细胞外基质在衰老过程中也会受到损伤。降低胰岛素/胰岛素样生长因子-1 信号（rIIS）可以延长整个进化谱系中的寿命，在幼年秀丽隐杆线虫中，也可以让转录因子 DAF-16/FOXO 诱导 dauer 形成，这是一种可以抵抗恶劣条件的休眠状态。有人认为，rIIS 通过在成年期激活 dauer 相关过程来延缓线虫衰老，但有些 rIIS 条件会延长寿命，而不会出现 dauer 样特征。在这里，我们表明 rIIS 可以通过一种与 dauer 途径在遗传上不同的程序来促进线虫的长寿，并且需要 Nrf（NF-E2 相关因子）直系同源物 SKN-1 与 DAF-16 平行作用。SKN-1 受 IIS 抑制，广泛参与长寿，但即使 dauer 相关过程的活性很弱，它也会使 rIIS 延长寿命变得可有可无。当 IIS 在不诱导 dauer 特征的条件下降低时，SKN-1 最显著地增加胶原蛋白和其他细胞外基质基因的表达。多种遗传、营养和药理学的长寿干预措施可以延缓胶原蛋白表达随年龄的下降。这些胶原蛋白介导成年期细胞外基质重塑，并且对于不涉及 dauer 特征的干预措施来延缓衰老也是必需的。通过遗传上区分 dauer 独立的 rIIS 衰老途径，我们的结果表明，IIS 在线虫成年期控制着广泛的保护机制，并且可能有助于阐明对长寿普遍重要的过程。在不同的抗衰老干预措施中，胶原蛋白的产生都很重要，这意味着细胞外基质重塑是长寿保证的一个普遍必需的特征，并且促进细胞外基质年轻化的药物可能具有全身益处。
