Intestinal Autophagy Improves Healthspan and Longevity in C. elegans during Dietary Restriction.
Intestinal Autophagy Improves Healthspan and Longevity in C. elegans during Dietary Restriction.
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DOI：
10.1371/journal.pgen.1006135
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发表时间：
2016-07
期刊：
影响因子：
4.5
通讯作者：
Hansen M
中科院分区：
文献类型：
--
作者：
Gelino S;Chang JT;Kumsta C;She X;Davis A;Nguyen C;Panowski S;Hansen M
饮食限制（DR）是一种延长许多生物体寿命的饮食方案。有助于DR对寿命的保守作用的一种机制是细胞再循环过程自噬，其响应于营养缺乏而被诱导，并增加胞质物质到双膜自噬体中的隔离，以在溶酶体中降解。虽然自噬在秀丽隐杆线虫DR介导的寿命延长中起着直接作用，但自噬在个体组织中的作用仍不清楚。在这项研究中，我们显示了自噬在肠道（一种主要的代谢组织）中的关键作用，以确保饮食限制的eat-2突变体的寿命延长。eat-2突变体的肠具有扩大的溶酶体隔室，并且通量测定表明自噬体的周转增加，这与该组织中自噬的诱导一致。这种肠自噬的增加可能是我们在eat-2突变体中观察到的改善的肠完整性的基础，因为eat-2突变体中对自噬的全身和胃肠道特异性抑制极大地损害了肠屏障功能。有趣的是，eat-2突变体中自噬的肠道特异性抑制导致运动性随着年龄的增长而降低，暗示了自噬在肠道中的潜在细胞非自主作用。总的来说，这些结果突出了自噬在饮食限制的C。优美的不引起营养不良的饮食限制（DR）对包括人类在内的许多物种的寿命具有强大的有益影响。自噬的细胞再循环过程有助于DR介导的寿命。自噬是由营养缺乏引发的，并增加了溶酶体中细胞质分子和细胞器的降解。使用线虫秀丽隐杆线虫作为模式生物，我们先前表明，参与自噬的基因是通过DR延长寿命所必需的;然而，尚不清楚个体组织中的自噬是否在DR介导的寿命中起关键作用。在这里，我们研究了自噬在遗传饮食限制eat-2突变体中的作用。我们的主要发现包括：（i）肠中自噬的抑制防止了在eat-2突变体中观察到的长寿命;（ii）eat-2突变体的肠含有扩大的溶酶体区室，并且通量测定表明自噬体周转增加，与该组织中自噬升高一致;（iii）肠自噬是在eat-2突变体中观察到的改善的肠完整性所需的;（iv）自噬抑制损害老年动物的运动性;和（v）肠中自噬的抑制加速Eat-2突变体的运动性下降。总的来说，这些研究表明肠道自噬在饮食限制的动物中起着关键作用，并强调了这一过程在保持健康和长寿方面的重要性。
Dietary restriction (DR) is a dietary regimen that extends lifespan in many organisms. One mechanism contributing to the conserved effect of DR on longevity is the cellular recycling process autophagy, which is induced in response to nutrient scarcity and increases sequestration of cytosolic material into double-membrane autophagosomes for degradation in the lysosome. Although autophagy plays a direct role in DR-mediated lifespan extension in the nematode Caenorhabditis elegans, the contribution of autophagy in individual tissues remains unclear. In this study, we show a critical role for autophagy in the intestine, a major metabolic tissue, to ensure lifespan extension of dietary-restricted eat-2 mutants. The intestine of eat-2 mutants has an enlarged lysosomal compartment and flux assays indicate increased turnover of autophagosomes, consistent with an induction of autophagy in this tissue. This increase in intestinal autophagy may underlie the improved intestinal integrity we observe in eat-2 mutants, since whole-body and intestinal-specific inhibition of autophagy in eat-2 mutants greatly impairs the intestinal barrier function. Interestingly, intestinal-specific inhibition of autophagy in eat-2 mutants leads to a decrease in motility with age, alluding to a potential cell non-autonomous role for autophagy in the intestine. Collectively, these results highlight important functions for autophagy in the intestine of dietary-restricted C. elegans. Dietary restriction (DR) without inducing malnutrition has robust beneficial effects on lifespan in many species, including humans. The cellular recycling process of autophagy contributes to DR-mediated longevity. Autophagy is triggered by nutrient scarcity and increases the degradation of cytosolic molecules and organelles in the lysosomes. Using the nematode Caenorhabditis elegans as a model organism, we previously showed that genes involved in autophagy are required for lifespan extension through DR; however, it is not clear whether autophagy in individual tissues plays critical roles in DR-mediated longevity. Here, we investigated the contribution of autophagy in genetically dietary-restricted eat-2 mutants. Our major findings include: (i) Inhibition of autophagy in the intestine prevents the long lifespan observed in eat-2 mutants; (ii) the intestine of eat-2 mutants contains an expanded lysosomal compartment and flux assays indicate increased autophagosome turnover, consistent with elevated autophagy in this tissue; (iii) intestinal autophagy is required for the improved intestinal integrity observed in eat-2 mutants; (iv) autophagy inhibition impairs motility in older animals; and (v) inhibition of autophagy in the intestine accelerates the motility decline in eat-2 mutants. Collectively, these studies suggest a critical role for intestinal autophagy in dietary-restricted animals, and highlight the importance of this process in maintaining fitness and longevity.