HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans.
HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1000486
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发表时间：
2009-05
期刊：
影响因子：
4.5
通讯作者：
Kapahi P
中科院分区：
文献类型：
--
作者：
Chen D;Thomas EL;Kapahi P
饮食限制（DR）延长了各种物种的寿命，也减缓了与年龄有关的疾病的发病。先前来自果蝇和酵母的研究已经证明雷帕霉素（TOR）通路的靶标对于由DR引起的长寿表型是必不可少的。TOR是一种保守的蛋白激酶，其响应于营养物和生长因子调节生长和代谢。虽然TOR的一些下游靶点与调节寿命有关，但仍不清楚该途径的其他靶点是否也调节寿命。研究表明，缺氧诱导因子-1（HIF-1）是哺乳动物细胞中TOR通路的靶点之一。HIF-1是一种转录因子复合物，在氧稳态、肿瘤形成、葡萄糖代谢、细胞存活和炎症反应中起关键作用。在这里，我们描述了一个新的作用，HIF-1在调节寿命延长的DR秀丽隐杆线虫。我们发现，HIF-1缺乏导致寿命延长，这与抑制RSKS-1/S6激酶（TOR途径的关键组成部分）重叠。使用基于固体琼脂平板上细菌食物浓度变化的改良DR方法，我们发现HIF-1以营养依赖的方式调节寿命。hif-1功能丧失突变体在丰富的营养条件下延长寿命，但在DR下未能显示寿命延长。相反，egl-9中的突变增加了HIF-1活性，减少了DR下的寿命延长。这种缺陷是由egl-9在特定神经元和肌肉中的组织特异性表达所拯救的。通过hif-1或DR增加寿命依赖于内质网（ER）应激调节因子肌醇需要蛋白-1（IRE-1），并与较低水平的ER应激相关。因此，我们的研究结果表明HIF-1在DR延长寿命中的组织特异性作用，涉及IRE-1 ER应激途径。饮食限制（DR）是延长各种物种寿命的最强大的环境操纵之一。DR也被证明可以减缓许多与年龄相关的疾病的发作。在模式生物如C. elegans可用于揭示决定DR有益作用的生物学机制。先前的研究表明，DR介导的寿命延长需要雷帕霉素（TOR）途径的营养敏感靶点。然而，TOR调节寿命的下游机制仍不清楚。在哺乳动物细胞中，TOR和下游S6激酶（S6 K）激活缺氧诱导因子-1（HIF-1）的表达，HIF-1在各种肿瘤中经常上调。利用C. elegans作为模型系统，我们表征了HIF-1在衰老中的新功能。我们发现，在丰富的营养条件下，HIF-1的抑制延长了寿命，而HIF-1水平的提高仅允许DR延长部分寿命。我们还证明了hif-1或DR增加的寿命取决于内质网（ER）应激调节因子肌醇需要蛋白-1（IRE-1），并与较低水平的ER应激相关，这是由于错误折叠/未折叠蛋白质过载到ER引起的。因此，我们的研究结果支持了HIF-1介导的蛋白质稳态变化在DR延长寿命中发挥关键作用的观点。
Dietary restriction (DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin (TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1 (HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway. Dietary restriction (DR) is one of the most robust environmental manipulations that extend lifespan in various species. DR has also been shown to slow the onset of a number of age-related diseases. Studies in model organisms like C. elegans can be used to uncover biological mechanisms that determine the beneficial effects of DR. Previous studies suggest that the nutrient-sensing target of rapamycin (TOR) pathway is required for DR-mediated lifespan extension. However, the downstream mechanisms by which TOR modulates lifespan remain unclear. In mammalian cells, TOR and the downstream S6 kinase (S6K) activate expression of the hypoxia-inducible factor-1 (HIF-1), which is frequently up-regulated in various tumors. Using C. elegans as a model system, we characterized novel functions of HIF-1 in aging. We find that inhibition of HIF-1 extends lifespan under rich nutrient conditions, whereas enhanced levels of HIF-1 only allow partial lifespan extension by DR. We also demonstrated that increased lifespan by hif-1 or DR depends on the endoplasmic reticulum (ER) stress regulator inositol-requiring protein-1 (IRE-1) and is associated with lower levels of ER stress, which is caused by overloading of misfolded/unfolded proteins to ER. Thus, our results support the idea that HIF-1–mediated changes in protein homeostasis play a key role in the lifespan extension by DR.
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