HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in <em>Caenorhabditis elegans</em>

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.饮食限制（Dietary restriction, DR）可延长多种物种的寿命，并延缓年龄相关性疾病的发生发展。此前针对果蝇与酵母的研究表明，雷帕霉素靶蛋白（target of rapamycin, TOR）通路是饮食限制所诱导长寿表型的必需调控通路。TOR是一类保守的蛋白激酶，可响应营养与生长因子信号调控机体生长与代谢过程。尽管已有部分TOR下游靶点被证实参与寿命调控，但该通路是否存在其他额外靶点亦可调控寿命，目前仍不明确。已有研究显示，缺氧诱导因子-1（hypoxia inducible factor-1, HIF-1）是哺乳动物细胞中TOR通路的下游靶点之一。HIF-1是一种转录因子复合物，在氧稳态维持、肿瘤发生、葡萄糖代谢、细胞存活及炎症反应中发挥关键调控作用。本研究揭示了秀丽隐杆线虫（Caenorhabditis elegans）中HIF-1在饮食限制诱导寿命延长过程中的全新功能。研究发现，HIF-1功能缺失可延长线虫寿命，该效应与抑制TOR通路关键组分RSKS-1/S6激酶（RSKS-1/S6 kinase）所产生的寿命延长效果相重叠。我们基于固体琼脂平板上细菌食物浓度梯度构建了改良的饮食限制模型，结果显示HIF-1以营养依赖的方式调控线虫寿命：在营养充足条件下，hif-1功能缺失突变体可延长寿命，但在饮食限制条件下则无法观察到寿命延长效应。反之，egl-9基因突变可增强HIF-1活性，该突变会削弱饮食限制诱导的寿命延长，而在特定神经元与肌肉组织中特异性表达egl-9可逆转这一表型缺陷。hif-1功能缺失或饮食限制所介导的寿命延长，均依赖于内质网（endoplasmic reticulum, ER）应激调控因子肌醇需求蛋白-1（inositol-requiring protein-1, IRE-1），且与内质网应激水平降低相关。综上，本研究证实HIF-1通过IRE-1介导的内质网应激通路，以组织特异性的方式参与饮食限制诱导的寿命延长。