Role of Endogenous hydrogen sulfide production in Longevity and Stress Resistance

项目总结/摘要 增加多因素的压力抵抗力是延长寿命的模型广泛共享的属性 跨越进化的界限生长激素（GH）和胰岛素样生长因子-1（IGF-1）受体 例如，在实验啮齿动物中延长寿命的缺陷，也增加了对急性毒性的抵抗力。 氧化应激物，如百草枯。饮食限制，除了在很大范围内延长寿命 实验生物，赋予保护免受许多临床相关的急性应激源， 包括对脑、肾和肝的缺血再灌注损伤以及对毒性副作用的保护- 化疗的效果。 利用饮食诱导的缺血性损伤保护作为模型系统，我们最近发现了一个新的作用， 转硫途径（TSP）产生的内源硫化氢（H2S）在植物抗逆中的作用 以及通过饮食限制来调节寿命。H2S是由TSP酶CBS和CGL产生的气体， 其主要作用是将必需氨基酸甲硫氨酸转化为半胱氨酸。外源H2S 可以赋予许多益处，从抵抗缺血性损伤和假死， 实验哺乳动物，延长寿命的苍蝇和蠕虫。然而，内源性H2S没有被 以前与饮食限制的好处有关。 在这里，我们提出测试的假设，增加内源性H2S生产TSP酶 是长寿模型所共有的抗应激和长寿益处的基础。为支持这一 假设，TSP活性和H2S产生在许多饮食限制方案中增加 跨越进化的界限，包括酵母，蠕虫和苍蝇，以及小鼠的多个器官， 禁食或饮食蛋白质限制。我们的初步数据表明，TSP酶的H2S生产是 受GH和mTOR信号转导抑制，另外两种途径高度参与长寿的调节， 抗逆性最后，药理学或遗传学抑制CGL和H2S的产生阻止了 短期蛋白限制对肝脏缺血性损伤的保护作用及对骨髓干细胞的保护作用 细胞免受电离辐射。 总之，这些数据保证了对内源性H2S产生的触发因素的调查， 它促进抗氧化应激和干细胞再生的机制及其相互作用 与其他长寿调节剂如线粒体肽humanin。

PROJECT SUMMARY/ABSTRACT Increased multi-factorial stress resistance is a property widely shared by models of extended longevity across evolutionary boundaries. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) receptor deficiencies, for example, which extend lifespan in experimental rodents, also increase resistance to acute oxidative stressors such as paraquat. Dietary restriction, in addition to extending longevity in a wide range of experimental organisms, confers protection against numerous clinically relevant acute stressors, including ischemia reperfusion injury to brain, kidney and liver as well as protection against the toxic side- effects of chemotherapy. Using diet-induced protection from ischemic injury as a model system, we recently identified a novel role for endogenous hydrogen sulfide (H2S) produced by the transsulfuration pathway (TSP) in stress resistance and longevity regulation by dietary restriction. H2S is a gas produced by TSP enzymes CBS and CGL, whose primary role is to convert the essential amino acid methionine to cysteine. Exogenously added H2S can confer numerous benefits ranging from resistance to ischemic injury and suspended animation in experimental mammals, to extended longevity in flies and worms. However, endogenous H2S had not been previously linked to the benefits of dietary restriction. Here, we propose to test the hypothesis that increased endogenous H2S production by TSP enzymes underlies stress resistance and longevity benefits shared by long-lived models. In support of this hypothesis, TSP activity and H2S production are increased in a number of dietary restriction regimens across evolutionary boundaries including in yeast, worms and flies, and in multiple organs in mice upon fasting or dietary protein restriction. Our preliminary data indicate that H2S production by TSP enzymes is repressed by GH and mTOR signaling, two other pathways highly involved in regulation of longevity and stress resistance. Finally, pharmacological or genetic inhibition of CGL and H2S production prevented the benefits of short-term protein restriction against hepatic ischemic injury and protection of bone marrow stem cells from ionizing radiation. Together, these data warrant an investigation into the triggers of endogenous H2S production, the mechanisms by which it promotes oxidative stress resistance and stem cell regeneration, and its interaction with other longevity regulators such as the mitochondrial peptide humanin.