Role of Endogenous hydrogen sulfide production in Longevity and Stress Resistance

项目摘要/摘要 提高多因素的抗应激能力是长寿模型广泛共享的特性 跨越进化的边界。生长激素和胰岛素样生长因子-1受体 例如，可以延长实验啮齿动物寿命的缺陷也增加了对急性呼吸道感染的抵抗力。 氧化应激源，如百草枯。饮食限制，除了广泛延长寿命外 在实验生物体中，提供对许多临床相关的急性应激源的保护， 包括对脑、肾、肝的缺血再灌注损伤以及对毒副作用的保护。 化疗的效果。 使用饮食诱导的对缺血损伤的保护作为一个模型系统，我们最近确定了一个新的作用， 跨硫途径(TSP)产生的内源硫化氢(H_2S)在抗逆中的作用 以及通过饮食限制来调节长寿。硫化氢是由TSP酶CBS和CGL产生的气体， 其主要作用是将必需氨基酸蛋氨酸转化为半胱氨酸。外源添加的硫化氢 可以提供许多好处，从抵抗缺血损伤和暂停生命在 实验哺乳动物，以延长苍蝇和蠕虫的寿命。然而，内源硫化氢还没有被 以前与节食的好处有关。 在这里，我们建议检验这样一种假设，即通过TSP酶增加内源硫化氢的产生 这是长寿模特所享有的抗压性和长寿益处的基础。为了支持这一点 假设、TSP活性和硫化氢的产生在一些饮食限制方案中增加 跨越包括酵母、蠕虫和苍蝇在内的进化边界，以及在小鼠的多个器官中 禁食或限制饮食蛋白质。我们的初步数据表明，TSP酶产生的硫化氢是 受生长激素和mTOR信号抑制，另外两条高度参与长寿调节的通路和 抗逆性。最后，药物或遗传抑制CGL和H_2S的产生阻止了 短期蛋白质限制对肝脏缺血损伤的保护和骨髓干细胞的保护作用 细胞免受电离辐射。 总而言之，这些数据值得对内源性硫化氢产生的触发因素进行调查 促进氧化应激抵抗和干细胞再生的机制及其相互作用 与其他长寿调节剂，如线粒体肽人素。

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.