Role of endogenous hydrogen sulfide production in longevity and stress resistance

内源性硫化氢的产生在长寿和抗应激方面的作用

• 批准号: 9074576
• 负责人: JAMES R. MITCHELL
• 金额: $ 13.58万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9074576
• 关键词: Acute; Adverse effects; Age; Aging; Aging-Related Process; Bioenergetics; Biological Models; Bone Marrow; Bone Marrow Stem Cell; Brain; Cell Maintenance; Cells; Cysteine; Data; Diet; Dietary Proteins; Disease; Energy Metabolism; Essential Amino Acids; FRAP1 gene; Fasting; Gases; Genetic; Hepatic; Hepatocyte; Hydrogen Sulfide; Hypoxia; In Vitro; Injury; Insulin; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Intervention; Investigation; Ionizing radiation; Kidney; Laboratory Organism; Left; Life; Link; Liver; Longevity; Lower Organism; Lyase; Mammals; Mediating; Metabolic; Methionine; Mitochondria; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Natural regeneration; Nutrient; Organ; Oxidative Stress; Paraquat; Pathway interactions; Peptides; Pharmaceutical Preparations; Phosphotransferases; Process; Production; Property; Proteins; Regimen; Regulation; Rejuvenation; Reperfusion Injury; Resistance; Rodent; Role; Signal Transduction; Somatomedins; Somatotropin; Stem cells; Stress; System; Testing; Tissues; Toxic effect; Vasodilation; Wild Type Mouse; Yeasts; acute stress; aged; animation; benefit sharing; chemotherapy; clinically relevant; cytotoxicity; dietary restriction; enzyme pathway; fitness; fly; growth hormone deficiency; humanin; immunoregulation; in vivo; liver ischemia; neuroprotection; novel; prevent; stressor; sulfhydration

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.

项目概要/摘要 增强的多因素抗压能力是延长寿命模型广泛共有的一个特性 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，缺陷可以延长实验啮齿动物的寿命，也可以增强对急性传染病的抵抗力。 氧化应激源，例如百草枯。饮食限制，除了大范围地延长寿命之外 实验生物体，提供针对许多临床相关急性应激源的保护， 包括对脑、肾和肝的缺血再灌注损伤以及对毒副作用的保护- 化疗的影响。 使用饮食诱导的缺血性损伤保护作为模型系统，我们最近发现了一种新的作用 转硫途径（TSP）产生的内源硫化氢（H2S）在抗逆性中的作用 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蛋氨酸转化为半胱氨酸。外源添加H2S 可以带来许多好处，包括抵抗缺血性损伤和假死 实验哺乳动物，以延长苍蝇和蠕虫的寿命。然而，内源性 H2S 并未被 以前与饮食限制的好处有关。 在这里，我们建议检验 TSP 酶增加内源 H2S 产量的假设 是长寿模型所共有的抗压能力和长寿益处的基础。为了支持这一点 假设，在许多饮食限制方案中，TSP 活性和 H2S 产量都会增加 跨越进化界限，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 酶产生的 H2S 是 受到 GH 和 mTOR 信号传导的抑制，这两种信号通路高度参与调节寿命和寿命 抗压能力。最后，CGL 和 H2S 产生的药理学或遗传抑制可防止 短期蛋白质限制对肝缺血损伤和保护骨髓干的益处 细胞免受电离辐射。 总之，这些数据需要对内源性 H2S 产生的触发因素进行调查， 它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，例如线粒体肽护脑素。