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.

项目摘要/摘要 增加的多因素应力抵抗力是通过延长寿命模型广泛共享的属性 整个进化边界。生长激素（GH）和胰岛素样生长因子1（IGF-1）受体 例如，缺乏症状会延长实验啮齿动物的寿命，也会增加对急性的抗性 氧化应激源，例如paraquat。饮食限制，除了延长寿命 在实验生物体中，对众多临床相关的急性应激源进行保护， 包括对脑，肾脏和肝脏的缺血再灌注损伤，以及防止有毒侧的保护 化学疗法的影响。 使用饮食引起的防御性损伤的保护作为模型系统，我们最近确定了新的作用 由反硫化途径（TSP）在应力抗性中产生的内源性硫化氢（H2S） 和通过饮食限制的寿命调节。 H2S是TSP酶CB和CGL产生的气体， 其主要作用是将必需的氨基酸蛋氨酸转化为半胱氨酸。外源添加H2S 可以赋予从抵抗到缺血性伤害和暂停动画的许多好处 实验性哺乳动物，以延长苍蝇和蠕虫的寿命。但是，内源性H2尚未 以前与饮食限制的好处有关。 在这里，我们建议测试以下假设，即TSP酶增加了内源性H2S的产生 长期模型共享的压力抵抗力和寿命益处的基础。支持这个 在许多饮食限制方案中，假设，TSP活性和H2S产生增加 跨越包括酵母，蠕虫和果蝇的进化边界，以及小鼠的多个器官 禁食或饮食蛋白限制。我们的初步数据表明，TSP酶产生的H2S是 受GH和MTOR信号的抑制，另外两种途径高度参与了长寿调节和 压力抗性。最后，CGL和H2S产生的药理或遗传抑制阻止了 短期蛋白质限制抗肝缺血性损伤和骨髓茎的保护的好处 电离辐射的细胞。 这些数据共同研究了内源H2S生产的触发器， 它促进氧化应激抗性和干细胞再生的机制及其相互作用 与其他寿命调节剂，例如线粒体肽人类。