Role of the Mitochondrial Peptide Humanin in Regulating Aging and Healthspan

线粒体肽人素在调节衰老和寿命中的作用 饮食和GH/IGF轴是衰老和长寿的核心。我们确定了新的线粒体的一个关键作用- 衍生多肽(MDP)，人蛋白，由小开放阅读框(SORF)编码 线粒体基因组(16S rRNA基因)在这方面。饮食控制，硫化氢供体的管理，以及 IGF-I的减少导致人素水平的增加，而人素本身模拟饮食限制(DR)。 多种途径，包括抑制IGF-I，增加IGFBP-1，改善胰岛素敏感性，减少 重量。人的水平随着年龄的增长而下降，并与寿命相关，而人的过度表达或管理 对各种生物都有促进健康和延长寿命的作用。类似于饮食干预和硫化氢， 人素保护免受各种侮辱，它的管理可以防止老年病的发展。 我们与项目1和项目3的合作研究表明，人素是饮食之间的中心联系 限制，胰岛素样生长因子的减少，以及硫化氢的表达，整合了衰老过程中的抗逆性和适应性。 我们的中心假设是：(1)人蛋白是一种线粒体激素，其表达受 调节衰老的干预措施，如饮食控制、硫化氢和减少IGF，(2)人素调节 通过下丘脑的直接活动循环IGF-I(模拟DR)，导致中央-肝脏效应， 抑制肝脏中IGF-I的产生(3)人给药的作用类似于DR和禁食模拟饮食 或蛋白质限制循环，硫化氢和生长激素/胰岛素样生长因子的阻断，以促进健康和可能的长寿。 我们将研究饮食、IGF-I和硫化氢调节人蛋白表达的机制；并研究 人蛋白-sORF的转录和转录后调控。我们将破译其中的机制 下丘脑介导的肝脏抑制参与人的DR模拟作用 IGF-I；以及对靶组织的直接保护作用。我们将描述人类免疫系统的影响 使用新的人基因转基因小鼠模型gp130- 抑制剂和胰岛素样生长因子加回实验。 总之，这个项目将展示人的生理意义，作为一种介体和调节 健康和长寿途径，包括与饮食、IGF-I和硫化氢有关的途径。我们希望证明这一点 HN是提高健康寿命/寿命的必要条件和充分条件。

Role of the Mitochondrial Peptide Humanin in Regulating Aging and Healthspan Diet and the GH/IGF axis are central to aging and longevity. We identified a key role for the novel mitochondrial- derived peptide (MDP), humanin, which is encoded from a small open reading frame (sORF) within the mitochondrial genome (16S rRNA gene) in this regard. Dietary manipulations, administration of H2S-donors, and IGF-I reduction lead to increases in humanin levels, while humanin itself mimics dietary restriction (DR) in multiple ways including suppressing IGF-I, increasing IGFBP-1, improving insulin sensitivity, and reducing weight. Humanin levels fall with age and correlate with lifespan, and humanin overexpression or administration to various organisms leads to healthspan and lifespan extension. Similarly to dietary interventions and H2S, humanin protects from a variety of insults, and its administration prevents the development of diseases of aging. Our collaborative studies with Projects 1 & 3 indicate that humanin is a central connecting link between dietary restriction, IGF reduction, and H2S expression, integrating stress resistance and fitness during aging. Our central hypotheses are (1) humanin is a mitochondrial hormone whose expression is directly regulated by aging-modulating interventions such as dietary manipulations, H2S, and IGF-reduction, (2) Humanin regulates circulating IGF-I (mimicking DR) by direct activity on the hypothalamus leading to a central-hepatic effect that inhibits IGF-I production in liver (3) humanin administration can act similarly to DR and fasting mimicking diets or protein restriction cycles, H2S, and GH/IGF-blockade, to promote healthspan and possibly longevity. We will study the mechanisms by which diet, IGF-I, and H2S regulate humanin expression; and study the transcriptional and post-transcriptional regulation of the humanin-sORF. We will decipher the mechanisms involved in the DR-mimetic effects of humanin action through hypothalamic-mediated suppression of hepatic IGF-I; as well as through direct protective effects on target tissues. We will characterize the effects of humanin on healthspan and identify the mechanisms involved, using novel humanin-transgenic mouse models, GP130- inhibitors, and IGF-add-back experiments. Together, this project will demonstrate the physiological significance of humanin as a mediator and regulator of healthspan and longevity pathways including those related to diet, IGF-I, and H2S. We hope to demonstrate that HN is necessary and sufficient for healthspan/lifespan enhancement.