Role of the Mitochondrial Peptide Humanin in Regulating Aging and Healthspan

线粒体肽Humanin对衰老和健康寿命的调节作用 饮食和GH/IGF轴是衰老和长寿的核心。我们发现了一个新的线粒体的关键作用- 衍生肽（MDP），人源蛋白，其由人源蛋白内的小开放阅读框（sORF）编码。 线粒体基因组（16 S rRNA基因）在这方面。饮食操作、H2S供体给药，以及 IGF-I减少导致humanin水平增加，而humanin本身模拟饮食限制（DR）， 多种途径包括抑制IGF-I、增加IGFBP-1、改善胰岛素敏感性和降低胰岛素抵抗。 重量. Humanin水平随着年龄的增长而下降，并与寿命、Humanin过表达或施用相关。 导致健康和寿命延长。与饮食干预和硫化氢类似， humanin保护免受各种各样的伤害，并且它的施用防止衰老疾病的发展。 我们与项目1和3的合作研究表明，humanin是饮食之间的核心联系， 限制，IGF减少和H2S表达，整合衰老过程中的抗应激和健身。 我们的中心假设是：（1）humanin是一种线粒体激素，其表达直接受 调节衰老的干预措施，如饮食控制，H2S和IGF减少，（2）Humanin调节 循环IGF-I（模拟DR）通过直接作用于下丘脑，导致中枢-肝脏效应， 抑制肝脏中IGF-I的产生（3）人胰岛素给药可以起到类似于DR和禁食模拟饮食的作用 或蛋白质限制循环，H2S和GH/IGF阻断，以促进健康和可能的长寿。 我们将研究饮食、IGF-I和H2S调节humanin表达的机制; humanin-sORF的转录和转录后调控。我们会破解 通过下丘脑介导的肝细胞凋亡抑制，参与人胰岛素作用的DR模拟效应。 IGF-I;以及通过对靶组织的直接保护作用。我们将描述人类的影响， 对健康跨度和确定所涉及的机制，使用新的humanin转基因小鼠模型，GP 130- 抑制剂和IGF-加回实验。 总之，这个项目将证明humanin的生理意义，作为一个调解人和调节器， 健康和长寿途径，包括与饮食，IGF-I和H2S相关的途径。我们希望证明， HN是必要的和足够的健康跨度/寿命增强。

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.