The Somatotropic Axis and Health Aging: A Search for Mechanisms

描述（由申请人提供）：拟议研究的长期目标是确定生长激素（GH）信号对哺乳动物衰老和长寿影响的机制。申请人在过去10年中进行的研究，以及其他实验室获得的结果，提供了明确的证据，证明小鼠生长激素缺乏和生长激素不敏感与平均寿命和最长寿命的显着增加有关。对gh缺乏和gh抵抗小鼠的年龄敏感特征和生存特征分析的研究表明，这些动物寿命的延长与生物衰老过程的延迟和/或减速相关联，并且很可能是由于这一过程的延迟和/或减速。我们的合作研究和其他研究者的工作确定了一系列机制，这些机制原则上可能将生长激素信号与寿命联系起来。在提议的工作中，我们将使用具有良好特征和新颖的小鼠突变体来探索这些特定机制中的几种。我们的目标是建立一个或多个连接GH或IGF-I信号减少与延长寿命的途径的令人信服的模型，并将这些途径与认知和身体功能的维持联系起来。拟议的合作研究将确定肝脏、脂肪组织和肌肉在调节生长激素和igf - 1对年龄敏感特征和寿命的影响中的作用；并阐明改变胰岛素信号，脂肪细胞分泌谱和应激抵抗在介导这些作用中的相互作用。项目1将把促生长和胰岛素信号与抗逆性和衰老联系起来。项目2将生产仅在肝脏、白色脂肪组织或肌肉中缺乏GHR/GHBP基因的新型动物。项目3将研究成纤维细胞和前脂肪细胞的应激抵抗机制，并评估项目2中开发的新型突变小鼠的寿命和年龄敏感特性。项目4将描述生长激素信号改变突变体的前脂肪细胞利用、特征和衰老。核心A将协调与咨询委员会的研究、信息交流和通讯，开发共享数据库并提供统计支助。核心B将评估肉眼和显微镜下的病理变化，重点是项目2开发的新突变体。提高对促生长和胰岛素信号在控制哺乳动物衰老中的作用的理解，对于设计生活方式和药物干预措施以维持人类衰老过程中的健康和功能是必要的。这些信息也需要为探索或阻止人类生长激素作为抗衰老剂的使用提供合理的依据。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to identify mechanisms responsible for the effects of growth hormone (GH) signaling on aging and longevity in mammals. Studies conducted by the applicants during the last 10 years, together with results obtained in other laboratories, have provided unequivocal evidence that GH deficiency and GH insensitivity in mice are associated with a marked increase in mean and maximal longevity. Studies of age-sensitive traits and analysis of survival characteristics in GH-deficient and GH-resistant mice indicate that increased longevity of these animals is coupled with and most likely due to a delay and/or deceleration of the process of biological aging. Our collaborative studies and work of other investigators defined a series of mechanisms that might, in principle, link GH signaling with longevity. In the proposed work we will use both well-characterized and novel mouse mutants to probe several of these specific mechanisms. Our aim is to develop a compelling model of the pathway or pathways that connect diminished GH or IGF-I signaling to extended longevity and to relate these pathways to maintenance of cognitive and physical function. The proposed collaborative studies will define the role of liver, adipose tissue and muscle in mediating the effects of GH and IGF-I on age-sensitive traits and longevity; and to elucidate the interactive effects of altered insulin signaling, adipocyte secretory profiles and stress resistance in mediating these effects. Project 1 will relate somatotropic and insulin signaling to stress resistance and aging. Project 2 will produce novel animals lacking the GHR/GHBP gene only in the liver, white adipose tissue or muscle. Project 3 will study mechanisms of stress resistance in fibroblasts and pre-adipocytes and evaluate longevity and age-sensitive traits in novel mutant mice developed in Project 2. Project 4 will characterize pre-adipocyte utilization, characteristics and senescence in mutants with altered GH signaling. Core A will coordinate research, information exchange and communication with Advisory Committee, develop shared data base and provide statistical support. Core B will assess gross and microscopic pathological changes with emphasis on novel mutants developed by Project 2. Improved understanding of the role of somatotropic and insulin signaling in the control of mammalian aging is needed for designing lifestyle and pharmacological interventions to maintain health and functionality during human aging. This information is also needed to develop rational basis for exploring or discouraging the use of human GH as an anti-aging agent.