The Somatotropic Axis and Health Aging: A Search for Mechanisms

生长轴与健康衰老：寻找机制

• 批准号: 8049162
• 负责人: Andrzej Bartke
• 金额: $ 175.66万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049162
• 关键词: Somatotropic; Axis; Health; Aging; Search

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.

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）信号传导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，表明小鼠的 GH 缺乏和 GH 不敏感与平均寿命和最大寿命的显着延长有关。对 GH 缺乏和 GH 抗性小鼠的年龄敏感特征的研究和生存特征的分析表明，这些动物的寿命延长与生物衰老过程的延迟和/或减速有关，并且很可能是由于生物衰老过程的延迟和/或减慢所致。我们的合作研究和其他研究人员的工作定义了一系列原则上可能将 GH 信号传导与长寿联系起来的机制。在拟议的工作中，我们将使用特征明确的新型小鼠突变体来探索其中的几种特定机制。我们的目标是开发一个令人信服的模型，将 GH 或 IGF-I 信号传导减弱与延长寿命联系起来，并将这些通路与维持认知和身体功能联系起来。拟议的合作研究将确定肝脏、脂肪组织和肌肉在调节 GH 和 IGF-I 对年龄敏感特征和寿命的影响中的作用；并阐明改变的胰岛素信号、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 将生长激素和胰岛素信号传导与应激抵抗和衰老联系起来。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征。项目 4 将表征 GH 信号传导改变的突变体中前脂肪细胞的利用、特征和衰老。核心A将协调研究、信息交流和与咨询委员会的沟通，开发共享数据库并提供统计支持。核心 B 将评估总体和微观病理变化，重点是项目 2 开发的新型突变体。需要更好地了解生长激素和胰岛素信号在控制哺乳动物衰老中的作用，以设计生活方式和药物干预措施，以在人类衰老过程中维持健康和功能。还需要这些信息来为探索或阻止使用人类 GH 作为抗衰老剂奠定合理的基础。