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: 7803678
• 负责人: Andrzej Bartke
• 金额: $ 166.11万
• 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/7803678
• 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负责生长激素（GH）信号对哺乳动物衰老和长寿的影响的机制。申请人在过去10年中进行的研究以及在其他实验室获得的结果提供了明确的证据，证明小鼠中GH缺乏和GH不敏感性与平均和最长寿命显著增加相关。对生长激素缺乏和生长激素抗性小鼠的年龄敏感性特征的研究和生存特征的分析表明，这些动物的寿命增加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/或减速。我们的合作研究和其他研究人员的工作定义了一系列机制，原则上可能将GH信号与长寿联系起来。在拟议的工作中，我们将使用充分表征和新的小鼠突变体来探测这些特定的机制。我们的目标是开发一种引人注目的通路模型，将减少的GH或IGF-I信号传导与延长的寿命联系起来，并将这些通路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，脂肪组织和肌肉在介导GH和IGF-I对年龄敏感性状和寿命的影响中的作用;并阐明改变胰岛素信号传导，脂肪细胞分泌特征和应激抗性在介导这些影响中的相互作用。项目1将生长激素和胰岛素信号与抗应激和衰老联系起来。项目2将产生仅在肝脏、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抗应激机制，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将描述前脂肪细胞的利用，特征和衰老的突变体与改变生长激素信号。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，并提供统计支助。核心B将评估大体和微观病理变化，重点是项目2开发的新型突变体。为了设计生活方式和药理学干预措施以维持人类衰老过程中的健康和功能，需要更好地了解促生长激素和胰岛素信号在哺乳动物衰老控制中的作用。这些信息也需要开发合理的基础，探索或劝阻使用人生长激素作为抗衰老剂。