The Somatotropic Axis and Health Aging: A Search for Mechanisms

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. RELEVANCE: 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. PRINCIPAL INVESTIGATOR: Dr. Bartke is Professor and Director of Geriatric Medicine in the Department of Internal Medicine at Southern Illinois University School of Medicine. His many years of experience studying the role of GH and IGF-I in mice brings a strong knowledge of endocrinology to this PPG. Dr. Bartke has developed a significant publication record in understanding animal models of aging and how manipulation of the growth hormone/IGF-I axis is related to extended longevity. His laboratory was the first to identify the link between the GH/IGF-1 signaling and longevity in the mouse. Dr. Barke has had substantial administrative experience and is very appropriate to be principal investigator of this PPG. CORE A - ADMINISTRATION; Dr. Andrzej Bartke, Core Leader (CL) DESCRIPTION (provided by applicant): A Program Project of this magnitude will require the coordination of personnel and technical expertise. The main functions of the Administrative Core will be to facilitate communication between the five laboratories involved in the proposed studies. This will entail development and maintenance of a shared database, statistical consultations, the solicitation of input from the Advisory Committee, and organization of an annual meeting of all participants in the Program Project. In addition, Core A will assist in issues related to the budget, distribution of animals and tissues, maintain regular contact with the Project Officer at NIA, and prepare annual progress reports/renewal applications. In Years 04 and 05, Core A will coordinate the planning of future directions of this Program Project and oversee preparation of the application for competing renewal. Five Specific Aims are proposed: 1. To facilitate communication between all participating investigators, all members of the participating laboratories including graduate students and postdoctoral fellows, and investigators and Advisory Committee. 2. To establish and maintain data management system that will facilitate exchange of samples and data between the participating laboratories and maximize utilization of every animal. 3. To provide statistical support and consultations for experimental design and data analysis, and to identify and recommend statistical approaches for combined analysis of data from different Projects/Cores. 4. To provide assistance and oversight of fiscal management of projects and Core B and of exchange of animals, tissues and other samples (plasma, tissue extracts, mRNA or cDNA preparations) between laboratories. 5. To prepare annual progress reports and coordinate preparation of a competing renewal application.