Our long-term objective is to elucidate the role of growth hormone (GH) in the control of aging. In mice, reduced somatotropic (GH / IGF-1) signaling leads to major increases in lifespan that are associated with various indices of delayed aging. We have proposed that reduced insulin release and enhanced insulin sensitivity are particularly important in mediating the effects of GH on aging. Our studies suggest that enhanced stress resistance is also involved. In the proposed studies, we will relate somatotropic signaling to insulin signaling in different tissues, stress resistance, physical function, healthspan and lifespan. We will use both well-characterized and novel models of whole animal or tissue-specific suppression of GH action, and pharmacological alterations of circulating GH levels or activity. The physiological role of GH at various stages of life history and its potential utility in geriatric medicine are poorly understood and controversial. To begin to address this issue, we will compare effects of GH in young, adult and aging animals. The following specific aims are proposed: 1: To determine the effects of GH replacement in hypopituitary mice on insulin signaling in different organs and cellular resistance to multiple forms of stress. 2: To determine the effects of liver-specific, adipose tissue-specific and muscle-specific deletion of GH receptor on insulin signaling, and expression of insulin-related genes in differentorgans. 3: To compare effects of adipocyte-specific GHR deletion to effects of surgical removal of visceral fat depots. 4: To compare the effects of replacement therapy with GH in young, middle-aged and old Ames dwarf mice. 5: To determine whether treatment of genetically normal mice with insulin sensitizers or a GH antagonist will improve stress resistance, promote maintenance of cognitive and physical function, health and vigor, and increase longevity. The results will identify alterations in the somatotropic axis and the importance of insulin signaling in the liver, muscle and adipose tissue that relate to enhanced stress resistance, improved cognition and increased healthspan and lifespan.
There is increasing evidence that the relationships of GH, IGF-1 and insulin to aging that were discovered in mice also apply to the human and, specifically, to the risk of age-related disease and to exceptional longevity. The results of the proposed research are expected to assist in development of interventions that may slow human aging and the associated functional decline and to provide factual basis for assessment of the potential utility of GH in geriatric medicine.
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