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Previous studies have provided compelling evidence that the Growth Hormone (GH)-IGF-1 axis is a conserved pathway important for determination of both healthspan and lifespan in diverse organisms. Data from several rodent models indicate that lifelong deficiency of GH and/or IGF-1 or perturbations that suppress their signaling pathways result in increased lifespan, reduced age-related pathologies and beneficial effects on cardiac and cognitive function. Nevertheless, the concept that reduced levels or signaling of these hormones are beneficial for the aging organism remains controversial since there are numerous studies that have reported beneficial effects of GH and/or IGF-1 replacement on the aging cardiovascular system and an overwhelming database indicating beneficial effects of these hormones on the aging brain. The question of whether reduced GH and IGF-1 levels are directly associated with increased longevity and whether GH and/or IGF-1 replacement have beneficial effects on individual organ systems (e.g. healthspan) remains a seminal question in the field of biogerontology. This controversy will continue until appropriate and translationally relevant animal models that can be used to regulate GH and IGF-1 levels throughout the lifespan are available. The necessity of new models for advancement of the field has been recognized by us and our colleagues in recent consensus reports. The proposed experiments are in response to PA-10-014 (Development and Characterization of Animal Models for Aging Research) and our goal is to conduct translationally relevant studies as well as basic lifespan, metabolic, behavioral and pathological analyses to address the hypothesis that deficiencies of hepatic IGF-1 initiated at different stages of the lifespan have unique effects on survival, end-of life pathology and metabolic parameters. The following specific aims are proposed: 1) Analyze the effects of hepatic IGF-1 deficiency initiated peri-natally by crossing alb-cretg/+ and igff/f mice or post-natally at 30 days, 6 or 16 months by injecting the igff/f mouse with MUP-iCre-AAV8 or control vector and assessing effects on lifespan and end-of-life pathology. 2) Determine the effects of hepatic IGF-1 deficiency initiated peri-natally or at 30 days, 6 or 16 months of age on a) accumulation of age-related pathological changes using a cross-sectional design, b) paracrine IGF-1 gene and protein expression, c) circulating hormone levels (thyroxine, leptin, insulin and glucose) as well as whole body insulin action, glucose production and rates of glucose utilization in individual tissues, d) kidney and liver function, as well as e) basic measures of food/water consumption, activity and lean/fat mass. Effects of IGF-1 deficiency on these endpoints will be assessed at 6, 16 and 26 months of age. 3) Assess whether hepatic IGF-1 deficiency initiated peri-natally or at 30 days, 6 or 16 months influences cellular redox homeostasis and inflammatory processes in vasculature, heart, liver, brain, muscle and kidney during aging. The studies presented are designed to produce one of the most comprehensive and rigorous analyses of the effects of IGF-1 deficiency on pathology and lifespan using a pre-clinical, translationally relevant approach.
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