NOVEL APPROACHES FOR REGULATION OF IGF-1 LEVELS THROUGHOUT THE LIFESPAN

描述（由申请人提供）：先前的研究提供了令人信服的证据，证明生长激素（GH）-IGF-1轴是一种保守的途径，对于确定不同生物体的健康寿命和寿命非常重要。来自几种啮齿动物模型的数据表明，GH和/或IGF-1的终身缺乏或抑制其信号传导途径的干扰导致寿命延长，年龄相关的病理学减少以及对心脏和认知功能的有益影响。然而，这些激素的水平降低或信号传导对衰老生物体有益的概念仍然存在争议，因为有许多研究报告了GH和/或IGF-1替代对衰老心血管系统的有益作用，并且大量数据库表明这些激素对衰老大脑的有益作用。GH和IGF-1水平降低是否与寿命延长直接相关，以及GH和/或IGF-1替代是否对个体器官系统（例如健康寿命）具有有益影响的问题仍然是老年医学领域的一个开创性问题。这一争论将继续下去，直到适当的和诊断相关的动物模型，可用于调节生长激素和IGF-1水平在整个生命周期是可用的。我们和我们的同事们在最近的协商一致报告中认识到，必须采用新的模式来推动这一领域的发展。拟定实验是对PA-10-014的响应（衰老研究动物模型的开发和表征），我们的目标是进行预防相关的研究以及基本的寿命，代谢，行为和病理分析，以解决在寿命的不同阶段开始的肝脏IGF-1缺乏对生存具有独特影响的假设，生命末期病理学和代谢参数。提出了以下具体目的：1）通过使alb-cretg/+和igff/f小鼠杂交来分析在围产期引发的肝IGF-1缺乏的影响，或者通过向igff/f小鼠注射MUP-iCre-AAV 8或对照载体来分析在出生后30天、6或16个月引发的肝IGF-1缺乏的影响，并评估对寿命和生命末期病理学的影响。2)确定在围产期或30天、6或16个月大时开始的肝脏IGF-1缺乏对a）使用横截面设计的年龄相关的病理变化的积累，B）旁分泌IGF-1基因和蛋白质表达，c）循环激素水平的影响（甲状腺素、瘦素、胰岛素和葡萄糖）以及全身胰岛素作用、葡萄糖产生和单个组织中的葡萄糖利用率，d）肾和肝功能，以及e）食物/水消耗、活动和瘦/脂肪质量的基本测量。将在6、16和26月龄时评估IGF-1缺乏对这些终点的影响。3)评估肝脏IGF-1缺乏症是否在围产期或30天，6或16个月开始影响细胞氧化还原稳态和血管系统，心脏，肝脏，大脑，肌肉和肾脏在衰老过程中的炎症过程。这些研究旨在使用临床前，预防相关的方法对IGF-1缺乏对病理学和寿命的影响进行最全面，最严格的分析。

DESCRIPTION (provided by applicant): 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.