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轴是一个保守的途径，对确定多种生物的健康寿命和寿命都很重要。来自几个啮齿动物模型的数据表明，生长激素和/或IGF-1的终身缺乏或抑制其信号通路的扰动导致寿命延长，减少与年龄相关的病理和对心脏和认知功能的有益影响。然而，这些激素水平的降低或信号传导对衰老生物体有益的概念仍然存在争议，因为有许多研究报道了生长激素和/或IGF-1替代对衰老心血管系统的有益作用，并且有大量数据库表明这些激素对衰老的大脑有益。GH和IGF-1水平的降低是否与寿命的延长直接相关，GH和/或IGF-1的替代是否对个体器官系统（如健康寿命）有有益的影响，这些问题仍然是生物老年学领域的一个开创性问题。这一争论将继续下去，直到有合适的和翻译相关的动物模型可以用于调节生长激素和IGF-1在整个生命周期的水平。在最近的协商一致报告中，我们和我们的同事已经认识到需要新的模式来促进这一领域的发展。根据PA-10-014（衰老研究动物模型的开发和表征）的要求，我们的目标是开展与翻译相关的研究以及基本的寿命、代谢、行为和病理分析，以解决肝脏IGF-1缺陷在生命的不同阶段对生存、生命末期病理和代谢参数有独特影响的假设。提出以下具体目标：1)通过杂交alb-cretg/+和igff/f小鼠，或在出生后30天、6个月或16个月向igff/f小鼠注射mupi - icre - aav8或对照载体，分析肝脏IGF-1缺乏的影响，并评估其对寿命和终末期病理的影响。2)确定围出生期或30天、6个月或16个月时肝脏IGF-1缺乏的影响：a)使用横断面设计的年龄相关病理变化的积累，b)旁分泌IGF-1基因和蛋白表达，c)循环激素水平（甲状腺素、瘦素、胰岛素和葡萄糖）以及全身胰岛素作用、葡萄糖生成和单个组织中葡萄糖利用率，d)肾脏和肝脏功能。e)食物/水消耗、活动量和瘦/脂肪量的基本测量。IGF-1缺乏对这些终点的影响将在6、16和26个月时进行评估。3)评估肝IGF-1缺乏是否在围产期或30天、6或16个月时开始影响衰老过程中血管、心脏、肝脏、大脑、肌肉和肾脏的细胞氧化还原稳态和炎症过程。所提出的研究旨在利用临床前、转化相关的方法，对IGF-1缺乏对病理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.