Aging, Calorie Restriction and Insulin Signaling

描述(由申请人提供)：这项研究的广泛、长期目标是阐明胰岛素对葡萄糖代谢敏感性增加的机制，这是卡路里限制(CR；随意摄入60%的AL)的标志和主要健康益处，并了解胰岛素信号在老年CR效应中的其他重要作用。我们的新模型是CR在胰岛素信号转导中诱导组织特异性和途径特异性的效应。该模型预测，对于内源性胰岛素的CR和AL大鼠(基础或静脉注射葡萄糖刺激后)，体内参与血糖调节的胰岛素信号在经典靶组织(骨骼肌、脂肪、肝脏)中相似或增加，但在非典型靶组织(脑、肾、主动脉)中减少，这些非胰岛素刺激的葡萄糖处置的主要部位。经典组织的糖调节过程的胰岛素信号增强可能是全身葡萄糖清除量增加的合理解释，尽管CR患者的胰岛素水平要低得多。该模型还预测，在经典和非经典组织中，与糖调节无关的胰岛素信号通路在CR和AL大鼠体内的激活程度将较低。目的1在成年(12mo)和老年(25mo)大鼠上阐明CR(始于3.5mo龄)改善胰岛素作用的机制。用CR识别肌肉中特定的信号步骤非常重要，因为到60-74岁时，~1/3的美国人患有糖耐量异常，而肌肉胰岛素抵抗是与年龄相关的2型糖尿病进展过程中的一个重要缺陷。除了胰岛素在血糖调节中的核心作用外，在原始生物(酵母、线虫和苍蝇)中的令人信服的证据表明，胰岛素信号通路是初级衰老的关键调节器。然而，关于长期CR对哺乳动物体内胰岛素信号的影响的了解非常有限。因此，AIMS 2(IV葡萄糖挑战)和AIMS 3(IV胰岛素挑战)将在成年和老年大鼠的多个组织(经典和非经典)中确定CR和AGE对体内胰岛素信号通路的影响，无论是否有糖调节作用。我们预计静脉注射胰岛素将在CR和AL(无论年龄)中诱导与糖调节相关的更多的胰岛素信号，但在非经典靶组织中不会。这些研究的结果将为CR和AGE对胰岛素信号的影响提供新的见解，这可能对开发针对年龄相关缺陷的干预措施有价值。

DESCRIPTION (provided by applicant): The broad, long-term objectives of this research are to elucidate the mechanisms underlying the increase in insulin sensitivity for glucose metabolism that is a hallmark and major health benefit of calorie restriction (CR; consuming 60% of ad libitum, AL, intake) and to understand other important roles of insulin signaling for CR effects in old age. Our novel model is that CR induces tissue-specific and pathway-specific effects on insulin signaling. The model predicts that for CR vs. AL rats with endogenous insulin (basal or after intravenous, IV, glucose challenge), in vivo insulin signaling involved in glucoregulation will be similar or increased in classic target tissues (skeletal muscle, adipose, liver), but reduced in non-classic target tissues (brain, kidney, aorta) that are not major sites of insulin-stimulated glucose disposal. Enhanced insulin signaling for glucoregulatory processes of classic tissues would be a plausible explanation for increased whole body glucose clearance despite much lower insulin with CR. The model also predicts that insulin signaling pathways that are not implicated in glucoregulation will have lower activation in vivo for CR vs. AL rats in both classic and non-classic tissues. Aim 1 will elucidate mechanisms leading to improved insulin action induced by CR (begun at ~3.5mo-old) in Adult (12mo) and Old (25mo) rats. Identifying the specific signaling steps in muscle with CR is important because by age 60-74yr, ~1/3 of Americans suffer from abnormal glucose tolerance, and muscle insulin resistance is an essential defect in age-related progression to type 2 diabetes. In addition to insulin's central role in glucoregulation, compelling evidence in primitive organisms (yeast, nematodes and flies) points to the insulin signaling pathway as a key modulator of primary aging. However, knowledge about the influence of long-term CR on in vivo insulin signaling in mammals is remarkably limited. Therefore, Aims 2 (IV glucose challenge) and 3 (IV insulin challenge) will ascertain the effects of CR and age on in vivo insulin signaling pathways either with or without glucoregulatory roles in multiple tissues (both classic and non-classic) of Adult and Old rats. We expect an IV insulin challenge to induce in CR vs. AL (regardless of age) greater insulin-signaling related to glucoregulation in classic, but not in non-classic target tissues. The results of these studies will provide novel insights into the effects of CR and age on insulin signaling that may be valuable for developing interventions to oppose age-related deficits.