Aging, Calorie Restriction and Insulin Signaling

描述（由申请方提供）：本研究的广泛、长期目标是阐明葡萄糖代谢的胰岛素敏感性增加的潜在机制，这是热量限制（CR;消耗60%的自由摄入量，AL，摄入量）的标志和主要健康益处，并了解胰岛素信号传导在老年CR效应中的其他重要作用。我们的新模型是CR诱导胰岛素信号传导的组织特异性和途径特异性效应。该模型预测，对于具有内源性胰岛素的CR与AL大鼠（基础或静脉内、IV、葡萄糖激发后），参与葡萄糖调节的体内胰岛素信号传导在经典靶组织（骨骼肌、脂肪、肝脏）中相似或增加，但在非经典靶组织（脑、肾、主动脉）中减少，这些靶组织不是胰岛素刺激的葡萄糖处置的主要部位。经典组织葡萄糖调节过程的胰岛素信号增强可能是全身葡萄糖清除率增加的合理解释，尽管CR时胰岛素水平低得多。该模型还预测，在经典和非经典组织中，与AL大鼠相比，CR大鼠体内的胰岛素信号传导途径在葡萄糖调节中不受影响，其活化程度较低。目的1阐明CR（开始于~ 3.5月龄）对成年（12月龄）和老年（25月龄）大鼠胰岛素作用的改善机制。确定CR肌肉中的特定信号步骤很重要，因为到60- 74岁时，约1/3的美国人患有糖耐量异常，肌肉胰岛素抵抗是与年龄相关的2型糖尿病进展的重要缺陷。除了胰岛素在糖调节中的核心作用外，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传导途径是原发性衰老的关键调节剂。然而，关于长期CR对哺乳动物体内胰岛素信号传导的影响的知识非常有限。因此，目的2（IV葡萄糖激发）和目的3（IV胰岛素激发）将确定CR和年龄对成年和老年大鼠多个组织（经典和非经典）中体内胰岛素信号通路的影响，无论是否具有葡萄糖调节作用。我们预期IV胰岛素激发在CR与AL（无论年龄）中诱导与经典靶组织中的葡萄糖调节相关的更大胰岛素信号传导，但在非经典靶组织中不诱导。这些研究的结果将为CR和年龄对胰岛素信号传导的影响提供新的见解，这对于开发对抗年龄相关缺陷的干预措施可能是有价值的。

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.