Aging, Calorie Restriction and Insulin Signaling

衰老、热量限制和胰岛素信号传导

• 批准号: 7909218
• 负责人: Gregory D. Cartee
• 金额: $ 5.05万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909218
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Adipose tissue; Adult; Age; Aging; American; Aorta; Attenuated; Brain; Caloric Restriction; Conflict (Psychology); Defect; Dexamethasone; Diet; Disease; Dose; Elderly; Event; Glucose; Health Benefit; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Intake; Intervention; Intravenous; Kidney; Knowledge; Link; Liver; Long-Term Effects; Longevity; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Mammals; Mitogen-Activated Protein Kinase 3; Mitogens; Modeling; Muscle; Nematoda; Non-Insulin-Dependent Diabetes Mellitus; Organism; Outcome; Pathway interactions; Phosphotransferases; Plasma; Preparation; Process; Rattus; Research; Research Personnel; Rodent; Role; Signal Transduction; Signaling Protein; Site; Skeletal Muscle; Testing; Tissues; Yeasts; age effect; age group; age related; anti aging; atypical protein kinase C; basal insulin; brain tissue; fly; glucose disposal; glucose metabolism; glucose tolerance; glucose transport; glucose uptake; improved; in vivo; insight; insulin receptor serine kinase; insulin sensitivity; insulin signaling; novel; programs; response

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.

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敏感性增加的葡萄糖代谢敏感性的基础机制，这是卡路里限制的标志性和重大健康益处（CR；消耗60％的Ad aD aDibitum，al，intake），并了解其他胰岛素信号的重要角色对CR效应的其他重要作用。我们的新型模型是CR诱导组织特异性和途径特异性对胰岛素信号的影响。该模型预测，对于具有内源性胰岛素（基底或静脉注射，IV，葡萄糖挑战之后）的CR与AL大鼠，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，脂肪，脂肪，肝脏）中会相似或增加，但在非级别的目标组织（brain brain，brain，brain，aorta）中却减少了。 处理。尽管使用CR的胰岛素要低得多，但增强了经典组织葡萄糖调节过程的胰岛素信号传导将是增加全身葡萄糖清除率的合理解释。该模型还预测，在经典组织和非经典组织中，与葡萄糖调节无关的胰岛素信号通路在葡萄糖调节中的活化较低。 AIM 1将阐明成人（12mO）和旧（25mO）大鼠Cr（始于〜3.5采）引起的胰岛素作用改善的机制。识别CR肌肉中特定的信号传导步骤很重要，因为到60-74岁，〜1/3的美国人患有异常的葡萄糖耐受性，而肌肉胰岛素抵抗是与年龄相关的2型糖尿病进展的必要缺陷。除了胰岛素在葡萄糖调节中的核心作用外，原始生物（酵母，线虫和苍蝇）中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剂。但是，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，目标2（IV葡萄糖挑战）和3（IV胰岛素挑战）将确定CR和年龄对在成年和老鼠多种组织（经典和非典型）中具有或没有葡萄糖调节作用的体内胰岛素信号通路的影响。我们预计，IV胰岛素的挑战会诱导CR与AL（不论年龄如何）与经典糖调节相关的胰岛素信号更大，但在非经典靶组织中却不相关。这些研究的结果将为CR和年龄对胰岛素信号的影响提供新的见解，这对于开发与年龄相关的缺陷可能很有价值。