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）：本研究的广泛、长期目标是阐明胰岛素对葡萄糖代谢敏感性增加的机制，这是热量限制（CR；随意摄入 AL 摄入量的 60%）的标志和主要健康益处，并了解胰岛素信号对老年 CR 效应的其他重要作用。我们的新模型是 CR 对胰岛素信号传导产生组织特异性和途径特异性影响。该模型预测，对于使用内源性胰岛素（基础或静脉注射、静脉注射、葡萄糖激发后）的 CR 与 AL 大鼠，参与血糖调节的体内胰岛素信号在经典靶组织（骨骼肌、脂肪、肝脏）中将相似或增加，但在不是胰岛素刺激葡萄糖主要部位的非经典靶组织（脑、肾、主动脉）中减少 处理。尽管 CR 时胰岛素水平低得多，但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。该模型还预测，与 AL 大鼠相比，CR 大鼠在经典和非经典组织中的体内不参与葡萄糖调节的胰岛素信号传导途径的激活程度较低。目标 1 将阐明导致成人 (12 个月) 和老年 (25 个月) 大鼠中 CR（从约 3.5 个月大开始）诱导的胰岛素作用改善的机制。识别肌肉中与 CR 相关的特定信号传导步骤非常重要，因为到 60-74 岁，约 1/3 的美国人患有葡萄糖耐量异常，而肌肉胰岛素抵抗是与年龄相关的 2 型糖尿病进展的一个重要缺陷。除了胰岛素在血糖调节中的核心作用之外，原始生物体（酵母、线虫和果蝇）中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，目标 2（IV 葡萄糖挑战）和 3（IV 胰岛素挑战）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）中具有或不具有葡萄糖调节作用的体内胰岛素信号传导途径的影响。我们预计 IV 胰岛素激发会在 CR 与 AL（无论年龄）中诱导经典靶组织中与葡萄糖调节相关的更大胰岛素信号，但在非经典靶组织中则不会。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，这对于制定对抗年龄相关缺陷的干预措施可能有价值。