CALORIC RESTRICTION, AGING AND CARDIOVASCULAR DISEASE

热量限制、衰老和心血管疾病

• 批准号: 2052019
• 负责人: William T. Cefalu
• 金额: $ 10.09万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-06 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2052019
• 关键词: Macaca fascicularis; adipose tissue; aging; atherosclerosis; biomarker; caloric dietary content; cholesterol; collagen; computed axial tomography; coronary artery; disease /disorder model; glycation; insulin sensitivity /resistance; longitudinal animal study; male; nutrition related tag; postmortem

Caloric restriction has been shown in numerous studies in rodents to extend the maximal life span, retard age-associated physiological changes and delay or prevent most age associated disease. If these findings are to be extrapolated to human beings, it will first be necessary to test varying dietary regimens in some higher species and evaluate the effect on an age-related disease process, particularly as it relates to human health. As such, age related disease such as atherosclerosis would be a valuable end point to study. To diminish atherosclerosis, the caloric restriction should alter pathogenic mechanisms contributing to the disease process. Therefore, the proposed research will evaluate a well characterized non-human primate model for human atherosclerosis and study dietary intervention in the form of caloric restriction compared to unrestricted diet with equivalent cholesterol content. We will evaluate for changes secondary to the dietary restriction on insulin resistance, arterial collagen glycation/advanced glycation, and adipose tissue distribution, particularly for intra-abdominal fat, all of which have been strongly implicated in contributing to cardiovascular disease. The changes in our parameters secondary to dietary intervention will be related to atherosclerosis extent of the coronary arteries assessed at study completion. To diminish atherosclerosis, caloric restriction should alter pathogenic mechanisms contributing to the disease process. Therefore, our specific hypothesis is that caloric restriction over a sustained period when compared with an ad libitum diet with equivalent cholesterol content, may diminish atherosclerosis by reducing age-associated increases in vascular levels of early/advanced glycated products (e.g. protein cross-linking), improving peripheral insulin sensitivity, and reducing intra-abdominal fat. To evaluate our hypothesis, we plan to study a non-human primate model of atherosclerosis using dietary intervention in the form of caloric restriction. At study baseline, animals will have an iliac artery removed to quantitate advanced glycated products (pentosidine, carboxymethyllysine). In addition an assessment of insulin sensitivity and computed tomographic scans will be done to quantitate intra-abdominal fat. The animals will then be randomized to receive either an ad libitum or caloric restricted diet. Both diets will have identical cholesterol content to evaluate the effect of caloric restriction on atherosclerosis. Animals will be followed for four years, with longitudinal assessment of insulin sensitivity, skin glycation/advanced glycation, and amount of intra-abdominal fat. At the end of a four year period, animals will be necropsied, vascular tissue removed for assessment of advanced glycation, and atherosclerosis extent evaluated. The primary objective of the proposed study is to evaluate the association between physiologic and glycation measures with atherosclerosis and to compare the glycation, insulin resistance and adiposity measures in monkeys between caloric restricted and ad libitum diet groups. The principal measure of the degree of atherosclerosis will be the mean coronary artery intimal area.

大量针对啮齿动物的研究表明，热量限制可以 延长最大寿命，延缓与年龄相关的生理变化 延缓或预防大多数与年龄相关的疾病。如果这些发现是 推断到人类身上，首先需要进行测试 在一些高等物种中改变饮食方案并评估其影响 与年龄相关的疾病过程，特别是与人类有关的疾病过程 健康。因此，动脉粥样硬化等与年龄相关的疾病将是 有价值的研究终点。为了减少动脉粥样硬化，热量 限制应该改变导致疾病的致病机制 过程。因此，拟议的研究将评估良好 人类动脉粥样硬化非人类灵长类动物模型的特征和研究 与限制热量形式的饮食干预相比 不限制饮食，胆固醇含量相当。我们将评估 对于胰岛素抵抗饮食限制继发的变化， 动脉胶原糖化/高级糖化和脂肪组织 分布，特别是腹内脂肪，所有这些都已被 与心血管疾病密切相关。变化 在我们的参数中，饮食干预的次要因素将与 研究中评估的冠状动脉粥样硬化程度 完成。 为了减少动脉粥样硬化，热量限制应该改变致病因素 促进疾病过程的机制。因此，我们的具体 假设是在持续一段时间内限制热量 与胆固醇含量相当的随意饮食相比，可能 通过减少与年龄相关的血管增加来减少动脉粥样硬化 早期/高级糖化产物的水平（例如蛋白质交联）， 改善外周胰岛素敏感性，减少腹内胰岛素 胖的。为了评估我们的假设，我们计划研究非人类灵长类动物 使用热量形式的饮食干预的动脉粥样硬化模型 限制。在研究基线时，动物将被切除髂动脉 定量高级糖化产物（戊糖素、 羧甲基赖氨酸）。此外，还需要评估胰岛素敏感性和 将进行计算机断层扫描以定量腹内脂肪。 然后，这些动物将被随机分配接受随意或 限制热量饮食。两种饮食含有相同的胆固醇 内容来评估热量限制对动脉粥样硬化的影响。 动物将被跟踪四年，并进行纵向评估 胰岛素敏感性、皮肤糖化/高级糖化以及胰岛素用量 腹内脂肪。四年期结束时，动物将 尸检，去除血管组织以评估晚期糖化， 并评估动脉粥样硬化程度。 拟议研究的主要目的是评估关联性 生理学和糖化测量与动脉粥样硬化之间的关系 比较糖化、胰岛素抵抗和肥胖指标 热量限制组和随意饮食组之间的猴子。这 动脉粥样硬化程度的主要衡量标准是平均数 冠状动脉内膜区域。