The regulation of health and longevity by branched-chain amino acids

项目摘要 在西方社会，与生殖器有关的疾病是发病和死亡的主要原因。卡路里 限制（CR），一种延长寿命的饮食干预，同时延迟或预防与年龄有关的疾病， 是减轻这些疾病负担的一种可行方法，但低热量饮食是众所周知的 难以维持。最近的研究强调了膳食蛋白质在健康和长寿中的重要作用， 低蛋白（LP）饮食显示出促进长寿和模仿CR的代谢益处。我们有 发现，特别是减少三种支链氨基酸（BCAAs）的饮食消耗- 亮氨酸、异亮氨酸和缬氨酸-促进年轻和老年小鼠的代谢健康， 早老症小鼠的寿命。确定低支链氨基酸饮食对长寿的影响，并确定 饮食中支链氨基酸影响代谢的生理和分子机制，将提供 对健康老龄化调节的机械性见解。最终，这将允许开发新的 预防或延缓与年龄有关的疾病的药理学方法。 在这里，我们将严格测试低BCAA饮食可以促进健康和长寿的假设， 研究长期低支链氨基酸饮食对寿命、代谢健康、心脏功能和 脆弱我们将确定是否减少消费的支链氨基酸介导的CR和LP的代谢作用 节食。最后，我们将研究支链氨基酸及其催化剂对功能的细胞自主作用。 以及使用新型代谢传感器离体检测原代肝细胞和胰岛的代谢， 这些效应的候选分子介质。 这项拟议的工作将研究支链氨基酸对健康和长寿的作用， 第一次，并解决长期存在的问题，如何饮食质量-具体组成的 饮食-影响健康的老龄化。重要的是，我们将获得新的见解， 这些机制推动了CR和LP饮食的有效作用。从长远来看，这项工作将使我们的 实验室和其他机构，以发展一个机械的理解，如何膳食支链氨基酸和 其他大量营养素调节健康和疾病的脆弱性，并确定新的目标， 药物治疗与年龄有关的疾病和促进健康老龄化。

Project Summary Age-related diseases are the major causes of morbidity and mortality in Western society. Calorie restriction (CR), a dietary intervention which extends lifespan while delaying or preventing age-related disease, is one plausible approach to lessen the burden of these diseases, but reduced-calorie diets are notoriously difficult to sustain. Recent studies have highlighted an important role for dietary protein in health and longevity, with low protein (LP) diets shown to promote longevity and to mimic the metabolic benefits of CR. We have found that specifically reducing dietary consumption of the three branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – promotes metabolic health in both young and aged mice, and promotes longevity in progeroid mice. Determining the effect of Low BCAA diets on longevity, and identifying the physiological and molecular mechanisms by which dietary BCAAs influence metabolism, will provide mechanistic insight into the regulation of healthy aging. Eventually, this will permit the development of new pharmacological approaches to prevent or delay age-related diseases. Here, we will rigorously test the hypothesis that a Low BCAA diet can promote health and longevity in mice, examining the effect of long-term Low BCAA diet on lifespan, metabolic health, cardiac function and frailty. We will determine if reduced consumption of the BCAAs mediates the metabolic effects of CR and LP diets. Finally, we will examine the cell autonomous effects of the BCAAs and their catabolites on the function and metabolism of primary hepatocytes and pancreatic islets ex vivo using novel metabolic sensors, and test candidate molecular mediators of these effects. The proposed work will examine the role of the branched-chain amino acids on health and longevity for the first time, and address long-standing questions regarding how dietary quality – the specific composition of the diet – impacts healthy aging. Importantly, we will gain new insight into the physiological and molecular mechanisms that drive the potent effects of CR and LP diets. In the long term, this work will enable our laboratory and others to develop a mechanistic understanding of how dietary branched-chain amino acids and other macronutrients regulate health and disease vulnerability, and to identify new targets for the pharmacological treatment of age-related diseases and the promotion of healthy aging.