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

项目摘要 与年龄相关的疾病是美国发病率和死亡率的主要原因。很多老年人 同时患有多种与年龄相关的疾病；同时，几乎每一种疾病的风险都会上升 随着年龄的增长，它们也会相互作用。例如，糖尿病和肥胖是神经退行性疾病的危险因素。 包括阿尔茨海默病(AD)。卡路里限制(CR)，一种饮食干预，延长寿命，同时 延缓或预防与年龄相关的疾病，是减轻多重年龄负担的一种看似合理的方法- 相关疾病同时发生，但低卡路里饮食是出了名的难以维持。最新研究 强调了饮食蛋白质在健康和长寿中的重要作用，并显示了蛋白质限制(PR) 以延长寿命，并模仿CR的新陈代谢、虚弱和认知益处。 在最初的项目期间，我们发现具体减少三个人的饮食消耗 支链氨基酸(BCAA)-亮氨酸、异亮氨酸和缬氨酸-对脆弱和 C57BL/6J小鼠的寿命。我们确定PR的代谢和分子效应既有性作用也有分子作用 依赖于菌株，并认为一种特定激素的作用可能更多地中介PR的影响 比之前怀疑的要有限，而且在性别和品系之间也有差异。最后，我们发现，BCAA 对代谢有不同的作用，限制异亮氨酸是代谢的必要条件和充分条件 公关的好处。在初步实验中，我们还发现异亮氨酸限制具有性二态 对遗传异种小鼠的健康和寿命的影响，以及PR对 阿尔茨海默病小鼠模型的认知和疾病病理学。 在这里，我们将严格检验异亮氨酸分级限制促进健康长寿的能力 在DBA/2J和C57BL/6J两种性别的小鼠上，检测了其对代谢健康、脆弱、认知和 寿命以及对病理学和分子水平的影响。我们将确定特定的角色 激素，FGF21，在异亮氨酸限制的代谢反应中。最后，我们将测试个人是否受到限制 支链氨基酸对于公关饮食预防或延缓AD的能力是必要的，也是充分的。 这项拟议的工作将研究支链氨基酸异亮氨酸在健康和长寿方面的作用 首次介绍了遗传背景，并回答了有关饮食结构如何构成的长期问题 影响健康的衰老。重要的是，我们将对驱动潜在影响的机制有新的认识。 限制异亮氨酸对健康衰老的影响，并开辟新的领域，确定个别支链氨基酸如何影响 AD的进展。从长远来看，这项工作将使我们的实验室和其他实验室能够开发出一种机械 了解饮食中的支链氨基酸和其他常量营养素如何调节健康和疾病的脆弱性，以及 确定促进健康老龄化的药物治疗新靶点。

Project Summary Age-related diseases are the major causes of morbidity and mortality in the US. Many elderly people suffer from multiple age-related diseases simultaneously; while the risk of almost every individual disease rises with age, they also interact. For example, diabetes and obesity are risk factors for neurodegenerative diseases including Alzheimer’s disease (AD). 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 multiple age- related diseases simultaneously, but reduced-calorie diets are notoriously difficult to sustain. Recent studies have highlighted an important role for dietary protein in health and longevity, with protein restriction (PR) shown to promote longevity and to mimic the metabolic, frailty, and cognitive benefits of CR. During the initial project period, we found that specifically reducing dietary consumption of the three branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine – has sex-specific benefits for frailty and lifespan in C57BL/6J mice. We determined that the metabolic and molecular effects of PR are both sex and strain dependent, and that the role of a specific hormone proposed to mediate the effects of PR may be more limited than previously suspected and also differ between sexes and strains. Finally, we found that the BCAAs have distinct roles on metabolism, with restriction of isoleucine being necessary and sufficient for the metabolic benefits of PR. In preliminary experiments, we have also found that isoleucine restriction has sexually dimorphic effects on healthspan and longevity in genetically heterogenous mice, and that PR has beneficial effects on cognition and disease pathology in a mouse model of Alzheimer’s disease. Here, we will rigorously test the ability of graded restriction of isoleucine to promote health and longevity in DBA/2J and C57BL/6J mice of both sexes, examining the effects on metabolic health, frailty, cognition and lifespan as well as the effects on pathology and at the molecular level. We will identify the role of a specific hormone, FGF21, in the metabolic response to isoleucine restriction. Finally, we will test if restriction of individual BCAAs is necessary and sufficient for the ability of a PR diet to prevent or delay AD. The proposed work will examine the role of the BCAA isoleucine on health and longevity in multiple genetic backgrounds for the first time and answer long-standing questions regarding how dietary composition impacts healthy aging. Importantly, we will gain new insight into the mechanisms that drive the potent effects of isoleucine restriction on healthy aging, and break new ground identifying how individual BCAAs impact the progression of AD. In the long term, this work will enable our lab and others to develop a mechanistic understanding of how dietary BCAAs and other macronutrients regulate health and disease vulnerability, and to identify new targets for pharmacological treatments to promote healthy aging.