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

项目摘要 在美国，糖尿病相关疾病是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有关的疾病;而几乎每一种疾病的风险都在上升 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）。热量限制（CR），一种延长寿命的饮食干预， 延迟或预防与年龄有关的疾病，是减轻多年龄负担的一种可行方法， 然而，低热量饮食是出了名的难以维持。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，蛋白质限制（PR）显示 以促进长寿并模拟CR的代谢、虚弱和认知益处。 在最初的项目期间，我们发现，特别是减少饮食中的三个消费量， 支链氨基酸（BCAA）-亮氨酸，异亮氨酸和缬氨酸-对脆弱性有性别特异性的好处， C57 BL/6 J小鼠的寿命。我们确定PR的代谢和分子效应是性别和 菌株依赖性，并且提出的介导PR效应的特定激素的作用可能更多 比以前怀疑的有限，也不同性别和菌株。最后，我们发现， 对代谢有不同的作用，限制异亮氨酸是代谢所必需和充分的， 在初步的实验中，我们还发现，异亮氨酸限制具有性二态性， 对遗传异质性小鼠的健康寿命和寿命的影响，PR对 阿尔茨海默病小鼠模型的认知和疾病病理。 在这里，我们将严格测试异亮氨酸的分级限制促进健康长寿的能力 在DBA/2 J和C57 BL/6 J两种性别的小鼠中，检查对代谢健康、虚弱、认知和 寿命以及对病理学和分子水平的影响。我们将确定一个特定的角色， 激素FGF 21在对异亮氨酸限制的代谢反应中的作用。最后，我们将测试是否限制个人 支链氨基酸是必要的和足够的PR饮食的能力，以防止或延迟AD。 拟议的工作将研究BCAA异亮氨酸对健康和长寿的作用， 遗传背景的第一次，并回答了长期存在的问题， 影响健康的老龄化。重要的是，我们将获得新的洞察力的机制，推动强大的影响， 异亮氨酸限制对健康老龄化的影响，并开辟新的领域，确定个人BCAAs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人能够开发出一种机制， 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， 确定药物治疗的新目标，以促进健康的老龄化。

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.