Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys

总结 年龄是一系列慢性疾病的最大风险因素，包括癌症、糖尿病、心血管疾病、 疾病和神经变性。这一共同风险的机制基础及其作为一种 年龄的作用还不太清楚。热量限制（CR）没有营养不良已被证明延迟 在不同的物种中，它延缓了许多与年龄有关的疾病的发生， 健康寿命。威斯康星州国家灵长类动物研究中心的恒河猴老化和CR研究 确定了CR在改善健康和生存方面的疗效：CR猴寿命更长，发病率更低 与年龄相关的疾病，更活跃，并保持更好的葡萄糖调节健康。分子特征分析研究 表明CR诱导代谢的主要重编程， 跨转录、蛋白质组学和翻译后修饰调控的协调途径 机制等迄今为止，我们有限的研究已经确定了CR机制的新方面，包括脂质 代谢和信号传导，以及基于RNA的调控机制的作用，包括转录加工 以及通过microRNA协调CR反应。拟议的研究有可能进一步揭示 在组织特异性水平上，衰老和CR过程中参与的调节机制衍生出相互作用网络 在组织内和组织间定义CR如何工作的分子细节，并将这些数据与整个动物相关联 生理学、健康、发病率和生存率。这群独特的猴子呈现出前所未有的 这是一个增进我们对衰老生物学理解的机会。虽然CR的干预可能不是一个 临床应用的合理选择，所提出的无偏高分辨率研究肯定会揭示 关于衰老本身如何在临床上被靶向的新见解。 有三个具体目标： 目标1.确定CR参与的共享和组织特异性机制。 目标2.确定CR的生命阶段消退全身反应。 目标3：整合CR的生理、全身和分子反应。 我们的研究旨在确定组织内和组织间以及整体对CR的综合反应 在灵长类动物的生物体水平，并确定这些CR参与机制如何协调， 延长寿命。恒河猴是人类衰老的高度转化模型，特别是关于 与年龄有关的疾病和病症的发病时间以及功能衰退的动态。我们的队列 是从一个独特的研究，有效实施CR，与生理数据和标本在手， 沿着有大量的纵向临床数据、健康记录和生命末期病理学。综合分析 组织内和组织间的高密度分子谱将为衰老生物学提供一个新的视角， 系统水平，并通过与临床结果的联系，将为人类衰老提供翻译见解。

SUMMARY Age is the greatest risk factor for a host of chronic diseases, including cancer, diabetes, cardiovascular disease and neurodegeneration. The mechanistic basis for this shared risk and its continued increase as a function of age is not well understood. Caloric restriction (CR) without malnutrition has been proven to delay aging in diverse species, and in mammals it delays the onset of numerous age-related diseases, increasing healthspan. The Aging and CR in Rhesus Monkeys study at the Wisconsin National Primate Research Center established the efficacy of CR in improving health and survival: CR monkeys live longer, have lower incidence of age-related diseases, are more active, and maintain better glucoregulatory health. Molecular profiling studies suggest that CR induces a major reprogramming of metabolism, with changes in key cellular homeostatic pathways coordinated across transcriptional, proteomic, and post-translation modification regulatory mechanisms. Our limited studies to date have identified novel aspects in CR's mechanisms including lipid metabolism and signaling, and the role of RNA-based regulatory mechanisms including transcript processing and coordination of the CR response through microRNA. The proposed studies have potential to uncover further regulatory mechanisms engaged during aging and CR at the tissue specific level, derive interaction networks within and among tissues to define the molecular details of how CR works, and relate these data to whole animal physiology, health, morbidity, and survival. This unique cohort of monkeys presents an unprecedented opportunity to advance our understanding of aging biology. Although the intervention of CR may not be a reasonable choice for clinical application, the proposed unbiased high-resolution studies are certain to reveal new insights into how aging itself might be targeted clinically. There are three Specific Aims: Aim 1. Determine shared and tissue-specific mechanisms engaged by CR. Aim 2. Determine the life stage-resolved systemic response to CR. Aim 3. Integrate the physiological, systemic, and molecular responses to CR. Our study is designed to define the integrated response to CR within and among tissues and at the whole organism level in primates, and to determine how these CR-engaged mechanisms might coordinate to confer enhanced longevity. Rhesus monkeys are a highly translational model for human aging, in particular with regards to the timing of onset of age-related diseases and disorders and the dynamics of functional decline. Our cohort is derived from a unique study of effective implementation of CR, with physiological data and specimens in hand, along with substantial longitudinal clinical data, health records, and end of life pathology. Integrative analysis of high-density molecular profiles within and among tissues will present a new perspective in aging biology at the systems level, and by linking to clinical outcomes will deliver translational insights for human aging.