Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys

摘要 年龄是许多慢性病的最大风险因素，包括癌症、糖尿病、心血管疾病 疾病和神经退行性变。这种共同风险的机制基础及其作为一种 年龄的作用还没有被很好地理解。没有营养不良的卡路里限制(CR)已被证明可以延迟 在不同的物种中，衰老，在哺乳动物中，它推迟了许多与年龄相关的疾病的发生，增加了 健康跨度。威斯康星州国家灵长类研究中心猕猴的年龄和认知能力研究 确定了CR在改善健康和生存方面的有效性：CR猴子活得更长，发病率更低 在与年龄相关的疾病中，更活跃，并保持更好的糖调节健康。分子图谱研究 提示CR引起新陈代谢的重大重新编程，改变了关键的细胞动态平衡 转录、蛋白质组和翻译后修饰调节之间的途径协调 机械装置。到目前为止，我们有限的研究已经确定了CR机制中的新方面，包括脂质 新陈代谢和信号，以及基于RNA的调节机制的作用，包括转录处理 以及通过microRNA对CR反应的协调。拟议中的研究有可能进一步揭示 在组织特异性水平上参与衰老和CR的调节机制，衍生相互作用网络 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联系起来 生理、健康、发病率和存活率。这群独特的猴子呈现出前所未有的 有机会增进我们对衰老生物学的理解。尽管CR的干预可能不是 合理选择临床应用，建议的无偏高分辨率研究肯定会揭示 对如何在临床上针对衰老本身的新见解。 具体目标有三个： 目的1.确定CR所涉及的共享和组织特异性机制。 目的2.确定生命阶段决定的全身对CR的反应。 目的3.整合对CR的生理、系统和分子反应。 我们的研究旨在确定组织内和组织间以及整体上对CR的综合反应 灵长类动物的生物体水平，并确定这些CR参与的机制如何协调以授予 延长寿命。恒河猴是人类衰老的高度翻译模型，特别是在 与年龄相关疾病和障碍的发病时间和功能衰退的动力学有关。我们这群人 来自对有效实施CR的独特研究，手头有生理数据和样本， 以及大量的纵向临床数据、健康记录和临终病理。综合分析 组织内和组织间的高密度分子图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链接，将提供对人类衰老的翻译见解。

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.