Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys

恒河猴衰老和热量限制的分子网络

• 批准号: 10579229
• 负责人: Rozalyn M. Anderson
• 金额: $ 61.88万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579229
• 关键词: Adipose tissue; Adult; Age; Age of Onset; Aging; Animals; Autopsy; Biology of Aging; Caloric Restriction; Cardiovascular Diseases; Cells; Child; Chromatin; Chronic Disease; Clinical; Clinical Data; Computer Models; Data; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Epigenetic Process; Female; Fibroblasts; Gene Expression; Genetic Transcription; Growth; Hand; Health; Histology; Homeostasis; Human; Incidence; Inflammation; Inflammatory; Intervention; Life; Link; Lipids; Liver; Logistic Regressions; Longevity; Longitudinal Studies; Macaca mulatta; Malignant Neoplasms; Malnutrition; Mammals; Messenger RNA; Metabolic; Metabolism; MicroRNAs; Molecular; Molecular Profiling; Monkeys; Morbidity - disease rate; Nerve Degeneration; Outcome; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Physical Function; Physiological; Physiology; Population; Post-Translational Protein Processing; Primates; Process; Proteome; Proteomics; Publishing; RNA; Randomized; Regulation; Research; Resolution; Rhesus; Risk Factors; Role; Sampling; Serum; Signal Transduction; Skeletal Muscle; Specimen; Statistical Models; System; Techniques; Time; Tissues; Transcript; Whole Organism; Wisconsin; Work; Yeasts; age related; clinical application; cohort; cytokine; density; design; detection of nutrient; dietary restriction; end of life; functional decline; health record; healthspan; human old age (65+); improved; indexing; insight; lipid metabolism; lipidomics; male; metabolic imaging; metabolomics; mortality; nonhuman primate; novel; programs; random forest; recruit; response; risk sharing; transcriptome; transcriptome sequencing; translational model

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.

概括 年龄是许多慢性疾病的最大危险因素，包括癌症、糖尿病、心血管疾病 疾病和神经退行性疾病。这种共同风险及其持续增加的机制基础 年龄的作用尚不清楚。没有营养不良的热量限制（CR）已被证明可以延迟 不同物种的衰老，以及哺乳动物的衰老，可以延缓许多与年龄相关的疾病的发生，增加 健康寿命。威斯康星国家灵长类研究中心的恒河猴衰老和 CR 研究 确定 CR 在改善健康和生存方面的功效：CR 猴子寿命更长，发病率更低 与年龄相关的疾病，更加活跃，并保持更好的血糖调节健康。分子谱研究 表明 CR 诱导代谢的重大重编程，并改变关键的细胞稳态 跨转录、蛋白质组和翻译后修饰监管的协调途径 机制。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 的调节机制（包括转录处理）的作用 以及通过 microRNA 协调 CR 反应。拟议的研究有可能进一步揭示 衰老和 CR 在组织特定水平上参与的调节机制，衍生出相互作用网络 在组织内部和组织之间定义 CR 工作原理的分子细节，并将这些数据与整个动物联系起来 生理学、健康、发病率和生存。这群独特的猴子呈现出前所未有的 增进我们对衰老生物学的理解的机会。尽管 CR 的干预可能并不能 为了临床应用的合理选择，所提出的公正的高分辨率研究肯定会揭示 关于如何在临床上针对衰老本身的新见解。 具体目标有以下三个： 目标 1. 确定 CR 所涉及的共享机制和组织特异性机制。 目标 2. 确定生命阶段对 CR 的系统反应。 目标 3. 整合 CR 的生理、系统和分子反应。 我们的研究旨在定义组织内部、组织之间以及整个组织对 CR 的综合反应 灵长类动物的有机体水平，并确定这些 CR 参与机制如何协调以赋予 延长寿命。恒河猴是人类衰老的高度转化模型，特别是在 与年龄相关的疾病和紊乱的发病时间以及功能衰退的动态。我们的队列 源自对有效实施 CR 的独特研究，并掌握了生理数据和样本， 以及大量纵向临床数据、健康记录和临终病理学。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新的视角 系统层面，并通过与临床结果联系起来，将为人类衰老提供转化见解。