Caloric Restriction and Aging in Rhesus Monkeys

项目摘要 热量限制（CR），没有营养不良的营养不良，提供了一个强有力的方式来探索机制， 延缓衰老CR是唯一的环境干预，反复和强烈增加最大 实验室啮齿动物的寿命和延迟生物老化。恒河猴提供了一种极其宝贵的 该模型用于测试CR延长灵长类动物健康寿命和寿命的能力。通过证明 CR延长了恒河猴的健康寿命和寿命，我们已经验证了一个杰出的模型， 生理、系统和分子衰老研究，直接转化为人类衰老。1989年，我们 开始了一项研究来测试成人CR可以减缓灵长类动物衰老过程的总体假设 物种重要的是，这些研究尚未完成，因为17%的猴子还活着。因此，少校 本申请的目标是从剩余动物中收集主动数据， 25年以上的研究数据，以及对CR机制的研究扩展。已经更新了 在生物学和医学研究中强调肥胖对健康和疾病脆弱性的影响。我们 初步分子谱数据表明，脂肪组织以某种方式对衰老和CR做出反应 这不仅仅是肥胖的反映。我们将检验脂肪组织与年龄有关的假设- 相关疾病的脆弱性和它的预防CR在仓库的具体方式在非人灵长类动物。我们 我提出两个具体目标：1）执行和促进深入，纵向分析生物老化 以及灵长类动物中中度（30%）成人发作CR的影响。健康、生物特征和临床措施 将进行长期CR研究动物，以最终确定CR对最大 寿命数据将被组合，以创建应对CR的健康结果的综合视角。所有 数据和可用组织的库存将通过新创建的在线策划提供， 可访问的数据库，以扩展对衰老和CR机制的研究，以进行广泛的合作研究 网络2)确定脂肪组织贮库对年龄和CR的特异性反应。康贝特人将以 通过高分辨率分子谱分析年龄和CR的特征，阐明脂肪的贡献 组织脂质和代谢物谱，并确定新的系统性健康状况指标， 潜在的临床价值。使用皮下和内脏（肠系膜）脂肪组织的库存标本 (44男性和女性，中位年龄26岁，年龄范围：13-33岁），我们建议推导分子 CR在代谢组学、脂质组学和转录组学方面的特征，并使用这些数据来识别储库 与增强对年龄相关疾病的复原力有关的具体过程和途径 CR.这项研究将通过充分定义CR对最长寿命的影响来推进衰老研究的生物学 在严格控制的条件下，在长寿的灵长类动物中， 在这个高度可转换的模型中深入了解与年龄相关的疾病脆弱性。

Project Summary Caloric restriction (CR), undernutrition without malnutrition, offers a powerful way to explore mechanisms of delayed aging. CR is the only environmental intervention that repeatedly and strongly increases maximum lifespan and delays biological aging in laboratory rodents. The rhesus monkey provides an extremely valuable model in which to test the ability of CR to extended healthspan and lifespan in a primate species. By proving that CR extends healthspan and lifespan in rhesus monkeys we have validated an outstanding model for physiological, systemic, and molecular aging studies that is directly translational to human aging. In 1989, we began a study to test the overall hypothesis that adult-onset CR could slow the aging process in a primate species. Importantly, these studies are not yet complete as 17% of the monkeys are alive. Thus, the major goals of this application are active data collection from remaining animals, integrative longitudinal analysis of 25+ years of study data, and expansion of studies into the mechanisms of CR. There has been renewed emphasis in biology and medical research on the impact of adiposity in health and disease vulnerability. Our preliminary molecular profiling data demonstrate that adipose tissues respond to aging and CR in a manner that is not simply reflective of adiposity. We will test the hypothesis that adipose tissue contributes to age- related disease vulnerability and its prevention by CR in a depot specific manner in nonhuman primates. We propose two Specific Aims: 1) To perform and facilitate in-depth, longitudinal analyses of the biology of aging and effects of moderate (30%) adult-onset CR in a primate species. Health, biometric and clinical measures of the long-term CR study animals will be conducted to ultimately determine the effects of CR on maximal lifespan. Data will be combined to create an integrative perspective on health outcomes in response to CR. All data and the inventory of available tissues will be made available through a newly created curated online accessible database to extend studies on aging and the mechanisms of CR to a broad collaborative research network. 2) To determine the adipose tissue depot specific response to age and CR. We will determine the signature of age and CR through high resolution molecular profiling, elucidate the contribution of adipose tissue to lipid and metabolite profiles in serum, and identify novel systemic indices of health status with potential clinical value. Using banked specimens of subcutaneous and visceral (mesenteric) adipose tissues (44 males and females, median age 26 years, age range: 13-33 years), we propose to derive the molecular signature of CR in terms of metabolomics, lipidomics, and transcriptomics, and use these data to identify depot specific processes and pathways associated with the enhanced resilience to age-related disease conferred by CR. This study will advance biology of aging research by defining fully the influence of CR on maximal lifespan under tightly controlled conditions in a long-lived primate species, and provide unparalleled mechanistic insights into age-related disease vulnerability in this highly translatable model.