Caloric Restriction and Aging in Rhesus Monkeys

 描述(申请人提供)：卡路里限制(CR)，在没有营养不良的营养下，提供了一种有效的方法来探索延缓衰老的机制。CR是唯一一种反复强烈地延长实验室啮齿动物最长寿命和延缓生物衰老的环境干预措施。恒河猴提供了一个非常有价值的模型，用来测试CR在灵长类物种中延长健康和寿命的能力。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直接与人类衰老相关的生理、系统和分子衰老研究的杰出模型。1989年，我们开始了一项研究，以检验成年发病的CR可以减缓灵长类物种衰老过程的总体假设。重要的是，这些研究还没有完成，因为17%的猴子还活着。因此，此应用程序的主要目标是从剩余动物中主动收集数据，对 25年以上的研究数据，以及对CR机制的研究的扩展。生物学和医学研究再次强调肥胖对健康和疾病脆弱性的影响。我们的初步分子图谱数据表明，脂肪组织对衰老和CR的反应方式不是简单地反映肥胖。我们将在非人类灵长类动物中测试脂肪组织有助于年龄相关疾病易感性的假设以及CR以储存库特有的方式预防它。我们提出了两个特定的目标：1)对灵长类物种的衰老生物学和中度(30%)成年性CR的影响进行深入的、纵向的分析。将对长期进行CR研究的动物进行健康、生物测定和临床测量，以最终确定CR对最长寿命的影响。数据将结合在一起，以创建一个关于健康结果的综合视角，以应对CR。所有可用组织的数据和库存将通过新创建的可在线访问的数据库提供，以将关于衰老和CR机制的研究扩展到一个广泛的合作研究网络。2)测定脂肪组织对年龄和CR的特异性反应。我们将通过高分辨率分子图谱来确定年龄和CR的特征，阐明脂肪组织对血清中脂质和代谢物的贡献，并识别具有潜在临床价值的新的系统健康状况指标。使用皮下和内脏(肠系膜)脂肪组织的银行样本(44名男性和女性，中位年龄26岁，年龄范围：13-33岁)，我们建议从代谢组学、脂肪组学和转录组学方面得出CR的分子特征，并使用这些数据来识别与CR增强对年龄相关疾病的抵抗力相关的仓库特定过程和途径。这项研究将通过充分定义CR在严格控制的条件下对长寿灵长类物种最长寿命的影响来推进衰老生物学研究，并为这一高度可翻译的模型中与年龄相关的疾病脆弱性提供无与伦比的机制洞察力。

 DESCRIPTION (provided by applicant): Caloric restriction (CR), under nutrition 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 translatabl model.