Caloric Restriction and Aging in Rhesus Monkeys

 描述（由申请人提供）：热量限制（CR），在没有营养不良的营养下，为探索延迟衰老的机制提供了一种强有力的方法。CR是唯一的环境干预，反复和强烈地增加最大寿命和延迟实验室啮齿动物的生物老化。恒河猴提供了一个非常有价值的模型，在其中测试CR延长灵长类物种的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，我们已经验证了生理，系统和分子衰老研究的杰出模型，该模型直接转化为人类衰老。1989年，我们开始了一项研究，以测试成年发病的CR可以减缓灵长类动物衰老过程的总体假设。重要的是，这些研究尚未完成，因为17%的猴子还活着。因此，该应用程序的主要目标是从剩余动物中主动收集数据， 25年以上的研究数据，以及对CR机制的研究扩展。生物学和医学研究重新强调肥胖对健康和疾病脆弱性的影响。我们初步的分子分析数据表明，脂肪组织对衰老和CR的反应方式并不仅仅是肥胖的反映。我们将在非人灵长类动物中检验脂肪组织有助于年龄相关疾病易感性及其通过CR以储库特异性方式预防的假设。我们提出两个具体目标：1）执行并促进对灵长类动物物种中的衰老生物学和中度（30%）成人发作CR的影响进行深入的纵向分析。将对长期CR研究动物进行健康、生物统计学和临床测量，以最终确定CR对最长寿命的影响。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策划在线访问数据库提供，以将有关衰老和CR机制的研究扩展到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。我们将通过高分辨率分子分析确定年龄和CR的特征，阐明脂肪组织对血清中脂质和代谢产物的贡献，并确定具有潜在临床价值的新的健康状况全身指标。使用皮下和内脏（肠系膜）脂肪组织的库存标本（44名男性和女性，中位年龄26岁，年龄范围：13-33岁），我们建议在代谢组学，脂质组学和转录组学方面推导出CR的分子特征，并使用这些数据来识别与CR赋予的对年龄相关疾病的增强弹性相关的储库特定过程和途径。这项研究将通过充分定义CR对长寿灵长类物种在严格控制条件下的最大寿命的影响来推进衰老研究的生物学，并在这个高度可翻译的模型中提供对年龄相关疾病脆弱性的无与伦比的机制见解。

 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.