Dietary Restriction and Aging in Rhesus Monkeys

描述（由申请人提供）：1989年，我们开始了一项研究，以确定成人发病的DR是否可以减缓灵长类动物的衰老过程。这项工作最初是由R01支持的，自1994年以来一直由国家老龄化研究所（NIA）通过计划项目资助（P01）机制资助。2010年1月，我们向NIA提交了一份申请，通过审查非常好的P01机制继续资助该项目（第18百分位）。不幸的是，由于目前的资金环境，这个应用程序不太可能得到资助。因此，我们的NIA项目官员强烈鼓励我们提交这份R01，以继续这项长期研究的关键方面。因此，我们请求从2011年到2016年（该研究将进入第27个年头）的支持，以继续这项独特而令人兴奋的努力，直到其最长寿命的自然结论。通过我们过去20多年的研究，我们已经证明了恒河猴衰老模型的适用性，最近，DR在减缓生物衰老的主要特征方面的功效。这些包括肌肉减少症、延迟发病、脑萎缩和死亡率。重要的是，后一项研究尚未完成，因为最初的76只猴子中有30只（39%）还活着。因此，这个应用程序的目标是在五年内获得所有动物的健康寿命和寿命数据。具体目标1：通过评估生物年龄、健康寿命和疾病模式等指标，确定DR对灵长类物种衰老速度的影响。我们正在雌性和雄性恒河猴身上测试一种中度成人发病DR（减少30%卡路里），并在这方面取得了重大进展；然而，完全实现这一目标还需要几年的时间，因为研究中最老的猴子（约30岁）现在才开始相当老（恒河猴的平均寿命约为27岁，最长寿命约为40岁）。在接下来的5年里，这些动物将处于与年龄相关的发病率增加的年龄。具体目标2：确定DR对灵长类动物最大寿命的影响。虽然我们在确定DR对衰老速度的影响方面取得了重大进展，但我们还无法确定DR改变灵长类动物最大寿命的能力。在接下来的5年里，这些动物将迅速接近一个能够确定DR是否能延长最大寿命的年龄。几十年来，老年学家一直在急切地等待这些数据。根据媒体对我们最近发表的《科学》杂志的反应，我们的研究具有广泛的普遍意义。一个主要的临床意义是DR代表了一种与2型糖尿病相反的代谢状态，迄今为止，DR在我们的猴子中已经完全预防了2型糖尿病。这一观察结果具有明显的公共卫生影响，而肥胖/糖尿病的流行是突出的。这些数据可能对公共卫生产生非常重大的影响，因为它们证明了DR对灵长类动物的健康和寿命有益，并应促使人们努力通过药物或饮食干预来模仿这些效果。

DESCRIPTION (provided by applicant): In 1989, we began a study to determine whether or not adult-onset DR could slow the aging process in a primate species. This work was originally supported by an R01, and since 1994 has been funded by the National Institute on Aging (NIA) through the Program Project Grant (P01) mechanism. In January 2010 we submitted an application to NIA for continued funding of this project through the P01 mechanism that reviewed very well (18th percentile). Unfortunately, due to the current funding climate, it is unlikely that this application will be funded. We were therefore strongly encouraged by our NIA program officer to submit this R01 to continue the key aspects of this long-term study. Accordingly, we request support to span 2011 - 2016 (when the study would be in its 27th year) to continue this unique and exciting endeavor to its natural conclusion of maximum lifespan. Through our previous 20+ years of research we have demonstrated the suitability of the rhesus monkey aging model and, quite recently, the efficacy of DR in slowing major features of biological aging. These include sarcopenia as well as delaying morbidity, brain atrophy and mortality. Importantly, these latter studies are not yet complete as 30 of the original 76 monkeys (39%) are alive. Thus, the goal of this application is to get five years closer to having data for all animals on healthspan and lifespan. There are two Specific Aims: Specific Aim 1: To determine DR's influence on the rate of aging in a primate species by evaluating indicators of biological age, healthspan and disease patterns. We are testing a moderate adult-onset DR (30% calorie reduction) on female and male rhesus monkeys and have made significant progress on this Aim; however, fully achieving it will require several more years as the study's oldest monkeys (~30 years) are only now becoming quite old (average rhesus lifespan is ~27 years, maximum lifespan is ~40 years). Over the next 5 years, these animals will be of an age at which increases of age-related morbidity are expressed. Specific Aim 2: To determine DR's influence on maximal lifespan in a primate species. While we have made significant progress in determining DR's influence on the rate of aging we are not yet able to determine the ability of DR to alter maximal lifespan in a primate species. Over the next 5 years, the animals will be rapidly approaching an age at which will be able to determine whether DR increases maximal lifespan. Gerontologists have eagerly awaited these data for decades. Based on the media response to our recent Science publication our study is of broad general interest. A major clinical implication is that DR represents a metabolic state opposite that of type 2 diabetes which, to date, has been completely prevented by DR in our monkeys. This observation has obvious public health implications while an obesity/diabetes epidemic is prominent. These data may have a very significant public health impact by demonstrating the health and longevity benefits triggered by DR in primates and should stimulate efforts to mimic these effects by drug or dietary interventions.