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，以确定成年发病的DR是否可以减缓灵长类动物的衰老过程。这项工作最初由R 01支持，自1994年以来一直由国家老龄化研究所（NIA）通过计划项目赠款（P01）机制资助。2010年1月，我们向NIA提交了一份申请，要求通过P01机制继续为该项目提供资金，审查结果非常好（第18百分位）。不幸的是，由于目前的资金环境，这是不太可能的应用程序将得到资助。因此，我们的NIA项目官员强烈鼓励我们提交本R 01，以继续这项长期研究的关键方面。因此，我们请求在2011年至2016年期间（研究将进入第27个年头）提供支持，以继续这项独特而令人兴奋的奋进，直至其自然得出最大寿命的结论。通过我们之前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疗效。这些包括肌肉减少症以及延迟发病、脑萎缩和死亡。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，该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。有两个具体目标：具体目标1：通过评估生物学年龄、健康寿命和疾病模式的指标，确定DR对灵长类动物衰老速度的影响。我们正在对雌性和雄性恒河猴进行中度成年发病DR（减少30%卡路里）测试，并在这一目标上取得了重大进展;然而，完全实现这一目标还需要几年时间，因为研究中最年长的猴子（约30岁）现在才变得相当老（恒河猴的平均寿命约为27岁，最大寿命约为40岁）。在接下来的5年中，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对灵长类动物最长寿命的影响。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，但我们还不能确定DR改变灵长类动物最长寿命的能力。在接下来的5年里，动物将迅速接近能够确定DR是否延长最大寿命的年龄。几十年来，老年学家一直在热切地等待这些数据。根据媒体对我们最近发表的《科学》杂志的反应，我们的研究受到了广泛的关注。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，我们的猴子已经完全被DR所预防。这一观察结果具有明显的公共卫生影响，而肥胖/糖尿病流行是突出的。这些数据可能会有一个非常显着的公共卫生的影响，通过证明在灵长类动物的DR引发的健康和长寿的好处，并应刺激努力模仿这些影响的药物或饮食干预。 公共卫生相关性：我们快速增长的老龄化人口认为，延迟或预防年龄相关疾病的干预措施具有巨大的公共卫生意义。DR（摄入较少的卡路里，但不缺乏必需营养素）是最有效的饮食干预措施，可以对抗实验室啮齿动物中广泛的与年龄相关的健康问题。这个长达21年的项目最近在猴子身上发现了类似的有益效果，并试图扩展这些发现，并了解DR如何能够延长健康寿命。!

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. PUBLIC HEALTH RELEVANCE: Our rapidly growing aging population deems interventions that delay or prevent age-associated disease to be of huge public health significance. DR (less calories eaten but without a shortage of essential nutrients) is the most potent dietary intervention that opposes a broad array of age-associated health problems in laboratory rodents. This 21-year-long project has recently discovered similar beneficial effects in monkeys and seeks both to extend these findings and to learn how DR is able to increase the healthy lifespan. !