Mechanisms Specific to the Beneficial Effects of Dietary Restriction

描述(申请人提供)：饮食限制(DR)是在动物模型中促进健康老龄化和老年性疾病抵抗力的最有效的方法。然而，DR的治疗潜力受到相关负面生理效应的限制，包括生长、免疫和生殖能力受损。虽然已经确定了DR的营养感知介质，如mTOR、FOXO/AS和sirtuins，但这些中央节点概括了整个反应，使它们成为次优的治疗靶点。我们的长期目标是发现仅具体介导DR延长寿命的分子机制，以开发最佳治疗方法。DR的一个关键介质是AMP激活的蛋白激酶(AMPK)，这是一种在能量水平较低时激活的细胞燃料计。然而，像DR一样，AMPK以损害生长和生殖为代价延长寿命。本应用的目的是使用遗传易处理的模型系统秀丽线虫来确定AMPK具体调节长寿的机制，以阐明仅概括DR促进健康的第一个分子靶点。中心假设是DR的有益和有害影响可以分离。为了支持这一假说，最近有研究表明，饮食中的特定氨基酸组合可以在维持正常生殖的同时延长寿命，从而确立DR对寿命的积极影响不需要一定的有害副作用。然而，将长寿与相关的负面影响分开的分子机制尚不清楚。我们已经发现了AMPK的一个长寿特异性靶点，即‘CREB调节的转录辅助激活因子(CRTC)-1’，它将AMPK的长寿效应与副作用分开。我们现在试图确定CRTC-1具体调节长寿的机制。这个项目的基本原理是，在我们能够从DR中产生可行的治疗方法用于临床应用之前，我们必须首先确定以下机制：1)仅概括DR的积极作用；2)在老年相关疾病诊断后的晚年应用时有效。基于强大的初步数据，我们将测试三个具体目标。1)我们将通过增加蛋白质保真度检查点来研究CRTC-1在促进健康衰老中的作用。2)我们将利用一种新的诱导系统来鉴定具有急性、迟发性有益效应的DR介体；3)我们将定义由CRTC-1调控的长寿特异性转录组，以确定在没有生理副作用的情况下特异性促进健康衰老的分子靶点。总体而言，我们希望这项工作将提供第一个解开DR正面和负面影响的分子途径的例子，这是将DR研究过渡到促进人类健康老龄化的关键一步。

DESCRIPTION (provided by applicant): Dietary restriction (DR) is the most potent method for promoting healthy aging and age-onset disease resistance in animal models. However, DR's therapeutic potential is limited by associated negative physiological effects, including impaired growth, immunity and reproductive capacity. Although nutrient- sensing mediators of DR have been identified, such as mTOR, FOXO/As and the sirtuins, these central nodes recapitulate the entirety of the response, making them sub-optimal therapeutic targets. Our long-term objective is to uncover molecular mechanisms that specifically mediate only the pro-longevity effects of DR to develop optimal therapeutics. A key mediator of DR is AMP-activated protein kinase (AMPK), a cellular fuel gauge activated when energy levels are low. However, like DR, AMPK increases lifespan at the cost of impaired growth and reproduction. The objective in this application is to use the genetically tractable model system C. elegans to identify mechanisms by which AMPK specifically mediates longevity, in order to elucidate the first molecular targets that recapitulate only the pro-health effects of DR. The central hypothesis is that beneficial and detrimental effects of DR can be uncoupled. In support of this hypothesis, specific amino acid combinations in the diet have recently been shown to increase lifespan while maintaining normal reproduction, establishing that the positive effects of DR on lifespan do not require obligate detrimental side effects. However, the molecular mechanisms that uncouple longevity from associated negative effects are unknown. We have uncovered a longevity-specific target of AMPK, the 'CREB regulated transcriptional coactivator (CRTC)-1', that uncouples the longevity effects of AMPK from side effects. We now seek to identify the mechanisms by which CRTC-1 specifically mediates longevity. The rationale for this project is that, before we can generate viable therapies from DR for clinical application we must first identify mechanisms that 1) recapitulate only the positive effects of DR and 2) are effective when applied late in life, post-diagnosis of age- related disease. Based upon strong preliminary data we will test three specific aims. 1) We will examine the role of CRTC-1 in promoting healthy aging via increases to protein fidelity checkpoints. 2) We will utilize a novel inducible system to identify DR mediators with acute, late-onset beneficial effects and 3) We will define the longevity-specific transcriptome regulated by CRTC-1, to determine molecular targets that specifically promote healthy aging without physiological side effects. Collectively, we expect this work to provide the first example of molecular pathways that uncouple the positive and negative effects of DR, a critical step in transitioning DR research to the promotion of healthy human aging.