Mechanisms Specific to the Beneficial Effects of Dietary Restriction

项目总结 限制饮食(DR)是促进健康老龄化和老年性疾病最有效的方法 动物模型中的抗药性。然而，DR的治疗潜力受到相关负面影响的限制 生理影响，包括生长、免疫和生殖能力受损。尽管营养丰富- 已经确定了DR的感觉介质，如mTOR、FOXO/AS和sirtuins，这些中央节点 概括整个反应，使它们成为次优的治疗目标。我们的长期目标 就是揭示专门调节DR的长寿效应的分子机制 最佳疗法。DR的一个关键介质是AMP激活的蛋白激酶(AMPK)，这是一种细胞燃料计 在能量水平较低时激活。然而，像DR一样，AMPK以损害为代价来延长寿命 生长和繁殖。本应用程序的目标是使用遗传易处理的模型系统C。 以确定AMPK具体调节长寿的机制，以阐明第一个 分子靶标仅概括了Dr.的促进健康效应中心假说是有益的 而DR的有害影响可能是分离的。为了支持这一假设，特定的氨基酸 最近有研究表明，饮食中的组合可以在保持正常生殖的同时延长寿命， 确定DR对寿命的积极影响不需要额外的有害副作用。 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，它是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。我们现在试图找出 CRTC-1特异性调节长寿的机制。这个项目的基本原理是，在我们 要从DR中产生可行的治疗方法用于临床应用，我们必须首先确定以下机制：1) 简而言之，DR的积极作用和2)在晚年、年龄诊断后应用是有效的 相关疾病。基于强大的初步数据，我们将测试三个具体目标。1)我们将研究 CRTC-1通过增加蛋白质保真度检查点在促进健康衰老中的作用。2)我们将利用 识别具有急性、迟发性有益影响的DR介体的新的诱导系统和3)我们将定义 由CRTC-1调控的长寿特异性转录组，以确定特定的分子靶点 促进健康衰老，无生理副作用。总体而言，我们期待这项工作提供第一个 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。

PROJECT SUMMARY 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.