Mechanisms Specific to the Beneficial Effects of Dietary Restriction

饮食限制的有益作用的具体机制

• 批准号: 8631334
• 负责人: William B Mair
• 金额: $ 33.11万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631334
• 关键词: 5' -AMP-activated protein kinase; Acute; Adult; Adverse effects; Age of Onset; Aging; Amino Acids; Animal Model; Animals; Biological Models; CREB1 gene; Caenorhabditis elegans; Cells; Data; Diagnosis; Diet; Disease; Disease Resistance; Eating; Gene Expression Profile; Genes; Genetic; Growth; Health; Human; Immunity; Intake; Intervention; Life; Link; Longevity; Longevity Pathway; Malnutrition; Mammals; Mediating; Mediator of activation protein; Methods; Mission; Molecular; Molecular Target; Neurons; Neurosecretory Systems; Nutrient; Nutritional; Outcome; Output; Pathology; Pathway interactions; Phosphorylation; Physiological; Process; Proteins; Public Health; Reproduction; Research; Role; Signal Transduction; Sirtuins; System; Testing; Therapeutic; Tissues; Transcript; Transcription Coactivator; United States National Institutes of Health; Work; age related; base; clinical application; cost; detection of nutrient; dietary restriction; endoplasmic reticulum stress; healthy aging; human FRAP1 protein; longevity gene; mortality; novel; novel therapeutics; prevent; public health relevance; reproductive; response; spatiotemporal; therapeutic target; trait; transcriptome sequencing

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.

项目摘要 饮食限制（DR）是促进健康老龄化和老年性疾病的最有效方法 动物模型中的阻力。然而，DR的治疗潜力受到相关的负性因素的限制。 生理影响，包括生长、免疫力和生殖能力受损。虽然营养- DR的感知介质已被确定，如mTOR、FOXO/As和sirtuins，这些中心节点 概括了整个反应，使它们成为次优治疗靶点。我们的长期目标 是揭示分子机制，专门介导的只有促长寿的影响， 最佳疗法DR的关键介质是AMP活化蛋白激酶（AMPK）， 当能量水平低时激活。然而，与DR一样，AMPK以受损为代价延长了寿命。 生长和繁殖。本申请的目的是使用遗传上易处理的模型系统C。 为了阐明第一种AMPK特异性介导长寿的机制， 分子靶点，仅概括DR的促健康作用。中心假设是， 并且DR的有害影响可以被解耦。为了支持这一假设，特定的氨基酸 饮食中的组合最近被证明可以增加寿命同时保持正常的繁殖， 确定DR对寿命的积极影响不需要强制性有害副作用。 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的长寿特异性靶点，即CREB调节的转录辅激活因子 （CRTC）-1 '，其将AMPK的长寿效应与副作用分开。我们现在寻求确定 CRTC-1特异性介导长寿的机制。这个项目的基本原理是，在我们 可以从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： 仅概括了DR的积极作用，2）在生命后期，年龄诊断后应用时有效- 相关疾病。基于强有力的初步数据，我们将测试三个具体目标。1)我们会研究 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 一种新的诱导系统，用于识别具有急性、迟发性有益作用的DR介质; 3）我们将定义 由CRTC-1调节的长寿特异性转录组，以确定特异性 促进健康衰老，无生理副作用。总的来说，我们希望这项工作能提供第一个 分子途径的例子，解偶联的积极和消极影响的DR，一个关键步骤， 将DR研究转变为促进健康的人类衰老。