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: 10118669
• 负责人: William B Mair
• 金额: $ 32.7万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10118669
• 关键词: 5' -AMP-activated protein kinase; Afferent Neurons; Age; Age of Onset; Aging; Amino Acids; Animal Model; Biological Models; Body Size; CREB1 gene; Caenorhabditis elegans; Cells; Centenarian; Chronic; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Developmental Delay Disorders; Diagnosis; Diet; Disease; Disease Resistance; Distal; Eating; Elderly; Energy Metabolism; Estrogen receptor positive; FRAP1 gene; Fasting; Funding; Genes; Geroscience; Goals; Growth; Health; Human; Immunity; Impairment; Intake; Life; Link; Longevity; Macronutrients Nutrition; Malnutrition; Mediating; Mediator of activation protein; Metabolic; Metformin; Methods; Mission; Mitochondria; Molecular; Molecular Target; Morbidity - disease rate; Neurons; Neurotransmitters; Nutrient; Nutritional; Octopamine; OmpR protein; Onset of illness; Organelles; Outcome; Output; Pathology; Pathway interactions; Pattern; Peripheral; Phosphorylation; Physiological; Protein Kinase; Public Health; RNA Splicing; Regulation; Reproduction; Research; Risk Factors; Role; SIRT1 gene; SKI gene; Signal Transduction; Sirtuins; System; Techniques; Testing; Therapeutic; Tissues; Transcription Coactivator; United States National Institutes of Health; Variant; Work; age related; base; cell type; clinical application; cost; defined contribution; dietary restriction; fitness; healthspan; healthy aging; hypoxia inducible factor 1; mitochondrial metabolism; novel therapeutics; peroxisome; pleiotropism; prevent; relating to nervous system; reproductive; response; sensor; side effect; therapeutic target

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 nutrientsensing 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 and DR 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. In addition, in the previous funding period we demonstrated that the transcriptional coactivator and AMPK direct target CRTC-1 could uncouple the longevity effects of AMPK from other negative side effects such as developmental delay, reproduction suppression and reduced body size. 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 functional role of neuronal CRTC-1 in promoting healthy aging. 2) We will use CRISPR editing of endogenous AMPK targets to delineate the roles of additional pathways downstream of this key energy sensor 3) We will define the contribution of mitochondrial and peroxisome remodeling in AMPK and DR longevity. 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.

项目概要 饮食限制（DR）是促进健康衰老和抗衰老疾病的最有效方法 在动物模型中。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、免疫力和生殖能力受损。尽管 DR 的营养感应介质 已被识别，例如 mTOR、FOXO/As 和 Sirtuins，这些中心节点概括了整个 反应，使它们成为次优的治疗目标。我们的长期目标是揭示分子 专门介导 DR 的延长寿命效应的机制，以形成最佳的 疗法。 DR 的一个关键介质是 AMP 激活蛋白激酶 (AMPK)，它是一种激活的细胞能量计 当能量水平较低时。然而，与 DR 一样，AMPK 可以延长寿命，但代价是生长受损和 生殖。 本应用的目标是使用遗传易处理模型系统线虫来识别 AMPK 和 DR 特异性介导长寿的机制，以阐明第一个分子 仅概括 DR 对健康的影响的目标。中心假设是有益且 DR 的有害影响是可以消除的。为了支持这一假设，特定的氨基酸组合 最近的研究表明，这种饮食可以延长寿命，同时维持正常繁殖，这证实了这一点 DR 对寿命的积极影响并不需要必然的有害副作用。另外，在之前的 资助期间我们证明转录共激活因子和 AMPK 直接靶向 CRTC-1 可以 将 AMPK 的长寿效应与其他负面副作用（例如发育迟缓）分开， 繁殖抑制和体型减小。 我们现在寻求确定 CRTC-1 特异性介导长寿的机制。这样做的理由 项目的目的是，在我们能够从 DR 中产生可行的疗法用于临床应用之前，我们必须首先确定 这些机制 1) 仅概括 DR 的积极作用，2) 在晚年应用时有效， 年龄相关疾病的诊断后。基于强有力的初步数据，我们将测试三个具体目标。 1） 我们将研究神经元 CRTC-1 在促进健康衰老中的功能作用。 2）我们将使用CRISPR 编辑内源性 AMPK 靶标，以描述该关键能量下游其他途径的作用 传感器 3) 我们将定义线粒体和过氧化物酶体重塑在 AMPK 和 DR 寿命中的贡献。 总的来说，我们期望这项工作能够提供第一个解开积极分子途径的例子。 以及 DR 的负面影响，这是将 DR 研究转变为促进人类健康老龄化的关键一步。