Mechanisms of Lifespan Modulation by Diet

饮食调节寿命的机制

• 批准号: 7963942
• 负责人: Sige Zou
• 金额: $ 25.15万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963942
• 关键词: Address; Adipose tissue; Aging; Biological; Biological Process; Blood Circulation; Caenorhabditis elegans; Carbohydrates; Cell Culture System; Cell model; Cells; Data; Diet; Drosophila melanogaster; Eating; Energy Intake; Excision; Food; Foundations; Gene Mutation; Genes; Genetic; Genetic Screening; Goals; Heat-Shock Response; Hippocampus (Brain); Human; Individual; Intervention; Journals; Kainic Acid; Knowledge; Longevity; Macronutrients Nutrition; Mammals; Manuscripts; Measures; Mediating; Methods; Modeling; Molecular; Nematoda; Neuraxis; Neurons; Organism; Pathway interactions; Peripheral; Play; Preparation; Primary Cell Cultures; Proteins; Regulation; Reproduction; Rodent; Role; Signal Pathway; Source; System; Testing; Tissues; Treatment Protocols; Yeasts; adiponectin; cytotoxicity; deprivation; dietary restriction; feeding; fly; functional genomics; insight; mutant; neuroprotection; non-genetic; response

Dietary restriction is a potent non-genetic dietary manipulation that has been shown to extend lifespan in almost all the species tested so far. Our understandings of molecular mechanisms of DR come primarily from studies of genetically amenable systems, including yeast, worms, and flies, where DR has been imposed by either diluting the food source or by using genetic mutations that reduce feeding efficiency. However, a major drawback of these approaches is that it remains substantially uncertain in determining the exact caloric intake of individuals under these DR paradigms, unlike this ability in studies of higher organisms, such as rodents. To address this issue, we previously developed an alternative dietary paradigm, dietary deprivation (DD), and found that it could extend lifespan in C. elegans compared to the control fed ad libitum (AL). Since this regimen involves complete removal of the food source, the problem of controlling food intake, which has hampered interpretation of past studies, is alleviated. Using this unambiguous method, we have investigated the genetic pathways necessary for lifespan extension by diet. We have conducted a genetic screen and have found that the heat shock response pathway is critical for DD response. The heat shock response pathway is evolutionarily conserved from the nematode to humans. A manuscript is under preparation to describe our findings. We are currently investigating how this conserved pathway modulates the lifespan of worms under the DD condition. Uncovering the conserved mechanisms will advance our knowledge on the effects of diet on aging and longevity in mammals, including humans. Drosophila melanogaster is another powerful genetic system that has been utilized extensively to address many basic biological questions including aging and dietary restriction (DR). To further investigate the effects of macronutrients in the diet on lifespan, we have measured lifespan of flies fed diets of various ratios of macronutritions, including protein and carbohydrates. In addition, to address the association of reproduction with lifespan, we have also measured the reproduction of flies in these conditions. We have found that dietary composition has profound effects on lifespan and reproduction but not in a coordinated manner. The results have provided us a foundation to investigate mechanisms of dietary regulation in D. melanogaster. We have been taking advantage of availability of a large number of fly mutants in the public stock centers, and conducting genetic screens to identify which genes are required for lifespan extension by DR. Identification of genetic pathways involved in DR will provide insight on lifespan regulation. Numerous studies in rodents have indicated that DR can extend not only lifespan but also healthspan. To investigate the mechanisms of DR on healthspan, we have employed the primary cell culture system to investigate the neuroprotective function of DR. Adiponectin is a 30 KD protein primarily produced by adipose tissues prior to its release into circulation, and is thought to have multiple functions in the peripheral and central nervous systems. The adiponectin level is significantly induced by DR. We hypothesized that adiponectin plays an important role in mediating the neuroprotection by DR. Using the cultured primary hippocampal cells, we found that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Our data also suggest that the AMPK pathway is involved in adiponectin-induced neuroprotection. A manuscript describing our findings is under review by a scientific journal. In summary, we have addressed several issues related to dietary regulation of lifespan in this project. By utilizing a unique and robust dietary regimen in C. elegans, we are dissecting molecular mechanisms of dietary regulation of lifespan. With D. melanogaster, we are studying mechanisms by which genes and which tissues are critical for lifespan extension by dietary restriction. Using the cellular model, we are investigating the signaling pathways involved in the beneficial effects of DR. This project will allow us identify the conserved pathways required for lifespan extension by DR, which will be valuable for understanding human aging and more importantly for developing efficient aging intervention strategies for humans.

饮食限制是一种有效的非遗传饮食操纵，迄今为止几乎所有测试的物种都可以延长寿命。我们对DR的分子机制的理解主要来自对遗传性熟悉的系统的研究，包括酵母，蠕虫和苍蝇，在这些系统中，通过稀释食物来源或使用降低喂养效率的基因突变来实施DR。但是，这些方法的一个主要缺点是，它在确定这些DR范式下个体的确切热量摄入量的确切热量摄入量与这种较高生物体（例如啮齿动物）的能力不同。为了解决这个问题，我们以前开发了一种替代性饮食范式，饮食剥夺（DD），并发现它可以延长秀丽隐杆线虫的寿命，而秀丽隐杆菌的寿命与对照喂养的饮食（AL）相比。由于该方案涉及完全去除食物来源，因此控制食物摄入的问题阻碍了过去研究的解释。使用这种明确的方法，我们研究了饮食延长寿命所需的遗传途径。我们已经进行了遗传筛查，发现热激响应途径对于DD响应至关重要。热休克响应途径在进化上是从线虫到人类的。手稿正在准备描述我们的发现。我们目前正在研究该保守的途径如何调节DD条件下的蠕虫的寿命。揭示保守的机制将提高我们对饮食对哺乳动物（包括人类）的衰老和寿命的影响的了解。 果蝇Melanogaster是另一种强大的遗传系统，已广泛利用它来解决许多基本的生物学问题，包括衰老和饮食限制（DR）。为了进一步研究大量营养素在饮食中对寿命的影响，我们测量了捕食各种大比例（包括蛋白质和碳水化合物）饮食的寿命。此外，为了解决繁殖与寿命的关联，我们还测量了在这些条件下蝇的繁殖。我们发现，饮食组成对寿命和繁殖具有深远的影响，但没有以协调的方式影响。结果为我们提供了调查Melanogaster饮食调节机制的基础。我们一直在利用公共库存中心中大量的蝇突变体的可用性，并进行遗传筛选以确定DR延长寿命所需的基因。鉴定DR中涉及的遗传途径将提供对寿命调节的见解。 对啮齿动物的大量研究表明，DR不仅可以延长寿命，还可以延长健康状态。为了研究DR在HealthSpan上的机制，我们采用了主要的细胞培养系统来研究DR的神经保护功能。脂联素是一种30 kD蛋白，主要由脂肪组织释放到循环之前，并被认为在周围和中枢神经系统中具有多个功能。 DR可显着诱导脂联素水平。我们假设脂联素在介导DR的神经保护作用中起着重要作用。使用培养的原发性海马细胞，我们发现脂联素可以保护培养的海马神经元免受海藻酸诱导的（KA）细胞毒性。我们的数据还表明，AMPK途径与脂联素诱导的神经保护有关。一份科学期刊正在审查描述我们发现的手稿。 总而言之，我们已经解决了与该项目中寿命的饮食调节有关的几个问题。通过利用秀丽隐杆线虫中的独特且坚固的饮食方案，我们正在解剖生命周期饮食调节的分子机制。使用D. melanogaster，我们正在研究通过饮食限制，基因和哪些组织对于延长寿命至关重要的机制。使用细胞模型，我们正在研究DR的有益作用所涉及的信号通路。该项目将使我们确定DR的寿命延长所需的保守途径，这对于理解人类衰老很有价值，更重要的是，对于制定人类的有效衰老干预策略。