Mechanisms of Lifespan Modulation by Diet

饮食限制是一种强有力的非遗传饮食操作，已被证明可以延长一些进化上不同物种的寿命，从酵母到蠕虫、苍蝇、啮齿动物，可能还有灵长类动物。我们对DR分子机制的理解主要来自对酵母、蠕虫和苍蝇等遗传顺从系统的研究，在这些系统中，DR是通过稀释食物来源或使用降低摄食效率的基因突变来施加的。然而，这些方法的一个主要缺点是，与高等生物体研究中的这种能力不同，在这些DR范例下确定个人的确切卡路里摄入量仍然存在很大的不确定性。我们之前已经描述了一种替代的饮食模式，饮食剥夺(DD)，它可以延长线虫的寿命。由于这种方法涉及完全去除食物来源，控制食物摄入量的问题得到了缓解，这一问题阻碍了对过去研究的解释。使用这种明确的方法，我们研究了通过饮食延长寿命所必需的遗传途径。我们已经进行了基因筛查，并发现热休克反应途径对DD反应至关重要。在接下来的一年里，我们将研究DD如何通过生化、遗传和基因组方法通过这一途径延长寿命。从线虫到人类，热休克反应途径在进化上是保守的。揭示这些保守的机制将促进我们对饮食对哺乳动物(包括人类)衰老和长寿的影响的了解。 果蝇也是一种强大的遗传系统，已被广泛用于解决许多基本的生物学问题，包括衰老和饮食限制(DR)。为了进一步研究饮食中大量营养素对寿命的影响，我们测量了喂食不同比例的大量营养素的果蝇的寿命，包括蛋白质和碳水化合物。此外，为了解决繁殖与寿命之间的关联，我们还测量了果蝇在这些条件下的繁殖。我们发现，饮食结构对寿命和生殖有深远的影响，但不是以协调的方式。本研究结果为进一步研究黑腹鱼的食性调控机制奠定了基础。在未来一年，我们将利用公共库存中心可获得的大量突变体，并进行基因筛选，以确定哪些基因是DR延长寿命所必需的，识别DR涉及的遗传途径将为寿命调控提供洞察力。 总而言之，在这项新倡议中，我们已经开始解决与饮食调节寿命相关的问题。通过利用线虫独特而健壮的饮食方案，我们正在剖析饮食调节寿命的分子机制。我们正在研究通过限制饮食延长寿命的基因和组织的机制。该项目将使我们能够确定通过饮食限制延长寿命所需的保守途径，这将对理解人类衰老，更重要的是为人类开发有效的衰老干预策略将是有价值的。

Dietary restriction is a potent non-genetic dietary manipulation that have been shown to extend lifespan in a number of evolutionarily divergent species, ranging from yeast, to worms, flies, rodents and possibly primates. Our understanding of molecular mechanisms of DR comes 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 substantial uncertainty in determining the exact caloric intake of individuals under these DR paradigms, unlike this ability in studies of higher organisms. We have previously described an alternative dietary paradigm, dietary deprivation (DD), which can extend lifespan in C. elegans. 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. In the coming year, we will investigate how DD extends lifespan through this pathway by biochemical, genetic and genomic approaches. The heat shock response pathway is evolutionarily conserved from the nematode to humans. Uncovering the conserved mechanisms will advance our knowledge on the effects of diet on aging and longevity in mammals, including humans. Drosophila melanogaster is also a 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 macronutritions 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. In the coming year, we will take advantage of availability of a large number of mutants in public stock centers, and conduct 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. In summary, we have started addressing issues related to dietary regulation of lifespan in this new initiative. 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. This project will allow us identify the conserved pathways required for lifespan extension by dietary restriction, which will be valuable for understanding human aging and more importantly for developing efficient aging intervention strategies for humans.