Mechanisms of Lifespan Modulation by Diet

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显示出延长寿命和健康寿命。我们对DR分子机制的理解主要来自于对遗传学系统的研究，包括酵母、蠕虫和苍蝇，其中DR是通过稀释食物来源或通过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，它仍然基本上不确定在这些DR范例下确定个体生物体的确切热量摄入。为了解决这个问题，我们以前已经开发了一种替代的饮食模式，称为饮食剥夺（DD），并发现它可以延长C。与随意喂食的对照蠕虫（AL）相比，由于该方案涉及完全去除食物来源，因此减轻了控制食物摄入的问题，这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。我们已经进行了遗传筛选，发现热休克反应途径对DD反应至关重要。从线虫到人类，热休克反应途径在进化上是保守的。一份描述C. elegans正在筹备中。我们目前正在研究其他保守的途径，可能调节的DD条件下的蠕虫的寿命。揭示保守的机制将推进我们对饮食对包括人类在内的哺乳动物衰老和长寿影响的认识。 黑腹果蝇是另一个强大的遗传系统，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）。保守的胰岛素样信号通路已被证明不仅在营养代谢中而且在寿命调节中发挥重要作用。为了研究膳食宏量营养素对寿命的影响和分子机制，我们测量了喂食不同比例的宏量营养素（包括蛋白质和碳水化合物）的果蝇的寿命。我们已经发现，膳食组成对寿命有深远的影响，胰岛素样信号通路与膳食营养素相互作用，以调节寿命。目前正在编写一份介绍这些结果的手稿。本研究为进一步研究D.黑腹菌通过利用公共库存中心大量苍蝇突变体的可用性，我们正在研究DR中涉及的遗传途径，这将提供对寿命调节的见解。 在啮齿类动物中的大量研究表明，DR不仅可以延长寿命，还可以延长健康寿命。脂联素是一种小分子蛋白质，主要由脂肪组织产生，然后释放到循环中。为了研究脂联素是否以及如何介导DR的神经保护作用，我们采用了原代大鼠海马细胞培养系统。 我们已经证明，脂联素可以保护培养的海马神经元对红藻氨酸（KA）诱导的细胞毒性。此外，我们发现保守的AMPK通路参与脂联素诱导的神经保护。描述本研究部分结果的手稿已被接受发表在AGE（2010）上。考虑到DR增加哺乳动物的脂联素水平，我们的研究结果表明，脂联素在介导DR的有益作用，包括神经保护中起着重要的调节作用。 总之，我们在这个项目中讨论了与饮食调节寿命有关的几个问题。通过采用独特的和强大的饮食方案，在C。我们正在解剖饮食调节寿命的分子机制。与D.我们正在研究哪些基因和哪些组织对通过饮食限制延长寿命至关重要的机制。使用细胞模型，我们正在研究参与DR有益作用的信号通路。该项目将使我们能够确定DR延长寿命所需的保守通路，这对于理解人类衰老以及更重要的是为人类开发有效的衰老干预策略具有价值。

Dietary restriction is a potent non-genetic dietary manipulation that has been shown to extend lifespan and healthspan 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 individual organisms under these DR paradigms. To address this issue, we have previously developed an alternative dietary paradigm, termed as dietary deprivation (DD), and found that it can extend lifespan in C. elegans compared to the control worms 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 describing the findings in C. elegans is under preparation. We are currently investigating additional conserved pathways that potentially modulate 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). The conserved insulin-like signaling pathway has been shown to play an important role not only in nutrient metabolism but also in lifespan regulation. To investigate the effects and molecular mechanisms of dietary macronutrients on lifespan, we have measured lifespan of flies fed diets of various ratios of macronutritions, including protein and carbohydrates. We have found that dietary composition has profound effects on lifespan and the insulin-like signaling pathway interacts with dietary nutrients to modulate lifespan. A manuscript describing these results is under preparation. This study provides us a foundation to investigate mechanisms of dietary regulation in D. melanogaster. By taking advantage of availability of a large number of fly mutants in the public stock centers, we are investigating the genetic pathways involved in DR, which will provide insight on lifespan regulation. Numerous studies in rodents have indicated that DR can extend not only lifespan but also healthspan. Adiponectin is a small protein primarily produced by adipose tissues prior to its release into circulation. To investigate whether and how adiponectin plays a role in mediating the neuroprotection by DR, we have employed the primary hippocampal cell culture system in rats. We have demonstrated that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Furthermore, we have found that the conserved AMPK pathway is involved in adiponectin-induced neuroprotection. A manuscript describing some results from this study has been accepted for publication in AGE (2010). Considering that DR increases adiponectin levels in mammals, our findings suggest that adiponectin plays an important regulatory role in mediating the beneficial effects of DR including neuroprotection. 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.