Molecular Mechanisms of Lifespan Extension by Dietary Restriction in Drosophila

描述（由申请方提供）：饮食限制（DR）为酵母、蠕虫、果蝇和啮齿动物等多种物种提供了延长寿命的最稳健方法。通过DR减少饮食中的营养物质不仅可以延长寿命，还可以预防许多与年龄相关的疾病，包括神经退行性疾病，癌症，糖尿病和心血管疾病。因此，可能的是，DR的分子机制的调查将促进更好地了解各种人类年龄相关疾病的发病机制，并帮助推进这些疾病的治疗方法的发展。由于它们的寿命短，易于遗传操作;无脊椎动物模型仍然是有用的模型，了解衰老和疾病。我们的实验室以前已经确定了营养感应TOR（雷帕霉素的目标）途径作为一个关键的调节营养调节苍蝇的寿命变化。这种遗传途径现在似乎在酵母、蠕虫、苍蝇和小鼠的寿命延长中发挥着保守的作用。我们以前已经证明，4 E-BP（真核起始因子4 E结合蛋白）在介导DR延长寿命中起着关键作用。我们还描述了全基因组翻译的变化，导致DR使用的方法，结合多聚体分析与微阵列。使用这种方法，我们已经鉴定了在DR时优先翻译的mRNA的子集，尽管整体翻译减少，包括参与线粒体功能、蛋白质折叠、脂肪代谢和钙信号传导的基因[1]。我们已经表明，在DR时，线粒体功能增加，这是DR介导的寿命所需的。我们假设线粒体功能的增加是向增强脂肪酸代谢的代谢转换的一部分，从而延长苍蝇的寿命。我们观察到，增强脂肪代谢增加肌肉活动，这在DR后的寿命延长中起着至关重要的作用。在这里，我们讨论了脂肪代谢的变化和肌肉活动增加在介导DR的寿命延长效应中起着因果作用的机制。我们的研究结果将对理解营养在人类衰老和年龄相关疾病中的作用产生重大影响。我们希望全面讨论D中DR的机制。通过解决以下具体目标来研究黑腹果蝇：1）表征脂肪代谢在DR后寿命延长中的作用。2）研究增强的脂肪周转增强DR后活性并延长寿命的机制，和3）检查脂肪代谢和增强的活性在长寿品系中寿命延长中的作用。我们认为，通过D.黑腹果蝇将有助于揭开人类衰老和与年龄有关的疾病的一些奥秘。

DESCRIPTION (provided by applicant): Dietary restriction (DR) provides the most robust method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. Reduction of nutrients in the diet by DR not only extends lifespan but also protects against a number of age related diseases including neurodegeneration, cancer, diabetes and cardiovascular diseases. It is therefore likely that investigation of the molecular mechanisms underlying DR will promote a greater understanding of the pathogenesis of various human age related diseases and help advance the development of therapeutics for these disorders. Due to their short lifespan and ease of genetic manipulation; invertebrate models continue to be useful as models for understanding aging and disease. Our laboratory has previously identified the nutrient sensing TOR (target of rapamycin) pathway as a critical regulator of nutrient modulated lifespan changes in flies. This genetic pathway now appears to play a conserved role in lifespan extension in yeast, worms, flies and mice. We have previously demonstrated that 4E-BP (eukaryotic initiation factor 4E binding protein) plays a key role in mediating lifespan extension by DR. We have also described the genome-wide translational changes that result from DR using a method that combines polysomal profiling with microarrays. Using this method we have identified a subset of mRNAs that are preferentially translated upon DR, despite a decrease in global translation which included genes involved in mitochondrial functions, protein folding, fat metabolism and calcium signaling [1]. We have shown that upon DR there is an increase in mitochondrial function which is required for the DR mediated longevity. We hypothesize that the increase in mitochondrial function is part of a metabolic switch towards enhanced fatty acid metabolism which extends lifespan in the fly. We observe that enhanced fat metabolism increases muscle activity which plays a critical role in lifespan extension upon DR. Here we address the mechanisms by which changes in fat metabolism and increased muscle activity play a causal role in mediating the lifespan extension effects due to DR. Our findings will have a significant impact on understanding the role of nutrition in aging and age related diseases in humans. We wish to comprehensively address the mechanism of DR in D. melanogaster by addressing the following specific aims: 1) To characterize the role of fat metabolism in lifespan extension upon DR. 2) To investigate the mechanisms by which enhanced fat turnover enhances activity and extends lifespan upon DR and 3) To examine the role of fat metabolism and enhanced activity in lifespan extension in long-lived strains. We believe that understanding the basic process of DR by conserved signaling pathways in D. melanogaster will help unravel some of the mysteries of aging and age-related diseases in humans.