Molecular Mechanisms of Lifespan Extension by Dietary Restriction in Drosophila

描述（由申请人提供）：饮食限制（DR）为酵母菌、蠕虫、果蝇和啮齿动物等多种物种提供了最有效的延长寿命的方法。DR减少饮食中的营养不仅可以延长寿命，还可以预防许多与年龄有关的疾病，包括神经退行性疾病、癌症、糖尿病和心血管疾病。因此，对DR的分子机制的研究可能会促进对各种人类年龄相关疾病的发病机制的更好理解，并有助于促进这些疾病治疗方法的发展。由于它们的寿命短，易于基因操作；无脊椎动物模型仍然是理解衰老和疾病的有用模型。我们的实验室之前已经确定了营养感应TOR（雷帕霉素靶点）途径是果蝇营养调节寿命变化的关键调节因子。这种遗传途径现在似乎在酵母菌、蠕虫、苍蝇和老鼠的寿命延长中起着保守的作用。我们之前已经证明，4E- bp（真核起始因子4E结合蛋白）在DR介导的寿命延长中起着关键作用。我们还描述了使用多染色体分析与微阵列相结合的方法导致DR的全基因组翻译变化。使用这种方法，我们已经确定了在DR时优先翻译的mrna子集，尽管全局翻译减少，其中包括涉及线粒体功能，蛋白质折叠，脂肪代谢和钙信号传导[1]的基因。我们已经证明，在DR上有线粒体功能的增加，这是DR介导的长寿所必需的。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，从而延长了果蝇的寿命。我们观察到，脂肪代谢的增强增加了肌肉活动，这在dr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的增加在dr的寿命延长效应中起因果作用的机制。我们的发现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。我们希望通过解决以下具体目标来全面解决DR在黑腹d.m anogaster中的机制：1)表征脂肪代谢在DR延长寿命中的作用；2)研究脂肪代谢增强活性和延长DR寿命的机制；3)研究脂肪代谢和活性增强在长寿品系中延长寿命的作用。我们相信，了解DR的基本过程，通过保守的信号通路在黑腹龙将有助于解开衰老和人类年龄相关疾病的一些谜团。

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.