Molecular Mechanisms of Lifespan Extension by Dietary Restriction in Drosophila

描述(由申请人提供)：饮食限制(DR)在酵母、蠕虫、果蝇和啮齿动物等各种物种中提供了最强有力的延长寿命的方法。DR减少饮食中的营养物质不仅可以延长寿命，还可以预防一些与年龄有关的疾病，包括神经退化、癌症、糖尿病和心血管疾病。因此，研究DR的分子机制将有助于更好地了解各种人类年龄相关疾病的发病机制，并有助于推动这些疾病的治疗方法的发展。无脊椎动物模型由于寿命短和易于基因操作，继续被用作了解衰老和疾病的模型。我们的实验室先前已经确定营养感应TOR(雷帕霉素的靶标)途径是营养调节果蝇寿命变化的关键调节因子。这一遗传途径现在似乎在酵母、蠕虫、苍蝇和老鼠的寿命延长方面发挥了保守的作用。我们以前已经证明了4E-BP(真核启动因子4E结合蛋白)在介导DR延长寿命的过程中发挥了关键作用。我们还描述了使用多聚体图谱和微阵列相结合的方法导致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mRNAs的子集，尽管全局翻译减少，包括参与线粒体功能、蛋白质折叠、脂肪代谢和钙信号转导的基因[1]。我们已经证明，在DR时，线粒体功能增加，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脂肪酸代谢增强的代谢转换的一部分，这延长了苍蝇的寿命。我们观察到，增强的脂肪代谢增加了肌肉活动，这在延长DR的寿命中起着关键作用。在这里，我们讨论脂肪代谢的变化和肌肉活动的增加在调节DR的延长寿命效应中起因果作用的机制。我们的发现将对理解营养在衰老和人类衰老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探讨DR的机制：1)表征脂肪代谢在DR延长寿命中的作用；2)研究增强的脂肪周转增强DR的活性和延长DR寿命的机制；3)研究脂肪代谢和增强的活性在长寿菌株延长寿命中的作用。我们相信，通过保守的信号通路了解DR的基本过程将有助于揭开人类衰老和与年龄相关的疾病的一些谜团。 公共卫生相关性：饮食限制是各种物种中最有力的延长寿命的环境方法，已被证明可以预防各种与年龄有关的疾病，包括糖尿病、癌症和神经退化。这项建议研究了肌肉活动和脂肪代谢通过限制饮食使用果蝇来调节延长寿命的机制。我们的发现将对理解雷帕霉素(TOR)途径的靶点和营养在人类衰老和老年性疾病中的作用具有重要影响。)

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. PUBLIC HEALTH RELEVANCE: Dietary restriction is the most robust environmental method of lifespan extension in various species and has been shown to protect against various age related diseases including diabetes, cancer and neurodegeneration. This proposal investigates the mechanism by which muscle activity and fat metabolism mediate the lifespan extension effects by dietary restriction using Drosophila. Our findings will have a significant effect on understanding the role of the target of rapamycin (TOR) pathway and nutrition in aging and age related diseases in humans. )