Mitochondrial function, TOR and Aging

描述（由申请人提供）：在北美，衰老仍然是人类疾病中最重要的单一风险因素，在人口结构发生巨大变化的时期，营养干预可以对年龄相关疾病的发作产生深远影响的想法至关重要。饮食限制（DR），减少饮食中的营养物质，为酵母、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。在啮齿类动物中已经显示，DR可以预防许多与年龄相关的疾病，包括亨廷顿病、癌症、糖尿病和其他心血管疾病。鉴于DR的普遍保护作用，研究其分子机制将促进对各种人类年龄相关疾病的发病机制的更好理解，这反过来将有助于促进这些疾病的治疗方法的发展。 我们已经确定了保守的营养感应TOR途径作为DR依赖性寿命变化的关键调节因子。使用生物化学，遗传学和基因组技术的组合，我们建议了解TOR，代谢和衰老之间的联系。我们假设TOR通路对mRNA翻译的调节导致ATP生成通路和线粒体功能的改变，线粒体功能介导TOR通路的寿命效应。该提案将研究TOR调节对果蝇和人类细胞之间线粒体功能的影响的保守性。此外，使用果蝇，我们将检查ATP生成途径和寿命之间的因果关系。 相关性：人们对降低疾病风险和延长健康寿命的营养干预措施非常感兴趣。由于人类和模式生物（如苍蝇和蠕虫）之间存在高度的遗传同源性，我们认为现在是了解这些简单生物中调节寿命和代谢的饮食因素的时候了。我们的发现将对帮助揭示营养在癌症和糖尿病等许多与年龄相关的疾病病因中的作用产生重大影响。

DESCRIPTION (provided by applicant): Aging remains the single most important risk factor in human disease in North America and the idea that nutritional interventions can have profound effect on the onset of age-related disease is vitally important during a time of dramatic demographic change. Dietary restriction (DR), a reduction of nutrients in the diet, provides the most robust method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. It has been shown in rodents that DR protects against a number of age related diseases including Huntington's, cancer, diabetes and other cardiovascular diseases. Given the universally protective effects of DR, investigating its molecular mechanisms will promote a greater understanding of the pathogenesis of various human age related diseases, which will in turn help advance the development of therapeutics for these disorders. We have identified the conserved nutrient sensing TOR pathway as a critical regulator of DR dependent lifespan changes. Using a combination of biochemical, genetic and genomic technologies we propose to understand the link between TOR, metabolism and aging. We hypothesize that modulation of mRNA translation by the TOR pathway leads to alterations in ATP generating pathways and mitochondrial function which mediates the lifespan effects of the TOR pathway. This proposal will examine the conservation of the effects of the TOR modulation on mitochondrial function between flies and human cells. Furthermore, using Drosophila we shall examine the cause and effect relationship between ATP generating pathways and lifespan. RELEVANCE: There is considerable interest in nutritional interventions that decrease the risk of disease and extend healthy lifespan. Since there is a high degree of genetic homology between humans and model organisms such as flies and worms, we believe it is timely to understand the dietary factors that regulate lifespan and metabolism in these simple organisms. Our findings will have a significant impact on helping uncover the role of nutrition in the etiology of a number of age-related diseases like cancer and diabetes.