Mitochondrial function, TOR and Aging

描述(申请人提供)：老龄化仍然是北美人类疾病中最重要的单一风险因素，在人口结构急剧变化的时期，营养干预可以对与年龄相关的疾病的发生产生深远影响的想法至关重要。限制饮食(DR)是减少饮食中的营养物质，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。研究表明，在啮齿动物身上，DR可以预防一些与年龄相关的疾病，包括亨廷顿氏症、癌症、糖尿病和其他心血管疾病。鉴于DR的普遍保护作用，研究其分子机制将有助于更好地了解人类各种与年龄相关的疾病的发病机制，这反过来将有助于推动这些疾病的治疗方法的发展。 我们已经确定保守的营养感知TOR通路是DR依赖寿命变化的关键调节因子。结合生化、遗传和基因组技术，我们建议了解TOR、新陈代谢和衰老之间的联系。我们假设，TOR途径对mRNA翻译的调控导致了ATP生成途径和线粒体功能的改变，线粒体功能介导了TOR途径的寿命效应。这项提案将研究TOR调制对果蝇和人类细胞之间线粒体功能影响的保守性。此外，我们将利用果蝇来研究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有相当大的兴趣。由于人类与苍蝇和蠕虫等模式生物之间存在高度的基因同源性，我们认为现在是时候了解这些简单生物中调节寿命和新陈代谢的饮食因素了。我们的发现将对揭示营养在癌症和糖尿病等许多与年龄相关的疾病的病因学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.