Increased Respiratory Chain Activity and Animal Aging

描述（由申请人提供）：衰老是由于损害随着时间的积累而影响生物体的功能和生存；然而，事实证明很难推断出导致衰老的许多过程的相对重要性。最近对多种模式生物的研究表明，延缓衰老过程的干预措施与线粒体呼吸链活性的增加有关。然而，目前尚不清楚线粒体活性的增加是否足以延长动物的寿命。我们开发了一种新的分子遗传方法来补充果蝇的内源性呼吸链机制，从而增加呼吸。果蝇系统提供了许多优势，包括所有的分子、遗传和生化工具，这些工具已经解决了许多其他重要的生物学问题。我们的果蝇模型提供了一个易于处理的遗传系统来直接研究呼吸增加和动物衰老之间的因果关系。在这里，我们建议通过探索三个广泛的问题来开展这些研究：1)呼吸增加对动物衰老的影响是什么？我们将增加呼吸链活动，在不同的细胞和组织中，在动物生命的不同阶段，并研究对寿命的影响。我们的假设是，增加某些组织的呼吸就足以延长寿命。2)呼吸增加对生活史特征、年龄相关行为和氧化应激有何影响？要测试的假设是，增加呼吸可以延长寿命，而不会对生育能力、发育时间或行为产生有害的副作用。3)呼吸链活性的增加与调节果蝇寿命的既定遗传途径之间的关系是什么？我们将研究胰岛素/IGF-1信号通路与线粒体呼吸链活性之间的相互作用。这项拨款提案中描述的工作将为老龄化研究的一个重要领域带来基础知识。同时，我们的发现可能会导致新的治疗方法来治疗人类与年龄有关的疾病。

DESCRIPTION (provided by applicant): Aging is due to the accumulation of damage over time that affects the function and survival of the organism; however, it has proven difficult to infer the relative importance of the many processes that contribute to aging. Recent studies in a broad spectrum of model organisms have suggested that interventions that retard the aging process are associated with an increase in mitochondrial respiratory chain activity. However, it is not yet known whether increased mitochondrial activity alone is sufficient to extend animal lifespan. We have developed a novel molecular genetic approach to supplement the endogenous respiratory chain machinery of the fruit fly Drosophila melanogaster and hence increase respiration. The Drosophila system offers many advantages, including all of the molecular, genetic and biochemical tools that have solved many other important biological problems. Our fly model provides a tractable genetic system to directly examine the causal relationship between increased respiration and animal aging. Here, we propose to pursue these studies by exploring three broad questions: 1) What are the effects of increased respiration on animal aging? We will augment respiratory chain activity, in different cells and tissues, and at different stages of the animal's life and investigate the effects on longevity. Our hypothesis is that increased respiration in certain tissues will be sufficient to promote longevity. 2) What are the consequences of increased respiration on life-history traits, age- related behavior and oxidative stress? The hypothesis to be tested is that increased respiration can promote longevity without detrimental side effects on fertility, developmental timing or behavior. 3) What is the relationship between increased respiratory chain activity and established genetic pathways that modulate fly longevity? We will examine the interaction between the insulin/IGF-1 signaling pathway and mitochondrial respiratory chain activity. The work described in this grant proposal will bring about fundamental knowledge in an important area of aging research. At the same time, our findings may lead to new therapeutic approaches to treat age-related diseases in humans. PUBLIC HEALTH RELEVANCE: Advanced age is the greatest risk factor for most cancers and neurodegenerative disorders. We are using the powerful genetics of the fruit fly Drosophila to better understand the basic biology of aging. The long-term aim of this research is to provide novel therapeutic targets to counteract age-related human diseases.