Increased Respiratory Chain Activity and Animal Aging

描述（由申请人提供）：老化是由于损伤随时间的积累而影响生物体的功能和存活;然而，已证明难以推断导致老化的许多过程的相对重要性。最近在广泛的模式生物中的研究表明，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，目前还不知道是否增加线粒体活性本身就足以延长动物的寿命。我们已经开发了一种新的分子遗传学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，包括解决许多其他重要生物学问题的所有分子，遗传和生物化学工具。我们的果蝇模型提供了一个易于处理的遗传系统，以直接检查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进行这些研究：1）呼吸增加对动物衰老的影响是什么？我们将在动物生命的不同阶段，在不同的细胞和组织中增加呼吸链的活性，并研究其对寿命的影响。我们的假设是，某些组织中呼吸作用的增加将足以促进长寿。2)呼吸增加对生活史特征、年龄相关行为和氧化应激有什么影响？有待检验的假设是，呼吸增加可以促进长寿，而不会对生育能力、发育时间或行为产生有害的副作用。3)增加呼吸链活性和建立调节果蝇寿命的遗传途径之间的关系是什么？我们将研究胰岛素/IGF-1信号通路和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带来老龄化研究的一个重要领域的基础知识。与此同时，我们的发现可能会导致新的治疗方法来治疗人类与年龄相关的疾病。

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.