Increased Respiratory Chain Activity and Animal Aging

说明(申请人提供)：衰老是由于随着时间的推移，损伤的积累影响了生物体的功能和生存；然而，事实证明，很难推断导致衰老的许多过程的相对重要性。最近对一系列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动的增加有关。然而，目前还不清楚仅仅增加线粒体的活性是否足以延长动物的寿命。我们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，包括解决了许多其他重要生物学问题的所有分子、遗传和生化工具。我们的苍蝇模型提供了一个易于处理的遗传系统，可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继续这些研究：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强呼吸链的活性，并研究其对寿命的影响。我们的假设是，某些组织中增加的呼吸足以延长寿命。2)呼吸增加对生活史特征、年龄相关行为和氧化应激有什么影响？需要检验的假设是，增加呼吸可以延长寿命，而不会对生育力、发育时间或行为产生不利的副作用。3)呼吸链活动增加与已建立的调节苍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带来老龄化研究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治疗人类年龄相关疾病的新疗法。 公共卫生相关性：高龄是大多数癌症和神经退行性疾病的最大风险因素。我们正在利用果蝇强大的遗传学来更好地了解衰老的基本生物学。这项研究的长期目标是提供新的治疗靶点来对抗与年龄相关的人类疾病。

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.