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.