The long-term objectives of this application are to determine how, when, and where optimized mitochondrial uncoupling could maximally extend life span through reduction of reactive oxygen species (ROS) production. In addition, the molecular mechanisms responsible for the life span extension mediated by mitochondrial uncoupling will be investigated. As an extension of this application, the impact of mitochondrial uncoupling on aging will be examined in mammalian models to further assess the cellular consequences including age-related ROS accumulation, oxidative damage, the interplay between the uncoupling protein and other ROS detoxifying enzymes, and ultimately, life span. These studies are readily feasible and could be revealing given the availability of a number of existing UCP knock out and transgenic mice. The candidate is committed to aging research as a long-term career goal. Training with Dr. Stephen Helfand at the UConn Health Center, a well-known expert in the aging field will allow the candidate to acquire both conceptual approaches and necessary skills for aging research through daily interactions and the opportunities in attending relevant courses and seminars and presenting research results regularly before the entire department for critical review. The UConn Center on Aging offers further intellectual resources including seminars on various topics on aging. Two additional Drosophila laboratories within the same department thus offer an intellectually stimulating environment for the candidate to attain pertinent training in aging research to become an independent, productive investigator. The oxidative stress hypothesis of aging states that the rate of accrual of oxidative damage, resulting primarily from ROS generated during oxidative metabolism in mitochondria, determines the rate of aging. A prediction of this hypothesis is that interventions that reduce oxidative damage should slow the rate of aging and extend life span. It has been hypothesized that an increase in mitochondrial uncoupling decreases mitochondrial ROS production and oxidative damage. In the preliminary results section of the current proposal I show that expression of human uncoupling protein 2 in the mitochondria of adult Drosophila melanogaster neurons extends mean life span by up to 20%. In this proposal, I will make use of transgenic approaches in Drosophila melanogaster to determine (i) where and when uncoupling must be increased to extend life span, (ii) how increased mitochondrial uncoupling may cause life span extension, and (iii) what are the physiological benefits and costs of increased mitochondrial uncoupling.
