PROJECT SUMMARY The single biggest risk factor for developing Parkinson’s disease is age, suggesting that age-related changes in the brain predispose to loss of dopamine (DA) neuron health and viability. Cell stressors such as oxidative stress and metabolic dysfunction increase with age in many species including humans, and DA neurons are particularly vulnerable to oxidative stress because of their high metabolic demands and intrinsic reactive oxygen species production. Despite a growing body of evidence linking elevated oxidative stress to aging and DA neuron degeneration, the role of oxidative stress-responsive signaling pathways in connecting this stress to enhanced DA neuron vulnerability with age are not well understood. Prior studies link activation of the HIF-1 (hypoxia-inducible factor-1) pathway to suppression of TOR (target of rapamycin) signaling and recent GWAS studies raise the possibility that the interaction of these pathways may be important in regulating lifespan, possibly in response to cellular stress signals. Key components of HIF-1/TOR signaling are also altered in human Parkinson’s disease substantia nigra DA neurons. The primary goal of this proposal is to determine whether age-related oxidative stress results in sustained upregulation of specific signaling mediators in the HIF-1/TOR signaling pathway that promote susceptibility of DA neurons to age- related death and limit organismal lifespan. Studies from multiple animal models including Drosophila indicate that TOR deregulation is a feature of nervous system aging and neurodegenerative disease. We will leverage the natural genetic variation in a collection of Drosophila genetic backgrounds that we find influences reactive oxygen species production, lifespan and DA neuron viability to achieve two primary goals: First, we will examine the effects of aging on brain expression of oxidative stress signaling mediators both in the whole brain as well as in specific vulnerable (i.e. DA) and spared neuronal populations. Second, we will determine the role of these signaling mediators on age-related DA neuron death and lifespan. These exploratory studies will pave the way for detailed characterization of how aging and age-related stress drives upstream regulators of this signaling pathway, and inform broader studies on the role of these signaling mediators in Parkinson’s disease neurodegeneration linked to additional genetic and environmental factors.