Mechanisms to Regulate Aging through Neurosensory and Reward Circuits

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DESCRIPTION (provided by applicant): The power of the central nervous system (CNS) to modulate our health and well-being is widely appreciated, and recent studies have demonstrated the importance of the CNS in regulating the aging process. Alteration of sensory input to the brain by genetic or environmental means is capable of regulating stress resistance, metabolism, and longevity, but how these inputs are integrated by the CNS is only beginning to be unraveled. In our recently published results, we discovered a set of sensory neurons, a specific pheromone receptor (ppk23), and a group of neurons in the brain expressing a conserved neuropeptide (NPF) that are components of a circuit capable of quickly and reversibly regulating stress resistance, fat storage, and lifespan in the fruit fly, Drosophlia melanogaster. The primary objective of this proposal is to completely define a neural circuit, from inputs to the ultimate effector signaling pathways, capable of regulating the aging process. In our first aim we will determine if mating-reward, which partially negates the effects of pheromone sensation on lifespan and metabolism, acts as an input to the same neural circuit to regulate aging. In our second aim, we will identify subsets of interneurons as well as neuroendocrine cells that are responsible for modulating whole-organism aging and physiology as a part of this neural circuit. Our final aim will elucidate how this neural pathway interacts wih known pathways that are capable of regulating aging. As both the biological basis of aging and the functional architecture of the CNS are highly conserved across taxa, the studies performed in this proposal will elucidate how the brain processes and integrates environmental inputs to directly regulate the aging process. We believe that these ambitious studies will push forward the development of successful anti-aging interventions.