Project Summary Scientists and laypeople have long been fascinated by the senses. Aristotle distinguished four of them, each linked with one of the four elements – vision with water, sound with air, smell with fire, and touch with earth. Since that time, we have become aware of many more, including those involving position or pain. Now, research across a range of disciplines has revealed that sensory perception can modulate many aspects of physiology and health. Indeed, this project has funded studies in our laboratory that have illuminated basic and translational principles of how sensory perception influences energy homeostasis, tissue physiology, and organism aging. Work from our lab has established that exposure of flies to food-based odorants limits the beneficial effects of dietary restriction, that loss of sensory neurons affects fly lifespan, and that perceptional experiences of food, sex, and danger modulate lifespan through neural circuits that utilize evolutionarily conserved neuropeptides. Ongoing work will continue to define a mechanistic framework for sensory modulation of aging by revealing neural circuits and signaling pathways that emanate from sensory tissues and that interface with the deeper regions of the central nervous system to orchestrate biological changes in peripheral tissues. In this renewal, we will interrogate the roles of the biogenic amines serotonin, dopamine, and octopamine, which regulate persistent neural activity in many systems, in modulating the long-term effects of sensory perception on health and aging. We will also employ an array of new technologies and behavioral assays to develop inference on the relationships among these signaling molecules, the associated neural circuits that modulate lifespan, and the neural states they induce. Additional work will establish similarities and differences in the ways that sensory inputs impact the activity of a core group of aging- regulatory neurons in the central complex of the fly brain and will determine how relevant neuromodulators influence these relationships. Discoveries from our laboratory and others have resulted in a detailed functional map of the fly brain, and several of the sensory effects on healthy aging described above, and the mechanisms that underlie them, have since been shown to be conserved in other organisms, including nematodes and mice, suggesting that a deeper understanding of the mechanisms through which the brain controls fly aging may lead to novel targets of intervention in humans.