The dynamic interplay between an animal's perceptual system and its physiological homeostasis plays an important role in biological aging. Genetic disruption of sensory input pathways or nutrient signaling components can induce potent effects on organismal fitness and lifespan. Likewise, dietary restriction paradigms, whether through reduction of food intake or nutrient availability, enhance longevity in nearly all species sufficiently examined. Since integrative processing of sensory inputs and nutrient levels is primarily mediated by the central nervous system (CNS), the brain has emerged as an attractive frontier for understanding the contribution of environmental inputs to the biological basis of aging. However, it remains unclear how the CNS coordinates these inputs with physiological systems to control longevity and healthspan. The primary objective of this proposal is to identify and characterize central brain circuits and neural signaling substrates tha control the progression of aging using the fruit fly Drosophila melanogaster as a genetically- tractable model organism. In our first aim, we will explore how manipulation of neuropeptide F and adipokinetic hormone signaling networks influences metabolism and aging phenotypes under various dietary regimes. In our second aim, we will determine how chemosensory receptors communicate with higher-ordered processing centers to regulate fly longevity and healthspan. In our third aim, we will identify and examine novel neural signaling substrates and central brain regions critical for the progression of healthy aging in flies. Given the high degree of conservation in both the biological basis of aging and the functional architecture of the CNS across taxa, we believe these ambitious studies will provide valuable insight into how specific neuronal circuits and signaling molecules integrate environmental inputs to directly affect aging in invertebrate models, mammals, and humans.
While modulation of sensory inputs and receptor function produces profound effects on organismal aging, the neural circuits and substrates underlying this phenomenon remain largely unknown. Elucidation of the downstream neural mechanisms important for healthy aging will provide potential therapeutic strategies that will offset prematur age-related decline.
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