Mechanisms of olfactory modulation of aging in Drosophila

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Ancient signaling pathways detect, decode, and use environmental stimuli to coordinate metabolism, growth, and maturation. The power of environmental cues to trigger alterations in life history patterns has long been recognized by field biologists, and the benefit of such plasticity is clear. Variable environmental conditions demand that individuals use external information to make calculated decisions, such as whether to wait out the bad times or commit to reproduction, to maximize reproductive fitness. Indeed, evidence from work in the nematode worm, Caenorhabditis elegans, and from our work in the fruit fly, Drosophila melanogaster, has shown that sensory control of aging is evolutionarily conserved. Ablation of specific sensory neurons in the worm affects lifespan, as do mutations in genes required for sensory signal transduction. Work in our laboratory has shown that exposure to food-based odorants reduces lifespan and partially rescues the benefits of dietary restriction. Moreover, mutation of a single odorant receptor, which leaves flies broadly anosmic, results in striking longevity: up to 60% (nearly 30 days) increase in median lifespan compared to wild-type animals. While mutant flies have normal size and metabolic rate, they are resistant to starvation and hyperoxia, and they exhibit increased triglyceride storage. We seek to elucidate (i) specific olfactory stimuli that regulate longevity; (ii) which cells, molecules, and pathways transduce relevant sensory information; and (iii) how this information directs subsequent outcomes that alter lifespan. We will determine whether the increased lifespan of olfactory mutant flies relies on known longevity pathways or involves novel pathways; whether olfactory signaling acts acutely in the adult stage; and whether specific odorant receptors regulate longevity in Drosophila. Our studies will provide molecular evidence for subsequent analysis of specific molecules and biological processes that regulate aging in Drosophila. These studies may also illuminate sensory signaling networks in mammals that control development, metabolism, and aging.