Determining the neural mechanisms of mechanosensory food perception in DR-mediated longevity

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Project Summary: The field of geroscience has identified multiple genetic, pharmaceutical, and lifestyle interventions that promote longevity and delay the onset of age-related disease. One of the most studied of these interventions is Dietary Restriction (DR), or a reduction in nutrient intake that does not cause malnutrition. DR can extend lifespan and healthspan across taxa, and many of the genetic mechanisms of DR were originally discovered in the nematode Caenorhabditis elegans. Unfortunately, dietary restriction is not a realistic solution to prevent age-related disease on a population level because following a DR protocol is very difficult for most people and because the benefits of DR can be blunted by environmental factors. For example, exposing fasted animals to food smells decreases the efficacy of DR in multiple model organisms. In C. elegans, food smells are perceived by sensory neurons that initiate circuits leading to neurotransmitter release from serotonergic and dopaminergic neurons. Signaling from these bioamine neurotransmitters ultimately conveys food availability information to the intestine through cell nonautonomous signaling. In the intestine, this signal suppresses the expression of fmo-2, a gene required for DR-mediated longevity. In the preliminary data collected for this proposal, we found that a second mode of food perception, mechanosensation of food, also suppresses DR-mediated fmo-2 induction and longevity in C. elegans. Much like food smell, mechanosensory suppression of DR requires the production of bioamine neurotransmitters to drive cell nonautonomous regulation of peripheral longevity genes. This project will identify key neurons and signaling components of the cell nonautonomous signaling pathway through which mechanosensory food perception regulates aging. To map this circuit, I will first identify the dopaminergic and tyraminergic neurons activated by mechanosensory food perception and determine whether mechanosensation increases or suppresses release of these neurotransmitters (Aim 1). Next, I will investigate elements of this pathway downstream of bioaminergic neurons by 1) determining the bioamine receptor-expressing interneurons directly downstream of the bioaminergic signal, and 2) identifying neuropeptides and neuropeptide receptors through which information about the food environment is conveyed to the intestine (Aim 2). Together, these aims will enhance our understanding of how different modes of food perception regulate aging through conserved signaling elements. Ultimately, we can use this information to create pharmaceuticals that mimic the benefits of dietary restriction regardless of environmental food cues.