Environmentalcues, like the type of food source, the level of food intake and many forms ofstress, have been shown to influence lifespan. These cues presumably modulatethe activities of signaling pathways that have previously been shown to affectlongevity. However, the mechanisms involved in integrating different types ofenvironmental information with these signaling pathways remain unknown.
In the worm C. elegans, at least a part of these interactions is mediated by the sensory system. A subset of neurons that function in taste and smell has been shown to shorten worm lifespan, whereas a different subset of taste neurons lengthens its lifespan. This suggests that sensory neurons can mediate the lifespan effects of specific food-derived cues. Consistent with this hypothesis, some of its bacterial food sources, like different E. coli strains, have also been shown to have different effects on C. elegans longevity.
Recently, we have shown that C. elegans sensory neurons affect lifespan through recognition of food types. We have also found that these neurons act with a neuropeptide receptor, which is similar to neuromedin U receptors in humans. Moreover, we have shown that this receptor, which is expressed in both the sensory system and the reproductive system, influences C. elegans lifespan in a manner dependent on the lipopolysaccharide (LPS) structure of its live E. coli food source.
Although our data suggest that this neuropeptide receptor, NMUR-1, is required in processing the information derived from specific food cues to influence lifespan, the precise mechanisms involved remain unclear. Thus, we aim to understand the mechanisms through which NMUR-1 mediates the sensory influence on lifespan and alters C. elegans physiology in a food source-dependent manner. We plan to:
(1) identify the cellular sites of NMUR-1 function, which should also help determine the type of sensory cues that might regulate its activity;
(2) determine how NMUR-1 regulates the different signaling activities of a sterol hormone receptor, which is required for NMUR-1 activity on the different food sources; and
(3) identify the transcriptional targets of the NMUR-1 pathway to determine how this pathway integrates environmental information and regulate physiological responses that affect lifespan.
Our discovery of a role for NMUR-1 in affecting C. elegans lifespan in a food source-dependent manner, together with the sensory system, provides a genetic framework from which one can elucidate the mechanisms that underlie the effects of specific food cues and the sensory influence on lifespan. Since this receptor is also found in humans, understanding how it affects C. elegans lifespan in a food source-dependent manner may lead us to understand how a similar pathway could function within us. Accordingly, the studies addressed in this grant proposal may also yield much needed insight into how different types of diet contribute to age-related diseases, like obesity and diabetes, which are prevalent within our population.