Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signaling.

The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age¹. Posttranscriptional regulators such as microRNAs control protein translation of target mRNAs with major consequences for development, physiology, and longevity^2,3. Here we show that food odor stimulates organismal proteostasis and promotes longevity in <i>Caenorhabditis elegans</i> through <i>mir-71</i>-mediated inhibition of <i>tir-1</i> mRNA stability in olfactory AWC neurons. Screening a collection of microRNAs that control aging³ we find that miRNA <i>mir-71</i> regulates lifespan and promotes ubiquitin-dependent protein turnover, particularly in the intestine. We show that <i>mir-71</i> directly inhibits the toll receptor domain protein TIR-1 in AWC olfactory neurons and that disruption of <i>mir-71/tir-1</i> or loss of AWC olfactory neurons eliminates the influence of food source on proteostasis. <i>mir-71</i>-mediated regulation of TIR-1 controls chemotactic behavior and is regulated by odor. Thus, odor perception influences cell-type specific miRNA-target interaction to regulate organismal proteostasis and longevity. We anticipate that the proposed mechanism of food perception will stimulate further research on neuroendocrine brain-to-gut communication and may open the possibility for therapeutic interventions to improve proteostasis and organismal health via the sense of smell, with potential implication for obesity, diabetes and aging.