The insulin/IGF-1-like signaling pathway (IIS) is known to have a conserved role in aging. IIS negatively regulates the activity of the FOXO transcription factor DAF-16 and the expression of its downstream target genes. In particular, DAF-16 activity in the intestinal cells is required for the lifespan extension of the IIS pathway mutants. The heat shock transcription factor HSF-1 appears to regulate lifespan and stress resistance as well in C. elegans. Previous studies have shown that hsf-1 overexpression extends lifespan, while knock down of HSF-1 by RNAi shortens lifespan. HSF-1, like DAF-16, is required for the IIS pathway mutations to extend lifespan. Moreover, HSF-1 and DAF-16 might act together to activate the expression of a specific subset of genes to promote longevity. Interestingly, previous studies indicated that neural overexpression of hsf-1 is sufficient to promote longevity and it requires the activity of intestinal daf-16. However, how might neuronal HSF-1 communicate with intestinal DAF-16 remains unknown. The aim of our studies is to further dissect the molecular mechanism underlying this inter-tissue communications between neurons and intestine. First, we confirmed that intestinal DAF-16 translocates to nuclear and is activated in response to neural HSF-1 over-expression. The release of neurotransmitters and/or neuropeptides, via synaptic (SVs) and/or dense-core vesicles (DCVs) respectively, constitutes the primary mechanisms for the communication between neighboring or distant cells and organs in response to stimuli. We found that the nuclear localization of DAF-16 is significantly suppressed when several genes involved in DCV trafficking is inhibited by RNAi. Thus, a neuropeptidergic regulation of intestinal DAF-16 may be involved in the longevity phenotypes of HSF-1 OE animals.