Heterotypic Signals from Neural HSF-1 Separate Thermotolerance from Longevity

Integrating stress responses across tissues is essential for the survival of multicellular organisms. The metazoan nervous system can sense protein-misfolding stress arising in different subcellular compartments and initiate cytoprotective transcriptional responses in the periphery. Several subcellular compartments possess a homotypic signal whereby the respective compartment relies on a single signaling mechanism to convey information within the affected cell to the same stress-responsive pathway in peripheral tissues. In contrast, we find that the heat shock transcription factor, HSF-1, specifies its mode of transcellular protection via two distinct signaling pathways. Upon thermal stress, neural HSF-1 primes peripheral tissues through the thermosensory neural circuit to mount a heat shock response. Independent of this thermosensory circuit, neural HSF-1 activates the FOXO transcription factor, DAF-16, in the periphery and prolongs lifespan. Thus a single transcription factor can coordinate different stress response pathways to specify its mode of protection against changing environmental conditions. [Display omitted] •HSF-1 in the nervous system increases longevity and thermotolerance in C. elegans•Heat protection by neural HSF-1 uses the thermosensory neural circuit, but not DAF-16•Age determination by neural HSF-1 requires the FOXO, DAF-16, in the intestine•Distinct signals by neural HSF-1 separate age regulation from thermal protection The heat shock transcription factor, HSF-1, regulates lifespan and stress resistance in C. elegans. Douglas et al. find that HSF-1 acts in neurons to emit divergent signals that independently regulate aging and thermotolerance. Thus, a single transcription factor can act within different neurons to modulate distinct protective responses in peripheral tissues.