Heterotypic Signals from Neural HSF-1 Separate Thermotolerance from Longevity

Abstract

SUMMARY Integrating stress responses across tissues is essential for 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.

Rethinking HSF1 in Stress, Development, and Organismal Health

“…Likewise, HSF1 has been generally considered to function only in the classical HSR to protect cellular health and tissue physiology. However, accumulating evidence in metazoans have challenged these traditional views and suggest that the HSR is tailored to specific cellular needs and regulated by cell-non-autonomous control through communication between tissues [23–25]. Further, HSF1 directs transcriptional programs in development and metabolism [26, 27] that are distinct from the classical HSR.…”

“…Further, HSF1 directs transcriptional programs in development and metabolism [26, 27] that are distinct from the classical HSR. These non-canonical HSF1 transcriptional programs influence the PN and other cellular functions in aging and disease in addition to the HSR [25, 28]. …”

The stress response paradox: fighting degeneration at the cost of cancer

“…HSF1 also modulates the expression of aldehyde dehydrogenases under times of stress to oxidize harmful aldehydes into less toxic carboxylic acids . Furthermore, HSF1 can also regulate the expression of several antioxidant enzymes through its activation of the forkhead transcription factor, FOXO3A .…”

“…Although chaperones likely play an important role in age regulation and degenerative disease, more recent work suggests that the inducible chaperone network seems dispensable for these processes . HSF1 more likely utilizes less well‐defined transcriptional networks through interactions with the FOXO transcription factor . It is these novel HSF1 targets which possess an alternative and perhaps more exciting mode of treatment for both age‐related degenerative disorders and cancer.…”

Signaling Networks Determining Life Span

“…Precisely, the rate of aging in individual tissues shows synchronization in the distinct transcriptional patterns for neural, vascular, and steroid-responsive tissues, as revealed by the Atlas of Gene Expression in Mouse Aging Project (AGEMAP) (166). The importance of systemic factors in the regulation of aging has been established in invertebrate models of proteostasis (167), as observed in cell nonautonomous regulation of the UPR mt , the UPR ER , and more recently the HSR, all of which require a prolongevity signal to be sent from neuronal to distal tissues in order to activate protective stress-signaling pathways and prolong life span (85,161,168). Similarly, in mammals the secretion of GH, IGF-1, and FGF-21 tightly controls metabolic cues to regulate longevity (see the section on Insulin and Insulin-Like Growth Factor Signaling for details).…”