Genes that are involved in stress response mechanisms have been often implicated in regulation of organismal longevity. Increased activity of the transcriptional regulator heat shock factor 1 (HSF-1) and some of its target genes have been shown to extend lifespan in C. elegans. This longevity-promoting role of HSF-1 in non-stressed conditions remains largely unexplored. Inhibition of an evolutionarily conserved negative regulator of HSF-1, termed as heat shock factor binding protein 1 (HSB-1), results in a robust
hsf-1-dependent lifespan extension in worms. These worms are longer lived than almost all known
hsf-1 overexpression models. We report that in the absence of HSB-1 regulation, HSF-1 acquires increased DNA binding activity to an endogenous heat shock element (HSE) and this binding is comparable to that observed in transient heat stress conditions. Interestingly, this induces only a small transcriptional upregulation of heat-shock proteins (hsps) in the
hsb-1 mutant. The lifespan extension and elevated DNA binding activity of HSF-1 in
hsb-1 mutant worms can be rescued by inhibition of a suppressor identified in a genome-wide RNAi screen. However, the increased expression of hsps was found to be genetically separable from the longevity phenotype of the
hsb-1 mutant. Using RNA-Seq comparison, we found that more than 60% of the transcripts that are differentially expressed in the
hsb-1 mutant do not have an altered expression in worms with constitutive
hsf-1 overexpression. We postulate that the increased longevity of
hsb-1 mutant is due to a specific alteration in the HSF-1-regulated transcriptome, which is distinct from that obtained via non-specific activation of HSF-1 transcriptional activity.