Inhibition of haao-1 enhances oxidative stress response by activating hormetic redox signaling in C. elegans.

3-hydroxyanthranilate 3,4-dioxygenase (HAAO) is an intermediate enzyme in the conversion from tryptophan (TRP) to nicotinamide adenine dinucleotide (NAD+) via the kynurenine pathway. The kynurenine pathway is the sole de novo NAD+ biosynthetic pathway from ingested tryptophan. Inhibition of several enzymatic steps in the kynurenine pathway increases lifespan in Drosophila melanogaster, Saccharomyces cerevisiae, and Caenorhabditis elegans. Knockout or knockdown of haao-1, the C. elegans gene encoding HAAO, or supplementation of its substrate metabolite 3-hydroxyanthranilic acid (3HAA), has been shown to promote healthy lifespan extension; however, the underlying mechanism remains unknown. In the present study, we report that haao-1 knockdown induces oxidative stress resistance against several reactive oxygen species (ROS) inducing agents by activating the Nrf2/SKN-1 oxidative stress response pathway. An examination of the redox state of animals with reduced haao-1 suggests that activation of the Nrf2/SKN-1 pathway is mediated by shifting the balance toward generation of ROS, generating a hormetic effect. Our results identify a novel mechanism for an endogenous metabolite (3HAA) that activates the oxidative stress response. These results provide a conceptual basis by which modulation of the kynurenine pathway can promote healthy aging and enhanced stress resistance. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/528568v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@1563682org.highwire.dtl.DTLVardef@114917dorg.highwire.dtl.DTLVardef@15bc7f2org.highwire.dtl.DTLVardef@a42023_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIKnockdown of haao-1 promotes oxidative stress resistance. C_LIO_LIKnockdown of haao-1 activates the Nrf2/SKN-1 oxidative stress response. C_LIO_LIThe shift in redox balance in haao-1 knockout animals suggests a hormetic mechanism for oxidative stress resistance. C_LI