Inhibition ofhaao-1enhances oxidative stress response by activating hormetic redox signaling inC. elegans

Abstract

Abstract3-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 inDrosophila melanogaster, Saccharomyces cerevisiae, andCaenorhabditis elegans. Knockout or knockdown ofhaao-1, theC. elegansgene 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 thathaao-1knockdown 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 reducedhaao-1suggests 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 AbstractHighlightsKnockdown ofhaao-1promotes oxidative stress resistance.Knockdown ofhaao-1activates the Nrf2/SKN-1 oxidative stress response.The shift in redox balance inhaao-1knockout animals suggests a hormetic mechanism for oxidative stress resistance.