The Emerging Role of 3-Hydroxyanthranilic Acid in Caenorhabditis elegans Aging Immune Function

Abstract

The kynurenine pathway is responsible for a majority of tryptophan metabolism. It has been intricately linked to both aging and immune function, yet its exact roles in the two processes has not been fully characterized. The only well-established regulation of the kynurenine pathway is the control of flux via activity of indoleamine 2,3-dioxygenase (IDO). We have chosen C. elegans and M. musculus to establish how some kynurenine pathway components impact aging and immune function and how these components are regulated. We found that accumulation of the kynurenine pathway intermediate metabolite 3-hydroxyanthranilic acid (3HAA) through supplementation or inhibition of the catabolizing enzyme 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) increases lifespan and several aspects of health. We also found that these kynurenine pathway interventions improve pathogen response and decrease infection progression. The kynurenine pathway is normally upregulated during pathogen response in C. elegans but we found that 3HAA may be regulated via tissue separation of synthesis by kynureninase (KYNU) in the hypodermal tissue and degradation by HAAO in the neuronal tissue. The special temporal separation of synthesis and degradation of 3HAA allow for intermediate function of the metabolite not previously characterized. Ultimately, 3HAA’s impact on immune function may be due to antimicrobial activity and localization to the interface between host and pathogen in the gut granules. The special temporal regulation of 3HAA combined with the immune enhancement may, in part, explain the life extending properties of supplementation and HAAO inhibition. This may also provide further insight into the overall role of these kynurenine pathway components in aging and immune function.