3-Hydroxyanthranilic Acid Intestinal Localization and Immune Function in Caenorhabditis elegans

Abstract

Aging is experienced by most eukaryotic organisms and age is the primary risk factor for many of the most common causes of death in humans. Age-related diseases not only increase risk of death in older adults, but significantly reduce their quality of life. Aging research is focused on understanding the molecular processes that drive age-associated decline with the goal of both extending lifespan and improving overall health. Recently, the kynurenine pathway, the primary tryptophan metabolic pathway, has proven to be a potential target for increasing both lifespan and healthspan. The kynurenine metabolite 3-hydroxyanthranilic acid (3HAA) has been shown to extend lifespan in C. elegans and in mice. Additionally, 3HAA exhibits antibiotic effects in liquid E. coli culture and increases pathogen resistance in worms. 3HAA co-localizes with bacteria in lysosome-related organelles (LROs) called gut granules in the worm intestine, providing a physical location at which 3HAA may directly inhibit bacterial growth in vivo. Gut granules have several biological roles, including the sequestration and storage of intracellular zinc. While 3HAA clearly accumulates in gut granules, the 3HAA trafficking mechanisms have yet to be determined. Through this work I aim to determine the molecular processes that transport 3HAA to the gut granule as well as characterize the immune function of 3HAA and stored zinc within the worm gut granule. I found that 3HAA is likely using vesicular transport to travel to LROs. Additionally, the combination of zinc and 3HAA treatment in E. coli liquid culture increases 3HAA’s existing antibiotic effect.