3-hydroxyanthranilic acid – a new metabolite for healthy lifespan extension

Abstract

The metabolism of tryptophan to nicotinamide adenine dinucleotide (NAD+) through the kynurenine pathway is increasingly linked to aging and age-associated disease. Kynurenine pathway enzymes and metabolites influence a range of molecular processes critical to healthy aging, including regulation of inflammatory and immune responses, cellular redox homeostasis, and energy production. Aberrant kynurenine metabolism is observed during normal aging and has been implicated in a range of age-associated pathologies, including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. In previous work, we and others identified three genes-kynu-1, tdo-2, and acsd-1-encoding kynurenine pathway enzymes for which decreasing expression extends lifespan in invertebrate models. Here we report that knockdown of haao-1, a fourth kynurenine pathway gene encoding the enzyme 3-hydroxyanthranilic acid dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated decline in health in Caenorhabditis elegans. This lifespan extension is mediated by increased physiological levels of the HAAO substrate 3-hydroxyanthranilic acid (3HAA). 3HAA increases resistance to oxidative stress during aging by directly degrading hydrogen peroxide and activating the Nrf2/SKN-1 oxidative stress response. Aging mice fed a diet supplemented with 3HAA are similarly long-lived. Our results identify HAAO and 3HAA as novel therapeutic targets for age-associated disease. This works provides a foundation for more detailed examination of the molecular mechanisms underlying the benefits of 3HAA, and how these mechanisms interact with other interventions both within and beyond the kynurenine pathway. We anticipate that these findings will bolster growing interest in developing pharmacological strategies to target tryptophan metabolism to improve health aging.

The Emerging Role of 3-Hydroxyanthranilic Acid onC. elegansAging Immune Function

“…The red 3HAA becomes visible under a dissection microscope by 11 days of age, or day 8 of adulthood ( Fig. 1B ) 9 . C. elegans , like mammals, experience a decline in immune function that results in increased susceptibility to pathogenic challenge with age.…”

“…C. elegans with deletion mutations in four genes— kmo-1, kynu-1, haao-1 , and umps-1 —were raised on a live gram-negative E. coli food source (strain HT115, which are mildly pathogenic to C. elegans ) 33 and challenged with the highly pathogenic gram-negative PA14 strain P. aeruginosa at the 4 th larval stage (L4). Deletion of kynu-1 and haao-1 , which encode kynureninase (KYNU) and HAAO, the enzymes are responsible for the synthesis and degradation of 3HAA, respectively and are both long lived on E. coli 9,34 and modestly resistant to PA14 challenge at L4 ( Fig. 1C ).…”

“…[5][6][7][8] We previously found that accumulation of the tryptophan metabolite 3-hydroxyanthranilic acid (3HAA) via supplementation or inhibition of its metabolizing enzyme 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) increases lifespan and extends many aspects of healthy aging in C. elegans and murine models. 9 3HAA and other kynurenine pathway metabolites have been characterized as both proinflammatory and pro-immunogenic as well as anti-inflammatory and immunosuppressive. [10][11][12][13][14][15][16][17][18][19][20][21] A similar conflicting dichotomy is seen in the kynurenine pathway metabolites in regards to being pro-oxidant and antioxidant.…”

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

“…1A ) and this metabolite modifies the redox state of the cell by modulating the redox properties of the environment. Our previous findings demonstrate that haao-1 knockdown induces an increase in 3HAA to up to 10-fold while just moderately decrease NAD+ in worms (Dang et al, 2021).…”

“…Oxenkrug showed that genetic (2010) or pharmacological inhibition (2013) of TDO (encoded by the vermillion gene) extended lifespan in the fruit fly Drosophila melanogaster . Knockdown of haao-1 , the gene encoding HAAO in C. elegans , or two other gene encoding kynurenine pathway enzymes, kynu-1 and tdo-2 , increases in lifespan (Dang et al, 2021; Sutphin et al, 2017; van der Goot et al, 2012). Our initial report on the benefits of haao-1 knockdown in aging suggested the importance of activating the Nrf2/SKN-1 oxidative stress response, but the specific mechanism of how this happens has not been fully elucidated (Dang et al, 2021).…”