3-HYDROXYANTHRANILIC ACID—A NOVEL MOLECULAR TARGET FOR LIFESPAN EXTENSION IN THE KYNURENINE PATHWAY

• Published in: Innovation in aging 2017-07, Vol.1 (suppl_1), p.857-857
• Main Authors: Sutphin, G.L., Korstanje, R.
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 2399-5300; 2399-5300
• DOI: 10.1093/geroni/igx004.3085

Identifying novel genetic factors that can be targeted to beneficially influence longevity, healthspan, and age-associated disease is an ongoing area of focus in aging science. In a recent study, we selected 82 Caenorhabditis elegans genes based on orthology to 125 human genes differentially expressed with age and conducted an RNAi lifespan screen. The clear outlier was kynu-1 , encoding the kynurenine pathway enzyme kynureninase. RNAi knockdown of kynu-1 extended lifespan by >20%. Kynurenine pathway gene expression and metabolite abundance is perturbed in individuals with a number of age-associated diseases, including neurodegenerative disease. Many intermediate kynurenine pathway metabolites have neuroactive or antioxidant properties, and pharmacological interventions targeting kynurenine pathway enzymes are being pursued for Huntington’s disease in particular. In an expanded survey of the kynurenine pathway, we identified two additional genes for which knockdown results in a similar degree of lifespan extension to kynu-1(RNAi) — haao-1 and tdo-2 . Knockdown of kynu-1 , haao-1 , or tdo-2 extended healthspan and delayed pathology in C. elegans models of Alzheimer’s and Huntington’s disease. Knockdown of haao-1 alone achieved these benefits without impairing reproduction or development. HAAO-1 encodes the enzyme 3-hydroxyanthraniate 3,4-dioxygenase, which converts the metabolite 3-Hydroxyanthranilic Acid (3HAA) into 2-amino-3-carboxymuconate semialdehyde. Worms lacking haao-1 have highly elevated 3HAA, which is thought to have both direct and indirect antioxidant properties. In ongoing work, we find that treatment of worms with 3HAA phenocopies reduced haao-1 in the context of aging and neurodegenerative pathology in C. elegans , suggesting that it may represent a potent metabolic target for treating age-associated cognitive disease.