The Therapeutic Potential for HAAO Inhibition in Aging and Disease

Abstract

The kynurenine pathway is the major metabolic route for tryptophan and has been of increasing interest to many fields of clinical science, including as a potential therapeutic target for the neuronal, cardiovascular, hepatic, renal, and immune systems. The pathway's activity increases with age and is dysregulated in various age-associated diseases. The kynurenine pathway enzyme 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) is a promising therapeutic target for diseases that would benefit from increased physiological concentrations of 3-hydroxyanthranilic acid (3HAA), the metabolite degraded by HAAO, or the inhibition of downstream metabolites. 3HAA is an anti-inflammatory molecule surrounded by a number of inflammatory proteins both up and downstream. Many inflammatory-related diseases exasperated by age, including cardiovascular, liver, and kidney disease, could benefit from an influx of 3HAA. HAAO catalyzes the conversion of 3HAA to quinolinic acid (QA), a neurotoxin found in excess levels in various diseases from liver disease to epilepsy. Inhibition of HAAO hinders QA and other downstream metabolites. The kynurenine pathway is also called the de novo synthesis pathway and is the sole producer of newly synthesized nicotinamide adenine dinucleotide (NAD) in cells. While the salvage and Preiss-Handler pathway recycle NAD and remain active after HAAO inhibition, supplementation of NAD may have synergistic effects. This review highlights the benefits of 3HAA other upstream metabolites from the kynurenine pathway and suggests that HAAO inhibition may have broad pharmacological benefits for aging and disease.