SYSTEMIC ELEVATION OF 3-HYDROXYANTHRANILIC ACID (3HAA) TO EXTEND LIFESPAN AND DELAY ALZHEIMER’S PATHOLOGY

Abstract

Dysregulation of the kynurenine pathway, the major route for tryptophan metabolism, is linked to a wide range of age-associated pathologies in humans. Interventions targeting different aspects of kynurenine metabolism are being pursued for several diseases of aging, including Alzheimer’s disease. We have identified the metabolite 3-hydroxyanthranilic acid (3HAA) as a particularly promising molecular target. In Caenorhabditis elegans, elevating 3HAA through either direct supplementation or inhibition of 3HAA dioxygenase (HAAO), the primary enzyme that degrades 3HAA, robustly increases lifespan and improves health with age. In mice, short-term treatment with 3HAA is protective in acute models of atherosclerosis, spinal cord injury, and autoimmune encephalomyelitis. Preliminary evidence suggests that the beneficial effects of 3HAA are mediated by reduced oxidative stress and improved protein homeostasis with age. We are now testing the hypothesis that chronic 3HAA elevation in mice will extend lifespan and delay functional decline with age. We are further assessing 3HAA via HAAO inhibition as a therapeutic strategy for Alzheimer’s disease. 3HAA is predicted to directly bind amyloid-beta (Aβ) and prevents aggregation in vitro. 3HAA supplementation or HAAO inhibition delays paralysis in a C. elegans Alzheimer’s disease model expressing amyloid-beta in body-wall muscle. Elevating 3HAA by inhibition HAAO has the further benefit of limiting production of the downstream metabolite quinolinic acid (QA). QA is a proposed mediator of tau hyperphosphorylation in response to neuroinflammation, an early step in the formation of neurofibrillary tangles (NFTs). HAAO inhibition can potentially limit formation of both Aβ plaques and NFTs, two hallmark pathologies in Alzheimer’s disease.