Targeting Kynurenine Metabolism to Extend Lifespan

Overview

The first molecular process identified in our comparative genetics pipeline was the kynurenine pathway.  The kynurenine pathway is the primary metabolic destination for ingested tryptophan and has been linked to multiple age-related pathologies, including neurodegeneration, kidney disease, and cardiovascular disease. In C. elegans, inhibiting multiple kynurenine pathway enzymes extends lifespan and improves healthspan. In ongoing work, we are using C. elegans to determine which of several kynurenine-associated molecular processes—oxidative stress, proteostasis, neuroreceptors regulation, NAD synthesis—mediates the observed effect on lifespan. We are also validating our C. elegans observations in mice by manipulating kynurenine enzymes and measuring lifespan and other age-associated phenotypes. We are particularly interested in the efficacy of kynurenine-based interventions at specifically treating cardiovascular, renal, and neurodegenerative disease.