Dual treatment with kynurenine pathway inhibitors and NAD⁺ precursors synergistically extends life span in Drosophila

Tryptophan catabolism is highly conserved and generates important bioactive metabolites, including kynurenines, and in some animals, NAD(+). Aging and inflammation are associated with increased levels of kynurenine pathway (KP) metabolites and depleted NAD(+), factors which are implicated as contributors to frailty and morbidity. Contrastingly, KP suppression and NAD(+) supplementation are associated with increased life span in some animals. Here, we used DGRP_229 Drosophila to elucidate the effects of KP elevation, KP suppression, and NAD(+) supplementation on physical performance and survivorship. Flies were chronically fed kynurenines, KP inhibitors, NAD(+) precursors, or a combination of KP inhibitors with NAD(+) precursors. Flies with elevated kynurenines had reduced climbing speed, endurance, and life span. Treatment with a combination of KP inhibitors and NAD(+) precursors preserved physical function and synergistically increased maximum life span. We conclude that KP flux can regulate health span and life span in Drosophila and that targeting KP and NAD(+) metabolism can synergistically increase life span.