Dual treatment with kynurenine pathway inhibitors and <scp>NAD</scp> <sup>+</sup> precursors synergistically extends life span in <i>Drosophila</i>
Mariann M. Gabrawy, Reyhan Westbrook, Austin King, Nick Khosravian, Neeraj Ochaney, Tagide deCarvalho, Qinchuan Wang, Yuqiong Yu, Qiao Huang, Adam Said, Michael Abadir, Cissy Zhang, Pratik Khare, Jennifer E. Fairman, Anne Le, Ginger L. Milne, Fernando Vonhoff, Jeremy Walston, Peter Abadir
Abstract
Abstract 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.