Gabrawy, M.M., Westbrook, R., King, A., Khosravian, N., Ochaney, N., DeCarvalho, T., Wang, Q., Yu, Y., Huang, Q., Said, A., Abadir, M., Zhang, C., Khare, P., Fairman, J.E., Le, A., Milne, G.L., Vonhoff, F.J., Walston, J.D., Abadir, P.M. (2024). Dual treatment with kynurenine pathway inhibitors and NAD[+] precursors synergistically extends life span in Drosophila.  Aging Cell 23(4): e14102.

FBrf0259275

Research paper

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.

PMC11019140 (PMC) (EuropePMC)