Shai Kaluski-Kopatch, Daniel Stein, Alfredo García-Venzor, Ana Margarida Ferreira Campos, Mélanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Ekaterina Eremenko, Miguel Portillo, Monica Einav, Alena Krejčı́, Uri Abdu, Ekaterina E. Khrameeva, Daniel Gitler, Sarah‐Maria Fendt, Debra Toiber
), and neurotransmitters (serotonin and melatonin). Impaired tryptophan catabolism, seen in aging, neurodegeneration and psychiatric diseases, affects mood, learning, and sleep; however, the reasons for those impairments in the elderly and in those suffering from these ailments remain unknown. Our results from cellular, Drosophila melanogaster, and mouse models indicate that Sirtuin 6 (SIRT6) regulates tryptophan catabolism by balancing its usage. Mechanistically, SIRT6 regulates tryptophan and sleep quality through changes in gene expression of key genes (e.g., TDO2, AANAT), which results in elevated concentration of neurotoxic metabolites from the kynurenic pathway at the expense of serotonin and melatonin production. Such neurotoxic metabolites can affect various processes in the brain. However, by redirecting tryptophan through TDO2 inhibition in a SIRT6 knockout D. melanogaster model, the impairments in neuromotor behavior and vacuolar formation - parameters of neurodegeneration - can be significantly reversed.