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Tryptophan is widely known for its connection to sleep, but its importance goes much further. The compounds produced from tryptophan help build proteins, generate cellular energy (NAD+), and create essential brain chemicals such as serotonin and melatonin. Together, these processes support mood, learning, and healthy sleep patterns.
As the brain ages or develops neurological disease, this system begins to break down. Scientists have repeatedly observed disruptions in how tryptophan is processed in aging brains, with even stronger effects seen in neurodegenerative and psychiatric disorders. These changes are linked to worsening mood, impaired learning, and disturbed sleep. Until now, however, researchers did not know what caused the brain to shift how it uses tryptophan in the first place.
SIRT6 Identified as a Key Regulator of Brain Chemistry
Prof. Debra Toiber and her research team at Ben-Gurion University of the Negev have now uncovered a clear biological explanation. Their work points to the loss of a longevity-related protein called Sirtuin 6 (SIRT6) as the driving factor behind this metabolic imbalance.
Using experiments in cells, Drosophila (fly), and mouse models, the researchers showed that SIRT6 plays an active role in controlling gene expression (e.g., TDO2, AANAT). When SIRT6 levels drop, this control is lost. As a result, tryptophan is redirected toward the kynurenic pathway, which produces neurotoxic compounds, while the production of protective neurotransmitters such as serotonin and melatonin declines.
Published Evidence and a Reversible Effect
The findings were recently published in Nature Communications.
Importantly, the researchers also found that the damage caused by this shift is not permanent. In a SIRT6 knockout fly model, blocking the enzyme TDO2 led to a significant improvement in movement problems and reduced the formation of vacuoles, which are signs of brain tissue damage. These results suggest that there may be a meaningful window for therapeutic intervention.
“Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology,” says Prof. Toiber.
Research Team and Funding Support
Additional researchers include: Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, Dr Ekaterina Eremenko — Sgibnev, Miguel Portillo, Monica Einav, Alena Bruce Krejci, Uri Abdu, Ekaterina Khrameeva, Daniel Gitler, and Sarah-Maria Fendt.
The study was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 849029), the David and Inez Myers foundation, the Israeli Ministry of Science and Technology (MOST), the High-tech, Bio-tech and Negev fellowships of Kreitman School of Advanced Research of Ben-Gurion University and The Israel Science Foundation (Grant no. 422/23). The RNA-seq data analysis was supported by the Russian Science Foundation (grant number 25-71-20017).
