Researchers at Ben-Gurion University have identified the protein SIRT6 as a key regulator of tryptophan metabolism in the brain, explaining how its loss leads to toxic byproducts in aging and diseased brains. The study reveals that declining SIRT6 shifts tryptophan toward harmful pathways, reducing protective neurotransmitters like serotonin and melatonin. Blocking a related enzyme showed potential for reversing brain damage in models.
Tryptophan, an amino acid known for aiding sleep, plays a broader role in brain health by supporting protein synthesis, cellular energy via NAD+, and production of mood-regulating chemicals such as serotonin and melatonin. These functions promote stable mood, learning, and restful sleep. However, in aging brains or those affected by neurological disorders, tryptophan's processing disrupts, favoring the production of neurotoxic compounds over beneficial ones. This imbalance correlates with memory decline, mood instability, and sleep disturbances.
A team led by Prof. Debra Toiber at Ben-Gurion University of the Negev pinpointed SIRT6, a longevity-associated protein, as the central controller of this metabolic shift. Through experiments on cells, fruit flies (Drosophila), and mice, they demonstrated that reduced SIRT6 levels impair gene expression for enzymes like TDO2 and AANAT. Consequently, tryptophan diverts to the kynurenine pathway, generating toxins while diminishing serotonin and melatonin synthesis.
The findings, published in Nature Communications on January 15, 2026 (volume 17, issue 1; DOI: 10.1038/s41467-025-67021-y), highlight a reversible aspect. In flies lacking SIRT6, inhibiting TDO2 improved locomotion and decreased vacuole formation—indicators of neural damage—suggesting therapeutic opportunities.
"Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology," Prof. Toiber stated. The study involved collaborators including Shai Kaluski-Kopatch, Daniel Stein, and Sarah-Maria Fendt, with funding from the European Research Council (grant 849029), the David and Inez Myers Foundation, and Israel's Ministry of Science and Technology.
This discovery offers insights into conditions like Huntington's disease and psychiatric disorders, where tryptophan dysregulation is prominent, potentially guiding interventions to restore brain chemistry balance.
