Tryptophan is widely known for its role in sleep, but its role in the body goes much further. Compounds derived from tryptophan help build proteins, generate cellular energy (NAD+), and produce essential brain chemicals such as serotonin and melatonin. Together, these processes support mood, learning, and healthy sleep patterns.
As the brain ages or as neurological disease develops, this system can begin to malfunction. Scientists have repeatedly observed disruptions in how tryptophan is processed in aging brains, with even stronger effects in neurodegenerative and psychiatric disorders. These shifts are associated with worsening mood, impaired learning, and disturbed sleep. Until recently, however, it was unclear what triggers the brain to change how it uses tryptophan in the first place.
SIRT6 Identified as a Key Regulator
Professor Debra Toiber and her team at Ben-Gurion University of the Negev report evidence pointing to the loss of a longevity-related protein, Sirtuin 6 (SIRT6), as a major driver of this metabolic imbalance.
In experiments using cells, fruit flies (Drosophila), and mouse models, the researchers found that SIRT6 helps regulate gene activity involved in tryptophan metabolism, including genes such as TDO2 and AANAT. When SIRT6 levels drop, this regulation weakens. Tryptophan is then pushed toward the kynurenine pathway, which produces compounds linked to neurotoxicity, while the production of protective neurotransmitters such as serotonin and melatonin declines.
Findings Suggest the Damage May Be Reversible
The results were published in Nature Communications.
The researchers also reported signs that the harmful shift is not necessarily permanent. In a fly model lacking SIRT6, blocking the enzyme TDO2 significantly improved movement problems and reduced the formation of vacuoles—structures associated with brain tissue damage. The findings suggest there may be a window for therapeutic intervention.
“Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology,” Toiber said.
Team and Funding
Additional researchers involved in the study included Shai Kaluski-Kopatch, Daniel Stein, Alfredo Garcia Venzor, Ana Margarida Ferreira Campos, Melanie Planque, Bareket Goldstein, Estefanía De Allende-Becerra, Dmitrii Smirnov, Adam Zaretsky, 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 under the European Union’s Horizon 2020 program, the David and Inez Myers Foundation, the Israeli Ministry of Science and Technology, fellowships from the Kreitman School of Advanced Research at Ben-Gurion University, and the Israel Science Foundation. RNA-seq data analysis was supported by the Russian Science Foundation.
