How Aging Brains Lose Balance in Tryptophan Metabolism
Scientists from Ben-Gurion University of the Negev have discovered how the enzyme (SIRT6) affects the metabolism of a key substance in the brain (tryptophan) and offer a new direction for treating sleep disorders, mood disorders, and age-related neurodegenerative diseases.
Tryptophan is more than a sleep molecule; its byproducts build proteins, fuel energy (NAD+), and synthesize key neurotransmitters like serotonin and melatonin. Yet, in aging and neurological disease, this balance is lost. Dysregulation of tryptophan catabolism is observed in aging brains and is more pronounced in neurodegenerative and psychiatric disorders, leading to detrimental effects on mood, learning, and sleep behavior. Despite these well-established severe effects, the molecular mechanisms behind the change in tryptophan usage was unknown.
Prof. Debra Toiber and her team at Ben-Gurion University of the Negev have identified a precise mechanism behind this loss: the lack of the longevity-associated protein Sirtuin 6 (SIRT6). They demonstrated across cellular, Drosophila (fly), and mouse models that SIRT6 actively reprograms gene expression (e.g., TDO2, AANAT), tipping the scales towards the production of neurotoxic kynurenic pathway at the expense of protective neurotransmitters.
Their findings were just published in Nature Communications.
Crucially, Prof. Toiber and her team show that this damage is not permanent. By inhibiting the enzyme TDO2 in their SIRT6 knockout fly model, they were able to significantly reverse both neuromotor decline and vacuolar formation, indicating a powerful therapeutic window.
"Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology," says Prof. Toiber.
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).
