Recent findings from Ben-Gurion University of the Negev suggest a single protein, SIRT6, holds the key to understanding how brain chemistry shifts from beneficial to harmful during aging. This discovery, published in Nature Communications, offers a new perspective on neurodegenerative processes and potential therapeutic targets.
Tryptophan, an essential amino acid, is widely recognized for its connection to sleep, yet its importance extends far beyond this singular function. It serves as a crucial building block for proteins and generates cellular energy (NAD+).
Furthermore, tryptophan is vital for creating essential brain chemicals like serotonin and melatonin. These compounds collectively support mood stability, cognitive functions such as learning, and healthy sleep patterns, underpinning overall brain health.
However, as the brain ages or develops neurological diseases, this intricate metabolic system often begins to break down. Scientists have consistently observed significant disruptions in how tryptophan is processed in aging brains, with even more pronounced effects noted in neurodegenerative and psychiatric disorders.
These metabolic shifts are directly linked to worsening mood, impaired learning abilities, and disturbed sleep patterns, significantly impacting an individual’s quality of life. Until now, researchers grappled with identifying the fundamental cause that triggers the brain to alter its use of tryptophan, leading to these detrimental outcomes.
Pinpointing this initial trigger was a critical missing piece in understanding and potentially treating age-related cognitive decline and various neurodegenerative diseases, making the recent findings particularly significant.
SIRT6 protein: the missing link in brain health
Professor Debra Toiber and her research team at Ben-Gurion University of the Negev have now uncovered a clear biological explanation. Their groundbreaking work points to the loss of Sirtuin 6 (SIRT6), a longevity-related protein, as the primary driving factor behind this metabolic imbalance.
Through meticulous experiments conducted in cell cultures, Drosophila (fruit fly) models, and mouse models, the researchers robustly demonstrated that SIRT6 plays an active and crucial role in controlling gene expression. Specifically, it targets genes like TDO2 and AANAT, which are key players in tryptophan metabolism.
When SIRT6 levels decline, this vital regulatory control is compromised. As a direct consequence, tryptophan’s metabolic pathway is rerouted towards the kynurenic pathway, which leads to the unfortunate production of neurotoxic compounds harmful to brain cells.
Simultaneously, the synthesis of protective neurotransmitters, such as serotonin and melatonin, essential for mood and sleep, significantly declines. This dual impact exacerbates brain vulnerability and accelerates neurodegenerative processes, creating a detrimental cascade.
This critical insight into SIRT6’s regulatory function and its impact on tryptophan metabolism was recently detailed in their study, titled “Histone deacetylase SIRT6 regulates tryptophan catabolism and prevents metabolite imbalance associated with neurodegeneration,” published in Nature Communications.
The significance of these findings was further highlighted by ScienceDaily on January 15, 2026, marking a pivotal moment in understanding the mechanisms of brain aging and neurodegeneration.
Reversing the damage: a window for intervention
Crucially, the Ben-Gurion University researchers also provided encouraging evidence that the damage caused by this metabolic shift may not be permanent. In a SIRT6 knockout fly model, where the protein was absent, scientists observed significant improvements when they blocked the enzyme TDO2.
This targeted intervention led to a remarkable reduction in movement problems, a common symptom of neurodegeneration, and a decrease in the formation of vacuoles. These vacuoles are tell-tale signs of brain tissue damage and degeneration, indicating a potential reversal of pathology.
These highly promising results suggest a meaningful and potentially broad window for therapeutic intervention. Professor Toiber confidently states, “Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology.”
This profound discovery opens entirely new avenues for developing innovative treatments that could potentially reverse or significantly prevent the cognitive decline and neurological damage associated with both natural aging and specific neurodegenerative diseases.
The implications are substantial for millions worldwide grappling with conditions like Alzheimer’s and Parkinson’s. By understanding how SIRT6 precisely influences tryptophan metabolism, researchers now have a clearer, more targeted path toward mitigating the neurotoxic effects observed in aging brains.
Future investigations will undoubtedly focus on developing specific therapies aimed at either restoring optimal SIRT6 levels or carefully modulating the kynurenic pathway. This offers renewed hope for enhanced brain health, improved cognitive function, and ultimately, greater longevity for an aging global population.
