Tel Aviv, December 21
Israeli and European scientists have uncovered a previously unknown molecular mechanism that helps explain why aging and neurological disease are so often accompanied by sleep disturbances, mood disorders, and cognitive decline -- and, crucially, how those effects may be reversed.
The study, published in the peer-reviewed journal *Nature Communications*, identified a longevity-linked enzyme as an active metabolic switch in the brain rather than a passive marker of aging.
The research centered on tryptophan, an essential amino acid commonly associated with sleep because it is a precursor to serotonin and melatonin. But researchers say that view is incomplete. Tryptophan also fuels a separate metabolic route that produces cellular energy, and the balance between these pathways is critical for brain health. For years, scientists have observed that this balance becomes disrupted in aging brains and even more severely in neurodegenerative and psychiatric disorders, contributing to impaired mood, learning, and sleep. Until now, the molecular cause of that disruption was unknown.
"This imbalance has been documented repeatedly, but the mechanism behind it remained a mystery," said Prof. Debra Toiber of Ben-Gurion University's Department of Life Sciences, who led the research.
Using human cell lines alongside mouse and fruit fly models, Toiber's team identified the enzyme sirtuin 6, or SIRT6, as the central regulator. SIRT6 is known for its role in longevity, but the study shows it also functions as a gatekeeper of tryptophan metabolism. When SIRT6 activity is intact, tryptophan is properly distributed between pathways that generate energy and those that produce serotonin and melatonin, neurotransmitters that protect the brain and regulate mood and sleep.
When SIRT6 activity declines -- a hallmark of aging -- that balance shifts dramatically. Tryptophan is diverted toward the kynurenine pathway, which supports energy production but also generates byproducts the researchers found to be toxic to nerve cells. At the same time, production of serotonin and melatonin drops, depriving the brain of compounds essential for neural stability.
"This is not just a gradual decline," Toiber said. "It is an active metabolic rerouting that damages the nervous system."
The scientists also demonstrated that the damage is not inevitable. In fruit fly models lacking SIRT6, the team inhibited a second enzyme, TDO2, which plays a key role in pushing tryptophan into the kynurenine pathway. Blocking TDO2 significantly prevented neuromotor deterioration and reduced pathological changes in brain tissue, pointing to a clear therapeutic opportunity.
"Our research positions the enzyme SIRT6 as a critical and primary drug target to combat degenerative brain pathology," Toiber said. "These findings change the way we understand the relationship between aging and brain function. It is not simply wear and tear, but a specific metabolic malfunction that can be corrected."
She added that the results open the door to the development of drugs that inhibit TDO2 or interventions, including nutritional strategies, that restore balance between tryptophan pathways. Rather than managing symptoms of sleep disorders, depression, or neurodegeneration, future therapies could aim to correct the underlying metabolic imbalance in tryptophan utilization. Compounds that enhance SIRT6 activity or selectively inhibit TDO2 could reduce the buildup of neurotoxic metabolites while restoring the production of serotonin and melatonin.
The study also raises the possibility of repurposing existing compounds. TDO2 has already been investigated in other fields, including cancer and immunology, meaning that experimental inhibitors and partial safety data may already exist. Redirecting or refining such compounds for neurological indications could significantly shorten development timelines compared to entirely new drugs.
Beyond treatment, the work suggests a path toward earlier diagnosis. Alterations in tryptophan metabolites or reduced SIRT6 activity could serve as biomarkers detectable in blood or cerebrospinal fluid, allowing clinicians to identify individuals at risk of cognitive decline, mood disorders, or sleep disturbances before symptoms become severe. Such biomarkers could also be used to more precisely monitor disease progression or response to therapy.
The international collaboration included researchers from Ben-Gurion University of the Negev, KU Leuven's VIB Center for Cancer Biology in Belgium, the Skolkovo Institute of Science and Technology in Russia, and the University of South Bohemia in the Czech Republic.
- ANI
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