New research finds the longevity protein’s absence shifts tryptophan pathways away from serotonin and melatonin production, impacting sleep and suggesting a new therapeutic target.
Key takeaways:
- The protein Sirtuin 6 (SIRT6) has been identified as a key mechanism behind the dysregulation of tryptophan metabolism in aging brains.
- Its absence leads to a shift toward a neurotoxic pathway, reducing the production of protective neurotransmitters like serotonin and melatonin.
- Reversing the effect by inhibiting the enzyme TDO2 in a fly model points to a potential therapeutic window for neurodegenerative conditions.
Researchers have identified the longevity-associated protein Sirtuin 6 (SIRT6) as a key mechanism behind the age-related dysregulation of tryptophan metabolism, which can negatively affect sleep, mood, and learning.
In aging and neurological disease, the balance of tryptophan catabolism is often lost, leading to adverse effects on sleep behavior. The molecular mechanisms behind this change were previously unknown.
In a study published in Nature Communications, a team led by Debra Toiber at Ben-Gurion University of the Negev demonstrated that a lack of SIRT6 is a precise mechanism behind this loss. Using cellular, Drosophila (fly), and mouse models, they found that SIRT6 actively reprograms gene expression, such as TDO2 and AANAT, shifting the balance toward the production of a neurotoxic kynurenic pathway at the expense of protective neurotransmitters.
The research also indicates that this damage may be reversible. By inhibiting the enzyme TDO2 in a SIRT6 knockout fly model, the team was able to significantly reverse both neuromotor decline and vacuolar formation.
“Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology,” says Toiber in a release.
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