SIRT6 Protein's Role in Tryptophan Metabolism May Open New Path to Treating Neurodegeneration

A single protein's absence may hold the key to why aging brains turn vital chemistry toxic and how to reverse the damage.

Tryptophan, an essential amino acid, supports brain chemistry, energy production, and neurotransmitter synthesis. However, in aging or neurological disease, its metabolism shifts toward harmful byproducts.

SIRT6—a longevity-related protein—regulates this process by controlling gene expression for enzymes like TDO2 and AANAT. When SIRT6 levels decline, tryptophan metabolism redirects toward the kynurenic pathway, producing neurotoxic metabolites linked to cognitive decline.

Experiments in cell cultures, fruit flies, and mice demonstrated this mechanism. In SIRT6-deficient flies, blocking TDO2 reversed movement impairments and brain tissue damage.

Mice studies showed similar protective effects when TDO2 inhibition was applied. These findings suggest a potential therapeutic strategy to mitigate neurodegeneration by targeting this metabolic shift.

Prof. Debra Toiber said:

"Our research positions SIRT6 as a critical, upstream drug target for combating neurodegenerative pathology."

The study, published in Nature Communications, was supported by the EU Horizon 2020 program, the Israeli Ministry of Science, and other grants. Researchers emphasized that while the results are promising, the study’s scope is limited to animal models.

Human clinical trials are needed to confirm relevance to human health. Experts caution that more research is required before clinical applications can be developed.

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