Tryptophan Metabolism: Linking Aging and Cognitive Health

Loss of SIRT6 reroutes tryptophan metabolism and may drive age-related cognitive decline.

Clinically, this metabolic shift reduces serotonin and melatonin synthesis while increasing kynurenine-derived neurotoxins, with downstream effects on mood, memory, and sleep. The pathway is mechanistically targetable, framing clear translational opportunities to mitigate age-associated cognitive deterioration.

This finding sharpens clinical thinking about metabolic drivers of cognitive aging by identifying a discrete regulatory node rather than a nonspecific decline in metabolic resilience. Clinicians scanning the literature should prioritize pathway-specific flux—rather than global tryptophan levels—when interpreting emerging biomarkers and potential interventions.

Tryptophan is metabolized along two principal branches: conversion to serotonin and melatonin, which support mood and sleep, versus diversion down the kynurenine pathway, which produces neuroactive and often neurotoxic metabolites. When flux shifts toward kynurenine products, microglial activation and excitotoxic mediators increase, promoting neuroinflammation as well as mood, sleep, and memory disturbances in older adults. An imbalance favoring kynurenine metabolites thus provides a plausible mechanistic link to common age-related cognitive and affective phenotypes.

SIRT6 acts as a chromatin-associated regulator that controls genes involved in tryptophan catabolism. In cell, Drosophila, and mouse models, investigators reduced or deleted SIRT6 and measured transcriptional changes, metabolite profiles, and behavioral or movement readouts across systems; results were directionally consistent across these preclinical models. Blockade of the downstream enzyme TDO2 reversed key metabolic changes, supporting a mechanistic role for SIRT6 in maintaining protective tryptophan processing.

In SIRT6-deficient experimental systems, inhibition of the rate-limiting enzyme TDO2 restored a more protective metabolic profile. Kynurenine-derived neurotoxin concentrations fell and behavioral or movement measures improved, with reductions in neuropathological markers such as vacuole formation.

These translational experiments show that enzyme-targeted intervention can reverse key pathological features in preclinical systems and highlight the pathway as a candidate for further therapeutic development.

Key Takeaways:

• SIRT6 loss diverts tryptophan toward neurotoxic kynurenine products, linking metabolic imbalance to cognitive, mood, and sleep dysfunction.
• Preclinical TDO2 inhibition reduced neurotoxin production and improved functional readouts in SIRT6-deficient models.
• Pathway-level biomarkers and enzyme-targeted strategies merit attention as potential translational avenues for age-related cognitive decline.