Exercise training restores longevity-associated tryptophan metabolite 3-hydroxyanthranilic acid levels in middle-aged adults

AIM: Recent pre-clinical evidence suggests that the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) and the related enzyme activity along the kynurenine metabolic pathway (KP) are associated with lifespan extension. We aimed to translate these findings into humans and expose exercise training as a potential non-pharmacological intervention to modulate this metabolic hub. METHODS: To explore whether recent pre-clinical findings might also be of relevance for humans, we analyzed the evolutionary conservation of KYNU and HAAO, the two core KP enzymes associated with 3-HAA. In a cross-sectional analysis of young-to-middle-aged adults (N = 84), we examined potential associations of serum 3-HAA and its precursor anthranilic acid with age. We then investigated whether 26 weeks of endurance exercise (increasing intensity (INC) during the intervention period (n = 17) vs. conventional moderate continuous training (CON) matched for energy expenditure (n = 17)) impacted 3-HAA levels, related metabolic ratios, and other KP metabolites. RESULTS: We demonstrate that the core KP enzymes associated with 3-HAA are evolutionarily conserved in humans. Serum 3-HAA and its precursor anthranilic acid were consistently associated with age in young-to-middle-aged adults. Both exercise modes tested induced an increase in 3-HAA levels of 134% (p < 0.001) and 85% (p < 0.001) compared with baseline, respectively, without a significant time*group interaction effect. CONCLUSION: We translate the association between systemic 3-HAA levels and age from animal models into humans and highlight longer-term exercise training as an efficient strategy to boost systemic 3-HAA levels in middle-aged adults. Our findings open promising research avenues concerning the mediating role of 3-HAA in training adaptations, health, and longevity.