Exercise-driven changes in tryptophan metabolism leading to healthy aging

Tryptophan metabolism is a critical regulator of physiological and pathological processes, primarily through the kynurenine (KYN), serotonin and indole pathways. Dysregulation of indoleamine 2,3-dioxygenase 1 (IDO1) activity, serotonin and indole gut-microbial metabolism has been linked to a broad range of age-related chronic conditions, including cancer, cardiovascular disease, sarcopenia, and neurodegenerative disorders. Exercise emerges as a potent modulator of these pathways, redirecting tryptophan utilization to limit the accumulation of KYN metabolites while maintaining balanced indole and serotonin production. By regulating IDO1 activity and KYN flux, exercise alleviates inflammation, restores metabolic homeostasis, improved muscle integrity, neuroprotection, and overall systemic health. Mounting evidence supports the notion that lifestyle-based interventions targeting IDO1 and its downstream metabolites, particularly by physical activity, may offer a promising avenue for extending health span and mitigating the burden of chronic disease. This review synthesizes current advances in understanding the regulation of tryptophan metabolism (KYN, Serotonin and Indole) and highlights the unique capacity of exercise to remodel these pathways, underscoring their therapeutic potential in the context of healthy aging.