Losing the Filter: How Kynurenine Pathway Dysregulation Impairs Habituation.

Habituation is a fundamental form of non-associative learning that allows organisms to filter out repetitive, non-salient stimuli but declines with age. While the kynurenine pathway (KP) of tryptophan metabolism is implicated in psychiatric and neurodegenerative diseases, its role in age-related habituation deficits has been overlooked. This review proposes a systems-level framework suggesting that age-related, chronic inflammation KP dysregulation is a key driver of habituation deficits. We present evidence showing that neurotoxic metabolites from the kynurenine-3-monooxygenase (KMO)-dependent branch drive a self-reinforcing cycle of oxidative stress, excitotoxicity, and glial reactivity that destabilizes the neural circuits required for habituation. This framework redefines KP modulation as context dependent: metabolites such as kynurenic acid (KYNA), which can be disruptive when elevated in youth, may become compensatory under the oxidative load of aging. Our findings that genetic KMO deletion preserves habituation in aged and old mice provide the first direct in vivo evidence supporting this model. We propose that inhibiting the KMO branch preserves habituation not by simply altering metabolite levels but by restoring homeostatic balance across neuroimmune, redox, and plasticity networks. KMO thus emerges as a critical node for maintaining cognitive resilience, offering a therapeutic target for preserving brain function during aging.