Ergothioneine and exercise: A match made in (cognitive) heaven?

Cognitive decline is one of the key challenges with aging, with significant implications for independence, quality of life, and healthcare burden. As pharmacological treatments remain limited in efficacy and often carry adverse effects, there is growing interest in safe, accessible, non-pharmacological strategies to preserve cognitive function. This Short Review explores the potential of combining two approaches that, individually, have shown beneficial effects on cognitive function: ergothioneine, a naturally occurring amino acid with antioxidant and anti-inflammatory properties, and physical exercise. Ergothioneine accumulates in the brain and other high-stress organs, where it modulates the redox balance, dampens chronic inflammation and supports mitochondrial function. Meanwhile, physical exercise has well-documented benefits for neuroplasticity, cerebral perfusion, and cognitive performance. Preclinical studies suggest ergothioneine supports exercise performance and muscle recovery without attenuating adaptive responses. Despite their distinct and complementary mechanisms, currently there are no available studies exploring the combined effects of ergothioneine and exercise on cognition. We propose a future research agenda that includes mechanistic animal studies, dose-response trials, and clinical interventions in at-risk populations. Together, the combination of ergothioneine and exercise may offer a low-risk, multifaceted approach to enhancing cognitive resilience in aging.