Effects of a three-month exercise programme on cognition, mood and neurogenesis: the NeuroFit randomised controlled trial

Middle age represents a critical window for mental and cognitive change, yet it remains relatively understudied as a target period for preventative lifestyle interventions. We conducted a three-month randomised controlled trial in healthy middle-aged adults in the UK (n = 52) to examine the effects of exercise on pattern separation, cognition and well-being, blood-based biomarkers, and hippocampal neurogenesis, using an in vitro parabiosis assay. No significant intervention-by-time effect was observed for the primary outcome, pattern separation (β = 0.33, p = 0.26). However, significant intervention-by-time effects were detected for depressive symptoms, as measured by the PHQ-9 (β = -1.18, adjusted p = 0.011), and for the percentage of proliferative cells in vitro (β = -0.23, adjusted p = 0.02), suggesting that exercise remodels the circulating milieu in ways that directly influence hippocampal progenitor biology. Overall, our findings suggest that a structured, instructor-led, live online exercise programme in midlife is feasible and may produce temporally staged adaptations, with early effects on mood, intermediate systemic biological changes influencing hippocampal progenitor dynamics, and cognitive benefits that may require longer exposure to emerge. The trial was prospectively registered at Clinicaltrials.gov ( NCT05397990 ).