The effects of acute ketone monoester supplementation on brain insulin responsiveness and cognitive performance: Results of a randomized, double-blind, placebo-controlled crossover trial in older men with overweight

INTRODUCTION: Nutritional ketosis may prevent age-related cognitive decline, but underlying mechanisms remain unclear. This study investigated acute ketone monoester (KME) supplementation on brain insulin responsiveness and cognitive performance in older men with overweight. METHODS: ) consumed KME (395 mg/kg body weight) or a taste-matched placebo. Brain insulin responsiveness (primary outcome) was assessed using pseudo-continuous arterial spin labeling (pCASL)-MRI by measuring cerebral blood flow (CBF) responses to intranasal insulin. Cognitive performance (CANTAB, secondary outcome), resting CBF, cerebral perfusion, and cardiometabolic risk markers were also assessed. RESULTS: KME was well tolerated and rapidly induced nutritional ketosis (peak β-hydroxybutyrate: 2.9 ± 0.4 mmol/L; P < 0.001). Compared with placebo, KME lowered insulin-induced CBF responses in ten brain clusters (all P ≤ 0.05), including five frontal gyri, three parietal/occipital regions, and two subcortical clusters, a pattern opposite to that typically observed in adults with peripheral insulin resistance. KME modestly improved attention and psychomotor speed (reaction time: -9 ms; 95%CI: -18 to -1; P = 0.029), but did not affect memory or executive function. KME ingestion also lowered resting whole-brain CBF (-4.7 mL/100 g/min; 95%CI: -6.4 to -3.0; P < 0.001) and cerebral perfusion (middle cerebral artery velocity: -5.1 cm/s; 95%CI: -9.6 to -0.7; P = 0.028), and induced changes in cardiometabolic markers, including blood pressure, circulating insulin, and glucose. CONCLUSIONS: Acute nutritional ketosis differentially modulates brain insulin responsiveness, reflected by lower insulin-induced CBF responses in insulin-sensitive brain regions, and is accompanied by modest improvements in attention and psychomotor speed in older men with overweight.