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 In a randomized, double-blind, placebo-controlled crossover trial, 18 men (age: 70.2 +/- 3.5 years, BMI: 27.2 +/- 1.5 kg/m(2)) 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 beta-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.