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(OR21-06-26) Acute Nutritional Ketosis Affects Brain Insulin Responsiveness and Cognitive Performance in Older Men With Overweight: A Randomized, Double-Blind, Crossover Trial

Monday, July 27, 2026
3:30 PM - 3:42 PM ET
Location: Maryland Ballroom C
Emerging Leaders in Nutrition Science Poster Competition Nutrition Translation Award Competition for Early Career Investigators

    Presenting Author(s)

  • Kevin M.R Nijssen, PhD

    Postdoctoral Researcher
    Maastricht University
    Maastricht, Limburg, Netherlands

    Disclosure(s): No relevant financial relationship(s) with ineligible companies to disclose.

    • Co-Author(s)

  • TA

    Tanja C. Adam

    Maastricht University, Netherlands

  • RM

    Ronald P. Mensink

    Maastricht University, Netherlands

  • Peter J. Joris, PhD

    Associate Professor
    Maastricht University
    Maastricht, Limburg, Netherlands

Disclosure(s):
Kevin M.R Nijssen, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Peter J. Joris, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: Nutritional ketosis may prevent age-related cognitive decline, but underlying mechanisms remain unclear. This study investigated whether acute ketone monoester (KME) supplementation affects 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/m2) consumed KME (395 mg/kg body weight) or a taste-matched placebo. The primary outcome was brain insulin responsiveness, assessed using pseudo-continuous arterial spin labeling (pCASL)-MRI by quantifying cerebral blood flow (CBF) responses to intranasal insulin. Cognitive performance (Cambridge Neuropsychological Test Automated Battery), resting CBF (pCASL-MRI), cerebral perfusion (transcranial Doppler), and cardiometabolic risk markers were also assessed.

Results: KME ingestion was well-tolerated and rapidly induced nutritional ketosis (peak blood β-hydroxybutyrate: 2.9±0.4 mmol/L; P < 0.001). Compared with placebo, KME reduced insulin-induced CBF responses in ten brain clusters (all P≤0.05), including five frontal gyri, three parietal/occipital regions, and two subcortical clusters. KME 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 lowered resting whole-brain CBF (-4.7 mL/100 g/min; 95%CI: -6.4 to -3.0; P < 0.001), cerebral perfusion (middle cerebral artery velocity: -5.1 cm/s; 95%CI: -9.6 to -0.7; P=0.028) and diastolic blood pressure (-2 mmHg; 95%CI: -5 to 0; P=0.046), while increasing heart rate (6 beats/min; 95% CI: 3 to 9; P=0.004). Circulating insulin significantly increased (iAUC0-120min: 3.1 mIU*h/L; 95%CI: 1.7 to 4.4; P < 0.001) and glucose decreased (iAUC0-120min: -0.2 mmol*h/L; 95%CI: -0.3 to -0.1; P=0.010).

Conclusions: Acute KME-induced nutritional ketosis modulated brain insulin responsiveness and improved attention in older men with overweight. These findings support dietary ketosis-based strategies for metabolic and cognitive health.

Funding Sources: This study was funded by a Kootstra Talent Fellowship awarded to K.M.R. Nijssen by Maastricht University Medical Center+.