Ketone Supplementation, Cardiometabolic Health, and Cognition in Humans

Cardiovascular disease (CVD) is the leading cause of death in the United States. Age is a primary risk factor for the development of CVD and middle-age is a vulnerable period where risk factors for the disease begin to exceed diagnostic thresholds. Interest has increased for the use of low carbohydrate high fat (LCHF) ketogenic diets due to their reported improvements for cardiometabolic health. Supplementation with exogenous ketone esters (KE) has been shown to increase plasma β-hydroxybutyrate (BHB) and mimic the metabolic effects of LCHF ketogenic diets. Evidence suggests elevated concentrations of plasma BHB may lower blood pressure, improve vascular function, attenuate hyperglycemic responses, and enhance cognitive function. The majority of research has been conducted in preclinical models, and whether exogenous KE supplementation has similar improvements in humans of any ages remains relatively unanswered. To address this we conducted a randomized, placebo controlled, crossover design study in healthy, sedentary, middle to older aged adults who received the exogenous KE (or placebo), and consumed the supplement for 2-weeks (3x/day, 15 minutes prior to each meal; breakfast, lunch, and dinner). Our first hypothesis was to test that KE supplementation would improve vascular function by increasing flow-mediated dilation, reducing arterial stiffness, and lowering blood pressure. Secondly, we hypothesized that KE supplementation would attenuate the glycemic response to an oral glucose tolerance test, improve glycemic variability, and show reductions in postprandial glucose levels. Thirdly, we tested the hypothesis that KE supplementation would improve cognitive performance by showing improvements in processing speed, memory, attention control, and executive functions. In support of our first hypotheses, KE supplementation increased flow-mediated dilation (8.1 ± 1.3 vs. 7.7 ± 1.2%, p = 0.023), but it did not show any difference in arterial stiffness or blood pressure. In contrast to our second hypotheses, following the KE supplementation intervention there were no significant difference from the placebo in terms of glycemic response, variability or mean 2-hour post-meal glucose. In support of our third hypotheses, we found a significant improvement in measures of working memory (7.55 ± 0.93 vs. 7.27 ± 0.29, p = 0.026) and inhibitory control (80 ± 38 vs. 87 ± 32ms, p = 0.035) following the 14-day KE supplementation. More research is needed to elucidate the effects of KE on cardiometabolic health and cognition.