Recent research published in Frontiers in Nutrition highlights the potential cognitive benefits of specific supplements. The study identified that both ketone ester (KetE) and medium chain triglycerides (MCT) are linked to significant improvements in cognitive function, influenced by the type and dosage of the supplement used.
Researchers from the University of Hasselt (Belgium), the Buck Institute for Research on Aging (USA), and Component Health (Ireland) expressed optimism about these findings. They stated, “Given the beneficial cognitive effects of endogenous ketones (EK) on both healthy and cognitively impaired individuals, coupled with an absence of known safety issues and favorable tolerance profiles, EK represent a valuable prospect for future inquiry and clinical application.”
They also noted, “Optimal benefits are likely achieved when EK are used in conjunction with additional interventions like diet and exercise; this avenue warrants future exploration.”
Understanding Ketones
Initial studies on exogenous ketones aimed to mimic the advantages of the ketogenic diet without dietary changes. When the body faces a shortage of carbohydrates (or glucose), it enters a state of ketosis, where it begins to convert fat reserves into ketones, which serve as an energy source. This process often occurs during fasting or extended physical activity.
“The primary function of ketone bodies, including β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone, is to provide metabolic substrates that support brain operation during development and when carbohydrate levels are limited,” the researchers noted in the meta-analysis. “Notably, classic experiments revealed that ketones entering the brain through specific, widely expressed monocarboxylate transporters could account for up to 60% of the brain’s metabolic requirements during extended fasting.”
Supplementing with exogenous ketones directly elevates ketone levels in the bloodstream, sidestepping the fat-burning process inherent to a keto diet. Beyond fueling the brain, heart, and skeletal muscles, ketosis is associated with a range of non-energy-related benefits, including improved cognitive functioning, reduced inflammation, weight management, reversal of metabolic syndrome, and enhanced immune response.
Despite numerous studies, a comprehensive review or meta-analysis consolidating data on exogenous ketones and cognitive performance had not been previously conducted.
Details of the Study
The researchers compiled data from 29 randomized controlled trials involving a total of 1,117 participants for this meta-analysis.
Findings indicated that exogenous ketone supplementation led to statistically significant enhancements in cognitive performance compared to a placebo.
Further analysis revealed that there were no significant differences based on the type of supplementation, study duration, participant demographics (healthy individuals vs. those with Alzheimer’s), or the presence of acute cognitive stressors. Additionally, a positive correlation was discovered between the daily dosage of exogenous ketones and cognitive improvement.
“Given that KetE results in a greater rise in circulating ketone concentrations than both MCTs and ketone salts, their application in long-duration cognitive studies is a promising direction for forthcoming research,” the researchers observed. “However, the well-researched ketone ester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is known for its bitter taste, potentially limiting its long-term use. In contrast, MCTs and medium chain fatty acid esters like bis-octanoyl (R),1-3-butanediol have a neutral flavor, making them more suitable for sustained consumption, albeit with lower ketone elevation. These considerations underscore the need to balance biological efficacy with practical application.”
The researchers urged for well-designed, long-term studies to determine optimal dosing, formulation, and clinical relevance.
Ketones and Aging: Implications Beyond Cognition
A further aspect of healthspan linked to ketosis is frailty. In 2023, the Buck Institute for Research on Aging initiated the first comprehensive clinical trial examining the effects of ketone supplementation on frailty, following a $3.5 million grant from the National Institutes of Health.
The multi-site investigation, named TAKEOFF (Targeting Aging with Ketone Ester in Older Adults for Function in Frailty), is actively recruiting 180 participants across the Buck Institute, Ohio State University, and the University of Connecticut Health Center.
“TAKEOFF will represent the most extensive and rigorous study of any ketone intervention targeting older adults,” stated John Newman, MD, PhD, assistant professor at the Buck Institute and principal investigator on the grant. “We are eager to evaluate this strategy within a population at risk of frailty, a condition that heightens the likelihood of serious issues in older adults, including falls, life-threatening infections, and loss of independence following surgery.”
Source: Frontiers in Nutrition, 2026, Volume 13, doi: 10.3389/fnut.2026.1802531. “The effect of exogenous ketone bodies on cognition across health and disease: a systematic review and meta-analysis.” Authors: B. Bonnechère et al.
