Mark P. Mattson, Ph.D.
Department of Neuroscience,
Johns Hopkins University School of Medicine
Regular exercise and intermittent fasting each improve a wide range of health indicators including reduced abdominal fat and inflammation, and improvements in glucose regulation, cardiovascular risk factors, mood, and cognition (Neufer et al., 2015; deCabo and Mattson, 2019). These health benefits are associated with a metabolic switch from the utilization of glucose to the utilization of the ketone body beta-hydroxybutyrate (BHB) as a cellular energy source. Compared to glucose, BHB is a more efficient fuel source for cells – more ATP (adenosine triphosphate) is generated per molecule of BHB compared to glucose. In addition, fewer free radicals are generated during the metabolism of BHB compared to glucose. During fasting or oral supplementation with BHB and/or its precursors (salt, ester, Kenetik, MCT oil,), plasma BHB concentrations rise from a baseline of less than 20 micromolar to levels of 1 millimolar or more.
Figure 1: Source – American Brain Council market research data. Error bars = 95% confidence interval for the sample mean. N sizes: Kenetik = 24, Mono Ester = 19, D-BHB Salts = 14, C8 MCT Oil = 4. Participants: men and women ages 40-80 years, body mass 50-94kg
Ketone bodies are particularly beneficial for cells with a high metabolic demand such as neurons and muscle cells. These excitable cells readily use ketones as fuels. For example, PET (positron emission tomography) studies have shown that brain cells switch their fuel source from glucose to ketones when humans consume a ketogenic diet (Courchesne-Loyer et al., 2017). Evidence summarized below suggests that oral supplementation with BHB is beneficial for healthy people as well as for those with several common chronic diseases.
As with many other species humans evolved in environments where food was sparse and competition intense. Accordingly, natural selection favored individuals that functioned well in a food deprived – ketogenic – state (Mattson, 2022). During periods of food deprivation, BHB, derived from fat stores, fuels cells of the body and brain. This enables them to sustain their performance for extended periods of time. In addition, evidence suggests that BHB can activate signaling pathways that bolster cellular growth and resilience (Newman and Verdin, 2017). Oral supplementation with BHB has been shown to enhance endurance and recovery from exercise in humans. A study of elite British cyclists showed that their performance improves when they consume a BHB ester (Cox et al., 2016). In the latter cross-over design study the cyclists consumed ~40 grams of BHB prior to a bout of vigorous cycling. The distance they were able to travel during the 30-minute time trial was significantly greater when they consumed the BHB compared to when they did not. Additional analyses showed that BHB supplementation resulted in a decrease in muscle glycolysis and plasma lactate concentrations. Moreover, BHB supplementation resulted in increased intramuscular triglyceride oxidation during exercise. Another study showed that BHB supplementation in the fed state following exercise significantly enhances muscle glycogen synthesis consistent with improved recovery (Holdsworth et al., 2017). Kackley et al. (2017) reported that ingestion of BHB salts prior to a cycling to exhaustion trial significantly improved endurance. However, the latter study also included ingestion of caffeine and amino acids together with BHB in the pretrial treatment, making conclusions regarding the relative contribution of the BHB to the improved performance problematic.
Results from animal studies support the notion that BHB can enhance endurance performance. Compared to mice fed ad libitum, those on an every-other-day fasting regimen exhibited elevated plasma ketone levels and significantly greater endurance after a 2-month period of daily treadmill running (Marosi et al., 2018). This improved endurance was not associated with an increase in the utilization of endogenous ketones without an increase in VO2 max. Analyses of leg muscles provided evidence that intermittent fasting enhances exercise-induced mitochondrial biogenesis which would be expected to increase ATP availability during exercise. In another study rats fed a diet supplemented with BHB ester ran more than 30 percent further than did rats fed an isocaloric diet supplemented with either palm oil or starch (Murray et al., 2016).
Cognition and Mood
The results of multiple human and animal studies support a benefit of BHB supplementation as one method of enhancing learning and memory and improving mood. One study showed that 14 days of supplementation with BHB monoester improved short-term memory in a digit symbol substitution test (Walsh et al., 2021). The improved memory was associated with increased cerebral blood flow. In a study of more than 900 healthy subjects that included those of ages ranging from 18 to 88, functional brain imaging demonstrated an increase in brain network instability increasing with age (Mujica-Parodi et al., 2020). The neuronal network instability was correlated with poorer performance on cognitive tests. A subset of subjects was administered either BHB ester or calorie-matched glucose. BHB supplementation stabilized neuronal network activity whereas glucose destabilized neuronal network activity. The results of animal studies have confirmed that BHB can enhance learning and memory. Murray et al., (2016) found that BHB ester supplementation for 5 days improved performance of rats on an 8-arm radial arm maze test. They solved the maze more quickly and made fewer errors in doing so.
Exercise and fasting, both of which elevate endogenous BHB levels, can reduce anxiety and relieve depression in humans (Ashdown-Franks et al., 2020). Dietary supplementation with BHB in either salt or ester form reduced anxiety levels in rats in an elevated plus maze test (Ari et al., 2016). Studies have shown that BHB administration reduces anxiety levels in rats subjected to either one prolonged stress or chronic unpredictable stress (Yamanashi et al., 2017; 2020). Human studies evaluating the potential benefits of BHB on mood remain to be performed.
Animal studies have elucidated the cellular and molecular mechanisms by which BHB enhances cognition and improves mood. In addition to providing an efficient energy source for neurons, BHB stimulates the production of BDNF (brain-derived neurotrophic factor) in neurons in the brain (Marosi et al., 2016; Sleiman et al., 2016). BDNF is known to play important roles in learning and memory and can protect neurons against damage in experimental models of epilepsy, Alzheimer’s disease, and Parkinson’s disease (Marosi and Mattson, 2014). In addition to BDNF there are likely many other beneficial effects of BHB on neurons. Indeed, BHB has been reported to activate two transcription factors – CREB and NF-kB – that are known to play important roles in synaptic plasticity and cellular stress resistance (Marosi et al., 2016; Li et al., 2021).
Diabetes and Cardiovascular Disease
Fasting and exercise increase endogenous BHB levels and enhance insulin sensitivity. Findings from a randomized controlled trial on people with obesity demonstrated that consumption of BHB ester reduces the glycemic response to an oral glucose challenge (Myette-Cote et al., 2019). Another study showed that BHB supplementation reduces fasting glucose and hemoglobin A1C lc levels in patients with type 2 diabetes (Thai et al., 2021). Dietary supplementation with BHB was reported to be effective in both the prevention and treatment of heart failure in a mouse model (Yurista et al., 2021). Altogether the available evidence suggests potential benefits of BHB supplementation in prevention and treatment of diabetes and cardiovascular disease.
Epilepsy, Alzheimer’s Disease and Parkinson’s Disease
Animal studies have shown that BHB administration can protect neurons in the brain against dysfunction in experimental models of epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD). It is well known that a ketogenic diet can reduce seizure occurrence and severity in patients with epilepsy. Evidence suggests that BHB mediates these beneficial effects of ketogenic diets. Dietary supplementation with BHB ester prevented seizures in a mouse model (Cheng et al., 2020). AD is characterized by progressive impairment in short-term memory which is associated with the accumulation of extracellular accumulation of aggregated amyloid beta-peptide plaques and intracellular accumulation of aggregates of hyperphosphorylated Tau in the hippocampus and cerebral cortex. These cognitive and pathological features are replicated in the 3xTgAD mouse model (Oddo et al., 2003). Dietary supplementation with BHB ester ameliorates cognitive deficits and lessens the accumulation of amyloid plaques and hyperphosphorylated Tau in in hippocampal and cerebral cortical neurons (Kashiwaya et al., 2013). Cell culture studies have shown that BHB can protect neurons against death in models relevant to AD and PD (Kashiwaya et al., 2000). Infusion of BHB preserved dopamergic neurons and ameliorated motor impairment in a mouse model of PD (Tieu et al., 2003).
Mild cognitive impairment is often prodromal of AD. Supplementation with medium chain triglycerides (MCTs) which are fatty acid precursors to BHB can improve cognition in elderly people with mild cognitive impairment (Fortier et al., 2021). Another study of 20 subjects with mild cognitive impairment or early AD showed that MCT oil supplementation increased plasma BHB levels and improved performance in a paragraph recall test (Reger et al., 2004). Eight weeks of dietary ketosis improved cognitive performance in PD patients (Krikorian et al., 2019). A recent study showed that consumption of a BHB ester enhances endurance performance in PD patients (Norwitz et al., 2020).
Ketogenic diets can elevate plasma BHB levels, but such diets typically contain excessive amounts of saturated fats, cholesterol and proteins, and may lack health-promoting nutrients provided by vegetables and fruits. In addition, ketogenic diets are often less palatable than diets containing carbohydrates. BHB has very bitter taste which has been problematic in the development of dietary BHB supplements.
Kenetik, the proprietary VitaNav BHB preparation, has a pleasant citrus taste and effectively elevates circulating BHB levels, thereby making it an attractive supplement for people interested in improving their physical and mental performance and reducing their risk for chronic diseases.
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