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 state of ketosis and 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 supplements compared to glucose. In addition, fewer free radicals are generated during the metabolism of BHB compared to glucose. During fasting or oral supplementation with ketones BHB and/or its precursors (salt, ketone 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.
Athletic Performance & Exogenous Ketones Supplements
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 exogenous ketone supplements 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 beta hydroxybutyrate 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 supplements can enhance endurance performance. Compared to mice fed ad libitum, those on an every-other-day fasting regimen exhibited elevated plasma ketone bodies 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. Beta hydroxybutyrate supplementation stabilized neuronal network activity whereas glucose destabilized neuronal network activity. The results of animal studies have confirmed that exogenous ketone supplements 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 beta hydroxybutyrate levels and enhance insulin sensitivity while burning fat. 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 keto BHB review/ 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 keto 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 beta hydroxybutyrate (BHB) supplements 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 state of 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 a very bitter taste which has been problematic in the development of dietary beta hydroxybutyrate supplements.
Kenetik, the proprietary VitaNav exogenous ketone supplement 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.
Ari C, Kovács Z, Juhasz G, Murdun C, Goldhagen CR, Koutnik AP, Poff AM, Kesl SL, D'Agostino DP.Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats.FrontMolNeurosci. 2016 Dec 6;9:137.
Ashdown-Franks G, Firth J, Carney R, Carvalho AF, Hallgren M, Koyanagi A, Rosenbaum S, Schuch FB, Smith L, Solmi M, Vancampfort D, Stubbs B.Exercise as Medicine for Mental and Substance Use Disorders: A Meta-review of the Benefits for Neuropsychiatric and Cognitive Outcomes.Sports Med. 2020 Jan;50(1):151-170.
Cheng A, Wang J, Ghena N, Zhao Q, Perone I, King TM, Veech RL, Gorospe M, Wan R, Mattson MP.SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model.JNeurosci. 2020 Jan 15;40(3):694-709.
Courchesne-Loyer A, Croteau E, Castellano CA, St-Pierre V, Hennebelle M, Cunnane SC.Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study.JCereb Blood Flow Metab. 2017 Jul;37(7):2485-2493.
Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K.Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes.CellMetab. 2016 Aug 9;24(2):256-68.
Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SHR, Saudou F, Mattson MP, Swerdlow RH, Millan MJ.Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing.Nat Rev Drug Discov. 2020 Sep;19(9):609-633.
Fortier M, Castellano CA, St-Pierre V, Myette-Côté É, Langlois F, Roy M, Morin MC, Bocti C, Fulop T, Godin JP, Delannoy C, Cuenoud B, Cunnane SC.A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT.Alzheimers Dement. 2021 Mar;17(3):543-552.
Holdsworth DA, Cox PJ, Kirk T, Stradling H, Impey SG, Clarke K.A Ketone Ester Drink Increases Postexercise Muscle Glycogen Synthesis in Humans.Med Sci Sports Exerc. 2017 Sep;49(9):1789-1795.
Kackley ML, Short JA, Hyde PN, LaFountain RA, Buga A, Miller VJ, Dickerson RM, Sapper TN, Barnhart EC, Krishnan D, McElroy CA, Maresh CM, Kraemer WJ, Volek JS.A Pre-Workout Supplement of Ketone Salts, Caffeine, and Amino Acids Improves High-Intensity Exercise Performance in Keto-Naive and Keto-Adapted Individuals.J Am Coll Nutr. 2020 May-Jun;39(4):290-300.
Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL.D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease.Proc Natl Acad Sci U S A. 2000 May 9;97(10):5440-4.
Kashiwaya Y, Bergman C, Lee JH, Wan R, King MT, Mughal MR, Okun E, Clarke K, Mattson MP, Veech RL.A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease.Neurobiol Aging. 2013 Jun;34(6):1530-9.
Krikorian R, Shidler MD, Summer SS, Sullivan PG, Duker AP, Isaacson RS, EspayAJ.Nutritional ketosis for mild cognitive impairment in Parkinson's disease: A controlled pilot trial.Clin Park RelatDisord. 2019 Aug 6;1:41-47.
Li Y, Zhang X, Ma A, Kang Y.Rational Application of beta-Hydroxybutyrate Attenuates Ischemic Stroke by Suppressing Oxidative Stress and Mitochondrial-Dependent Apoptosis via Activation of the Erk/CREB/eNOSPathway.ACSChemNeurosci. 2021 Apr 7;12(7):1219-1227.
Marosi K, Mattson MP.BDNF mediates adaptive brain and body responses to energetic challenges.Trends Endocrinol Metab. 2014 Feb;25(2):89-98.
Marosi K, Kim SW, Moehl K, Scheibye-Knudsen M, Cheng A, Cutler R, Camandola S, Mattson MP.3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons.JNeurochem. 2016 Dec;139(5):769-781.
Marosi K, Moehl K, Navas-Enamorado I, Mitchell SJ, Zhang Y, Lehrmann E, Aon MA, Cortassa S, Becker KG, Mattson MP.Metabolic and molecular framework for the enhancement of endurance by intermittent food deprivation.FASEB J. 2018 Jul;32(7):3844-3858.
Mujica-Parodi LR, Amgalan A, Sultan SF, Antal B, Sun X, Skiena S, Lithen A, Adra N, Ratai EM, Weistuch C, Govindarajan ST, Strey HH, Dill KA, Stufflebeam SM, Veech RL, Clarke K.Diet modulates brain network stability, a biomarker for brain aging, in young adults.Proc Natl Acad Sci U S A. 2020 Mar 17;117(11):6170-6177.
Murray AJ, Knight NS, Cole MA, Cochlin LE, Carter E, Tchabanenko K, Pichulik T, Gulston MK, Atherton HJ, Schroeder MA, Deacon RM, Kashiwaya Y, King MT, Pawlosky R, Rawlins JN, Tyler DJ, Griffin JL, Robertson J, Veech RL, Clarke K.Novel ketone diet enhances physical and cognitive performance.FASEB J. 2016 Dec;30(12):4021-4032.
Myette-Côté É, Caldwell HG, Ainslie PN, Clarke K, Little JP.A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial.Am J ClinNutr. 2019 Dec 1;110(6):1491-1501.
Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, Harms HJ, Frøkiær J, Eiskjaer H, Jespersen NR, Mellemkjaer S, Lassen TR, Pryds K, Bøtker HE, WiggersH.Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients.Circulation. 2019 Apr 30;139(18):2129-2141.
Neufer PD, Bamman MM, Muoio DM, Bouchard C, Cooper DM, Goodpaster BH, Booth FW, Kohrt WM, Gerszten RE, Mattson MP, Hepple RT, Kraus WE, Reid MB, Bodine SC, Jakicic JM, Fleg JL, Williams JP, Joseph L, Evans M, Maruvada P, Rodgers M, Roary M, Boyce AT, Drugan JK, Koenig JI, Ingraham RH, Krotoski D, Garcia-Cazarin M, McGowan JA, Laughlin MR.Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits.CellMetab. 2015 Jul 7;22(1):4-11.
Newman JC, VerdinE.beta-Hydroxybutyrate: A Signaling Metabolite.Annu Rev Nutr. 2017 Aug 21;37:51-76.
Norwitz NG, Dearlove DJ, Lu M, Clarke K, Dawes H, Hu MT.A Ketone Ester Drink Enhances Endurance Exercise Performance in Parkinson's Disease.FrontNeurosci. 2020 Sep 30;14:584130.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerlaFM.Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.Neuron. 2003 Jul 31;39(3):409-21.
Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, Hyde K, Chapman D, Craft S.Effects of beta-hydroxybutyrate on cognition in memory-impaired adults.Neurobiol Aging. 2004 Mar;25(3):311-4.
Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, Ulja D, Karuppagounder SS, Holson EB, Ratan RR, Ninan I, Chao MV.Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate.Elife. 2016 Jun 2;5:e15092.
Soto-Mota A, Norwitz NG, Evans R, Clarke K, Barber TM.Exogenous ketosis in patients with type 2 diabetes: Safety, tolerability and effect on glycaemiccontrol.Endocrinol Diabetes Metab. 2021 May 20;4(3):e00264.
Stubbs BJ, Cox PJ, Evans RD, Santer P, Miller JJ, Faull OK, Magor-Elliott S, Hiyama S, Stirling M, Clarke K.On the Metabolism of Exogenous Ketones in Humans.Front Physiol. 2017 Oct 30;8:848.
Thai PN, Miller CV, King MT, Schaefer S, Veech RL, Chiamvimonvat N, Bers DM, DedkovaEN.Ketone Ester D-beta-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice.J Am Heart Assoc. 2021 Oct 5;10(19):e020729.
Tieu K, Perier C, Caspersen C, Teismann P, Wu DC, Yan SD, Naini A, Vila M, Jackson-Lewis V, Ramasamy R, Przedborski S.D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease.JClin Invest. 2003 Sep;112(6):892-901.
Walsh JJ, Caldwell HG, Neudorf H, Ainslie PN, Little JP.Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial.J Physiol. 2021 Nov;599(21):4763-4778.
Yamanashi T, Iwata M, Kamiya N, Tsunetomi K, Kajitani N, Wada N, Iitsuka T, Yamauchi T, Miura A, Pu S, Shirayama Y, Watanabe K, Duman RS, Kaneko K.Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses.Sci Rep. 2017 Aug 9;7(1):7677.
Yamanashi T, Iwata M, Shibushita M, Tsunetomi K, Nagata M, Kajitani N, Miura A, Matsuo R, Nishiguchi T, Kato TA, Setoyama D, Shirayama Y, Watanabe K, Shinozaki G, Kaneko K.Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model.Sci Rep. 2020 Dec 10;10(1):21629.
Yurista SR, Matsuura TR, Silljé HHW, Nijholt KT, McDaid KS, Shewale SV, Leone TC, Newman JC, Verdin E, van Veldhuisen DJ, de Boer RA, Kelly DP, WestenbrinkBD.Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.Circ Heart Fail. 2021 Jan;14(1):e007684.