Bach A.C., Babayan V.K. This level of ketonemia is most likely insufficient to improve cerebral metabolism and further suggests that some increase in ketone body levels is necessary to achieve a cognitive improvement [94]. Why Eating Quinoa Is Good for the Body and the Brain, A Diet to Manage Sertraline (Zoloft)-Induced Weight Gain, New Study: Serious Mental Illness Improves on Ketogenic Diet. The same research group has further demonstrated that supplementation of a precursor of ketone bodies alleviates ALS-motor impairment together with an increase in mitochondrial oxygen consumption rates in the spinal cord. Supplying exogenous ketone bodies thus represents an intriguing means to mitigate cerebral metabolic disturbances which are found in most neurodegenerative diseases. Hence, future studies implementing other ketogenic approaches will strengthen the evidence of a ketone-induced cognitive improvement. Neuronal UCPs are important for the regulation of ROS production by reducing the mitochondrial membrane potential, thus normally leading to lower ATP generation [84]. The backup is. Like in the acute setting in humans, the metabolic adaptations did not result in detectible changes in ATP levels. MCTs are the only known transporters for ketone bodies and are distributed throughout the brain [9]. During starvation, the brain must be supplied with fuel in the form of glucose or ketone bodies. I believe that what we eat has a lot to do with the health of our brains, though of course, mental illness (like physical illness) has multifactorial causes, and by no means should we diminish the importance of addressing all the causes in each individual. How do ketone bodies benefit the brain? The liver produces ketones when carb intake is very low. SUMMARY Low carb and ketogenic diets are similar in many. Courchesne-Loyer A., Croteau E., Castellano C.-A., St-Pierre V., Hennebelle M., Cunnane S.C. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study. (A caveat: I don't recommend intermittent fasting for anyone with an eating disorder without some extra support and consideration). infusion of BHB caused approximately 14% decrease in cerebral glucose consumption while oxygen use was unchanged, suggesting that ketone bodies, even when supplied acutely, enter the brain and may be utilized immediately as an alternative fuel to glucose [51]. It can become GABA (inhibitory), or aspartate (excitatory and, in excess, neurotoxic). Wium-Andersen I.K., Rungby J., Jrgensen M.B., Sandbk A., Osler M., Wium-Andersen M.K. The brain cannot DIRECTLY use fat for energy. Remember that the brain does require some glucose for fuel. Acetoacetyl-CoA is then converted back into two acetyl-CoAs ready to enter the TCA by the reversible action of thiolase (the first enzyme of ketogenesis). Henderson S.T., Morimoto B.H., Cummings J.L., Farlow M.R., Walker J. [77] demonstrated that both the L- and D-isoform of BHB and acetoacetate possess direct scavenging effects on ROS (BHB effects were specific to hydroxyl radicals). In addition, ketogenic diets were calorie-restricted to just 75 to 90 percent of what would be considered a child's usual calorie intake, and often they were fluid-restricted too (1)! Overview of cognitive domains affected by ketogenic interventions in patients with mild cognitive impairment or AD. Illustration is solely based on studies using a randomized-controlled study design (cross-over or parallel groups). Both the increased NAD+/NADH ratio and the BHB itself may stimulate the antioxidant defence system through activation of different transcription factors [76,79]. Fu S.P., Wang J.F., Xue W.J., Liu H.M., Liu B.R., Zeng Y.L., Li S.N., Huang B.X., Lv Q.K., Wang W., et al. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. In those places, we must use glucose itself (via glycolysis) to create ATP.) In fact, the brain can perform quite well running on ketones. Cunnane S., Nugent S., Roy M., Courchesne-Loyer A., Croteau E., Tremblay S., Castellano A., Pifferi F., Bocti C., Paquet N., et al. Glucose, or sugar, is the standard, primary fuel for the brain. Besides fasting, ketogenic diets and nutritional ketogenic supplements can increase the circulatory pool of ketone bodies. All authors contributed to the conceptualization, writing, and editing of this manuscript. and transmitted securely. The potential cognitive benefit from exogenous ketones has not been described in detail. Pathways and control of ketone body metabolism: On the fringe of lipid biochemistry. In AD, Parkinsons disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington disease (HD), glucose hypometabolism in affected brain regions is prominent, which correlates to disease severity [14,15,16,17]. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Overall effects on cognition are shown in Figure 3. Therefore, an adequate and continuous supply of energy is necessary to maintain brain cellular function since only a limited amount of glycogen is stored inside the brain [5]. Blzquez C., Woods A., de Ceballos M.L., Carling D., Guzmn M. The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. Effect of Hyperketonemia and Hyperlacticacidemia on Symptoms, Cognitive Dysfunction, and Counterregulatory Hormone Responses During Hypoglycemia in Normal Humans. Know when your hopes are well-founded and how to turn your deep desires into results. Antidiabetic medication and risk of dementia in patients with type 2 diabetes: A nested casecontrol study. If indeed there is a defect in glucose metabolism it might be beneficial to supplement energy metabolism with an alternate substrate. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimers disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. AI tools like ChatGPT offer novel ways for men to jumpstart self-care and take better care of their health. Westhaus A., Blumrich E.M., Dringen R. The Antidiabetic Drug Metformin Stimulates Glycolytic Lactate Production in Cultured Primary Rat Astrocytes. This motor neuron protection is in agreement with results obtained in animal models with chronic AMPA-induced neurodegeneration, showing that BHB infusion prevents motor deficits and paralysis [118]. Implications for the risk and treatment of Alzheimers disease. $\begingroup$ "The brain gets a portion of its fuel requirements from ketone bodies when glucose is less available than normal (e.g., during fasting, strenuous exercise, low carbohydrate, . Cheng B., Yang X., An L., Gao B., Liu X., Liu S. Ketogenic diet protects dopaminergic neurons against 6-OHDA neurotoxicity via up-regulating glutathione in a rat model of Parkinsons disease. Zilberter Y., Zilberter M. The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction. Mller N. Ketone Body, 3-Hydroxybutyrate: Minor MetaboliteMajor Medical Manifestations. Isn't it that sugar makes foods taste better? Cunnane S.C., Courchesne-Loyer A., St-Pierre V., Vandenberghe C., Pierotti T., Fortier M., Croteau E., Castellano C.A. The energetic brainA review from students to students. While the brain is also capable of utilizing ketone bodies as an alternative fuel source, the testes, renal medulla, and erythrocytes all rely exclusively on glucose . While the brain primarily relies on glucose as the main fuel, other substrates may contribute to metabolism, especially when glucose supply is restricted or inadequate, e.g., during fasting and low carbohydrate diets [7,8]. Especially in AD, the glucose consumption monitored by 18F-FDG PET uptake correlates closely with cognitive performance and may be used as part of the diagnostic procedure [65]. Gejl M., Brock B., Egefjord L., Vang K., Rungby J., Gjedde A. Blood-Brain Glucose Transfer in Alzheimers disease: Effect of GLP-1 Analog Treatment. Federal government websites often end in .gov or .mil. Xu Q., Zhang Y., Zhang X., Liu L., Zhou B., Mo R., Li Y., Li H., Li F., Tao Y., et al. Notably, increased age and type 2 diabetes (both characterized by insulin resistance) significantly increase risk of AD, and both have been associated with cerebral glucose hypometabolism [10]. Kashiwaya Y., Pawlosky R., Markis W., King M.T., Bergman C., Srivastava S., Murray A., Clarke K., Veech R.L. Brain fuel metabolism, aging, and Alzheimers disease. Tieu K., Perier C., Caspersen C., Teismann P., Wu D.-C., Yan S.-D., Naini A., Vila M., Jackson-Lewis V., Ramasamy R., et al. THE BASICS What are healthy approaches to dieting? After being metabolized by the liver, it becomes ketone bodies, which are supplied to the brain for energy consumption. The authors declare no conflict of interest. Not only do many people report they can "feel" ketosis, but also that they gain a boost of mental clarity and focus. Abstract During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This fact means that while there are essential requirements for both fat or protein (meaning we would die without eating at least some fat and at least some protein), we can live quite happily while consuming no carbohydrate at all. Cahill G.F., Jr. Fuel metabolism in starvation. The actual research diets used in the past were pretty dismal and seemed to involve drinking a lot of cream and eating a lot of mayonnaise (premade ketogenic formulas are nightmarish combination of omega 6 seed oils and corn solids). BBB is a highly selective semipermeable membrane that separates the brain from circulating blood and protects the brain from foreign substances in the blood. When glucose availability is acutely reduced by experimental hypoglycemia, additional provision of ketones either by infusion or ingestion of MCFA preserves cognitive functions in patients with type 1 diabetes and healthy individuals, and increases the glycaemic threshold for symptoms and the counter-regulatory hormone response (i.e., greater hypoglycemia was required for initiation) [59,60]. Since an acute cognitive improvement was found in three studies, it could imply that increased energy supply during ketone treatment, partly explains the neuroprotective effect, since other signalling properties of ketone bodies might be expected to require more time. Mitochondria are the power plants of our cells, where all the energy is produced (as ATP). In this review, we focus on different ketogenic approaches and describe the metabolic actions of ketone bodies in the brain and highlight key clinical data that support the neuroprotective effects of ketones in diseases of neurodegeneration. In astrocytes, degradation of fatty acids results in ketone body release to neighbouring neurons [47]. And does the high carbohydrate, low-fat diet of constant snacking have a cost to our brains by robbing us of more regular and deeper bouts of ketosis? Brain and behavioral perturbations in rats following Western diet access. Recently, it was reported that elevated ketone levels improve total energy metabolism in humans. We know (more or less) what all this means for epilepsy (and babies!). Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Mostly, the brain derives energy from glucose, glutamate, lactate, and ketone bodies because these metabolites have specialized carriers that can cross the blood-brain barrier (BBB). That's not saying there aren't some disadvantages or side effects to a so-called "zero-carb" diet, but it won't cause the massive health problems and death that consuming zero fat or zero protein would. They are acetoacetate, beta-hydroxybutyrate, and acetone. The brain, for example, requires approximately 120 g of glucose in 24 hours. Oxidative stress may lead to mitochondrial dysfunction, further increasing production of ROS [79]. Ketosis occurs with carbohydrate and protein restriction, MCT oil use, or fasting. Another in vitro study in neocortical neurons and isolated mitochondria, showed that a combination of BHB and acetoacetate reduced ROS production stimulated by calcium induced glutamate excitotoxicity, and that this effect was due to enhanced NADH oxidation and thus, an increased NAD+/NADH ratio [78]. Vanitallie T.B., Nonas C., Di Rocco A., Boyar K., Hyams K., Heymsfield S.B. Another common feature in neurodegenerative diseases is the loss of specific neurons (AD: pyramidal neurons in Ammons horn of the hippocampus; PD: dopaminergic neurons from substantia nigra pars compacta in the basal ganglia; HD: enkephalin-positive medium spiny neurons from striatum in basal ganglia; ALS: fast-fatigable motor neurons in the spinal cord). The physiological response to energy shortage, as seen during fasting, is fat degradation and ketone body formation, thereby supplying fuel to the brain [7] and saving protein (the main source of gluconeogenesis) [63]. It is true that some parts of some brain cells can only burn glucose, but fortunately our bodies can turn protein into glucose through a process known as gluconeogenesis. On a ketogenic diet, ketones are the primary fuel source for the brain. Attempting to understand how to fuel your brain optimally is a challenging task indeed. Nagpal R., Neth B.J., Wang S., Craft S., Yadav H. Modified Mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimers disease markers in subjects with mild cognitive impairment.