Key points
- Ketogenic diets and ketones are broadly neuroprotective
- Positive benefits for the treatment of neurodegenerative disorders and bipolar type 2 disorder have been shown
- The benefits are likely to be due to a combination of factors including improved fuelling, reduced excitation of neurones, increased neural repair, reduced inflammation and oxidation, and positive changes to supportive glial cells of the brain and nervous system
Ketosis refers to the metabolic state that typically occurs during fasting or carbohydrate restriction. In this state ‘ketone bodies’ are created from fats and some amino acids. In the early stages of carbohydrate restriction, the body continues to use considerable amounts of glucose provided by liver glycogen, a process known as ‘HGO’ or hepatic glucose output. When these glycogen reserves become depleted, an alternative fuel source is needed, especially for the central nervous system (CNS), including the cells of the brain and spinal cord, which cannot effectively use fat for fuel and so, they rely on glucose.[a] Some dietary fats, such as short and medium-chain triglycerides (found in lesser amounts in full-fat dairy and coconut oil) can easily cross the blood-brain barrier and can be used extensively by neurons, but they are not plentiful in the diets of most people.
Neuroprotection and Neurodegeneration
Neurodegenerative disorders (NDs) are increasingly common. They result in progressive debility and short survival times. For example, the average survival time after diagnosis with Alzheimer’s Disease is only 3-9 years. Neurodegenerative disorders result from the loss of structure and function of neurons (brain and nervous system cells). The NDs include Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease. These disorders are considered to be primarily genetic, i.e. ~ 70% in AD, but also result from environmental and lifestyle factors, especially head injuries and hypertension, and in the case of Parkinson’s, past pesticide exposure.
In addition to the NDs, there is an increasing awareness of ‘brain health’ in general. Most people suffer some degree of age-related cognitive decline as they age, and in the internal polling of our network of patients and colleagues, improved cognition, clarity, and ‘energy’ are the most common desired results from seeking treatment and this is in contrast to the most desired outcome ~10 years ago, which was overwhelmingly weight loss. This is both positive (that there is a greater focus on function and health of the body rather than simply weight) and also somewhat worrying that cognitive decline and poor mental health are becoming so prevalent, for so many…
Ketone Bodies
The ketone bodies are ‘brain- and body-friendly’ fuels derived from fatty acids and some amino acids, especially leucine and lysine (which can only be converted to ketones, not to glucose). The ketone bodies are acetoacetate, ß-hydroxybutyric acid (BOHB) and acetone. These ketone bodies are produced through a process called ‘ketogenesis’ in the liver. Acetoacetate is the primary ketone body, and this is converted to BOHB, which functions as the main fuel ketone.[b] It is important to note that during ketosis blood glucose levels stay within normal physiological limits due to the creation of glucose from glucogenic amino acids and via the liberation of glycerol during fatty oxidation.[c] All these factors of ketone, fatty-acid and glucose regulation are crucially important, as certain cell types—in particular, red blood cells (RBCs), which lack mitochondria, are only able to use glucose as a fuel source and thus, the preservation of stable glucose levels is critical for survival.
Ketogenic Diets
Ketogenic diets (KDs) are low enough in carbohydrate and high enough in fat to encourage the creation of ketone bodies in higher than normal amounts (the body always produces a small amount of the ketone bodies). This ketonaemia (the presence of ketones in the blood) is called nutritional ketosis, which is typically just called ketosis. Very low carbohydrate ketogenic diets typically result in BOHB levels of ≥ 0.5 mmol/L, 1 and this level is used as a ‘cut off’ point for achieving ketosis by nutrition researchers, 2-4 and the ten-fold range of BOHB from 0.5 to 5.0 mmol/L had previously been indicated low-carbohydrate researchers Stephen Phinney and Jeff Volek as the functional definition for nutritional ketosis. 5, 6 I had the opportunity of asking Dr Phinney how they originally determined this range, and the lower cut-off and he said that they arrived at these figures based on the point at which participants symptoms of keto-induction were mitigated in their studies.[d] However, time to ketosis and the reduction in keto-flu related to ketone levels had not actually been quantified until my team and I performed research specifically on this, later published in The Journal of Nutrition and Metabolism. 4
a ketogenic diet is simply a diet very low in carbohydrate, low-to-high in protein, and high in fat
Exogenous Ketones
Exogenous ketone supplements provide BOHB directly to the body without requiring ketogenesis and without concurrent elevations in free fatty acids.7 They are considered to be a safe and effective way to increase ketone body concentrations,8 and are being studied for their use as potential treatments for brain injury,9 cancer,10, 11 Angelman syndrome,12 and Alzheimer’s disease,13 amongst other conditions.
Ketone supplements have positive effects on anxiety,13 mental performance, and memory,13 and reduce inflammation by suppressing activation of the NLRP3 inflammasome.14
Exogenous ketone supplements are available as either salts or esters of BOHB. Supplements containing ketone salts are some combination of sodium-, magnesium-, calcium or potassium-BOHB, and are available commercially from several companies under patent.15 Ketone esters have only recently become available for use by the public but are not common at the time of writing and are prohibitively expensive. Both ketone esters and salts elevate BOHB to levels consistent with NK.16 Ketone esters increase ketone levels more than equivalent amounts of ketone salts with fewer gastrointestinal symptoms per increment of increase.17
The distinction needs to be made between ketonaemia and ketogenesis. While exogenous ketones increase blood ketones levels, they do not encourage the production of ketones within the body. So, it is more accurate to say that exogenous ketones mimic the positive effects of NK, rather than inducing it.3
While exogenous ketones increase blood ketones levels, they do not encourage the production of ketones within the body
One human study has shown that exogenous administration of intravenous AcAc by inhibits endogenous ketone production.18 However, this effect was very moderate (approx. 10-30% inhibition of endogenous ketone production) and increased linearly with the baseline levels of ketones after long-term fasting (between 3 and 10 days). So, any effect of exogenous ketones on endogenous production is likely to be extremely modest and of no clinical significance.
Ketogenic Supplements
Many supplements are purported to be ketogenic (increasing the internal creation of ketones) including leucine, lysine, short-chain fatty acids, and medium-chain triglycerides (MCTs). Of these, leucine and lysine have limited effects on ketone levels. There is also limited evidence in humans for the effect of short-chain fats (such as acetic acid from vinegar, or butyric acid), however they are likely to be ketogenic and might be more so than MCT.3 The most compelling evidence currently exists for the use of MCTs for ketogenesis, as they reliably and consistently increase ketone concentrations in the blood in a dose-dependent fashion.3
Ketogenic Diets, Ketosis, and the Brain
The potential role of ketogenic diets for brain health has been hinted for over a century and keto-diets have been used to successfully treat childhood epilepsy since the 1920s.19-22
Evidence is now emerging that keto-diets could be a first-line treatment option for neurodegeneration. The exact mechanisms are not completely known at this time, but they are likely to be related to the known effects of ketones which include reduction of neuronal hyperexcitability, neuroprotection and neurogenesis, and improved fuel efficiency in the brain.
It is known that high carbohydrate diets play a role in the causation of Alzheimer’s Disease and cognitive decline, and ketogenic diets offer a potential treatment option.23 Both calorie-restricted diets and ketogenic diets are broadly neuroprotective,24 probably due to reduced carbohydrate intake (i.e. reduced glucose-related damage to neurons) and due to the elevation of ketones and resultant reductions in oxidation and inflammation.25
In pilot studies, elevated ketones improve memory in adults with Alzheimer’s and reviews of the evidence show a positive role for the keto-diet in its treatment. Early research also suggests that keto can reduce Parkinson’s disease activity.26, 27
Animal studies show benefits for reducing the plaque deposits that are part of the damage inflicted by Alzheimer’s,28 along with improvements in motor function and improved neuronal fuelling.29, 30 In human studies the keto-diet has been easily tolerated by Alzheimer’s patients while improving cognition and memory performance vs a higher-carbohydrate control group.31, 32
elevated ketones improve memory in adults with Alzheimer’s
Ketogenic diets also reduce inflammatory damage in Parkinson’s disease.33 In rat models, a ketogenic diet protects dopamine-producing neurons of the substantia nigra. These neurons are cells damaged by endotoxicity in Parkinson’s, resulting in the loss of motor and other functions and so their protection is a key target of therapy,34 and keto-diets improve motor function in rats with Parkinson’s.35
In mouse studies, ketogenic diets reduce the loss of motor neurons on amyotrophic lateral sclerosis (ALS or ‘Lou Gehrig’s disease) and reduce muscle wasting.36 Similarly, a ketogenic diet reduces wasting in Huntington’s disease.37
Case study evidence is also beginning to show mood stabilising effects from the ketogenic diet used to treat type 2 bipolar disorder. 38
Exogenous Ketones and Brain Health
Brain injury
Because of their anti-inflammatory actions and due to their availability as a priority fuel source for the brain, ketones are considered a potential adjunct treatment for brain injury.9
Alzheimer’s disease
There are almost certainly positive effects for Alzheimer’s disease from ketone supplementation due to improved fuel efficiency, cognition, and the neuro-relaxing effect of ketones, likely due to reduced glutamate and increased adenosine levels in the brain.39 Ketone therapy decreased amyloid plaque (the cause of neural degeneration in Alzheimer’s) deposition in the brains of mice and improved behavioural defects.13
Anxiety
Results of behavioural tests suggest that ketone supplemented mice exhibit significantly less anxiety.13
Mental performance and memory
Ketone supplemented mice exhibited significant improvements in performance on learning and memory tests.13
Why do Ketones Have these Effects on the Brain?
Reduced inflammation
β-hydroxybutyrate directly reduces inflammation by suppressing activation of the NLRP3 inflammasome.14 Interestingly, inflammatory messengers like tumour-necrosis factor-alpha (TNF-α) might reduce the body’s ability to produce ketones,40 and so, taking exogenous ketone supplements, or MCTs, might help the body to reduce inflammation, while also allowing there to be a better internal environment for ketogenesis. While ketones can inhibit ketogenesis, they have a relatively trivial effect on ketone production, and MCTs encourage ketogenesis, along with ketonaemia.
Reduced accumulation of malformed proteins and plaques
Proteins (like tau-protein) in the brain become distorted (mainly due to hyperphosphorylation) and accumulate in the brains of Alzheimer’s patients. These cause neuronal dysfunction and additional damage to neurons. These malformed and aggregated proteins are present in most people and can cause damage even if that person does not have Alzheimer’s. These proteins and plaques (β-amyloid) present in AD and other neurodegenerations are reduced by ketogenic diets/ketones.
Improved fuelling
Almost all cells, except those lacking mitochondria, such as red blood cells, can also utilise lipid-derived fatty acids (via β-oxidation) and most cell types (such as neurons and cardiac tissue) have a high affinity for ketone fuels. The entry of long-chain fats (the common dietary fats) into the brain and central nervous system tissue, is limited because the use of these fuels by neurons can cause hypoxia (lack of oxygen) and cell death. When the blood-brain barrier and cell membranes in the brain are damaged by trauma and injury, or by endotoxicity and protein damage, long-chain fats can enter the brain and neurons, causing further injury. Interestingly astrocytes in the brain and CNS might ‘scavenge’ some of these fatty acids, to convert them to ketones for use as fuel, thus, preventing some of that damage.41
astrocytes in the brain and CNS might ‘scavenge’ fatty acids to convert them to ketones for use as fuel, thus, preventing damage
Glucose in excessive amounts is also undesirable, despite it being the main fuel for the brain. When glucose levels are consistently elevated, there is greater potential for glycation or damage to proteins caused when sugars ‘stick’ to proteins, which causes them to become dysfunctional. Ketones, on the other hand, are able to be used by neurons, without the raft of negative effects caused by long-chain fats and excessive carbohydrate intake.
Ketones are also protective against the effects of ischemia (loss of blood supply to tissue),42, 43 and cell damage caused by hypoglycaemia.44
Ketones are also protective against the effects of ischemia (loss of blood supply to tissue) and cell damage caused by hypoglycaemia
Reduced excitotoxicity and neurotoxicity
Ketones improve the GABA to glutamate ratio. Gamma-aminobutyric acid (GABA) is a relaxing neurotransmitter, conversely, glutamate is an excitatory neurotransmitter. When there is an imbalance of these (too much glutamate, and too little GABA), excitotoxicity occurs. Excitotoxicity refers to the overstimulation of neurons, especially by glutamate. This causes an increase in calcium uptake into neurons which in turn, signals the activation of various enzymes which in excess, damage DNA, cell membrane, and other structures directly, and by damaging cell membranes, allow additional damage to those cells. This toxicity is implicated in Alzheimer’s, ALS, Parkinson’s, Huntington disease, brain injury and concussion, multiple sclerosis, alcoholism, and drug withdrawal. Excitotoxicity is reduced by ketones and a ketogenic diet, and worsened by excessive carbohydrate intake and rebound hypoglycaemia (low blood sugar, often caused by insulin resistance/pre-diabetes).45
Neurogenesis
Ketones initially increase oxidative stress but a rapid adaptation, along with increased antioxidant activity and reduced excitotoxicity also results in increased brain-derived neurotrophic factor (BDNF).46 This makes it highly likely that ketones can help the neurons of the brain to both survive, and to ‘regrow’ and repair.
ketones can help the neurons of the brain to both survive, and to ‘regrow’ and repair.
What does this all mean?
Ketones provided by diet or supplements can help to support the healthy functioning of the brain and reduce damage to neurons. They provide fuel, reduce damage to neurons, and reduce the accumulation of plaques and proteins implicated in neurodegeneration. Furthermore, they help to reduce over-stimulation of the neurons and improve anxiety.
In conclusion, a ketogenic diet is a valuable tool for the preservation of brain health or the treatment of neuronal conditions. In addition, MCTs and exogenous ketones allow for therapeutic levels of ketones to be achieved without the need for traditional, more aggressive ketogenic diet regimes.
a ketogenic diet is a valuable tool for the preservation of brain health or the treatment of neuronal conditions
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[a] For an in-depth explanation of why fat is inefficiently used by neurons see The Carbohydrate Appropriate Diet
[b] Technically BOHB is not a ketone body as the ketone moiety has been reduced to a hydroxyl group
[c] In silico models further suggest a plausible conversion of fatty acids to glucose more likely to occur in periods of carbohydrate restriction.
[d] Oral communication, August 28th, 2014
