Introduction to ketosis and associated terms
The body’s primary source of energy is glucose Blood Sugar. When the body does not have enough glucose for energy, it burns stored fats instead. After a few days of reduced carbohydrate intake, glucose reserves become insufficient for normal fat oxidation so the body is ‘forced' to find alternative energy sources; this leads to the production of higher-than-normal levels of ketones. The state of using ketones for energy is called ketosis. Some people encourage ketosis by following a ketogenic diet or, more simply, a low-carb diet.
Access to the ketone “fuel tank” has been likened to deep storage because it is not easily accessed. It is like a freezer in the basement when it is so much easier to just grab something unfrozen from the kitchen fridge. For those who are mechanically oriented, think of Dr Ted Naiman's hydraulic model for metabolism. The body has a very limited capacity for storing glycogen in its small reservoir. The fat reservoir is huge, but given “the mechanics” of how the body works, only when carbohydrates and sugar are low will the body use fat for energy.
Simply following a low-carb diet doesn’t assure achieving ketosis. Ketones are made by the liver (hepatically) as a product of breaking down fatty acids. The liver is constantly breaking down fatty acids, so ketones are constantly being made in the body. The level of ketones needs to be high enough to be considered ketosis. This range is between 0.5 mmol/dl and 5 mmol/dl. Dr Stephen Phinney, arguably the premier expert on ketosis, termed this range nutritional ketosis.
When a person has been producing ketones within the nutritional ketosis range long enough for the body to switch to fat as the primary fuel source, then that person is keto adapted or fat adapted. The terms are interchangeable. Keto adaptation can take anywhere from a month to over a year. But when a person is adapted and able to easily switch the glucose and fat “fuel tanks,” they are said to have metabolic flexibility. There are those who say ketosis isn't the true goal, but rather this metabolic flexibility. Mark Sisson discusses why this is in his article Where I Part Ways with the Popular Keto Movement
During the keto adaptation process, some experience keto flu. Processed foods with their chemical additives, added sugars, refined oils, and carbohydrates are addictive, so this keto flu is a withdrawal process. The keto flu makes a person feel lousy, but typically isn’t debilitating. Symptoms can include fatigue, dizziness, light nausea, irritability, and headaches. This keto flu can last anywhere from one day to a few weeks. Once the keto flu has passed, this does not mean one has keto adapted, as that process still continues. The good news is after the keto flu passes many people experience an increase in energy levels.
Ketone Bodies (KB) are also known as ketones; the terms are interchangeable. There are three types of ketones:
- Acetaoacetate - precursor to the other two, excreted through urine
- Beta-hydroxybutyrate (BHB) – the most abundant ketone, circulates in blood, used for energy
- Acetone – exhaled through breath
Dr Dale Bredesen, (see Bredesen Protocol in his book The End of Alzheimer's), recommends mild ketosis to generate beta-Hydroxybutyrate (BHB). BHB increases Brain Derived Neurotrophic Factor (BDNF), an important neuron and synapse supporting molecule. He recommends achieving mild ketosis through:
- a low-carb diet
- fasting at least 12 hours, with 16 hours preferred for ApoE4s
- consuming certain fats.
The range of beta-Hydroxybutyrate Dr Bredesen recommends is between 0.5 mmol/L to 4.0 mmol/L. To determine this level, ketones can be measured one of three ways: urine, blood, and breath. The book cautions that urine testing is imprecise. Ketones in urine are waste products. It is conceivable the body can be making ketones and using all of them, with no leftover ketones to excrete, so a meter is a better method for determining ketosis. Appendix B of Dr Bredesen’s book discusses ketone meters. Since the publication of Dr Bredesen’s book, a blood meter has been introduced that measures both ketones and glucose. There is no need to buy two meters; it is called Keto-Mojo
Ketogenesis is the biochemical process by which the body uses ketone bodies through the breakdown of fatty acids and ketogenic amino acids. This supplies energy to certain organs, particularly the brain.
Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies AND high levels of glucose. This combination produces acidic blood which is dangerous. However, as reflected in the hydraulic model of metabolism, normally there’s a reciprocal relationship between these two, i.e. in the presence of glucose, there should be low-to-no ketones, or if ketones are up there should be low glucose. When both ketones and glucose develop to high levels this is because there is lack of insulin, but unless you’ve been fasting a very long time, there is enough insulin in the body to suppress the liver from producing excess glucose. The three main causes of ketoacidosis are alcoholism, starvation, and Type 1 diabetes. Exclusive of those conditions, ketoacidosis is not a potential side effect while following a mildly ketogenic diet.
Exogenous ketones are ketone bodies that are ingested through a nutritional supplement; in other words you ingest ketones vs. the body making the ketones. Exogenous ketones come in 3 main forms: ketone salts (bound to a salt), ketone esters (raw BHB), and ketone oils (MCT oil powder). Consuming exogenous ketones alone will not result in ketosis, but they can aid with heightening levels of ketones in the body.
Ketogenic Diet. A ketogenic diet is a low carbohydrate diet that is followed for the specific intention of maintaining ketosis. The ketogenic diet was developed in the 1920s as a therapeutic treatment of pediatric epilepsy. It was widely used until the introduction of anticonvulsant drugs. Ketogenic diets are practiced differently given the objective: to lose weight, to fight cancer, for epileptic seizures, to address insulin resistance, athletic performance, etc. Dr Dom D'Agostino has been working with the military and NASA to use the neuroprotective qualities of ketone therapy in severe environments (space, undersea diving.). But each of those ketogenic strategies have unique nuances, for example, in a ketogenic diet for cancer the objective is a fairly deep level of ketosis, 3-6 mmol/L. This is different than a mildly ketogenic diet of 0.5 mmol/L to 4.0 mmol/L that Dr Bredesen recommends for cognitive health.
A more indepth discussion on the ketogenic diet can be found further down in this article. (coming soon)
Ketosis and ApoE4
Ketones burn “cleaner” than glucose since they produce fewer Reactive Oxygen Species (ROS) and secondary free radicals, so the mitochondria’s exposure to oxidative damage drops significantly, thus improving mitochondrial function, the root of chronic diseases. Ketosis is also said to improve certain metabolic pathways.
Positive health advantages caused by ketosis can be seen in epilepsy, weight loss, Type 2 Diabetes, polycystic ovarian syndrome, respiratory inflammation, cancer, depression and others. But the primary health concerns for ApoE4s are:
- cognition - brain health
- cardiovascular disease
- reduced longevity
Ketosis and the brain
Proportionately, the brain consumes a great amount of energy, about 20-30% of the body’s total energy needs. Most of the brain’s energy consumption goes toward sustaining neurons, and it needs this energy 24 hours a day. The brain typically gets its energy from glucose (blood sugar), but ketone bodies (ketones) are the brain’s main reserve fuel when glucose supply is compromised. (Stephen C Cunnane, et al., 2016)
There is a significant link between Alzheimer’s disease (AD) and impaired fuel metabolism in the brain, (see Insulin Resistance) specifically disturbed cerebral glucose metabolism. (Berger AL, 2016) In Alzheimer’s, the uptake and metabolism of glucose in the brain deteriorates. This reduced glucose metabolism is likely both:
- contributing to AD development (hypothesized, not yet scientifically proven), and
- a consequence of AD (known fact). (Stephen C Cunnane, et al., 2016)
In other words, there’s a vicious cycle: the slowed brain glucose uptake (hypometabolism) leads to chronic brain energy deprivation, that in turn deteriorates the neuronal function, which further diminishes the demand for glucose thereby furthering cognitive decline. This hypometabolism may begin 30 or more years before the onset of AD especially in individuals with ApoE4 genotype or maternal family history of AD. Brain metabolic deregulation in AD was found to be specific to glucose metabolism, while ketone metabolism is unaltered. (Rand T. Akasheh, 2016 at 18:33, Richard S. Isaacson, MD; Stephen C. Cunnane, PhD; Russell H. Swerdlow, MD, 2013)
Since introducing ketone bodies to AD patients has resulted in improvements to cognitive ability, mild ketosis is one of the lifestyle strategies recommended in the Bredesen Protocol for reversal or treatment of cognitive decline. (Dale E. Bredesen, MD, 2014, Bredesen Protocol)
Ketosis or metabolic flexibility is also practiced among some ApoE4s who have not yet experienced cognitive decline, but given that it can take 30 years or more of hypometabolism before symptoms manifest, it is adopted as a preemptive measure.
Additional Ketosis and cognition references
A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer’s (Mary T. Newport, et al, 2016)
- “In patients with preclinical AD, fluorodeoxyglucose-positron emission tomography (FDG-PET) discloses a consistent pattern of reduction in the cerebral metabolic rate of glucose (CMRglu) in the posterior cingulate, parietal, temporal, and prefrontal locations."
- "To the extent impairment of glucose utilization contributes to AD’s pathogenesis, providing the AD brain with sufficient ketone bodies(KB)—the brain’s principal alternative fuel during prolonged fasting[5,6]—would likely mitigate the energy deficit, as shown in Fig. 1.”
- The study goes on to discuss “TP” An ApoE4 63 year-old man with advanced Alzheimer’s who began consuming coconut oil and medium chain triglycerides to increase ketone levels. After just 2.5 months, his score on the Mini Mental State Exam, which tests global cognitive function, increased from 12 (very low) to 20 (out of a max 30). After two years, his cognitive ability and daily living functions both improved and his MRI showed no further brain atrophy.
Ketones block amyloid entry and improve cognition in an Alzheimer's model (Jun XiangYin, et al, 2016)
- “Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD. In this study, we discovered a novel neuroprotective mechanism of ketones in which they blocked amyloid-β 42, a pathologic hallmark protein of AD, entry into neurons.”
- “Most importantly, we show that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic mouse model of AD. These observations provide us insights to understand and to establish a novel therapeutic use of ketones in AD prevention.”
Dietary ketosis enhances memory in mild cognitive impairment (Robert Krikorian, et al, 2013)
- “These findings indicate that very low carbohydrate consumption, even in the short-term, can improve memory function in older adults with increased risk for Alzheimer’s disease.” (Effect not stratified by APOE status.)
Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet (Bough KJ, et al, 2006)
- “These data show that a calorie-restricted KD [Ketogenic diet] enhances brain metabolism. We propose an anticonvulsant mechanism of the KD involving mitochondrial biogenesis leading to enhanced alternative energy stores.”
Effects of beta-hydroxybutyrate on cognition in memory-impaired adults (Reger MA, et al, 2005)
- “Elevation of plasma ketone body levels through an oral dose of medium chain triglycerides (MCTs) may improve cognitive functioning in older adults with memory disorders.”
- “On cognitive testing, MCT treatment facilitated performance on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) for 4- [non ApoE4] subjects, but not for 4+ [ApoE4] subjects (P=0.04). Higher ketone values were associated with greater improvement in paragraph recall with MCT treatment relative to placebo across all subjects (P=0.02). Additional research is warranted to determine the therapeutic benefits of MCTs for patients with AD and how APOE-4 status may mediate beta-OHB efficacy.”
Ketosis and cardiovascular disease
- “However, the majority of recent studies seem instead to amply demonstrate that the reduction of carbohydrates to levels that induce physiological ketosis (see above ‘What is ketosis?' section) can actually lead to significant benefits in blood lipid profiles.15, 17, 27 The VLCKD effect seems to be particularly marked on the level of blood triglycerides,24, 28 but there are also significant positive effects on total cholesterol reduction and increases in high-density lipoprotein.24, 28, 29”
A Low-Carbohydrate, Ketogenic Diet versus a Low-Fat Diet To Treat Obesity and Hyperlipidemia: A Randomized, Controlled Trial (William S. Yancy Jr., et al, 2004)
- “In between-group comparisons, the low-carbohydrate diet group had statistically greater changes in triglyceride level, high-density lipoprotein (HDL) cholesterol level, and ratio of triglycerides to HDL cholesterol (P = 0.004, P < 0.001, and P = 0.02, respectively) (Table 2)."
A Ketogenic Diet Favorably Affects Serum Biomarkers for Cardiovascular Disease in Normal-Weight Men (Matthew J. Sharman, et al, 2002)
- “Twelve men switched from their habitual diet (17% protein, 47% carbohydrate and 32% fat) to a ketogenic diet (30% protein, 8% carbohydrate and 61% fat) and eight control subjects consumed their habitual diet for 6 wk. Fasting blood lipids, insulin, LDL particle size, oxidized LDL and postprandial triacylglycerol (TAG) and insulin responses to a fat-rich meal were determined before and after treatment.“
- “To our knowledge this is the first study to document the effects of a ketogenic diet on fasting and postprandial CVD biomarkers independent of weight loss. The results suggest that a short-term ketogenic diet does not have a deleterious effect on CVD risk profile and may improve the lipid disorders characteristic of atherogenic dyslipidemia.”
Ketosis and longevity
A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice (Megan N. Roberts, et al, 2017)
- A low-carbohydrate, ketogenic diet extends longevity in adult male mice
- Motor function, memory, and muscle mass are preserved in aged ketogenic mice
- Protein acetylation is increased in the liver and skeletal muscle of ketogenic mice"
D-beta-hydroxybutyrate extends lifespan in C. elegans (Edwards C, et al, 2014)
- “The ketone body beta-hydroxybutyrate (βHB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of βHB supplementation on the lifespan ofC. elegans nematodes. βHB supplementation extended mean lifespan by approximately 20%.”
Ketone bodies as signaling metabolites (John C.Newman, EricVerdin, 2014)
- Ketone bodies have signaling functions as well as being a mobile source of cellular energy.
- Ketone bodies inhibit histone deacetylases and control gene transcription.
- Histone deacetylase function is implicated in the regulation of aging.
- Ketone bodies may link environmental cues such as diet to the regulation of aging.”
A ketogenic diet is a low carbohydrate diet used to maintain ketosis. It is assumed those reading this article are interested in ketosis to address ApoE4 health concerns, specifically maintaining/regaining cognitive function.
So what does a ketogenic diet for an ApoE4 consist of? It is a low carbohydrate diet that is made of:
- 1. Adequate protein – Protein, particularly animal sourced protein, can stimulate negative metabolic pathways, specifically the mTOR pathway, so some feel lowering protein in a diet is more important than lowering the carbs (advocates include Dr Ron Rosedale, Dr Joe Mercola, Dr Steven Gundry and author Travis Christofferson). Additionally, because the body will convert excess protein into glucose via a process called gluconeogenesis, protein consumption could actually inhibit ketosis. Dr Gundry recommends a total of 2 to 4 ounces of animal protein a day, with sources of this protein for ApoE4s restricted to wild caught white fish, wild caught shellfish, and Omega-3 or pastured eggs only (no grass fed beef, no pastured poultry, no cheese). With that said, as people age, some are unable to absorb protein like they used to, likely because of gut health issues, so they need to eat more protein just to absorb the amount they need.
- 2. Moderated amounts of good carbs, no bad carbs – This means mostly a variety of vegetables and, in moderation, resistant starches. This facilitates mitochondrial and gut biome health. Vegetables can be eaten in fairly large quantities because they are low in net carbs. Net carbs are the grams of total carbohydrates minus its grams of fiber. Because fiber is a carbohydrate that your body cannot digest, it does not raise your blood sugar levels or trigger an insulin response.
- Starchy vegetables should be avoided, but including certain resistant starches can offer unique health benefits. It sounds counter-intuitive to add starch to a low carb diet but this carb isn’t like other carbs. A resistant starch “resists digestion” as it makes its way past the small intestine to the large intestine where intestinal bacteria ferment it, turning it into short-chain fatty acids. Because it is incompletely digested, we only extract about 2 calories of energy per gram versus about 4 calories per gram from other starches. Resistant starches help with satiety, feed good bacteria in the gut, and even help with fat burning.
- 3. Lots of good, healthy fats – Avocados, nuts, and healthy oils such as olive oil, avocado oil, algae oil, macadamia oil, perilla oil, walnut oil, red palm oil, rice bran oil, sesame oil, flavored cod liver oil. The use of coconut oil and MCT oil for ApoE4s has been debated on the ApoE4.info forums, and consensus is coconut oil should be avoided. This is probably also true of MCT oil, but evidence is not conclusive.
Avoiding certain foods is as important as eating certain foods. Foods which should be avoided are those full of sugar and starch such as: fruit, white potatoes, pasta (even whole grain), soda, juice, candy, donuts, bagels (even whole grain), rice, beer, and bread (although there are low carb alternative recipes available on the internet). Oils which should be avoided: soy, grape seed, corn, peanut, cottonseed, safflower, sunflower, partially hydrogenated vegetable oil, canola.
To aid with compliance to a ketogenic diet, the Cronometer website is an excellent tool. It provides an accurate, not crowd sourced, database of nutrition information, it is free, and they don’t spam you with e-mails after you’ve signed up. By using this website you can accurately determine protein levels, net carbs, macronutrient ratios, Omega-3 to Omega-6 ratios, etc. A very useful tool.
Since a ketogenic diet can be overwhelming and confusing to a novice, it also helps to have virtual support groups. In addition to the forums on the ApoE4.info website, there are many websites and Facebook groups dedicated to exchanging recipes, questions, and challenges faced when pursuing a ketogenic diet. This website Diet Doctor in particular is excellent at helping a novice navigate a ketogenic diet by addressing concerns, suggesting recipes, providing motivation, etc.
Common Criticisms of Ketogenic Diets Addressed
A common criticism of the ketogenic diet is that the long term effects are unknown. This can be interpreted to suggest there are insufficient clinical trials. But we do know long term effects. It’s called human history. For most of the history of man, we went through periods of little/no food. During these times, humans practiced metabolic flexibility by switching from glucose to ketones, not by choice but because of food availability. There are some who advocate following a yearly cycle of abundant food during the summer and fall followed by fasting/calorie restriction during the winter and spring months. It has only been in recent years that humans have had virtually unlimited food quantities available 24 hours a day, 365 days a year. Only since the nutritional guidelines for Americans changed in 1980 have carbohydrates come into prominent consumption. For the vast majority of human history, the body capitalized on switching to/from glucose/ketones. Burning ketones for energy was an adaptive coping mechanism to maintain physical ability and mental clarity during times of food paucity, and it enabled man to survive weeks to months with inadequate food sources.
Another criticism of a ketogenic diet is ketoacidosis. Ketoacidosis is a metabolic state associated with high concentrations of ketone bodies AND high levels of glucose. This combination produces acidic blood which is dangerous. However, normally, there’s a reciprocal relationship between these two, i.e. in the presence of glucose, there should low-to-no ketones, or if high ketones there should be low glucose. A ketogenic diet is often used by Type 2 diabetics and those with insulin resistance to lower levels of glucose. When both ketones and glucose are high, this is because there is lack of insulin. Unless you’ve been fasting a very long time, there is enough insulin in the body to suppress the liver from producing glucose. The three main causes of ketoacidosis are alcoholism, starvation, and Type 1 diabetes. Exclusive of those conditions, ketoacidosis is not a potential side effect of following a mildly ketogenic diet. So this is a largely invalid criticism.
The Atkins Diet has shed negative light on ketogenic diets, and this has merit but there are many caveats to consider here. First, the intention of this diet was weight loss, not metabolic or cognitive health. Secondly, followers of the diet tended to consume too much animal protein and not enough vegetables. Third, there was also no guidance with regard to food quality. Followers consumed large quantities of grain-fed beef, hormone laden chicken, A1 casein dairy, and refined vegetable oils. On top of that, Atkins products that were sold were processed foods with artificial sweeteners. So the Atkins diet was highly inflammatory.
Kidney damage. Many who have practiced ketogenic diets consumed too much protein. There are even some who practice meat-only ketogenic diets. This can lead to possible kidney damage due to high levels of nitrogen excretion during protein metabolism, but it can be avoided by lowering protein intake. It is possible to be a vegan, ingest adequate protein, and be ketogenic.
Some Questions and Answers regarding Ketosis and the Ketogenic Diet
I don’t want to buy a ketone meter, is there some way to tell if I’m in ketosis? A meter is the best way to tell if you really are in ketosis and levels don’t need to be tested frequently once the learning curve of how to eat and maintain ketosis levels off. But there are indicators of being in ketosis: dry mouth and increased thirst, increased urination, keto breath (this is the ketone body acetone, the breath smells “sweet” or like nail polish remover), reduced hunger, increased energy, clearer thinking. If you get blood tests that include a measuring carbon dioxide or free fatty acid, the carbon dioxide will measure on the low end of the range out of the “normal” range, and free fatty acid will measure high, also likely out of the “normal” range.
How many carbs can I eat? The general rule of thumb for eating on a ketogenic diet is 70% -75% fat, 15% - 20% protein, and carbs 5%-10% or less than 50 grams, but it is individual. Some are able to eat more than others. It may also be a function of where a person stands on the cognition spectrum. For example, if a person is young, has never had biomarkers indicating Insulin Resistance and there are no cognitive issues, just following a Low Carb/High Fat (LCHF) diet may be adequate. But if there are cognitive issues, then a mild ketogenic diet is likely in order, and if experiencing Alzheimer’s, then a strict ketogenic diet should be followed.
I can’t afford to lose weight, can I go on a keto diet? Just because you are burning fat, doesn’t mean you’re constantly losing weight. A person can be in ketosis and maintain a steady weight.
Doesn’t the brain need glucose? The brain needs a constant supply of energy. The brain can burn ketones, but even under the best of circumstances, ketones can only provide about 2/3rds what the brain needs. The brain’s energy supply needs to include glucose, so yes, the brain needs glucose. This doesn’t mean you need to eat sugar or carbohydrates to ensure your brain gets glucose. The body can make its own glucose, a process called gluconeogenesis, through breaking down proteins or glycerol from triglycerides. But just because glucose is present doesn’t mean the brain can access it. The brain cannot metabolize glucose without insulin, it could be swimming in glucose without the ability to use it. This is one of the reasons avoiding/reducing insulin resistance is so important for ApoE4s. See Insulin Resistance. A ketogenic diet helps with lowering insulin resistance, so in addition to providing a secondary source of fuel for the brain, it helps the brain access the primary source of fuel.
If I splurge at a wedding, special family gathering, etc. will it knock me out of ketosis? You may fall out of ketosis temporarily, but it doesn’t mean you’ve lost metabolic flexibility, you still have the ability to make ketones if you return to eating ketogenically in a timely manner. In fact, periodic, short term detours from eating low carb might be a good thing. There are some who advocate a cyclic ketogenic diet or carb nights. This is based on the concept of hormesis, i.e. a beneficial effect is achieved from a low dose of a stressful event which would otherwise be highly detrimental in higher doses. After all, our ancestors ate according to seasonal cycles, fattening up for the winter. So an occasional celebration may not be such a bad thing. But individual results may vary. If cognitive issues result from any dietary deviation, then it is probably best to stick to the diet.
Is a low carb diet and a ketogenic diet the same thing? A ketogenic diet is a low carb diet, but a low carb diet isn’t necessarily a ketogenic diet. A ketogenic diet is followed with the purpose of maintaining ketosis. Just being low carb does not guarantee ketosis. Additionally, the level of carbohydrate intake for reaching ketosis is individual. Some are able to eat more than 50 grams of carbs and maintain ketosis, especially if they practice intermittent fasting and exercise. Conversely, there are those who react greatly to any carbohydrate intake and must be very strict with maintaining low levels. This was why the Atkins diet recommended different phases where you start with low carbohydrate intake, then add carbs in 5 gram increments to determine the level of carbohydrates needed for that was right.
Can you be ketogenic as a vegan? One can be maintain ketosis with a vegan diet very easily by using avocados, olive oil, nuts and intermittent fasting.
Who shouldn’t do a ketogenic diet? If you are diabetic and on medication, e.g. insulin, if you are on medication for high blood pressure, or if you are breastfeeding it would be best to seek support from a medical professional familiar with ketogenic diets before pursuing one.