Ketosis and Ketogenic Diet
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, in other words a low-carb, high good fat diet. One can encourage ketones in the body through exogenous (supplemental) ketone ingestion, see Coconut Oil, MCT oil, and other Ketone/Cognition Boosters (salts, esters), but that is not a ketogenic diet. Additionally, while supplementing with a ketone booster can be a very beneficial strategy when transitioning to a ketogenic diet, it should be a temporary measure. Dr Dale Bredesen, internationally recognized expert in the mechanisms of neurodegenerative diseases, refers to coconut oil and MCT oil by saying, ”But both may also have drawbacks for ApoE4-positive individuals …If you are ApoE4 positive, think of MCT and coconut oil as temporary crutches to ease your segue into fat burning mode.”
Access to the ketone “fuel tank” has been likened to deep storage because it is not easily accessed. It is like the 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, can the body use fat for energy.
Simply following a low-carb, high fat 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; therefore, 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. See http://www.artandscienceoflowcarb.com/. 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. But there are things that can be done to mitigate these symptoms. This website provides good advice, Low Carb side effects & how to cure them. 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.
Once a person has been burning fat for a while and is truly keto adapted, the liver will become more efficient at producing ketones. The brain’s energy needs are high but static, the liver will “learn” to produce just the right amount of ketones that the brain needs and will no longer produce excess in the urine (one of the reasons urine strips for monitoring ketones is not ideal) and through the breath (eliminating the“keto breath” that some experience when initially transitioning.)
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 one's level of ketosis, ketones can be measured one of three ways: urine, blood, and breath.
Urine Strips. Urine strips are good for the beginner trying to get into ketosis, but Dr Bredesen’s book cautions that urine testing is imprecise. Ketones in urine are waste products and highly dependent on sweat and intake of fluid. It’s conceivable the body can be making ketones and using all of them, with no leftover ketones to excrete. Conversely, especially if ingesting products for the purpose of raising ketones (exogenous ketones), if the body doesn’t use the ketones, it will just excrete them via the urine, so the high level of urine in ketones may just reflect what the body is not using.
Blood Meter. Many use a blood ketone tester via a finger stick, similar to glucose meters. Appendix B of Dr Bredesen’s book discusses ketone meters. Since the publication of Dr Bredesen’s book, blood meters have been introduced that measure both ketones and glucose: Keto-Mojo, Abbott Precision Xtra or KetoCoach. These dual glucose/ketone meters are very handy since both glucose and ketone measurements provide important dietary insight. The drawback to these meters, both single ketone meters and dual ketone/glucose meters, is in the recurrent cost of strips, although once one has learned they are in ketosis and understand their body’s response to food, the need to test, thus the cost, diminishes. Blood meters measure the ketone Beta-hydroxybutyrate (BHB), which is the current buffer of ketone energy in blood; in other words the BHB is in storage ready for use. When the body’s store of BHB raises, this indicates that the body is purposefully making ketones for energy and that person is in ketosis, so a blood meter is a very good tool that produces consistent results and is easy to use. However it’s important to understand the limitations. For example, if a person has been ingesting exogenous ketones (discussed below), a high value on the blood meter may indicate the body is making ketones and is in ketosis, or it may be reflecting the exogenous ketones. Additionally, especially after a person has been practicing a ketogenic diet for a while and the body becomes more efficient at using ketones, a zero or low value may indicate that the person is in ketosis but out of stores for BHB, or it could just mean that person is not in ketosis. So if using a blood ketone meter, it helps to understand one’s body and the other indications of being in ketosis.
Breath Meter. Breath meters measure the ketone called acetone, the resultant by-product of using Beta-hydroxybutyrate (BHB) that a person exhales. It provides a real time measure of the ketones the body is using, vs the BHB in blood storage, so it reflects actual ketosis. A properly taken measurement of zero or low value means you are out of ketosis. A significant value means your blood sugar levels are low enough to trigger ketosis and you are in ketosis. Breath meters only require the upfront cost of purchase, and there are no additional recurring costs, but they do require some experience to master in order to get consistent results. Acetone is heavier than most the air in the lungs, so one must exhale fully to get an accurate measurement. The measurement one gets from a breath monitor is different than a blood monitor, so one cannot correlate a breath measurement to the 0.5 mmol/L to 4.0 mmol/L range recommended by Dr Bredesen.
This 16 minute video might help better explain the difference between the two meters: Michel Lundell - To assess-ketosis by blood or breath-testing?
This is an interview conducted by Chris Kresser with Trey Suntrup, product head of the ketone breath meter Biosense. In the interview they discuss different ketone testing options and, of course, the breath meter Biosense. This link includes an audio recording to listen to the 48 minute interview, a link to a video, and a transcript to read if that’s your preference. RHR: How to Accurately Measure Ketones, with Trey Suntrup posted Oct 27, 2020
Ketogenesis is the biochemical process by which the body makes 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 (coconut oil, MCT oil, MCT oil powder). Consuming exogenous ketones can aid with heightening levels of ketones in the body and cognition, but exogenous ketones alone may not result in a person being ketogenic. For a deeper discussion of exogenous ketones, see Coconut Oil, MCT oil, and other Ketone/Cognition Boosters (salts, esters).
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, which 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.
Ketosis and ApoE4
Ketones generate more energy than glucose. Ketones increase Gibbs free energy for ATP by 27% compared to glucose. ATP is the energy that the mitochondria produce for our cells, so in other words, when calorically matched, we get more energy from ketones. Ketones burn “cleaner” than glucose. 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. A ketogenic diet reduces inflammation, see Dr Stephen Phinney – Inflammation, Nutritional Ketosis and Metabolic Disease Ketones increase Brain Derived Neurotrophic Factor (BDNF) see Ketone beta-hydroxybutyrate up-regulates BDNF expression through NF-κB as an adaptive response against ROS, which may improve neuronal bioenergetics and enhance neuroprotection . Ketones also work as signaling molecules Ketone bodies as signaling metabolites and is said to improve certain metabolic pathways. Ketones also stabilize brain network communication. (L. R. Mujica-Parodi, et al, 2020)
Positive health advantages due to ketosis have been 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) (Chen, Z, et al., 2013) 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, 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 is also recommended for dementia by Dr Steven Gundry. He offers specific dietary guidelines for this in his "Keto Plant Paradox" plan as discussed in his book The Plant Paradox. See Dr Gundry's 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.
Some Videos/audios for more information on ketones and Alzheimer’s
- Dr. Stephen Cunnane - Brain Glucose and Ketone Metabolism Oct 31, 2018
- Dr Steven Cunnane - Can Ketones Slow Down Alzheimer's Mar 8, 2018
- Dr Dom D'agostino - The Ketogenic Diet & Alzheimer's and the Brain Feb 12, 2018 - includes some discussion of ApoE4
Additional references on ketosis or the introduction of ketones on cognition /Alzheimer’s
- Diet modulates brain network stability, a biomarker for brain aging, in young adults (L. R. Mujica-Parodi, et al, 2020)
- Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.
Accompanying this paper is this STEMtalk interview with the primary author, Dr Lilianne Mujica-Parodi, PhD. The 57 minute mark is where she discusses the area of most interest to ApoE4s: ketones, insulin resistance, and glucose hypometabolism.
- Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (Wu L et al, 2018)
- SIGNIFICANCE STATEMENT We uncovered hexokinase as a key cytosolic point in the glucose metabolism that is differentially modulated by the three ApoE genotypes. The differences in hexokinase expression and activity exhibited in the three ApoE brains may underlie their distinct impact on brain glucose utilization and further susceptibility to AD. Therefore, a therapeutic approach that could circumvent the deficiencies in the cytosolic metabolism of glucose by providing glucose metabolizing intermediates, e.g., pyruvate, may hold benefits for ApoE4 carriers, who are at high risk for AD. The bioenergetic robustness may translate into enhanced synaptic activity and, ultimately, reduces the risk of developing AD and/or delays the onset of clinical manifestation.
- The ketogenic diet as a potential treatment and prevention strategy for Alzheimer's disease(Gina M. Broom et al, Oct 2018)
- •Impaired brain glucose metabolism and amyloid β plaques are associated with Alzheimer's disease pathology.
- •Ketones provide an alternative metabolic precursor to glucose in the brain.
- •Ketogenic diets likely reduce amyloid plaques and may reverse their neurotoxicity.
- •Modern diets high in carbohydrates may contribute to increasing Alzheimer's incidence.
- •The ketogenic diet (including carbohydrate restriction) might be useful in the management of Alzheimer's disease.
- A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease (E. Croteau et al, Jul 2018)
- •Brain energy hypometabolism in MCI and AD is specific to glucose.
- •Mild ketone hypermetabolism occurs in some regions in MCI
- •Ketogenic interventions may correct the brain glucose deficit in MCI or AD.
- 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 the patient “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.”
- Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β‐amyloid toxicity, and astrocyte function (Hertz, L. et al, 2015)
- Concluding remarks Alzheimer's disease as well as some forms of epilepsy can be treated more or less effectively with ketogenic diet. In epilepsy, it appears advantageous to administer the highest possible fraction of the patients’ calorie need in the form of ketone bodies, which may reduce glucose metabolism sufficiently to impair glutamate production in neurons. Much lower doses of ketone bodies can have therapeutic effect in Alzheimer's disease by different mechanisms. Enabling ketone bodies to supply a fraction of needed ATP may partly compensate for the deficiency in glucose metabolism in Alzheimer's patients. An alternative mechanism of action could be to prevent or reduce gliotransmitter release of glutamate. Stimulation from subcortical nuclei can induce gliotransmitter release besides decreasing inflammation and enhancing metabolism. The early destruction of these nuclei has up till now provided little or no impetus for drug development, but the recent conclusions regarding their importance by Heiko Braak, a giant in Alzheimer research, may hopefully lead to a change.
- 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.”
- Nutrition and Alzheimer's disease: The detrimental role of a high carbohydrate diet (Seneff S et al, 2011)
- Learning points
- The amyloid-β present in Alzheimer's plaque may not be causal, since drug-induced suppression of its synthesis led to further cognitive decline in the controlled studies performed so far.
- Researchers have identified mitochondrial dysfunction and brain insulin resistance as early indicators of Alzheimer's disease.
- ApoE-4 is a risk factor for Alzheimer's disease, and ApoE is involved in the transport of cholesterol and fats, which are essential for signal transduction and protection from oxidative damage.
- The cerebrospinal fluid of Alzheimer's brains is deficient in fats and cholesterol.
- Advanced glycation end-products (AGEs) are present in significant amounts in Alzheimer's brains.
- Fructose, an increasingly pervasive sweetening agent, is ten times as reactive as glucose in inducing AGEs.
- Astrocytes play an important role in providing fat and cholesterol to neurons.
- Glycation damage interferes with the LDL-mediated delivery of fats and cholesterol to astrocytes, and therefore, indirectly, to neurons.
- ApoE induces synthesis of Aβ when lipid supply is deficient.
- Aβ redirects neuron metabolism towards other substrates besides glucose, by interfering with glucose and oxygen supply and increasing bioavailability of lactate and ketone bodies.
- Synthesis of the neurotransmitter, glutamate, is increased when cholesterol is deficient, and glutamate is a potent oxidizing agent.
- Over time, neurons become severely damaged due to chronic exposure to glucose and oxidizing agents, and are programmed for apoptosis due to highly impaired function.
- Once sufficiently many neurons are destroyed, cognitive decline is manifested.
- Simple dietary modification, towards fewer highly-processed carbohydrates and relatively more fats and cholesterol, is likely a protective measure against Alzheimer's disease.
- Learning points
Boldface added to direct attention to learning points addressing ketosis
- 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
- Nutritional modulation of heart failure in mitochondrial pyruvate carrier–deficient mice (K. S. McCommis, et al, Oct 2020) The full text of this paper is behind a paywall, but according to this article about this paper, High fat or 'ketogenic' diets could prevent, reverse heart failure among other take-aways:
- • These results suggest that ketogenic diets do not enhance cardiac ketone body metabolism, but rather stimulates fatty acid oxidation, which may be responsible for the improved cardiac remodeling and performance.
- Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets (A Paoli, et al, 2013)
- “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.”
One type of ketogenic diet is a low carbohydrate diet that is followed 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. When mTOR is not activated, the body turns to repair and maintenance processes: autophagy, see Enhance autophagy, ketogenesis, DNA repair, and activates intracellular antioxidents and Heat Shock Proteins (HSPs), that in turn contributes significantly to healthy longevity. So some feel lowering protein in a diet is more important than lowering the carbs. Additionally, because the body will convert excess protein into glucose via a process called gluconeogenesis, protein consumption could actually inhibit ketosis. Dr Gundry seeDr Gundry's Protocol, 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 as 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. Fruit, except for avocados, should be eaten sparingly and seasonally, see the Limit Fruit section in Insulin Resistance. Eating this way 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 counterintuitive to add starch to a low carb diet but this carb isn’t like other carbs. A resistant starch is a type of starch that “resists digestion” 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 see Fats, Omega -3(ω-3) & -6(ω-6), DHA and More– Avocados, nuts, and healthy oils such as olive oil, avocado oil, algae oil, macadamia oil, perilla oil, walnut oil, red palm oil (not to be confused with palm kernel 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. Dr. Gundry, in looking at both the cardiovascular and dementia risk, has concluded that ApoE4s should avoid coconut oil and has not yet determined the safety of MCT. When addressing coconut oil for ApoE4s on the Gundry Matrix Group Facebook page, he said, "Saturated fats compete for space within the Apolipoprotein 4's molecules ability to recycle cholesterol. No such problem exists if you don't carry the 4. As I write in PP [Plant Paradox] using ketones once you are fighting dementia is for a whole different purpose, and I prefer MCT oil." He has observed that coconut oil elevates sdLDL levels in ApoE4s, sdLDL is the cholesterol that oxidizes ultimately resulting in cardiovascular issues and potentially contributing to vascular dementia. Dr. Bredesen recommends a measured approach with both coconut oil and MCT (preferable) for ApoE4 carriers. When exhibiting symptoms of cognitive decline and/or insulin resistance, he encourages their use in the context of a low carb diet to address reduced cerebral glucose utilization. Once glycemic markers and cognition improve, he recommends using MUFAs and PUFAs (high polyphenol EVOO, olives, avocados, nuts and seeds) to achieve ketosis to avoid an elevation in LDL-p and ApoB. For more info on coconut oil and MCT oil see Coconut Oil, MCT oil, and other Ketone/Cognition Boosters (salts, esters) for mor info on fats, such as MUFAs and PUFAs, see Fats, Omega -3(ω-3) & -6(ω-6), DHA and More
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, they don’t spam you with e-mails after you’ve signed up, and 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. Do note, however, some of the recipes on the website don't align with the recommendations for ApoE4s.
Common Criticisms of Ketogenic Diets Addressed
A common criticism of the ketogenic diet is that the long term effects are unknown. This can probably be interpreted to mean there are insufficient clinical trials. But we do know long term effects. It’s called human history. In terms of evolutionary biology, we'd been on a ketogenic diet for about 3,000,000 years. Man often went through periods of little/no food. We were in a feast or famine mode all the time switching from glucose to ketones, metabolic flexibility, not by choice but because of food availability. When we had excess calories, we would deposit those calories in the form of triglycerides, our livers would make fat, adiposity. When the famine came, our bodies would then utilize the deposited fat. There are some who advocate following a yearly cycle of abundant food during the warm months followed by fasting/calorie restriction during the cold months, similar to what our ancestors experienced. 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 and since that time rates of obesity have increased significantly (source: Centers for Disease Control and Prevention). 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, it enabled man to survive weeks to months with inadequate food sources. In other words, to get through the winter or to hang in there until the animal migration occurred.
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 include 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, urine that smells different, 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 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. 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 very low carbohydrate intake, then add carbs in 5 gram increments to determine the level of carbohydrates that is right for that individual. The level of a person's carb intake may also be directed by where that 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 and maintaining metabolic flexibility 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 is recommended.
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.
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, a person can even gain weight on a ketogenic diet if they consume excess calories. Those who do lose too much weight with this approach, may need to change the way they are achieving ketosis. Rather than using long fasts, they may need to eat more healthy dietary fat over several meals until a healthy weight has been achieved. There is a difference between starvation ketosis and nutritional ketosis.
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. (See Insulin Resistance in the brain) 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 it’s doubly advantageous for APOEε4s, in addition to providing a secondary source of fuel for the brain, it helps the brain access the glucose it needs.
I heard ketosis can raise glucose and cause insulin resistance, isn’t that bad? It is true that some people who go low carb or ketogenic discover their fasting glucose levels become elevated (> 90 mg/dL). This has been called Physiological Insulin Resistance, but it is benign, it's a condition very different from the insulin resistance associated with Type 2 Diabetes. More recently Physiological Insulin Resistance has been referred to as Adaptive Glucose Sparing to more accurately reflect what’s occurring. Physiological Insulin Resistance aka Adaptive Glucose Sparing occurs as a result of metabolic adaptation when the muscle tissue becomes insulin resistant in order to preserve serum glucose availability for the brain, a rather elegant solution to maximizing fuel availability for the brain. It can, however, result in a failed glucose tolerance test. If directed to take an oral glucose tolerance test, increase carbohydrate intake to ~150g for a few days and then take the test. The few days of increased carbohydrate intake will let the body adapt to increased carbohydrate availability and the physiological insulin resistance will go away.
Isn't all that saturated fat bad? If you eat a high saturated fat diet as an ApoE4, then that is likely a poor combination. So don't eat so much saturated fat! A ketogenic diet does not have to equate to a high saturated fat diet. For more information on fats see Fats, Omega -3(ω-3) & -6(ω-6), DHA and More
If I splurge at a wedding, special family gathering, etc. will it knock me out of ketosis? Recognize the longer you've been in ketosis, the faster you'll bounce back. You may fall out of ketosis temporarily, but if you are keto-adapted or fat adapted, 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.
Can you be ketogenic as a vegan? One can maintain ketosis with a vegan diet by using avocados, olive oil, nuts and intermittent fasting. It’s more difficult than being vegetarian with some fish/eggs, but it can be done. One resource, Vegan Keto Made Simple group on Facebook.
What about keto crotch? There is no medical evidence to suggest nutritional ketosis can cause offensive vaginal odors, rather just the opposite is indicated. This headline appears to be based on a handful of anecdotes from old reddit discussion boards, fake news, perhaps instigated by interest groups aimed at keeping the benefits of a ketogenic diet diminished.
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.