Ketosis

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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.

From Dr Ted Naiman’s presentation "Hyperinsulinemia" Low Carb Breckenridge, Feb 25, 2017, http://denversdietdoctor.com/ted-naiman-hyperinsulinemia/, at ~17:10.

Access to the ketone “fuel tank” has been likened to deep storage because it is not easily accessed. It is 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, it’s a 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 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. 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, that process still continues. The good news is after the keto flu passes many people experience an increase in energy levels.


Urine is considered imprecise, a meter is perhaps the best method for monitoring personal ketone 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, 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
  • exercise
  • fasting at least 12 hours, with 16 hours preferred for ApoE4s
  • and 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’s 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, no need to buy two meters, it is called Keto-Mojo


Dr Bredesen recommends mild ketosis or about 0.5 mmol/L to 4.0 mmol/L.

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 and cognition.

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, 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.

Other positive health advantages that have been cited with ketosis are: 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 needs this energy 24 hours a day. The brain typically gets it’s 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)

Source: Stephen C Cunnane, et al., 08 July 2016, “Can Ketones Help Rescue Brain Fuel Supply Later in Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease” Frontiers in Molecular Neuroscience, 9-53, DOI: 10.3389/fnmol.2016.00053

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:

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 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[3]."
"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.”


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

Ketosis and longevity

Ketogenic Diet

Common Criticisms of Ketogenic Diets Addressed

Some Questions and Answers regarding Ketosis and the Ketogenic Diet