What is ketosis and why do humans enter it? An introduction to the evolutionary biology of ketosis, fasting, and the ketogenic diet.

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The following is an early, edited draft of a subsection of an upcoming scientific review.

Definition of ketosis and composition of the ketogenic diet

Ketones are always being produced in the liver, released into the blood, and utilized by the peripheral tissues, even in the fed state [1,2]. Transgenic mice lacking SCOT, a gene critical for utilizing ketones, die within two days from ketoacidosis [3]. A calorie-restricted diet, even one that does not specifically restrict carbohydrate but reduces all macronutrient calories equally, will produce higher blood ketones and higher ketone utilization than a non-restricted diet [4,5]. Enhanced ketogenesis and ketosis also occurs after an overnight fast and after vigorous exercise [6]. Thus, in an important sense, ketosis and ketonemia is the constitutive state of most living organisms. Ketosis as a metabolic state is thus not dichotomous but a sliding scale.

There are three ketone bodies. These ketone bodies define ketosis. They are acetoacetate (AcAc), beta-hydroxybutyrate (BHB), and acetone. In the normal individual, levels of BHB and AcAc are below 0.1 mM, and acetone is undetectable. In human starvation, levels of BHB can reach nearly 6 mM, AcAc above 1 mM, with acetone concentrations similar to AcAc [7].

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Acetone has conventionally been thought of as a “minor” ketone body of relatively little biological importance, the product of spontaneous, non-enzymatic decarboxylation of AcAc in the blood [8]. Recent studies have suggested a minor role for acetone in the biosynthesis of acetate and therefore of cholesterol and fatty acids [9], and perhaps even a role in the anti-epileptic effects of the ketogenic diet [10]. Most research however has focused on the biological effects of BHB and AcAc.

Because ketone production and metabolism are often the means to a particular therapeutic endgoal, ketosis is often considered for practical purposes as having a “cutoff”. This cutoff has been defined by important figures in the field as around 0.5 mM [11,12], and this definition is generally accepted. According to this framework, nutritional ketosis is defined as between 0.5 mM to 3 mM and fasting ketosis as BHB between 5 and 10 mM, each of which are far below the 15-25 mM seen in diabetic ketoacidosis [12], which requires insufficient insulin signaling such as in type 1 diabetes to develop. Except in rare cases [13,14], in healthy people, nutritional ketosis does not lead to and has none of the harmful effects of ketoacidosis [12].

It is important to note that the above definition of nutritional ketosis is largely based on a carbohydrate-restricted diet similar to that advocated by Atkins. Substantially higher values than 3 mM are reported among those consuming MCT oil diets and classic ketogenic diets [15]; anecdote and some evidence suggests that ketogenic diets higher in unsaturated fatty acids might also produce higher blood ketones than on the typical animal-rich ketogenic dietary pattern [16–18].

Ketosis is increased and nutritional ketosis induced by carbohydrate, protein, and fat restriction (in that order of importance). The more one restricts carbohydrate and protein, the higher the expected blood ketone levels, mimicking the fasted state. The 3:1 and 4:1 classical ketogenic diets, so-called because they consist of a three-to-one and four-to-one ratio of fat grams to carbohydrate and protein grams, respectively, produce the highest degree of ketosis, while the modified Atkins diet and low-glycemic index treatment produces among the lowest.

In the diabetes and obesity fields and in the popular and scientific press more generally, ketogenic diets are defined somewhat differently than they are in the epilepsy field specifically (though terminology frequently crosses over). This is because specific blood ketone targets are often less the goal than carbohydrate restriction is. A review article written by many of the most influential contemporary scientific proponents of a carbohydrate-restricted diet for the treatment of obesity, diabetes, and other chronic diseases defines a low-carbohydrate diet as being in the range of 50-150 grams per day, and a very-low-carbohydrate ketogenic diet as in the range of <20-50 grams per day [19].

Major ketogenic diet types and their compositions are listed below.

Diet name F:C&P* Fat kcal % Carb + protein kcal % References
Classic 4:1 4:1 90% 10% [19–22]
Classic 3:1 3:1 87% 13%
MCT oil diet 1.9:1 50%/21%** 29%
Low glycemic index treatment 1:1 60% 30%
Modified Atkins diet 0.8:1 65% 35%
Low-carbohydrate diet N/A N/A 50-150 g/d carbs
Very-low-carbohydrate ketogenic diet N/A N/A <20-50 g/d carbs
* F:C&P is the ratio of fat to protein and carbohydrate. This is calculated in grams, not kilocalories.
** Percent of calories from medium chain triglycerides / long chain triglycerides (MCT/LCT)
Ketogenic diets used in clinical practice may deviate substantially from the above.

Why ketosis?

In most prokaryotes, ketone polymers in the form of complexed polyhydroxybutyrate (cPHB) are an important energy storage molecule and ketone bodies an important source of energy. This energy system may be as old as 2-3 billion years and may have evolved as an important energy substrate under conditions of oxygen deprivation, due to the higher ratio of ATP produced to oxygen consumed characteristic of ketone bodies [23]. While low levels of circulating cPHB are found in human serum, in cells (reportedly in granules), as essential non-protein components of ion channels, and may have a multitude of other important biological effects that have yet to be fully characterized [23,24], this energy storage form is not thought to be important source of energy in normal mammalian physiology. Conceivably, this is because monomeric BHB can be readily generated from fatty acids, which in mammals are stored in triglycerides; in contrast, prokaryotes do not have generate or use triglyceride molecules [23].

Although polymeric BHB is not an important energy storage form of BHB, BHB itself is readily produced and oxidized by mammals in periods of starvation as an alternative to glucose. Ketone bodies are an alternative to glucose as an energy source in mammals. Classic experiments by George Cahill and others in the 1960s and 70s demonstrated the role of ketone bodies and especially beta-hydroxybutyrate in the maintenance of cognitive function during starvation. In one study of three obese subjects fasted for 5-6 weeks each, arteriovenous metabolite concentration differences showed that a mean of 65% of energy substrate used by the brain directly derived from beta-hydroxybutyrate and acetoacetate, 55% and 10% respectively [25]. Indeed, evidence in rodents suggests that as ketosis proceeds, the proportion of energy derivable from ketone bodies also increases due to increases of the blood-brain barrier permeability to ketones [26,27]. After Cahill’s initial studies, another pair of studies conducted by Cahill and a group at UCLA almost concurrently showed that subjects subjected to long-term starvation and then injected with insulin to produce profound hypoglycemia showed no symptoms and intact cognition [28,29]. The subjects reached blood glucose readings as 0.5 mM, i.e. 6-fold lower than the 3.0 mM that in normal circumstances produces symptoms and is regarded as dangerous. These levels are typically regarded as fatal, and these studies were landmark demonstrations of BHB as an alternative fuel source in the brain.

Why is the brain in particular so effective at using ketone bodies?

Due to their ancient evolutionary pedigree, before the split between archaea and prokaryotes [23], production and metabolism of ketones are ubiquitous among animals, including fish [30] and insects [31]. Yet humans produce more ketone bodies in response to starvation than any other known species, and this is likely because the human brain accounts for a larger proportion of the body’s energy expenditure compared to the brains of other species [23]. The brain does not metabolize such fatty acids to any appreciable degree due to an oxidative defect in neurons and astrocytes, probably due to the high energetic demands of the brain and vulnerability to oxidative stress [32]. The brain is therefore heavily reliant on glucose. If this reliance on glucose persisted during the course of starvation, i.e. in the absence of exogenous glucose in the form of dietary carbohydrate, the body would need to provide for the brain’s glucose needs by breaking down the body’s protein (mainly skeletal muscle) and converting it to glucose.

This would quickly lead to muscle loss and rapid death. Since the brain requires 100-145g of glucose per day [33], and the theoretical maximum rate conversion of protein to glucose is 60% [34], and the body’s protein stores are approximately 6,000g but only about 3,000 can be mobilized before death, and the body would need to catabolize 170-240g of protein per day to sustain the energy needs of the brain alone, it follows a starving human would survive for a maximum of 18 days and a minimum of 12, depending on how much energy their brain required [1]. Furthermore, a human surviving just a short period of starvation, e.g. 1 week, would be rendered frail due to skeletal muscle loss, impairing physical function and probably odds of future survival.

Ketones, produced when exogenous glucose and thus insulin is sufficiently low, fill the gap, allowing mammals to survive for extended periods of time while fueling the brain and minimizing the impact to the body’s own protein and thus to skeletal muscle. Early experiments in starved subjects showed clearly that glucose infusions were sufficient to drastically reduce both nitrogen excretion and blood ketone levels, and that each of these increased in tandem on the day that the glucose infusions were stopped, after which nitrogen excretion then declined, a classic sign of compensatory response [23]. Correspondingly, upon BHB infusion, endogenous glucose production by the liver is decreased [35], tissue uptake of glucose is impaired in many tissue types [35,36], and blood levels of important gluconeogenic amino acids decline [36,37]. Extended fasting periods far exceed anything possible if the brain consumed strictly glucose; this is shown by the famous case report of A.B., a 27-year-old male who survived a 382-day therapeutic fast [38]. The opposite is also true: individuals homozygous for the CPT1A P479L variant show impairment in hepatic fatty acid oxidation are hypoketotic and hypoglycemic in response to carbohydrate restriction and cannot tolerate fasting [39]. Ketonemia, or high levels of blood ketones, is therefore critical to muscle maintenance during fasting or during periods of low-carbohydrate intake (such as occurs on the ketogenic diet).

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