Kim [16] has discussed the origin of the so-called ‘ketogenic diet’ (ketone generating, high-fat, and low carbohydrate diet) developed by Dr. Russell Morse Wilder in the 1920s. Wilder’s work represents the first recorded application of the ketogenic diet for epilepsy management. The ketogenic diet utilisation for epilepsy management evolved in fact from a diabetic clinical case investigated/reported in 1922 (although, fasting type diets were developed in advance of the 1920s) as discussed additionally elsewhere [17–19]. The diet developed thereafter into sport applications gradually (key work in the 1980s [19]) with weight management applications in parallel [20]. The complementary low carbohydrate Atkin’s weight management/loss diet [21, 22] was actually initiated in the 1960s and 1970s (Table 3). The whole basis of the ketogenic dietary approach is to generate ketone bodies (Figure 1 and Table 4) from fat (fatty acid metabolism) for energy rather than using glucose as the primary energy source. Glucose reserves in the body (glycogen) are depleted rapidly (during work) compared to fat stores. This is the underlying mechanism considered desirable for optimal sport performance and weight management (Table 3, and discussed elsewhere in the text) by many. On the other hand, medically it is the neurological excitability role of glucose that is managed by a high lipid diet for epilepsy/seizures (Table 3); where ketone bodies are utilised by the brain instead for energy.

There are actually a number of different formats (four essentially) of the original ketogenic (low carbohydrate/ketogenic) diet:

(i)

Original ‘long-chain triglyceride’ variant (4:1 or 3:1 fat:protein plus carbohydrate).

These forms of diet are discussed in more detail elsewhere [18, 25–32].

Details about the ketogenic diet in terms of metabolism and impact on blood glucose control especially, may be found in a recent review by Qi and Tester [33]. This provides more information about the key ketone bodies generated as an energy source from lipid metabolism—acetoacetate, acetone, and β-hydroxybutyrate (Figure 1). Their alternative names are used often, too, as defined in Table 4. In terms of energy provision and impact, blood ketone concentrations above 0.5 mM represent a state of ‘nutritional ketosis’ where 3–5 mM can be achieved on the ketogenic diet [34].

It is very hard when reviewing the literature to come to a definitive position with respect to the long-term impact of the ketogenic diet on sport performance and weight loss [20]. Most success for the diet is reported on time-frames of up to (less than) one year [35]. Optimising sporting performance is a long-term commitment. According to Kaspar et al. [19] with respect to sport applications, low carbohydrate-high-fat and low carbohydrate ketogenic diets provide minimal benefit to athletes’ performance across different events. Harvey et al. [36] acknowledge that although ketogenic diets may result in undesirable side effects (such as altered blood lipid profiles, abnormal glucose homeostasis, increased adiposity, fatigue, and gastrointestinal distress) ketone body supplements can induce ketosis and as a consequence provide energy for exercise performance. The same authors indicate that the ketogenic diet provides a promising strategy to treat obesity, diabetes, and cardiac dysfunction whilst other authors see this potential less favourably. For weight loss, low carbohydrate diets are unlikely to produce significant long-term weight loss and in fact, may lead to serious health problems [37]. Seizure management control success due to consumption of the ketogenic diet is much better documented (discussed in more detail below).

High-fat (especially animal fat, with relatively high saturated fatty acid contents and presence of cholesterol) diets are associated with cardiovascular, diabetes, and cancer risks amongst others. It may be that a high plant-derived fat diet is altogether different in health outcomes than one rich in animal fats although that is not clear. The health debate concerning high-fat diet impacts on health has been reviewed in detail elsewhere [38, 39]. Although a high intake of dietary fats, especially saturated, has been linked to an increased risk of diabetes and cardiovascular disease the Mediterranean type-diet provides healthy monounsaturated fats which are apparently more effective in preventing cardiovascular mortality and coronary artery disease than low-fat, low-cholesterol diets [38]. The antioxidant and anti-inflammatory effects of these types of diets are potential mediators of these benefits [38].

Increasing the source of ketone bodies in the diet may be achieved by consuming a high-fat diet and by consuming the ketone bodies themselves. In recent years ketone body salts (for example calcium, magnesium, and sodium salts of 3-hydroxybutyrate) or specific lipid precursors of ketone bodies (e.g., medium chain triglycerides) have been added to nutrition/sport nutrition products directly (‘exogenous’ supply of the molecules). This approach is designed to drive upward the ketone concentration of the blood and thereafter ketone utilisation by the body. This area of nutrition research has been reviewed by many authors; although it is in its relative infancy [34, 40, 41]. No obvious detrimental health effects of eating these molecules at the concentrations used have been reported. In fact, four main exogenous routes of indirect/direct ketone body supply have been utilised in recent years [34, 42]:

(i)

Medium chain triglycerides (a mixture of 8 and 10 carbon fatty acids).

The calorific value of exogenous ketone bodies is approximately 4 kcal/g (17 kJ/g). However, according to Owen and Hanson [43], acetoacetate enters cells from either the (i) extracellular fluid or (ii) mitochondria, generated from β-hydroxybutyrate conversion by β-hydroxybutyrate dehydrogenase. This conversion in parallel, reduces nicotinamide adenine dinucleotide (NAD) to NADH. The β-hydroxybutyrate has a greater calorific content than acetoacetate of 4.5 kcal/g (19 kJ/g) versus 4 kcal/g (17 kJ/g). A comparison of this energy content is made with food macronutrients in Table 5. They are similar to digestible carbohydrate and protein in energy value.

Exogenous ketone consumption can certainly create ketosis [44]. According to many reports ketone bodies (such as the four exogenous forms described above) can in fact have a range of desirable therapeutic applications [29, 30, 35, 45]. One such application is cardiovascular disease as discussed by Yurista et al. [42]. They report that ketones (ketone bodies) can provide fuel for a failing heart, with a large range of other effects. These include improving endothelial function, ameliorating oxidative stress, improving mitochondrial function, exerting anti-inflammatory action, and mitigating cardiac remodelling. In addition, they report broad physiological impacts on body weight, blood pressure, glycaemia, and blood lipid profile. Takahara et al. [45] have described similarly the therapeutic benefits of ketone bodies during heart failure. Ketogenic metabolic therapy has been proposed for (breast) cancer [46]. In a recent review Neha and Chaudhary [47] discuss the ketogenic diet’s impacts on cancer more generally they indicate that the diet can augment the efficacy of conventional therapies by impacting on the ‘metabolic dynamics of cancer cells’. Diabetic benefits of a ketone generating/consuming diet are perhaps an obvious therapeutic option, in view of the reduced consumption of digestible carbohydrate and the associated impact on circulating insulin concentrations etc. [30], where ketogenic diets improve insulin sensitivity in particular [48]. Impacts on brain health are relevant too. Brain focussed ketone body therapy for diseases such as epilepsy, Alzheimer’s Disease, and psychiatric disorders have been discussed by Hashim and VanItallie [49] and Kovács et al. [50]. Apart from the many physical and psychiatric benefits of the ketogenic diet/ketones [30], there are also positive impacts on the body’s gut microbiome (profile) and more generally/systematically at the epigenome level of genetic expression [30]. Signalling roles of β-hydroxybutyrate link the outside environment to both gene regulation and cellular activity, relevant to a range of different human diseases and the aging process [51]. Whilst some authors [52] promote the long-term benefits of ketogenic diets for weight management in particular, where in parallel it decreases blood concentrations of triglycerides, low-density lipoprotein cholesterol, and blood glucose whilst increasing high-density lipoprotein cholesterol more recent reviews are not always as committed. Batch et al. [35] for example report that although the diet has a favourable impact on high-density lipoprotein cholesterol, there in fact a concomitant increase in low-density lipoprotein cholesterol and very-low-density lipoproteins which may lead to increased cardiovascular risks. Thus, further research is necessary to evaluate the long-term implications of the ketogenic diet according to these authors.

Aside from the health benefits of consuming the ketogenic diet discussed above, Crosby et al. [29] have indicated that although for most individuals the benefits outweigh risks, there are many risks consumers (of these types of diet) need to consider. For very low carbohydrate diets:

(i)

Increased exposure to low-density lipoprotein-cholesterol.

More broadly, because non-carbohydrate-based food consumption increases for high-fat diets, increased exposure to lipids and proteins may have positive and negative disease-causing impacts (depending largely on amount and frequency consumed), which include:

(i)

Alzheimer’s disease (some potential benefits).

Wali et al. [38] have explored these issues—noting that ‘It is widely accepted that increased intake of fat, especially saturated fat, is a major driver of the increase in obesity and increased incidence of cardiometabolic disease.’ with further reference to EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA) [56] and Eckel et al. [57] in particular.

High-fat low-carbohydrate diets may exacerbate or cause hypercholesterolaemia in patients, be they with or without underlying genetic hyperlipidaemia [58]. These authors expanded their views further, especially for people with preponderance to dyslipidaemias, indicating that elevations of low-density lipoproteins with these diets does have the potential to create premature cardiovascular disease (especially with patients seeking to control their body weight).

With respect to epilepsy management, Williams and Cervenka [59] have also discussed the types of adverse effects of the diet on patients. These include:

(i)

Gastrointestinal effects (constipation, diarrhoea, and vomiting).

Overall, on one hand, essential fatty acids and unsaturated fatty acids are required/desirable in the diet, whilst on the other hand, saturated fatty acids and cholesterol are associated with poor health impacts [60–62]. They are all, regardless, providers of unnecessary calories if consumed in excess. Their major health-related aspects/impacts are highlighted in Figure 2. It is very important to avoid carrying excess body fat but retain a desirable body mass index (although the measurement does not reveal where the fat is, but acts as a general overview). See for example Nuttall [63]. Law [64] was very explicit about the risk of eating saturated fat: ‘Reducing dietary saturated fat by 7% of energy, a realistic target, would reduce serum cholesterol by 10% and mortality from ischaemic heart disease by 25–30%.’. Hence, it is critical when consuming a ketogenic type diet that an understanding of fat quality underpins the products consumed. Vegan focused products would provide a much healthier fat profile than fats derived from the majority of animal (including and perhaps especially dairy) related sources.