Traditionally thought of as a toxic byproduct of fat oxidation, ketone bodies are now seen in a more favourable light. New therapeutic roles have emerged for them in health, disease and even exercise performance. This article will provide a brief overview of what ketone bodies are, how they are generated and their therapeutic potential for health and disease.
What Are Ketone Bodies?
Strictly speaking, ketone bodies encompass three compounds, namely, acetoacetate, beta-hydroxybutyrate (BHB) and acetone, with the major circulating form being BHB (1). Ketone bodies are typicalled generated under conditions of limited carbohydrate availability, such as fasting or low carbohydrate diets (1). In such instances, the body’s stores of carbohydrates are depleted and it is forced to increase use of fatty acids to make up the energy deficit.
In fact, whenever the body significantly accelerates its use of fatty acids, it starts to generate ketone bodies. Which is why they are called a by-product of fatty acid oxidation. This process of making ketones (i.e. ketogenesis) occurs primarily in the liver.
Physiological vs Pathological Ketosis
Ketogenesis was originally thought to be a ‘back-up’ energy system for the body to fuel key organs such as heart and brain during times of food restriction or starvation. However, in today’s western world where hunger and poverty are not major problems, individuals are rarely in a state of starvation. This is in contrast to our ancestors who lived largely as hunter/gatherers and as such had days at a time where food intake was negligible (2, 3).
Under such conditions, ketogenesis is the primary mechanism used by the body to meet its energy requirements. However, blood levels of ketones under these circumstances is not as high as levels reached during uncontrolled diabetes.
In such instances, blood ketone bodies can reach up to 20mmol/l; several orders of magnitude greater than the levels achieved (i.e., up to 7/8mmol/l) under conditions of very low carbohydrate intake (i.e. <50g/day) or fasting (4).
Famous biochemist Hans Krebs was the first to coin the phrase “physiological ketosis” to distinguish it from the severe pathological state of ketoacidosis commonly seen in uncontrolled diabetes (5).
Weight Loss & Ketosis
Nowadays ketogenic diets are most popular for their efficacy in treating obesity and diabetes. There is strong evidence showing low carbohydrate-high fat diets are more effective than low fat diets when it comes to losing weight; even when the diets have equal caloric value (6).
Of particular note is very low carbohydrate diets have been shown to be more effective for long term weight loss. This article will not go into great detail re the mechanisms by which ketogenic diets help with weight loss as the topic is covered well in our article on low carbohydrate high fat diets.
Suffice to say, one of the major mechanisms is by increasing insulin sensitivity and fat burning. Along with weight loss, successful treatment of cardiovascular disease (7, 8, 9) and diabetes (10, 11) with ketogenic diets also has sound supporting scientific evidence.
Ketone Bodies & Neurological Health
One of the most promising and interesting research areas for the therapeutic use of ketones is in the area of neurological health (4).
This interest is underpinned by the long established benefits of a ketogenic diet for children with non-responsive epilepsy, which were discovered almost accidentally back in 1920.
Research across a range of different areas has suggested ketogenic diets may have potential in the treatment of a range of neurological disorders as broad as headache, neurotrauma, Alzheimer’s & Parkinson’s disease, sleep disorders, autism and multiple sclerosis (12).
While it is beyond the scope of this article to delve into the finer points and mechanisms by which ketogenic diets may help various neurological diseases, this area of research is growing rapidly. It will be exciting to see what comes of it with the massive burden that chronic neurological diseases such as Alzheimer’s & Parkisons disease place on the health system.
Other Diseases That Ketogenic Diets Might Help
Theres also evidence that ketogenic diets may have promise in the treatment of acne (14, 15, 16), cancer (21), polycystic ovarian syndrome (17), amyotrophic lateral sclerosis (18, 19) and respiratory disorders (20). However, the supporting evidence for such conditions is weaker than that for obesity and associated disorders (4).
Ketone Bodies & Anti-Aging
One of the most significant recent findings is the ability of ketones to affect the expression of a major class of enzymes in the body associated with oxidative stress (and associated aging). In this study, ketones were shown to produce this effect by enzymes called class I histone deacetylases (HDACs) (22).
While the term HDACs will mean nothing to the average consumer, this class of enzymes are a major target for pharmaceutical companies in the development of ‘anti-aging’ drugs. The inhibition of HDACs was achieved either through administering ketone bodies, fasting or calorie restriction.
Ketone Bodies and Performance
The use of ketones (either via oral administration or via ketogenic diet) to improve exercise performance is another exciting area of research.
Noted ketone researcher and author, Dr Stephen Phinney, was the first to show in 1983 that elite cyclists could perform equally well after 4 weeks on a low carb-high fat diet (i.e., 80+% fat, 15% protein, <2% carbs) as on a high carb diet (i.e., ~30% fat, 15% protein, 55% carbs). The performance measures used in the study were VO2max and time to exhaustion (23).
Metabolic testing of the cyclists revealed they were able to achieve this feat by dramatically altering their fuel usage during exercise. For example, there was a three-fold drop in glucose oxidation and a four-fold reduction in muscle glycogen use, while fat oxidation capacity dramatically increased.
Phinney's study is unique by virtue of the fact it used a 4 week ‘keto-adaption’, which is the longest period cited in the literature to date.
A number of other studies have been published where athletes were put on ketogenic diets, albeit for shorter periods of between 1 and 2 weeks. Most of these studies show a trend for increased rate of fat burning and a decreased rate of glycogen use, but with equivocal effects on performance (24, 25, 26).
Ketone Bodies & Strength Performance
In terms of resistance exercise and ketogenic diets, there is much less research, however a recent study of elite gymnasts showed that 30 days on a ketogenic diet resulted in a significant drop in body weight and fat mass, without any detrimental effects on strength and performance (27).
Oral Ketones & Performance
One of the most interesting research areas in ketones and performance is oral (i.e. exogenous) intake of ketone esters. Professor Keiren Clarke from the University of Oxford, UK, is one of the world’s leading researchers in this area.
Clarke and her colleagues have pioneered the development of a ketone ester (a bond of two ketone bodies) that can be administered orally.
In contrast with popular ketone salts, ketone esters don’t carry any salts (i.e. magnesium, calcium or sodium). This means individuals can essentially take as much as they like, without worrying about the gut discomfort that typically comes with high dose ketone salts.
As such it’s possible to achieve high blood ketone levels very quickly with oral ketone esters.
Professor Clarke and her colleagues have published positive findings on the effects of orally administered ketone esters in animal models (28, 29), and humans (30, 31, 32, 33, 34). Studies in humans show performance enhancements for cycling time trial, muscle recovery & strength and cognitive performance.
Ketone esters are expected to be an exciting area of research for sports product development into the future.
In conclusion, ketone bodies are naturally occurring compounds in the body; the levels of which are highly regulated depending upon carbohydrate availability and intake.
With the exception the retina and red blood cells, most major tissues and organs in the body can utilise ketone bodies as a viable energy source. This raises the possibility that individuals can maintain normal health on a ketogenic diet.
However, with the established beneficial effects of ketone bodies on cardiovascular health, diabetes, weight loss, neurological health, anti-aging and even exercise performance, the research on ketones is set to gain pace.