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Even for the average fitness enthusiast, the term ketone or ketone body may not mean much. There are some who associate it with the highly popularised “ketogenic diet” (also called Atkins diet), while some science graduates may recall it being mentioned in their biochemistry classes. Traditionally thought of as a toxic by-product of fat oxidation, ketone bodies are rapidly being seen in a more favourable light within the health and fitness industry as new therapeutic roles are found 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, b-hydroxybutyrate and acetone, with the major circulating form being beta-hydroxybutyrate1. Ketone bodies are generated under conditions of limited carbohydrate availability, such as fasting or low carbohydrate diets1. In such instances, the body’s stores of carbohydrates are depleted and the body is forced to increase its use of fatty acids to make up the energy deficit from depleted glucose stores (i.e. glycogen). Whenever the body significantly accelerates its use of fatty acids, it starts to generate ketone bodies, which are essentially a by-product of fatty acid oxidation. This process of making ketone bodies (i.e. ketogenesis) occurs primarily in the liver.

Physiological vs Pathological Ketosis

Ketogenesis was originally thought to be a ‘back-up’ energy system used by the body to fuel key organs such as the 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 negligible2, 3. Under such conditions, it is believed that ketogenesis is the primary mechanism used by the body to meet its energy requirements. However, the blood level of ketones under these circumstances is not as high as the levels that are reached during conditions like 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 fasting4. The 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 diabetes5.

Weight Loss & Ketosis

Specially formulated ketogenic diets (i.e. carbohydrate intake 30g-50g/day) are most popular for their efficacy in treating obesity and diabetes. There is a very strong body of evidence now 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 value6. Of particular note is that 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 disease7-9 and diabetes10, 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 health4. This interest has been underpinned by the long established benefits of a ketogenic diet for children with non-responsive epilepsy, which were discovered almost accidentally way 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 sclerosis12. While these various diseases are notably different from each other, a common underlying characteristic is abnormal cellular energy utilization. As such, ketogenic diets are thought to have neuroprotective effects because they have been shown to raise ATP levels in neurons as well as reduce the production of free radicals13. 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 so 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.

There is also emerging evidence that ketogenic diets may have promise in the treatment of acne14-16, cancer21, polycystic ovarian syndrome17, amyotrophic lateral sclerosis18, 19 and respiratory disorders20. However, the supporting evidence for such conditions is weaker than that for obesity and associated disorders4.

Ketone Bodies & Anti-Aging

One of the most significant findings concerning ketone bodies in recent times is their ability to affect the expression of a major class of enzymes in the body associated with oxidative stress. A recent study published in the prestigious journal of Science in December 2012 showed in an advanced mouse model that ketone bodies act to increase the expression of a wide range of genes associated with antioxidant protection and therefore protection against oxidative stress22. Ketones were shown to produce this effect by inhibiting a major class of enzymes called class I histone deacetylases (HDACs). While the term HDACs will mean nothing to the average consumer, it’s important to note that this class of enzymes are a major target of pharmaceutical companies in the development of ‘anti-aging’ drugs. This significant 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 researcher and author on ketogenic diets, Dr Stephen Phinney, was one of the first researchers 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) in terms of VO2max and exercise time to exhaustion23. Metabolic testing of the cyclists revelaed that 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 onto 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 performance24-26.

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 performance27.

Oral Ketone Bodies & Performance

However, one of the most interesting research areas in ketones and performance is direct oral supplement with ketones (in the form of ketone esters). Professor Keiren Clarke from the University of Oxford, UK, is one of the world’s leading researchers. Clarke and her colleagues have pioneered the development of a ketone ester (a bond of two ketone bodies) that can be administered orally. The advantage of an orally administered form of ketones is that one can achieve high blood levels of ketones (and their associated benefits) without the need to employ the strict dietary regime required by a ketogenic diet. Professor Clarke has published positive findings on the effects of orally administered ketones in animal models28, 29, and recent news reports suggest Clarke has been able to extend her findings in a group of elite rowers30. Ketone bodies or ketone esters therefore are expected to be an exciting area of research for sports product development into future.

In conclusion, ketone bodies are naturally occuring compounds in the body; the levels of which are highly regulated depending upon carbohydrate availability and intake. With the exception of tissues such as the retina and red blood cells, most major tissues and organs in the body can utilise ketone bodies as a viable energy source, thus raising 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 ketone bodies is set to gain pace. Accordingly, there is a very real possibility oral ketone bodies may be widely available as a supplement in the near future.

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