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Exogenous Ketones

Emerging evidence supports the health benefits and the therapeutic potential of exogenous ketones in weight loss, athletic performance, and therapeutic properties. As a result, exogenous ketones like BHB are becoming a popular nutritional dietary supplement in Australia.

This blog aims to give a general overview about exogenous ketones and explore some of their potential benefits.

What are exogenous ketones?

In general, the human body generates energy by transforming glucose produced by breaking down carbohydrates. However, when glucose is lacking during periods of low food intake, diet, starvation, intense exercise or conditions like hypoglycemia, the body begins to break down other alternative sources like ketones to generate energy.

Biochemistry

A ketone can be defined as an organic compound made of a central carbon atom attached to an oxygen with a double bond and two carbon-containing substituents (R and R') to yield a general formulas RC(=O)R'. The replacement of R and R' by methyl groups (-CH3) yields the smallest structure of ketones, known as acetone (CH3C(=O)CH3).

The human body produces three main ketones known as ketone bodies: acetone, acetoacetate, and beta-hydroxybutyrate (BHB), structurally shown in Fig. 1. Compared to the structures of acetone and acetoacetate, BHB contains two alcohol functions (-OH), thus technically not a ketone but rather an aldehyde. However, since BHB is easily converted by the body to energy, it is categorized among ketone bodies.

Ketones Australia
Fig. 1: The molecular structures of ketone bodies.

These three water-soluble ketone bodies are produced by the liver, and thus called endogenous ketones. When the ketones are ingested through nutrition or outside intake, they are called exogenous ketones.


Exogenous ketones based on BHB

BHB is the most utilised ketone because it is easily employed by the body tissues to convert into energy when the blood glucose is low. Hence, most ketone supplements are prepared using BHB. Upon ingestion of BHB supplements, the body uses enzymes to break down BHB into acetoacetic acid and then to acetone.

BHB based exogenous ketones could be taken as liquids, powder, or pills made of BHB salts (for example, KetoCaNa or KetoForce) or esters. The structures of ketones based on salts and esters are depicted in Fig. 2.


Fig. 2: Structures of a sodium BHB salt and ester.

Most commercially available BHB supplements are made of salts (sodium, potassium, or calcium) because they are much easier to dissolve and thus absorb by the body tissues.


Examples of commercially available ketone salts include KetoCaNa and KetoForce. For example, KetoCaNa is a source of exogenous ketone body BHB containing 11.7 grams of BHB per serving, which is available in the powder form. These commercialised BHB salts are also available under various names, including Ketone Mineral Salts or BHB Mineral Salts.

Ester based BHB ketones are synthesised by attaching an alcohol function (-OH) into the ketone to form an ester function. Thus, ester based BHB ketones are more difficult to break down by the body as the ester function requires first to be metabolized in the liver to form ketones. They may also induces several side effects like gastrointestinal distress because they are more difficult to digest and metabolise1. Thus, ketone esters are mainly employed for research purposes.


Research relating to the Health benefits of exogenous ketones

Ketones and Weight loss
A number of studies performed on animal models and human subjects revealed the benefit of exogenous ketones like BHB in reducing weight gain. The mechanism by which ketones reduces weight is believed to be related to suppression of appetite, and thus an overall decrease in food intake2-6.
Some recent findings also suggested that weight loss induced by ketogenic diet could be maintained for longer periods after cessation of the diet. The reason for this was linked to circulating hormones and nutrients associated with appetite, which seemed to be altered after weight loss induced by a ketogenic diet. In particular, levels of the circulating hunger hormone known as ‘’ghrelin’’ could be maintained stable after a course of the ketogenic diet. By contrast, other weight reduction diets often increase ghrelin concentrations after cessation of the diet7.

Athletic performance
A few published papers suggested the benefits of exogenous ketone on sports performance, mainly due to their long lasting effects after ingestion. Another reason for the enhanced performance is related to elevated levels of ketones in the blood, which might be converted into energy without having the need for drawing stored glycogen in the muscle of athletes 1-2,8. A strong evidence linking ketogenic diet to sports performance still, however, requires further investigations. What is clear at the moment is the positive effect of ketones on weight loss and body fat without negatively affecting the strength performance in high-level athletes9.

Prevention and therapy
A number of studies have shown the link between ketogenic diet and improvement in several disease states like brain tumor (astrocytomas), autism, depression, migraine headaches, polycystic ovary syndrome, and type 2 diabetes10.

Cognitive function
The ketone bodies BHB is capable of crossing the blood-brain-barrier to reach the central nervous system 11. This induces an increase in levels of phospholipids and growth of the fatty white substance surrounding the axon of some nerve cells called myelin. This substance is known for its vital role for the proper functioning of the nervous system and better cognitive function12. However, the exact mechanisms by which BHB could help cognitive function are still under examination.

Control of epileptic seizures
The most known and pertinent use of ketogenic diet for disease therapy is in control of epileptic seizures in children. A substantial body of data demonstrated the positive correlation between BHB levels and degree of seizure control13. However, a little is still known about the mechanisms involved during this process. What is currently clear is that ketone bodies are able to pass into the brain to generate energy, and elevated levels of ketone bodies in the blood or ketosis have been linked to a reduction in the frequency of seizures.

Neurodegeneration and brain impairment
BHB is linked to increased levels of brain-derived neurotrophic factor (BNDF) levels, which supports the survival of certain neurons and help the growth and differentiation of new ones11. These findings could have clinical relevance for the treatment of diseases, like cognitive impairment, depression, and anxiety.

Several recent studies indicated the benefit of the ketogenic diet in the disease-modifying activity of many neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Parkinson's, Alzheimer's disease, multiple sclerosis (MS), and may also protect against brain injury and stroke 10,14-16.

In 2009, the US Food and Drug Administration (FDA) approved Caprylic triglyceride as a medical diet. Caprylic triglyceride is broken down into ketones to provide the brain with an energy source. This medical food marketed under the name of Axona is employed as a dietary management to improve the symptom of mild to moderate Alzheimer's disease. In patients with Alzheimer's, glucose metabolism in the brain is impaired and ketone bodies may improve the disease signs by providing alternative energy sources17.

Anti-cancer properties
Unlike healthy body cells which are capable of processing ketone bodies, cancer cells are inefficient to perform the process and rely on glucose. Thus, the ketogenic diet has been proposed to treat cancer like glioma 19-21. In mice model, dietary ketone supplements have been shown to raise survival rates 22. However, these data require further confirmation by future clinical trials.

Anti-inflammation
The anti-inflammatory properties of ketones bodies on inflammation have also been reported and explained by the particular action of ketone bodies on some proteins of the immune system 23. This includes inflammation associated with aging that leads to the development of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease induced by the reduction of glucose metabolism in the brain superscript. Ketone bodies have also been suggested to improve oxygen usage in the brain which may protect against inflammation, toxicity, and cell death26.

Conclusions
These findings demonstrate the promising health benefits of ketones ranging from weight loss and athletic performance to disease prevention and treatment. However, further research and clinical trials are needed to back up these data and strengthen the evidence.

References

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  2. G. D. Brinkworth, M. Noakes, P. M. Clifton, and J. D. Buckley, Effects of a low carbohydrate weight loss diet on exercise capacity and tolerance in obese subjects. Obesity (Silver Spring). 2009, 17: 1916.
  3. A. Paoli, A. Rubini, J. S. Volek, and K. A. Grimaldi, Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013, 67(8):789.
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  7. P. Sumithran, L. A. Prendergast, E. Delbridge, K. Purcell, A. Shulkes, A. Kriketos, and J. Proietto, Ketosis and appetite-mediating nutrients and hormones after weight loss. European Journal of Clinical Nutrition 2013, 67:759.
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  9. A. Paoli, K. Grimaldi, D. D’Agostino, L. Cenci, T. Moro, A. Bianco, and A. Palma, Ketogenic diet does not affect strength performance in elite artistic gymnasts, Journal of the International Society of Sports Nutrition, 2012, 9:34.
  10. A. L. Hartman, E. P. Vining, "Clinical aspects of the ketogenic diet". Epilepsia. 2007, 48 (1): 31.
  11. S. F Sleiman, J. Henry, R. Al-Haddad, L. El Hayek, E. Abou Haidar, T. Stringer, D. Ulja, S. S Karuppagounder, E. B Holson, R. R. Ratan, I. Ninan, and M. V. Chao, Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate,eLife. 2016, 5: e15092.
  12. Y. Y. Yeh, P. M. Sheehan, Preferential utilization of ketone bodies in the brain and lung of newborn rats. In Federation proceedings, 1985, 44 (7):2352-2358.
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  16. M. Storoni, G. T. Plant, Gordon, "The Therapeutic Potential of the Ketogenic Diet in Treating Progressive Multiple Sclerosis". Multiple Sclerosis International. 2015: 1. 
  17. Axona Prescribing Information (PDF). Accera, Inc. 2011. Archived 2 March 2012.
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  21. R. J. Klement, U. Kämmerer.. "Is there a role for carbohydrate restriction in the treatment and prevention of cancer?". Nutr Metab, 2011, 8:75.
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  23. Y. H. Youm, K. Y. Nguyen, R. W. Grant, E. L. Goldberg, M. Bodogai, D. Kim, and S. Kang, The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature medicine, 201, 21(3):263.
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Kunal K
Kunal K

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Co-Founder, OptimOZ.com.au