Exogenous Ketones – Here To Stay?

The Benefits Of Exogenous Ketone Use

Exogenous ketone supplements may provide a multitude of benefits. 

These include athletic performance enhancement, more efficient weight loss, cancer prevention, cognitive improvement and anti-inflammatory properties.

Weight Loss Goals

Appetite suppression: As shown above in figure 1, a 4-week trial done on rats showed that exogenous ketones were effective at reducing weight gain. It is likely that this reduction in weight gain was the result of the exogenous ketones reducing the overall food intake.
The fate of excess ketones: In the event someone has an excessive amount of ketones in the blood, the body (specifically the kidneys) will work as quickly as possible to filter out ketones via urine rather than converting them to adipose tissue. 3 This is not to say that you can’t gain fat if you consume an exorbitant amount of exogenous ketones, but that they are less prone to be converted to fat than other nutrients.

More tolerable than MCT oil: MCT oil has been known to cause gastrointestinal distress in users, especially when taken in higher amounts. Exogenous ketones in the form of ketone salts, in comparison, are generally well-tolerated. Thus they enable one to avoid adverse GI events while providing the body with similar types of benefits (see Ref. 2). Figure 1 shows that MCT oil can be effective in reducing body weight. A combination of MCT oil and exogenous ketones may aid weight loss and allow a lower loading of ketone supplements, without the GI distress seen with MCT oil.

Performance Goals

Athletic enhancement: Exogenous ketone supplementation has a promising outlook for enhancing athletic performance for a variety of reasons. Firstly, ingested ketone bodies induce an acute ketosis that lasts for several hours and mimics the physiology of starvation.Secondly, exogenous ketones present a way to elevate ketone levels without having depleted muscle glycogen stores (low muscle glycogen is well known to impair sustained physical performance). 4 This being said, at this time there is little direct data that shows performance enhancements after ingesting exogenous ketones. A very well formulated study by Volek et al. 5 has shown that fat adapted athletes have much higher glycogen stores than was previously anticipated and the athletes can replenish glycogen stores as efficiently as athletes on a carbohydrate based diet. The hypothetical premise behind their use is sound nevertheless.

Improved cognition:Elevated plasma ketone concentrations divert the brain to utilize ketone bodies for synthesis of phospholipids, which drives growth and myelination. Normally, glucose would be the preferred substrate, which is much less efficient.6

Health & Longevity

Anti-carcinogenic properties: Data seems to suggest that exogenous ketones are an effective anti-carcinogen. The reason behind this is that cancer cells are unable to use ketone bodies effectively, unlike most healthy tissues in the body. In fact, dietary ketone supplementation has been shown to increase survival rates of mice with systematic cancer by as much as 70%.7

Neuroprotection: As humans age, the brain becomes more susceptible to neurodegeneration and subsequent conditions such as Alzheimer’s and Parkinson’s disease. Exogenous ketone supplementation appears to ameliorate the typical decline in cognitive function that comes with aging. The likely mechanism for this neuroprotective property is that ketone bodies reduce the inflammation and hyperexcitability that is normally exhibited as glucose metabolism declines in the brain.8, 9

Anti-Inflammatory properties: There is evidence that ketone bodies play a crucial role in reducing inflammation by inhibiting a specific class of proteins called inflammasones.10

Gene regulation profile change: There is evidence that gene sets can be up regulated or down regulated. Still early days but an example of this is a change in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) in rats on a ketogenic diet.

Mechanisms: How Exogenous Ketones Work

Exogenous ketones have a variety of physiological effects shortly after ingestion:

• For starters, ingesting ketones (especially ketone esters) is an efficient way to elevate BHB in the blood by upwards of 2 mMol for nearly 8 hours (see Ref. 2). Ketone salts don’t appear to elevate BHB in the blood as efficiently (or significantly) as ketone esters do, though.
• Exogenous ketone supplementation causes blood glucose to decrease significantly, likely due to the acute increase in insulin sensitivity. Therefore, exogenous ketones may present a potential therapy for type-2 diabetics via regulation of blood glucose.
• Exogenous ketones also improve oxygen utilization, especially in the central nervous system (CNS).11 This effect decreases the likelihood of oxygen reaching potentially toxic levels in the CNS, which in turn has a number of other positive health ramifications (such as those discussed in the previous section).

Possible Downsides To Ketone Supplementation

As with almost any nutritional supplement, side effects and downsides are possible after consuming exogenous ketones. That being said, they tend to be rather benign and will most likely improve as exogenous ketone supplementation becomes more prominent. The most common side effects to be aware of when using exogenous ketones include:

Electrolyte Imbalance –The physiological reasoning behind electrolytes becoming depleted during a state of ketosis is due to lack of water retention and frequent urination. When supplementing with exogenous ketones, the acute state of ketosis will likely increase the frequency of urination, but it won’t deplete glycogen stores. Therefore, it may be useful to drink an electrolyte solution if you are urinating a lot after taking exogenous ketones, but it’s dependent upon how you feel.

Halitosis (bad breath) – If you’re on a ketogenic diet you are probably aware that as the body starts to metabolize fat, ketones can cause poor breath. There is very little one can do about this, it’s just the nature of the beast. Unfortunately, this can also arise when using exogenous ketones, but it’s not as lasting as when on a ketogenic diet. Chewing gum or mints is about the best option if it becomes a noticeable issue. This maybe caused by over consumption of the ketone supplement, tailoring the quantity consumed may prevent excess BHB being converted to acetone, which is likely excreted by the lungs.
Possible GI distress (flatulence) at exceptionally high doses – In the studies referenced in this article, exogenous ketones taken in large doses occasionally resulted in GI distress, especially flatulence. However, the cause of this is hypothesized to be due to the fact that ketones were mixed in a milky fluid that wasn’t very palatable. If you’re taking a nominal dose of exogenous ketones the likelihood of GI distress is rather low. Moreover, if some GI distress is prevalent, it should improve as you become accustomed to taking ketones.
Hypoglycemia: why not to be concerned – Taking exogenous ketones can drive blood glucose levels quite low, but you are not likely to feel the typical symptoms of hypoglycemia. This is because when ketone levels are high enough, they dominate as fuel in the brain; hence, you will feel just fine despite having low blood glucose. A highly-cited study by George Cahill, found elevated ketone levels could protect fasted participants when they were administered insulin to induce hypoglycemia.
Future Applications & Research

Most current research on exogenous ketones focuses on the health and longevity applications of their use. Much of Dominic D’Agostino’s current work is on the cancer prevention aspect of exogenous ketones.

Another area that is targeted, is the psychological benefits of exogenous ketones, especially with how they can help protect brain tissue from degradation. As mentioned earlier, this has implications for the prevention of conditions like Alzheimer’s disease, Parkinson’s disease, and epileptic seizures.

Hopefully, in the not-too-distant future research will also focus more on the athletic performance benefits of exogenous ketones, specifically with regards to resistance training and cardiovascular exercise. The data on each of these applications is very limited at this time.

References:

1. I.F. Gaunt, M. Sharratt, J. Colley*, A.B.G. Lansdown, P. Grasso (1970). Acute and short-term toxicity of p-hydroxybenzyl acetone in rats. Food and Cosmetics Toxicology, 8(4), 349-358.
2. Shannon L. Kesl,corresponding author Angela M. Poff, Nathan P. Ward, Tina N. Fiorelli, Csilla Ari, Ashley J. Van Putten, Jacob W. Sherwood, Patrick Arnold, and Dominic P. D’Agostino (2016). Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague–Dawley rats. Nutrition & Metabolism, 13(9).
3. Clark, V. L., & Kruse, J. A. (1990). Clinical methods: the history, physical, and laboratory examinations. JAMA, 264(21), 2808-2809.
4. Cox, P. J., & Clarke, K. (2014). Acute nutritional ketosis: implications for exercise performance and metabolism. Extreme Physiology & Medicine, 3, 17. http://doi.org/10.1186/2046-7648-3-17.
5. Volek, J. Freidenreich, D.J. Saenz, C. Kunces, L.J. Creighton, B.C. Bartley, J.M. Davitt, P.M. Munoz, C.X. Anderson, J.M. Maresh, C.M. Lee, C.E. Schuenke, M.D. Aemi. G. Kraemer, W.J. Phinney, S.J. (2016). Metabolic characteristics of keto-adapted ultra-endurance athletes. 65(3), 100-110.
6. Yeh, Y. Y., & Sheehan, P. M. (1985, April). Preferential utilization of ketone bodies in the brain and lung of newborn rats. In Federation proceedings (Vol. 44, No. 7, pp. 2352-2358).
7. Poff, A. M., Ari, C., Arnold, P., Seyfried, T. N., & D’Agostino, D. P. (2014). Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International journal of cancer, 135(7), 1711-1720.
8. Hashim, S. A., & VanItallie, T. B. (2014). Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester. Journal of lipid research, 55(9), 1818-1826.
9. Hertz, L., Chen, Y., & Waagepetersen, H. S. (2015). Effects of ketone bodies in Alzheimer’s disease in relation to neural hypometabolism, β‐amyloid toxicity, and astrocyte function. Journal of neurochemistry, 134(1), 7-20.
10. Youm, Y. H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … & Kang, S. (2015). The ketone metabolite [beta]-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nature medicine, 21(3), 263-269.
11. D’Agostino, D. P., Pilla, R., Held, H. E., Landon, C. S., Puchowicz, M., Brunengraber, H., … & Dean, J. B. (2013). Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 304(10), R829-R836.