What is Ketosis? Whenever the word ketone or ketogenic gets brought up, two questions tend to immediately follow. In relation to the ketogenic diet, the question is, “oh, is that like the Atkins diet?” Whereas when talking about exogenous ketones, it switches to, “oh, you mean raspberry ketones right? I heard about those on Dr. Oz.” We’ll be discussing both, so as to provide context, but the latter is our particular focus for today.
What are ketones?
Ketones, from a organic chemistry standpoint, simply refer to an organic compound composed of a carbonyl group, or carbon-oxygen double bond and two R-groups, which are a stand in for whatever is replacing it. The simplest of these is acetone, which is composed of the carbonyl group and two methyl (CH3) groups.
When discussed specifically in a nutritional context, they refer to the 3 fatty acid derived molecules acetoacetate, beta-hydroxybutryate and the aforementioned acetone [1]. Acetoacetate and beta-hydroxybutyrate often interconvert in the body, whereas acetone is predominantly a byproduct [2]. While acetoacetate and acetone are true chemical ketones, beta-hydroxybutyrate, which is the most physiologically active is classed with them as ketone bodies for convenience sake based on its metabolic role [2].
What is ketosis?
Ketosis refers to the metabolic state whereby the body shifts to ketone bodies as the primary fuel substrate, particularly for the heart, brain and skeletal muscles [1]. It was historically the mechanism humans and other animals used to survive during starvation periods [3]. However, today it is possible to purposefully induce nutritional ketosis, by severely restricting carbohydrates and moderately restricting protein [1, 2].
** Warning science alert, read if you want to really dig deep **
The reason this occurs is due to an excess of acetyl groups combined with insufficient oxaloacetate [4]. Oxaloacetate is an essential substrate, which along with acetyl CoA, starts and ends the Krebs, citric acid or tricarboxylic (TCA), cycle [5]. This metabolic pathway is crucial to the generation of energy in the form of adenosine triphosphate (ATP) [5].
Carbohydrates, and protein either directly or through the production of another TCA cycle intermediate, provide the primary source of oxaloacetate [2]. Amino acids can be directed towards the production of glucose, by way of gluconeogenesis [4, 5]. Once liver glycogen is depleted, ketogenesis is ramped up to provide an alternative fuel source for the brain, while sparing muscles from wasting due to catabolism of their proteins [2]. However, if dietary protein intake remains high enough to replenish adequate amounts of oxaloacetate, the body will not shift completely towards ketogenesis [1].
When it comes to amino acids, some are termed glucogenic, as they contribute to gluconeogenesis, others are ketogenic, as they can contribute to ketogenesis, while a third group can go either direction [1]. Leucine and lysine are the only exclusively ketogenic amino acids, whereas isoleucine, phenylalanine, threonine, tryptophan and tyrosine can contribute to both pathways [5]. In humans, the other thirteen dietary amino acids are exclusively gluconeogenic, as they are converted into TCA cycle intermediates, which provides direct or downstream oxaloacetate [5].
In fact, fact roughly 48-58% of dietary amino acid intake is gluconeogenic, thus protein can be a significant contributor [6]. Conversely, those ketogenic amino acids result in the production of acetyl CoA, as they contribute to the aforementioned excess of acetyl groups, without replenishing oxaloacetate [5].
** If you skipped it, welcome back. **
So, when fats are beta-oxidized into acetyl CoA AND oxaloacetate is restricted, by way of reduced dietary intake of carbohydrate and protein (particularly the glucogenic amino acids), the body initiates the process of ketogenesis, once stored liver glycogen is depleted [1].
I understand we got pretty heavy with this, but the purpose was to make clear why the endogenous (in the body) production of ketones is not the same as taking exogenous (supplemental) ketones, like KetoOS. Simply put, despite claims to the contrary, supplementing with exogenous ketones will not put your body into a state of nutritional ketosis.
So does that mean you shouldn’t be taking them?
Well, that really depends on why are you taking them? If you are only looking to burn fat, then probably not. Go back and reread what I wrote about how ketosis is actually achieved.
If however, you are looking to support a condition or to improve athletic performance, that is where things get interesting.
Brief history of the ketogenic diet
The ketogenic diet represents a nutritional therapy originally developed to combat seizures. It has been known since the days of Hippocrates that fasting can reduce or outright eliminate seizures [7]. An unfortunate side effect of fasting for too long, however, is… Death. As such, it wasn’t until the turn of the 20th century that medical science started to examine the potential mechanisms of how this work.
Thanks to two independent breakthroughs in 1921, by researchers Woodyat and Wilder, it was was determined that fasting, as well as diets that were very low carbohydrate and high fat, resulted in the production of beta-hydroxybutyrate and acetone in the blood [7]. It was then proposed that the benefits of inducing ketonemia, or ketones in the blood, through fasting, might be extended to these types of diets.
As a result, the ketogenic diet was born to mimic the physiological, hormonal and metabolic benefits of fasting, while still enabling the epileptic to eat. Unfortunately, the development of anti-seizure medications, starting in 1938, led to the diet falling out of favor, but it was not completely forgotten. In the subsequent century, science has elucidated an incredible array of other conditions for which the ketogenic diet has efficacy beyond its anti-seizure activity.
Potential health benefits of the ketogenic diet
Similar to the benefits demonstrated in epilepsy, the ketogenic diet has demonstrated protective effects against other neurological disorders, including Alzheimer disease, amyotrophic lateral sclerosis (ALS), autism, brain trauma, depression, migraines and Parkinson disease, [8, 9, 10].
A likely mechanism is though to be by way of inducing mitochondrial expression, increasing ATP levels, as well as reducing and scavenging reactive oxygen species (ROS), or free radicals [11]. The shift to the use of ketones as the primary fuel source for the brain, leads to an increased metabolic efficiency and decreases glucose consumption in the brain, thereby reducing oxidative stress [12].
However, these mechanisms, may also play a role in fighting cancer, particularly those of the brain, such as glioblastomas [13, 14]. Additionally, cancer cells are not particularly metabolically flexible. Their primary fuel source is glucose; so it’s restriction, paired with an alternative fuel source for healthy cells, by way of the ketogenic diet could be a powerful tool in combatting cancer [13, 14, 15].
Building off of that thought, impaired glucose metabolism is at the heart of the obesity and metabolic syndrome epidemics in the United States. Nutritional Ketosis protocols have shown efficacy at reducing blood sugar, improving insulin sensitivity, improving blood lipid markers and increasing fat loss [16, 17, 18].
But, what if you don’t have a major health condition?
Research has found that ketones can improve cognitive and athletic performance, particularly of the endurance variety [19, 20].
Unfortunately, the ketogenic diet may not be for everyone. Some people with thyroid issues or high amounts of stress do not always do great with the ketogenic diet [21]. Others who have issues with foods, particularly cravings, can have issues, if using a poorly designed ketogenic diet. Moreover, high-level athlete who are not fully fat-adapted can have issues with high level performance when they attempt a ketogenic diet [22].
So what about exogenous supplemental ketones?
Exogenous ketones can provide many of the potential therapeutic effects of a ketogenic diet, with a more moderate carb intake. Unfortunately, in terms of the research, we are mostly in the preclinical phase, meaning that most of it has been carried out in rats. As such, the results are not completely applicable, but they have been very impressive so far nonetheless.
With respect to cancer, it would that presumed that one would need to be on a ketogenic diet, as glucose, and potentially caloric restriction, are the major drivers of its benefit. Interestingly, however, elevated blood ketones and beta-hydroxybutyrate does appear to have some anti-carcinogenic properties, in isolation [23, 24]. In fact, research demonstrated that ketone supplementation decreased tumor cell viability, at least in the animal model [24].
Moreover, their use has been shown to lower both blood glucose and blood insulin, indicating improved insulin sensitivity [25, 26, 27]. This mechanism of getting off the blood sugar roller coaster to help reduce cravings could be part of the reason people experience fat and weight loss when supplementing with KetoOS. In fact, preclinical data on supplemental ketones has demonstrated voluntary reduced food intake [25, 28].
Similar to the results seen in nutritional ketosis, preclinical data on ketone supplementation has also demonstrated improved cognitive and physical performance [29]. There is also preclinical evidence of their ability to reduce anxiety [30].
All of this comes with the caveat that, similar to alcohol, ketones take metabolic priority and could inhibit the other substrates, fat, carbohydrate and protein metabolism. In fact, in the short term, they may even inhibit lipolysis, or the breakdown of as fats [22]. Timing is also important, as they exhibit better efficacy when consumed fasted, than when taken with a meal [31].
However, it is worth noting that one animal trial, on supplemental ketones, did find an increased expression of brown adipose tissue, which is associated with thermoregulation and utilizes white adipose tissue in this process [25]. As such, it appears exogenous ketones may have both lipolytic and anti-lipolytic mechanisms.
Either way, it is important to remember that this is not a situation of more is better. If you are simply adding them to your current diet, they aren’t going to be effective and may even slow your results. It is also important to remain properly hydrated and to ensure adequate electrolyte levels, due to the diuretic effect of ketones [17].
Final takeaways on exogenous ketone supplementation
The therapeutic potential is amazing and we are only at the beginning of what they can possibly achieve. Everyday more research is coming out and we are starting to move into the clinical phase with humans. That being said, the anecdotal and empirical evidence is clearly mounting, as well.
Like any other food or supplement, the devil is in the details and it is important to find the appropriate dose. Maybe that is 1 serving per day, maybe it is a 1/2 packet, or maybe it is 1.5 servings. Just like with any other macronutrient, you may need to titrate up or down based on your needs and goals.
There should be enough to reduce cravings and improve performance, but low enough to not inhibit lipolysis. If you are working on a condition, you may need to take more, but just be aware of what else you are eating.
However, at the end of the day you are actually making appropriate dietary changes and actually eating real food. KetoOS and other exogenous ketone supplements are not a magic pill, but they can be a tremendous tool in your arsenal for improving health, longevity and performance.
References:
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