Ketones: The Fourth Macronutrient

Our bodies run on three main groups of macronutrients (nutrients we need in larger quantities that provide us with energy and keep us healthy): carbohydrates, fats, and proteins. However, experts are now looking at a potential fourth group called ketone bodies. You may have heard of ketone bodies from the increasingly popular ketogenic diet, but they are much more than a fad diet. Ketone bodies are naturally created within our bodies through a series of events that allow us to use fat as a fuel source to create more energy. In addition to their ancient application as a remedy for epilepsy traced back as far as 400 BC, they are currently being researched for their potential to aid in the treatment of some health conditions.

Let’s look at how we got to the “fourth macronutrient”, what the keto diet is, and how ketone bodies have a place in our diets.

What are ketones and where do they come from?

Our bodies typically convert glucose, which is a type of simple sugar obtained from the foods we consume, into energy that powers all our bodily functions. However, when our body runs low on glucose, it switches to using ketone bodies as fuel instead. Under normal circumstances, ketone bodies are produced in the liver through a process known as ketogenesis, usually during a period of starvation, fasting, or a diet with little to no carbohydrates. This switch from glucose to ketone body use triggers the breakdown of fat as the main source of fuel — a bodily condition known as ketosis.

Around 400 BC, the Greek physician Hippocrates detailed what is widely considered to be the first description of what we know today as epilepsy, describing the symptoms of seizures and noting for treatment:

“…enforcing abstinence from…many articles of food which are unwholesome to men in diseases.”

In other words, the earliest treatment for epilepsy was fasting, to “administer nothing to eat or drink as medicines” and trigger a state of starvation that would result in the creation of ketone bodies. While not a sustainable long-term treatment for the condition, this observation by early practitioners of medicine would unknowingly pave the road for the development of the ketogenic diet centuries later.

Portrait of Hippocrates (Image: Wikimedia Commons)

In the 1920s, Dr. Russell Wilder first coined the term “ketogenic diet” (“ketogenic” — relating to the production of ketone bodies) in a publication from the Mayo Clinic, in which he detailed a high-fat, low-carbohydrate diet as a treatment for epileptic seizures. However, the use of this diet faded out after the introduction of anti-epileptic medications. In 1972, the Pediatric Ketogenic Diet Center was established at Johns Hopkins, which brought the keto diet back into public attention. This center started using the keto diet as an alternative treatment to the medications that once outperformed it, especially for children with forms of epilepsy that did not respond well to pharmaceutical medications. This allowed for slight modifications to the keto diet as treatment, which now allows for additional adjustments to suit the individual needs and preferences of patients.

I’ve heard about the benefits of the keto diet for weight loss, but is there a catch?

In 2020, “keto” was the most Googled food topic, with over 25.4 million searches indicating a peak of interest in the keto diet. Compared to the historical application of the diet as an anti-epileptic measure, 84% of people on the diet now cite weight loss as their primary motivation for adopting the keto diet. Though the reduction in carbohydrates helps drive weight loss, activating ketosis in the body isn’t without drawbacks; most common is the onset of a group of symptoms collectively known as “keto flu”: digestive discomfort, nausea, sleep disruption, and increased hunger, to name a few. These are thought to occur because of the sudden shock to the body by switching fuel sources, as the Western diet has acclimated many people to foods that are rich in carbohydrates, unlike the low-carb, high-fat keto diet.

Certain individuals with underlying conditions such as diabetes, pancreatitis, and liver failure can suffer from adverse health effects upon switching to the keto diet — in those cases, prior consultation with a physician is crucial.

Can we consume more ketone bodies without fully switching to the keto diet?

Transitioning to the keto diet can be challenging, since it requires both a complete dietary overhaul and strict adherence to the diet afterwards. As such, recent research has explored the possibility of ketone supplements that could deliver health benefits without requiring a major lifestyle change to achieve ketosis. A few common ketone supplements include:

● Ketone salts: designed as a powdered drink mix, ketone salts combine BHB (Beta-hydroxybutyric acid, a type of ketone body) with amino acids or minerals, in the same way that sports drinks contain electrolytes. However, while these drinks have a more appealing taste than other ketone supplements, they are less effective at delivering ketone bodies to the bloodstream and pose a risk of salt overconsumption if used too often.

● Ketone esters: first developed in the early 90’s by Oxford University and the National Institutes of Health, ketone esters were intended for the development of foods that could ensure mental sharpness and top physical performance. In the body, ketone esters are broken down in two steps, allowing for a prolonged supply of BHB to cells and maintaining increased ketone levels in the blood. However, producing ketone esters has proven to be expensive, and their taste is generally considered to be unpleasant.

● Medium-chain triglycerides (MCTs): though not ketones themselves, MCTs directly enter the liver after consumption, where they are turned into ketones, rather than fat. Typically found in oil or powdered supplement form, MCTs can fuel ketogenesis in the body, though they lack the efficiency of the delivery from ketone salts and esters and still share some of the digestive discomfort side effects.

Consumers are drawn to ketone supplements primarily because they aim to enhance physical and mental performance, as well as to trigger ketosis on demand for those following a low-carb diet. However, individuals often face issues with taste and cost in pursuit of these improvements, as mentioned earlier. Though the science behind ketone bodies is constantly developing, there remains inconsistency between marketed benefits and observed improvements, suggesting that refinement will be needed to ensure that customers are getting what they pay for in these supplements.

What are the health benefits of ketone bodies?

Beyond treating epilepsy, ketone bodies are demonstrating increasing promise for general health improvement at the individual level. For example, the ketogenic diet can be used to manage diabetes, where restricting carbohydrates can help with restoring glucose metabolism and lowering insulin resistance. More recently, the keto diet is also being applied to cancer treatments, as cancer cells increase their glucose intake to fuel their distinctive out-of-control growth. By combining typical cancer treatments like chemotherapy with the keto diet, cancer cells are starved for energy from cutting off carbohydrates, making them more susceptible to the therapy and resulting in better patient outcome.

Diagram of ketogenesis during ketosis. (Image: UCSF Diabetes Teaching Center)

On the supplement side, ketone bodies have been shown to improve brain health. When the body enters a state of ketosis, the brain fulfills 75% of its energy requirement by using ketone bodies, with glucose providing the remaining 25%. In this case, BHB can providing even more energy than glucose during ketosis. Studies have shown that ketone bodies are effective in dealing with neurodegeneration (when cells in the brain or nervous system start to breakdown and ultimately die) that occurs during aging, where participants with cognitive impairment or Alzheimer’s consumed ketogenic supplement drinks over six months, resulting in an improvement in mental acuity and memory recall. Additionally, further research has suggested that ketone bodies are involved in reducing inflammation and oxidative stress, as well as maintaining neuron activity, offering a window into the potential for what ketone supplements may do to protect the brain.

Ketone supplements may also help with preventing metabolic syndrome (also called insulin resistance syndrome, a combination of conditions that cause serious health issues such as stroke, diabetes, heart disease and more) by managing diabetes and reducing the risk of heart failure. In one study, pre-diabetic individuals who drank BHB supplements saw not only an increase in their blood ketone levels but also an overall decrease in blood glucose, suggesting that ketone supplementation may be a possible way to prevent the onset of diabetes. For heart health, ketone bodies have been shown to reduce cardiac inflammation, lower blood pressure, and generally contribute to health factors preventing heart disease, another prevalent condition in the metabolic syndrome health crisis.

Though still early in their development, research is increasing our understanding of how supplementing ketone bodies may play a role in muscle health and immunity. For example, ketone supplementation may help reduce inflammation during exercise and promote muscle development. On the other end, this has raised questions as to whether the intense energy consumption of workout activity will react negatively to ketosis in the body. Preliminary studies are examining the potential of ketones to boost our immune systems, specifically in terms of strengthening our defenses against viruses and reducing negative outcomes following infection, such as cytokine storms (a massive release of inflammation-causing proteins) caused by SARS-CoV-2. However, these studies have yet to be completed in humans, and are presently limited to ketogenic diet usage and not ketone supplementation.

Overall, ketone bodies have proven to be a promising avenue as both medical treatments and consumer supplements for improved wellness. Though the keto diet remains popular for weight loss, both the challenges of adhering to the diet and disagreement with supplement tastes represent concerns that must be addressed before the benefits of ketones can be more widely spread. Though causing ketosis remains a stark change to our bodies’ natural function, further research will be necessary to not only understand the extent of its effects on our metabolism, but also to develop our understanding of how ketone bodies can affect and potentially improve different aspects of our health.

Adapted from “Ketones: The Fourth Macronutrient” white paper.



Innovation Institute for Food and Health

The Innovation Institute for Food and Health (IIFH) reimagines markets for metabolic health leading to happier, healthier, longer lives for everyone.