In the search of eternal life and power, the ketone emerged from the depth of the abyss and was ostracized as an “abnormal and undesirable by-products of incomplete fat oxidation”[1], ignorant humans moved on with their lives.
Then perhaps the ketones uselessness helped some drug resistant epileptic children in the 1920s. Then in 1967 perhaps the brain could use ketones instead of glucose. Then perhaps greater benefits were discovered from this ugly molecule, like therapeutic treatment for rare genetic disorders that involve neuronal utilization of glucose. Then perhaps the disgusting ketones are efficiently used by the mitochondria for ATP generation, protect vulnerable neurons from free radical damage, and may benefit patients with Parkinson’s Disease (PD), and Alzheimer’s disease (AD) and other neurodegenerative disorders. Nonetheless, beware the ketone
Ketoacidosis
This is the terror from ketones. A large concentration of ketones was measured in the urine of diabetic coma patients, and this massive overproduction of ketones became life-threatening, and can lead to death. Enter the original sin of ketones.
There are three main threats from ketoacidosis, 1) Diabetic Ketoacidosis, 2) Alcoholic Ketoacidosis and 3) Starvation Ketoacidosis.[2]
Diabetic Ketoacidosis happens to T1 and late stage T2 diabetics, where the lack of insulin doesn’t allow for a controlled level of ketones in the blood, therefore ketone levels continue to rise. In a healthy individual, insulin kicks in to cap the amount of ketones in the blood.
At what level of ketones, is it considered ketoacidosis? 10+ mM, Virta Health addresses it here – they state 15-25 mM.
As the name implies, Alcoholic ketoacidosis occurs with chronic alcohol abuse and liver disease.
The same applies for starvation ketoacidosis, whereby glucose and glycogen is depleted after a period of several days of fasting. This is the main threat to nondiabetic individuals. Some use language to describe ketoacidosis as the mere production of ketones after 12-14 hours of fasting. As noted above, ketoacidosis has a specific blood millimolar level of concern. Healthy individuals may not see this level even during a prolonged fast.
To sum up, the discovery of ketones happened in unhealthy individuals and has been thought as evil since then.
The Organs and Ketones
In Robinson’s and Williamson’s “Physiological roles of Ketone bodies as substrates and signals in mammalian tissues”[3] ketone bodies and their utilization are discussed. The main conclusions were that ketones can be used as energy (oxidative substrate), and ketones have a regulatory role for proteolysis (breakdown of protein for energy). This makes sense as having ketones as an alternative energy source to glucose, means there is less need of protein breakdown to provide glucose. Energy from fat instead of muscle.
In this paper, several organs are mentioned. The main theme being that ketones are an adequate energy source for those organs. I found a paragraph that condenses the bulk of it, however many more organs are discussed.
The image below shows the original text, so I’ll highlight the points that stood out for me. Fetuses develop a high capacity to utilize ketone bodies; muscles can increase their ketone capacity through training. Adaptation to use ketones happens because necessary functions need to happen
Ketone adaptation happens - For milk synthesis, the mammary gland develops capability of ketone uptake as it becomes highly active and needs a variety of energy sources to keep up
Ketone adaptation happens - For Synthesis of cholesterol and triacylglycerol in fetal tissue,
Ketone adaptation happens - For myelin synthesis in developing brain
Oxidative Stress and Ketones
Oxidative Stress is described by D.J. Betteridge as “Oxidative stress, defined as a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses, is discussed in relation to its possible role in the production of tissue damage in diabetes mellitus.”[4] This is basically trying to say that there is an imbalance between free radicals and antioxidants.
Free radicals are molecules with an unpaired electron, making them unstable and highly reactive. The free radicals target all kinds of molecules in the body, lipids, nucleic acids, and proteins.[5]
Antioxidants are molecules that protect against free radicals. Therefore, when the balance is unfavorable, meaning free radical generation is greater than antioxidants, there can be damage to lipids, proteins, and nucleic acids.
To expand more on oxidative stress and its concerns, is that it is a contributor to diseases, like atherosclerosis, certain cancers, inflammatory conditions like arthritis, and the process of aging. [6]
On to the good part, Ketones. In a study by Shimazu et al. titled “Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor” as the title states, Shimazu explains that ketones are protective against oxidative stress. β-Hydroxybutyric acid (BHB) is produced in the liver using fatty acids, so it is a naturally produced ketone body. BHB production only happens endogenously through keto diets or fasting.
Shimazu et al, ran through several in vitro and in vivo experiments to evaluate if HDAC gets inhibited by BHB. HDAC is Histone Deacetylases, and they are involved in multiple stages of cancer, and has been linked to a different malignancies like solid and hematological tumors. “High level of HDACs is associated with advanced disease and poor outcomes in patients”[7] therefore inhibiting HDAC is a positive outcome. Shimazu et al, concludes that HDAC was inhibited when BHB was introduced, meaning BHB promotes stress resistance. Shimazu also refers to ketogenic diets, and its ability to produce endogenous BHB, could contribute to beneficial effects on health, Shimazu also mentioned calorie restriction or fasting as these can also produce BHB.
Ketones and the Mitochondria
In a lecture by my favorite professor, Dr. Benjamin Bikman, “Insulin vs Ketones: The Battle for the Mitochondrion” he talks about fascinating points on Ketones. The three highlights of elevated ketones led were:
Enhanced mitochondrial biogenesis
Increased mitochondrial fusion
Favorable mitochondrial function
Great stuff, I know. It is important to understand that he was comparing two states, high ketones versus hyperinsulinemia, a state of high insulin normally seen in diabetic people. Insulin levels dictate what is used as a fuel source, therefore if insulin is high, there are no ketones, and if insulin is low there are ketones.
Mitochondrial Biogenesis refers to when the mitochondrion in a cell multiplies, so your mitochondria number increases. The key regulator for mitochondrial biogenesis, is PGC-1α and insulin inhibits PGC-1α, therefore when insulin rises, the amount of mitochondria diminishes or the ability to reproduce decreases. On the flip side, an elevated number of ketones has a positive effect on the mitochondria number.
Mitochondria fusion refers to when two adjacent mitochondria join, and fission when one mitochondrion separates into two. In a state of high insulin, you get loss of ATP production, insulin resistance, increased oxidative stress, increased fat gain. Fission inhibition increases longevity[8]
Increased fusion is associated with increased longevity[9] and higher ketones lead to greater shift towards mitochondrial fusion.
Mitochondrial function is something you are probably already familiar with, the mitochondrion produces ATP which is energy, and heat. In the process of producing ATP, there are inefficiencies and Reactive Oxygen Species (ROS) are produced as a result. These are the free radicals that cause oxidative stress as mentioned earlier. Insulin disrupts mitochondrial function, meaning higher ROS and oxidative stress.
Ketones when used as a fuel by the mitochondria produces fewer reactive oxygen species, therefore it is considered a ‘cleaner’ fuel. Ketones also provide a robust ability to defend against ROS because ketones activate glutathione peroxidase, a very powerful antioxidant[10]
Summary
Ketones continue to have a bad reputation because some consider any ketone in the blood as ketoacidosis, however this is only after an elevated level of ketones (+10mM) and this will not happen to healthy individuals as insulin will rise to keep ketones in check. Ketones can be utilized as energy by many different organs, and the organs develop this capability mainly because there is a higher energy demand. For example, mammary glands increased their uptake of ketones for synthesis of milk, and there was higher synthesis with ketones compared to glucose.
Ketones provided protection against oxidative stress via HDAC inhibition. The mitochondria had positive effects when ketone was used as a fuel. Ketones also increase the number of mitochondria, the mitochondria function was improved, and there was a favorable shift towards mitochondria fusion.
I believe that ketones are the preferred fuel source, and that our initial assumption that glucose was our preferred fuel source has biased all of our observations.
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