Ketosis is our natural state.
Open any textbook describing human metabolism and it will begin with positioning “carbohydrates (glucose)” as the foundation and core of the entire human metabolic process. Despite this “glucocentric” assertion being ubiquitous in relevant literature and education, I strongly suspect that it is wrong. The standard narrative goes a bit like this following horror story: “During starvation, fasting or a shortage of glucose, ketones are used as alternative fuel in the body. High levels of ketones as experienced by diabetics or alcoholics with liver disease can lead to acidosis of the blood and death.” The goal of this series of articles is to turn this very negative glucocentric paradigm on its head and show that many, if not most chronic health problems are really due to a deficiency of ketones! At root, ketosis is our natural state for health and energy.
Glucose is the foundation of metabolic process at the bottom of the food chain. Plants create and store glucose. Humans are at the opposite end of the food chain and this frees us from dependence upon glucose.
Biochemistry is mind bogglingly complex and it is easy to get completely lost in detail. With this issue in mind I intend to avoid as much technical jargon as possible, though a minimum will be necessary.
The entire evolution of early life on planet Earth in 3 minutes flat
Let’s start at the beginning with “the evolution of cells” to see where our metabolic system comes from:
1 ) 3.7 billion years ago the first cellular life appeared on Earth; “archaea”. Archeae was anaerobic, meaning it required no oxygen. There was virtually no oxygen in the atmosphere.
2) Almost 3 billion years ago “cyanobacteria” emerged. Although sometimes referred to as blue green algae, Cyanobacteria isn’t algae. Cyanobacteria uses photosynthesis and converts sunlight, CO2 and water into glucose ( C6H12O6 ) and oxygen. This transformed the Earth’s atmosphere over the next billion years.
(Cyanobacteria used iodine as a powerful antioxidant. Only after both iodine and oxygen became major constituents of the atmosphere did eukaryotes and multicellular organisms arise. Hence why today all human cells require iodine for good health.)
3) 2.9 billion years ago aerobic bacteria, consuming oxygen, emerged. (ref 4)
4) 2.7 billion years ago the first organisms with a nucleus emerged – Eukaryotes.
Eukaryotes (including all human and plant cells) are simply combinations of the first three cells listed above; one huge anaerobic archaea engulfing and then containing aerobic bacteria and if a plant cell then sometimes containing a photosynthesising bacteria. The engulfed aerobic cells were able to break down the large cell’s wastes for energy and also supply energy to the large cell. They became the mitochondria of eukaryotic cells. The engulfed photosynthesising cells were able to make food. They shared the food with the large cell. They became the chloroplasts of eukaryotic cells.
Eukaryotic cells, made possible by “endosymbiosis” (engulfing and symbiosis), were powerful and efficient, giving them the potential to evolve new characteristics; multicellularity, cell specialization, large size and the emergence of today’s spectacular diversity of animals, plants, and fungi (ref 5)
Covering the entire evolution of early life on planet Earth in 3 minutes flat should be enough to show where the “cellular respiration” of the human metabolic system comes from.
Every living organism can convert glucose to energy, including plant cells, archaea, algae, fungi and chemotrophic bacteria. Chemotrophic bacteria are organisms that normally only feed on iron, magnesium, hydrogen sulphide etc. Every living thing can use glucose to extract energy. (ref 6)
The Food Chain
DNA, RNA, lipids, carbohydrates, proteins all contain the elements of glucose; carbon, hydrogen and oxygen. The human body is 65% oxygen, 18% carbon and 10% hydrogen. Considering the omnipresence of glucose and its components, it’s hardly surprising that we end up with a totally glucocentric impression of human metabolism.
The food chain starts at the bottom with photosynthesis in algae and plants, the plants storing their extra glucose as starch. Plants consume their own glucose for energy through cellular respiration.
Plants also produce fats but not for energy storage.
Animals eat algae, plants and other animals. Animals store their extra glucose as glycogen and fats. All you see in the shops or fields as food are carbohydrates, fats and proteins. That’s all we eat along with trace minerals and vitamins.
The term “essential”used in the context of human nutrition has a special meaning. An essential nutrient is one that the body can’t manufacture its own and must acquire from food (exogenous). There are specific essential fats (omega 3 and 6), proteins, minerals including all vitamins but no essential carbohydrates. Mammalian, reptile and bird predators do not need carbohydrates as food due to the capacity to convert fats and proteins internally into glucose when required.
Breaking Down Food and Body Reserves
Proteins, fats (lipids), and carbohydrates (polysaccharides) make up most of the food we eat. Foods must be broken down into smaller molecules before our cells can use them; either as a source of energy or as building blocks for other molecules.
Once broken down (either from stored fats, glycogen, proteins or digestion of food) the molecules can enter the appropriate eukaryotic cell. Inside the cell there are around 500 chemical reactions involved in cellular respiration.
Ketones are smaller molecules synthesised mainly in the mitochondria of the liver. However, the liver does not have the critical enzyme necessary to use ketones for itself so the liver only produces ketones. Ketones are just another recombination of the three elements carbon, oxygen and hydrogen.
The Ketone Bodies
In chemistry there are many ketones and they are pervasive in nature. The formation of organic compounds in photosynthesis occurs via ketones. Many sugars are ketones; known collectively as ketoses. Fructose is a ketose. Fatty acid synthesis proceeds via ketones. (ref 7)
The human body produces three types of ketones all synthesized from acetyl-CoA molecules in the mitochondria. Human synthesized ketones are “ketone bodies”. (Not a technical term – only indicates ketones particular to metabolism)
β-Hydroxybutyrate ( βOHB ) is the most abundant of the ketone bodies. Acetoacetate (AcAc) is next and acetone the least abundant.
- Acetoacetate (AcAc), which can be converted by the liver into β-hydroxybutyrate, or spontaneously turn into acetone
- Acetone, which can then be further metabolized to pyruvate, lactate and acetate (usable for energy)
- β-hydroxybutyrate (βOHB), (not technically a ketone)
Ancient Cellular Origins of β-hydroxybutyrate
The use of β-hydroxybutyrate (βOHB) to store energy is evolutionarily ancient. Many species of bacteria synthesize polymers of βOHB for energy storage. Industry exploits this reaction for the production of biopolymers as a plastic substitute. Early in evolution a full range of βOHB biosynthetic enzymes emerged in eukaryotes including those in plants; mainly implicated in the biosynthesis of cholesterol and not for energy production.
Advanced Modern Ketone Metabolism
Ketone body metabolism in the mitochondria, emerged recently and gradually, only in vertebrates comprising the reptiles, birds, and mammals. (ref 8)
Metabolism of ketones in the mitochondria is a relatively recent step in evolution. It is a metabolic game changer, relegating carbohydrates to minor support roles. To fully understand the implications of this we have to look at what this means to a human and human evolution itself. (Part 2) My own definition of ketosis would be as follows… “Mitochondria oxidising ketones from fats, instead of pyruvate from glucose.”
Here’s a very well produced and engaging short video on ketosis. It is insightful and informative but still considerably underestimates the full role of ketones…
Cellular Energy Production
Before exploring the manifold, powerful, functional values of ketosis it’s worth preparing the way with just a bit more understanding of cellular respiration…
The problem we have here is that all conventional texts on basic metabolism practically ignore ketones and treat them as if they were an insignificant “intermediate” byproduct. There are many detailed diagrams and intricate explanations that would make you think ketones simply don’t exist. The good news is that we are going to ignore most of that!
Fuel supplied to the cells is all transported in the blood in the form of glucose, fatty acids, amino acids, lactic acid and ketones. Those are smaller molecules from breaking down food or body reserves such as glycogen, fats and proteins.
Inside the cell all of the fuels are channeled into making the complex organic energy molecule “ATP”. (Adenosine Triphosphate – C10H16N5O13P3 ). In one single day you will make as much as 70 kilograms of ATP in your body.
The eukaryotic cell (human cell) contains a cytoplasm (main body of the cell) and a nucleus. The cytoplasm contains the organelles (including Mitochondria) and the remaining space in the cytoplasm is called the cytosol. When the fuels enter the cell they all enter the cytosol. That’s where only glucose out of all the fuels can produce ATP through glycolysis. Glycolysis gives only 2 ATP for each glucose molecule but does this very rapidly. This becomes very useful, particularly when you have to run fast for more than 10 seconds.
Progressive breaking down of fuel molecules is called “oxidation”. However, in glycolysis this doesn’t mean it uses oxygen it only means “losing an electron”. Glycolysis is anaerobic – uses no oxygen. Glucose (carbohydrate) has now become 2 ATP + 2NADH (energy carrier) + 2 pyruvate molecules. Pyruvate is a smaller organic molecule but not a carbohydrate. Along with the NADH molecule pyruvate can now enter the mitochondria.
Amino acids and lactic acid that entered the cell cytosol are also oxidized into pyruvate but without any ATP production. Some of the amino acids are oxidised into ketones (depending on which type of amino acid). All the pyruvate, fatty acids and ketones in the cytosol can now enter the mitochondria. Once inside the mitochondria all of those fuels are oxidized into acetyl-CoA and then this time using oxygen, oxidized to ATP, H2O and CO2 .
Pyruvate (x2) gives 34 ATP,
Fatty Acid gives 129 ATP,
Ketones give 22 ATP
It’s important to know however that nobody yet knows the ratio of energy overall produced in cells between fatty acid oxidation and ketone oxidation!
Roughly 109 molecules of ATP are in solution in a typical cell at any instant. Every 1-2 minutes, In many cells, all of the ATP is turned over (used up and replaced). Energy efficiency is nearly 50% with heat from the rest warming the body. In contrast a typical combustion engine is only 20% efficient. (ref 3)
We don’t eat ketones and they only emerge internally. We never see ketones anywhere or notice their presence in healthy people (though acetone on the breath can have a smell). Ketones are not (yet!) found on the supermarket shelves. Doctors see ketosis only through the lens of diabetes or liver disease. However: Ketosis is our natural state!
References for all of the keto series:
- https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(13)00156-2
- Jeff S. Volek, Daniel J. Freidenreich, Catherine Saenz, Laura J. Kunces, Brent C. Creighton, Jenna M. Bartley, Patrick M. Davitt, Colleen X. Munoz, Jeffrey M. Anderson, Carl M. Maresh, Elaine C. Lee, Mark D. Schuenke, Giselle Aerni, William J. Kraemer, Stephen D. Phinney. Metabolic characteristics of keto-adapted ultra-endurance runners. Metabolism, 2015; DOI: 10.1016/j.metabol.2015.10.028
- https://www.ncbi.nlm.nih.gov/books/NBK26882/
- https://www.sciencemag.org/news/2012/01/first-oxygen-users
- https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_Introductory_Biology_(CK-12)/5%3A_Evolution/5.5%3A_Evolution_of_Eukaryotes
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957730/
- https://en.wikipedia.org/wiki/Ketone
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176946/
- https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30355-2.pdf
- Survival of the Fittest – Mike Stroud
- Michael Pollan “The Omnivore’s Dilemma”
- http://www.thesallyedwardscompany.com/sallyedwards/sally-edwards-news.php?article=8
- https://www.triathlete.com/2019/02/nutrition/the-greatest-nutrition-lessons-of-dave-scotts-career_353431
- https://www.em-consulte.com/en/article/80600
- https://academic.oup.com/fqs/article/3/2/61/5475954
- https://juniperpublishers.com/crdoj/pdf/CRDOJ.MS.ID.555746.pdf
- https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1467-3010.2008.00706.x
- https://www.researchgate.net/publication/324157111_Potential_Synergies_of_b_-Hydroxybutyrate_and_Butyrate_on_the_Modulation_of_Metabolism_Inflammation_Cognition_and_General_Health
- http://genesdev.cshlp.org/content/26/3/271.full
- http://www.ketotic.org/2014/01/babies-thrive-under-ketogenic-metabolism.html
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280569/
- https://books.google.fr/books?id=PmMhBQAAQBAJ&pg=PA79&lpg=PA79&dq=cold+exposure+ketone+levels&source=bl&ots=sboucv9-0L&sig=ACfU3U02xcUHb9Cwi1dn4_muhS-rlC24mg&hl=en&sa=X&ved=2ahUKEwj7i6zN5oTlAhXJxYUKHXFqBhUQ6AEwBnoECBEQAQ#v=onepage&q=cold%20exposure%20ketone%20levels&f=false
- https://podcastnotes.org/2018/07/03/attia-patrick/
- https://www.amazon.com/Biochemical-Individuality-Roger-Williams/dp/0879838930/ref=sr_1_1?keywords=biochemical+individuality&qid=1570277237&sr=8-1
- note: While animal cells readily convert sugars to fats, they cannot convert fatty acids to sugars. (But they can convert them to ketones)
- note: Acetyl-CoA can be converted into pyruvate and lactate (lactic acid) through the ketogenic pathway.
- note: oxaloacetate is made from pyruvate (from glucose) but pyruvate itself is a ketone (though this fact is usually never mentioned