When we say ketones, we are talking about the primary circulating fatty acid metabolites beta-hydroxybutyrate (OHB) and acetoacetate (AcAc). More on ketone basics here. Exogenous ketones (also called ketone supplements) and well-formulated ketogenic diets share at least one thing in common. They both result in increased circulating concentrations of beta-hydroxybutyrate (BOHB), but ultimately are associated with very different patterns of ketosis, as well as differing metabolic and physiologic outcomes. In a nutshell, they must not be assumed to have equivalent effects simply because they achieve similar BOHB blood levels. With that said, there are many reasons we must continue to study the different forms and potential applications of ketone supplements.
For the past few million years, the only method for humans to make use of ketones for fuel was to restrict carbohydrates low enough and long enough to induce the liver to ensure they are. This can be admittedly hard for many people to accomplish in a world that also believes that dietary carbs are great and fats are bad. An emerging alternative would be to consume ketones being a health supplement. The research into how these function in the body and what benefits they can confer remains early stage, but we already have several such products available for sale. Within this section, we shall discuss how exogenous ketones affect blood ketone levels, and just how they may influence health and disease compared to ketones produced in the human body.
Both predominant ketones produced by the liver are beta-hydroxybutyrate (BOHB) and acetoacetate (AcAc). Here’s a brief summary of basic info about these ketones:
It is actually estimated that the keto-adapted adult can make 150 or even more grams of ketones daily after adjusting to an overall total fast (Fery 1985), and maybe 50-100 grams per day on the well-formulated ketogenic diet.
Some AcAc naturally breaks down to form acetone, which will come out from the lungs and kidneys, giving a chemical odor to the breath when ketones are high.
Much of the AcAc made in the liver is found by muscle and transformed into BOHB.
Included in the keto-adaptation process, how muscles and kidneys handle BOHB and AcAc changes over the first few weeks and months, and so the ratio of AcAc to BOHB in the blood changes considerably inside the first couple of weeks.
As the ultimate fate of most ketones inside the blood is to be burned for fuel, BOHB and AcAc seem to have differing roles in regulating genes and cellular functions.
Particularly with gene regulation, BOHB appears to play a more significant regulatory role than AcAc, but AcAc may have a particular role in signaling muscle regeneration .
Sources and Formulations of Exogenous Ketones – Both compounds commonly referred to as ‘ketone bodies’ (BOHB and AcAc) are made and used for multiple purposes across nature from algae to mammals, but seldom in concentrations ideal for extraction as human food. For that reason, the cause of most exogenous ketones is chemical synthesis. Furthermore, most current research and use of ketone supplements concentrates on BOHB. This is because AcAc is chemically unstable – it slowly breaks down to create acetone by releasing of a single molecule of CO2.
In a keto-adapted individual where ketone metabolism is brisk with as many as 100 grams or more being oxidized (i.e., ‘burned for energy’) daily, the small amount lost in breath and urine as acetone is minor. But because this breakdown occurs spontaneously without having the aid of enzymes, it also happens to AcAc in a stored beverage or food (even in an air-tight container), making the shelf-lifetime of AcAc-containing products problematic. Thus all current ketone supplements contain BOHB in certain form instead of uolcok natural mixture of BOHB and AcAc made by the liver.
Another important distinction between endogenous and exogenous BOHB is the fact most synthetic BOHB used in dietary supplements is a mixture of the two ‘D’ and ‘L’ isomers, whereas endogenously produced BOHB consists of just the D-isomer. Metabolically, both isomers are very different, and current published information shows that most of the energy and signaling benefits of BOHB derive through the D-form. This can be potentially problematic because the L-isomers are certainly not metabolized via the same chemical pathways because the D-forms (Lincoln 1987, Stubbs 2017), plus it remains unclear whether humans can convert the L-form towards the D-form.
Thus, as the L-isomers tend not to look like toxic, they are not very likely to impart exactly the same benefits since the D-forms. Additionally, the current assays for blood ketones are specific for the D-isomer, therefore it is hard to track blood levels and clearance of the L-isomer taken in a supplement.