The ketogenic diet, a.k.a. “keto,” is becoming a popular eating regimen for athletes, biohackers, and people looking to lose weight and improve their metabolic health. Initially, this diet was used to treat epilepsy,
While you might know the basics of keto—for instance, that it’s a high-fat and low-carb diet—you might not know exactly how it works, or what ketogenic even means.
And that’s OK; it’s a pretty deep topic, involving a lot of complex (but interesting) physiology. The good thing is, you won’t need a Ph.D. in biochemistry to understand some of the fundamentals of the keto diet.
In particular, the first thing you need to know when learning about keto is the basics of what ketones are. In this case, we will start with one of the most talked-about (and important) ketone bodies: beta-hydroxybutyrate.
What is BHB?
Beta-hydroxybutyrate, known as beta-hydroxybutyric acid or BHB, is one of the three “physiological” ketones that are produced by the body (specifically in our liver). Ketone bodies work in several ways: acting as a fuel source for organs, signals for gene transcription, and regulators of metabolism.
Ironically, BHB is not a “ketone” in the technical sense.
While we won’t get into the details here, this is based on the specifics of its chemical structure. “True” ketone bodies have a chemical structure that contains a carbonyl bond, where a carbon molecule is attached to oxygen with a double bond and two other carbon atoms with a single bond. While BHB has a double bond to oxygen, it is bound to only one carbon.
Despite this fact, BHB is still considered a ketone body because it is closely related to the other ketone bodies acetoacetate (AcAc) and acetone.
BHB also has similar physiological effects as AcAC and acetone and in fact, is the predominant ketone body circulating throughout the body.
BHB makes up about 80% of the total circulating ketones in our blood. Acetoacetate and acetone make up the remaining 20% and ~1%, respectively.
Interestingly, two forms of BHB exist. The two forms of BHB are known as “chiral” molecules, essentially two molecules that are “mirror images” of each other but with otherwise identical structures.
One form, R-BHB, is the molecule produced normally in human and animal metabolism—fasting, exercise, and ketogenic diets can all boost levels of R-BHB in the blood. R-BHB is the only form of BHB that we can break down into acetyl-CoA and, eventually, ATP for energy.
The other form of BHB is known as S-BHB. S-BHB is actually just an intermediate (a step before) R-BHB is produced from fatty acid oxidation. In fact, S-BHB doesn’t even stay around long enough to leave our mitochondria and enter circulation.
So, as far as this article goes, any reference to BHB is talking about the R form. With that being said, let’s take a look at how BHB is produced.
Overview of Ketosis
BHB, along with AcAc and acetone, can be found circulating in the blood when you are in a state of ketosis (and at much smaller levels under “non-ketotic” conditions). Physiological ketosis is defined as a state in which blood ketones are elevated to a level above 0.5 millimolar (mM).
When someone is in ketosis, this means that the body is oxidizing (burning) fat for energy through beta-oxidation and turning it into ketones in the liver. Ketosis can be contrasted with the metabolic state of carbohydrate oxidation, or glycolysis—where glucose is burned for energy.
There are two types of ketosis: endogenous ketosis and exogenous ketosis.
Endogenous ketosis means that the body is producing ketone bodies “on its own” without support from some sort of ketone supplement. Basically, you’re burning your own fat (or fat from food) for energy.
One important point: don’t get ketosis confused with diabetic ketoacidosis (DKA). DKA is actually a dangerous condition experienced in people with type 1 diabetes (and also but less often in those with diabetes mellitus or type 2 diabetes). In DKA, a high amount of ketones build up in the blood, leading to blood acidity. What differentiates DKA from physiological ketosis is the fact that during DKA, ketones are elevated, but so is blood glucose.
On the other hand, exogenous ketosis is achieved through the use of exogenous ketones like ketone esters or ketone salts. Ingesting ketone supplements can raise blood ketones to ketosis levels. However, the ketones aren’t coming from body fat oxidation.
Endogenous ketosis is postulated to be an adaptation that we’ve maintained across human evolution. If we had to rely only on glucose oxidation for energy, this would have meant trouble for our ancestors if they were faced with a shortage of food. Involuntary fasting would have wiped us out if we didn’t have some alternative energy-producing pathway. This is where ketosis comes in.
When ketones are produced, they can cross the blood-brain barrier to provide energy for the brain—ensuring cognitive function under food-deprived conditions. Other functions of ketones, like glycogen and protein sparing, may have also been critical to maintaining survival under fasting conditions throughout history.
This might make it seem like ketosis is only something you’ll need if a hurricane wipes out your city’s food supply. This isn’t the case though. Ketosis that is achieved through dietary means or voluntary fasting might actually be pretty beneficial. BHB might play a big role in these benefits.
The Basics of BHB Production
BHB is produced through a process known as ketogenesis (“the origin of ketones”).
When our body is in a fasted or glucose-depleted state (and muscle and liver glycogen are also low), insulin levels fall. Low insulin levels allow the process of lipolysis to occur, which means that fat cells begin to release free fatty acids out of our internal stores. These fatty acids are then sent to the liver and broken down into a molecule known as acetyl-coenzyme A (acetyl-CoA).
In the liver, acetyl-CoA goes through a process of steps that eventually leads to the production of the ketone body acetoacetate (AcAc).
An enzyme known as BHB-dehydrogenase converts AcAc into BHB. Once BHB is produced, specialized transporters then shuttle it out of the liver and into circulation, where it’s used as a fuel. Using BHB for energy essentially involves a process that is a reversal of ketone production—acetyl-CoA is produced from BHB breakdown and then used to create ATP.
How exactly does BHB move around? It’s transported out of the liver through a transporter known as the monocarboxylate transporter (MCT)—not to be confused with MCT oil (short for medium-chain triglyceride oil).
In the brain, BHB uses the MCT transporter to cross the blood-brain barrier.
Molecules of BHB also dissolve very easily in water and blood, making it super efficient at circulating through the body. This might be one reason why we have more BHB than AcAc.
It may be an evolutionary advantage that our brains use BHB instead of its precursor, fatty acids. Using fatty acids for energy in the brain could lead to problems such as 1) causing a hypoxic (oxygen-poor) environment for neurons due to the greater amount of oxygen needed for the oxidation of fatty acids; 2) oxidation of fatty acids increases the production of the oxygen-free radical superoxide, which can cause damage to the brain; and 3) oxidation of fatty acids is a “slow” process, meaning the brain wouldn’t have the energy it would need to make quick decisions that could dictate life or death.
This process is pretty intricate and fine-tuned. But it’s completely natural and something our bodies have evolved to do. But besides “starvation,” how else can we increase BHB in our blood?
How to Raise BHB Levels
Sure, BHB production and ketosis were once “survival” mechanisms activated in response to starvation. But this doesn’t mean we have to undergo famine to reap the benefits of BHB.
In fact, several lifestyle modifications can raise your beta-hydroxybutyrate levels and get you into ketosis.
Intermittent fasting (IF) or other fast “mimicking” conditions like time-restricted feeding (TRF) can induce nutritional ketosis by reducing blood glucose/glycogen levels to kick-start your body’s endogenous ketone production.
Normally, our blood contains some BHB (even if you aren’t fasting or on a keto diet), but the levels are barely detectable—and too low to have any noticeable physiological effects.
After 12–16 hours of fasting, blood ketones rise a bit to a few hundred micromolar. After about two days of fasting, blood BHB rises to 1mM–2mM. Under more prolonged conditions of “starvation” (6–8 days), blood levels of BHB might be anywhere from 6mM–8mM.
There haven’t been many studies that specifically measure BHB levels in response to fasting (at least in humans). However, one study in healthy older adults found that after two days of fasting, BHB levels in the brain rose to 0.6mM. After the third day of fasting, brain BHB rose further, reaching an average level of ~1mM.
The level of ketosis reached on a short-term fast will depend on several other factors like how much (or if) you exercise during your fast, your glycogen levels before starting the fast, and general physical activity during the fast.
Not looking to restrict food intake? Fortunately, there is another way to get into ketosis that doesn't necessarily involve eating a diet void of carbohydrates or fasting for extended periods of time.
Prolonged exercise (especially aerobic exercise in the morning before you eat) is another way to induce physiological ketosis.
This phenomenon is called “post-exercise ketosis,” defined as an increase in blood or bodies during the phase from exercise (i.e., in the immediate time period after exercise ends).
Post-exercise ketosis occurs for a variety of reasons that might include: a depletion of glucose and glycogen during exercise; elevation of circulating free fatty acids released during exercise; and an alteration of hormones that regulate ketogenesis.
How long do you need to sweat for? Studies have shown that after about 90 minutes of intense exercise, blood BHB can reach up to 1mM-2mM.
BHB can also be increased by consuming a high-fat and low-carbohydrate diet—a.k.a the ketogenic or “keto” diet. In fact, restricting carbohydrate intake is one of the most efficacious ways to increase blood ketone levels and induce nutritional ketosis.
Furthermore, in contrast to both short-term fasting and exercise, keto diets are a way to achieve consistently elevated levels of ketones for a long duration of time. If you want to “live in ketosis,” carb-restricted diets are the way to go.
Constant levels of blood BHB above 2mM have been observed in people consuming a diet devoid of carbohydrates.
Perhaps one of the longest-running studies of a ketogenic diet intervention has shown that blood BHB can be consistently elevated through compliant and prolonged carbohydrate restriction. Throughout a 2-year keto diet intervention in type 2 diabetics, average blood BHB was maintained around 0.27mM. Over 61% of participants achieved a blood BHB level >0.5mM (“physiological ketosis”) at least once during the study.
Exogenous BHB Supplementation
Can the benefits of BHB and ketosis be achieved without manipulating lifestyle or diet? This might seem impossible.
But as previously discussed, ketosis can also be achieved using exogenous means—in this case through BHB supplements. Exogenous ketone supplements are a quicker alternative to boosting blood BHB and might have some use for athletes or people looking for a mental edge.
Exogenous ketones come in many forms including ketone salts, MCT oil, and ketone esters.
Let’s take a look at how each of these can be used to raise BHB.
BHB salts are supplements that contain a ketone (BHB) bound to a mineral, like sodium or potassium.
When these supplements are consumed, the salt dissociates into its individual ions and releases BHB, which then raises circulating concentrations of BHB in the blood to levels around 0.5mM-1mM.
Ketone salts might be a cost-effective way to increase blood BHB (they’re cheaper than a lot of other ketone supplements), but they may have some downsides. Studies on ketone salts have revealed side-effects including GI distress in some individuals,
One advantage of using a BHB salt to induce ketosis could be the added benefit of minerals and electrolytes. If the BHB is bound to sodium or potassium, for instance, this could help boost your body’s electrolytes and prevent an imbalance resulting from a keto-diet-induced loss of minerals through the urine.
You’ve probably heard of MCT oils. They’re a popular “supplement” used by people on a keto diet, and recipes for MCT oil in coffee have been floating around the keto community for some time.
MCT oil doesn’t actually contain BHB. Rather, medium-chain triglycerides (MCTs) are a type of fat found in some foods like coconut oil.
In particular, the MCT C8 (caprylic acid) is highly ketogenic,
In fact, studies have shown that C8 consumption results in the highest plasma ketones compared to other MCTs—it’s about three times more ketogenic than C10 and six times more ketogenic than C12.
For this reason, MCT oil (C8 specifically) can be used as a “ketone supplement.”
MCT oils (and MCT oil powders) require a bit more processing in the body than other ketone supplements, and they’ll take longer to raise levels of blood BHB for this reason. The ketogenic “efficiency” of these supplements might be less than BHB salts or BHB ketone esters (discussed later).
MCT oils are also a bit more calorie-dense than other ketones supplements. However, this might not be an issue when used in the “correct” dose.
If you’re looking for a way to raise blood BHB, MCT oils can do the job.
BHB Ketone Esters
Ketone esters are a newer type of ketone supplement. They consist of a raw ketone molecule (BHB) bound to a ketone precursor such as butanediol or glycerol.
Ketone esters can result in rapid and sustained elevation of blood BHB. BHB ketone esters have been shown to increase blood BHB to levels around 3mM-6mM within 30 minutes of ingestion.
Raising blood BHB through exogenous supplementation might have benefits—some similar to and some distinct from those of endogenous ketosis. These may involve both health-related and performance-related benefits.
For instance, BHB supplementation in the diet improves cognitive performance in rats,
Furthermore, acute ingestion of a BHB-containing ketone supplement improves cycling endurance capacity, increases mTOR activation after exercise (a marker of protein synthesis), helps to resynthesize muscle glycogen post exercise, and may even prevent overtraining.
Raising BHB through supplementation could thus helps athletes achieve a physical edge.
R-1,3-butanediol (R-1,3-BDO) is another exogenous ketone that can be used to raise BHB levels. It is a chirally pure form of butanediol, meaning that it cannot be superposed on its mirror image by any number of rotations, translations, or other changes. When consumed, R-1,3-BDO undergoes a series of oxidation steps in the liver and is converted into the ketone bodies R-3-hydroxybutyrate and acetoacetate.
H.V.M.N. Ketone 2.0 contains chirally pure R-1,3-BDO and may raise blood BHB levels to the optimal range of 1.5 mM–2.5 mM for as long as 4 hours. In an internal H.V.M.N. study, a dose of 0.5 g/kg body weight of BDO raised blood BHB up to 2.1 mM. Papers by Scott et al. and Shaw et al. examined the effects of BDO in human athletes and found that the exogenous ketone can consistently raise blood BHB up to 1 mM.
As this molecule is relatively new in the market, the body of literature studying R-1,3-BDO is limited. Based on preliminary research and the fact that it can raise blood BHB to an optimal range, it is theoretically possible that R-1,3 BDO can induce all the benefits shown in previous exogenous ketone studies. However, interest in R-1,3-BDO is growing among the research community—meaning that it is only a matter of time before these benefits are affirmed through clinical studies.
Benefits of BHB
BHB, it turns out, might be much more than just an energetic fuel source for the body.
Some functions of BHB include novel roles as signaling molecule for gene expression, lipid metabolism, neuronal function, and metabolic rate.
The primary function of BHB is to act as a cellular energy source.
The brain, heart, skeletal muscle, and other bodily tissues are able to break down ketones and produce ATP to fuel themselves. Using aerobic (“with oxygen”) respiration, a process known as ketolysis breaks down ketones inside the mitochondria.
We can also use glucose and the direct oxidation of fatty acids to produce energy. In this case, you might be wondering if there is any benefit to using ketones as fuel vs. other energetic substrates. Some evidence indicates that the answer to this may be yes.
Burning ketones for energy is highly efficient and may even lead to lower production of reactive oxygen species (ROS), which are normal byproducts of metabolism. However, while necessary, ROS and free radicals can have damaging effects at high levels, since they can interact with and create dysfunction of proteins and other molecules within cells.
Ketone breakdown leads to less ROS production. This is because the high heat combustion of BHB increases the efficiency of ATP production by the mitochondria, reducing the production of free radicals.
Furthermore, BHB actually protects against oxidative stress within cells.
This evidence suggests that substantial health and longevity benefits might come from reducing your reliance on glucose oxidation (“carb burning”) and increasing your metabolism of ketones—whether through fasting, exercise, or a low-carb diet.
Our brains love BHB. Since we have monocarboxylate transporters on our blood-brain barrier, this means that BHB (and other ketone bodies) can travel across this membrane with relative ease.
Once inside the brain, BHB can trigger the release of neurotrophic factors—chemicals that support the health of our neurons.
In particular, BHB enhances expression of a molecule known as brain-derived neurotrophic factor (BDNF), which is associated with cognitive enhancement as well as reduced anxiety and depression.
BHB also helps increase the synthesis of GABA—an inhibitory neurotransmitter that we need for proper brain health. This is probably one reason why ketogenic diets are beneficial for epilepsy; GABA can “calm down” over-excited neurons that are one of the causes of seizures.
Another role for BHB may be in reducing age-related cognitive decline.
BHB has been shown to inhibit a complex known as the NLRP inflammasome, which could reduce levels of inflammation within the brain. Studies support this—BHB is associated with better cognitive performance and memory in Alzheimer’s disease and mild cognitive deficit. In one study, BHB actually reversed symptoms of Alzheimer’s disease.
Besides boosting brain health with age, BHB could also be a cognitive enhancer. However, we have to rely on mainly anecdotal evidence for this. Many people report that the ketogenic diet and exogenous ketones give them extra mental energy, clarity, and focus. This might be one benefit you need to experience for yourself.
Aging and Longevity
Direct effects of BHB on lifespan enhancement haven’t been observed—in humans at least. However, one study provided evidence that BHB supplementation can extend the lifespan of the C. elegans nematode by as much as 20%, an effect similar to calorie restriction.
Besides direct effects of ketone body supplementation, many of the interventions that boost lifespan in organisms like flies and mice—fasting and calorie restriction—probably involve an increase in ketone bodies.
Other lifespan-enhancing effects of BHB might be due to signaling effects within the body, including inhibition of histone deacetylases (HDACs), inflammation, and mTOR (a key player in cell growth and metabolism).
Lifespan extension is a hot topic. It’s too early to say if BHB might have a role in a healthy and long life, but some early data in animal research is promising.
All this talk about the effects of BHB might have you wondering: "how can I figure out my BHB levels to determine if I’m actually in ketosis?"
The answer? You measure. Here’s how.
Since it’s present at the highest levels in the blood, BHB is the “easiest” and most preferred ketone to measure.
Measuring BHB in the blood is preferred because blood levels of BHB are an indication of what your body is actually using.
Measuring other ketones like AcAc and acetone give you a snapshot of blood ketones, but these methods measure ketones that show up in urine and breath. Essentially, they measure excreted ketones.
You can measure BHB using a blood ketone meter, which is similar to a blood glucose monitor except for the strips you insert into the device. Once you purchase the actual device, measuring blood BHB involves only a few steps.
First, you insert the lancet (the needle that sticks your finger) into the lancing device—this is what you’ll use to draw blood. Next, insert the strip into the ketone test meter, swab your finger with alcohol (to sterilize), and prick your finger to get a drop of blood. Touch the end of the test strip to the blood droplet, wait a few seconds, and then look at the monitor for your results.
Testing for BHB (as opposed to AcAc or acetone) has several advantages. Blood testing is the most accurate ketone testing method using a commercial device. This means it probably gives you a better snapshot of your ketosis state than breath or urine ketones do. Furthermore, you only have to buy the device once (though you’ll need to buy replacement strips every so often).
A few downsides to blood testing include the cost (initially for the meter and then replacement strips), and the invasiveness of the measure. If you’re against drawing your own blood, this method might not be best for you.
You might be asking why you should even measure BHB.
Simply put, measuring BHB can tell if your is working. High ketones are confirmation that what you are eating is getting you into ketosis. Ketone testing during fasting or after exercise is also a great way to see how you respond to these regimens. Testing for BHB gives invaluable biofeedback about your lifestyle habits.
Understanding BHB, and how it works, brings you one step closer to becoming a keto expert.
But there are many steps to creating a keto lifestyle that actively works toward your goals. The first step is usually defining those goals. Are you embarking on keto for metabolism? To meet performance benchmarks? That’s up to you.
Once your goals are established, it’s time to get to work. Things like a keto shopping list and keto macronutrient calculator can help you optimize your approach for best results. Keep learning, checking in with yourself, and creating the best routine to help you achieve the best possible outcome.
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