Ketosis Fundamentals

Authored by Nate MartinsDr. Brianna Stubbs and Brady Holmer • 
November 11, 2019
 • 28 min read
ketosisketo-dietexogenous-ketones

Browse the shelves of any supermarket, and you’ll probably notice that a new category of products has emerged. 

Some go by names like “fat bombs” or “keto cookies” and all are designed to be included in a diet that many are following these days—the ketogenic diet

Table of Contents

The diet, “keto” for short, has taken the nutrition sphere by storm. While popular and evidence-based, many might not know exactly what ketosis is, how it works, and why it’s such a big deal. That’s what we’re here for. 

What is Ketosis? 

When we think about using energy, we often think about the process of “burning” carbohydrates and fats to provide the necessary fuel for cells to do work. Glucose is one of the main sources of energy for humans and animals—it’s usually obtained through dietary intake of carbohydrates: breads, fruits and vegetables, legumes, and some other less-healthy sources of refined carbohydrates and starches. 

Some of the carbohydrates we consume are used to maintain blood glucose levels and fuel organs that can’t use substrates like fat for fuel, including red blood cells, some cells in the eye, and the brain. Any glucose not used is stored in the liver and muscle in glucose “chains” known as glycogen or will be converted into adipose tissue (body fat). 

In certain situations, like during exercise or during the fasting state (~2+ hours after consuming a meal), we can “liberate” glycogen from storage sites and turn it into glucose if no external sources of glucose are coming in through diet. This is one way which we maintain blood sugar levels.

For instance, during prolonged exercise or fasting, muscle glycogen is broken down to provide energy.

Depending on fuel availability and the energy demands of the body, we are able to switch fuel sources from glucose to fat, and vice versa. This is termed “metabolic flexibility.”

No glycogen, no problem. The body can break down and release fatty acids into the bloodstream. 

Fat is an energy-rich substrate, is a great source of fuel for the body, and most people have enough fat stores to last the body a long time. But, it turns out, some organs, like the brain and red blood cells, can’t use fatty acids as a fuel substrate—they lack the necessary enzymes to do so. Thus, they rely solely on glucose, either obtained through food or created through gluconeogenesis

What happens then, if no glucose is available?

First, glycogen will be liberated from the liver and used for energy production. After about 24 hours, however, glycogen will begin to deplete unless carbohydrates are consumed from an external source.1 Now we need some sort of energy for organs which will otherwise become “starved” of energy.

Luckily, evolution has found a workaround to this problem—ketosis.

In response to glycogen depletion and low blood glucose, a slew of hormonal signals are initiated inside the body: insulin falls, glucagon rises, and cortisol increases, among others. These shifts are a signal for the body to burn fat; and stored fat is released from adipose tissue into the blood as free fatty acids (FFAs). 

Once in the blood, FFAs trigger the production of ketone bodies, which occurs inside the liver. The process, termed “ketogenesis,” results in elevated levels of ketone bodies in the liver, including beta-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone. 

Unlike fats, ketones can cross the blood-brain barrier2 and serve as a fuel source for our brain, with some research suggesting that up to 60% of the brain’s energy during starvation can come from ketone metabolism.3 This important adaptation was survival insurance. 

Long ago, when cavepeople went long periods without an external source of energy, ketosis ensured they could not only survive periods of starvation, but allow for high-level body and brain function.4 Food needed to be hunted or gathered, and ketones provided the energy to do so.

What Role Does Ketosis Play Today?

For most of us, food availability today is nothing like that of prehistoric humans. 

We can easily access high-energy, high-carbohydrate food sources. Our metabolic state is constantly on “fed.” On one hand, this is great—who doesn’t love a taco at 2am? But, our food-plenty lives come with a cost. Heart disease, type 2 diabetes, and other diseases of modernity have been attributed to increased consumption.

Many people are rarely exposed to a period of more than a few hours without food (other than sleep). We aren’t food-deprived, and therefore our bodies are never forced into a ketogenic state. This might be seen as a blessing of modern day. 

But, are we missing out on some of the benefits ketosis can provide bodies? A little “stress” is sometimes a good thing.

Most research says yes, and this has paved the way for a rising interest in ketogenic diets—which are basically a form of a low-carbohydrate high-fat diet. The big difference between a “normal” diet and a very low carb diet (~20-50g carbs/day) is that on a ketogenic (keto) diet, the severe carbohydrate restriction results in the production of ketones by the liver. 

As we will see, ketones act in a myriad of ways to exert several health benefits. 

Ketosis vs. Ketoacidosis

Let’s clear the air here. People sometimes (incorrectly) confuse the terms ketosis and ketoacidosis. These are entirely different physiological states, and should be differentiated before we move on.

Diabetic ketoacidosis (DKA) is a condition often occurring in type 1 diabetes. It’s characterized by both high levels of blood glucose and high blood ketones—something that shouldn’t normally occur in human physiology.5 

Since people with type 1 diabetes don’t produce insulin, levels in the body stay low, and the signal for muscles to take up blood glucose is absent, meaning glucose levels in the blood stay high as they are not being brought into cells to be used for energy. Low insulin levels, however, also signal for fatty acids to be released into the bloodstream. The result is increased liver ketone production, leading to abnormally high blood ketones and blood that becomes acidic (hence “acidosis”). Ketoacidosis is very harmful.

Ketosis, while also characterized by elevated blood ketones, occurs in the presence of LOW blood glucose. It’s a response to carbohydrate depletion; it’s completely physiological and an evolutionary advantage.

Beware of any articles that cite “ketoacidosis” as a negative aspect of ketosis or the ketogenic diet, unless in the context of diabetes. 

How to Achieve Ketosis

Being in ketosis means blood ketones levels are elevated—classically defined as a blood ketone reading of >0.5 millimolar (mM).

However, ketosis can be achieved in one of two ways; endogenously or exogenously. How ketosis is achieved will determine some of the benefits experienced.

Endogenous Ketosis

Endogenous ketosis refers to when the body (specifically, the liver) is actually producing ketones. In this case, you would be considered “ketogenic”. Endogenous ketosis can occur due to a ketogenic diet, intermittent fasting, and endurance exercise (with no caloric consumption).

Originally, all of the endogenously produced ketones start as acetoacetate (AcAc). However, BHB is the ketone found circulating at the highest levels in the blood, with AcAc in lower amounts.6 There’s probably a reason for this.

BHB is more “stable” when traveling throughout the body, and many cells in the body express a transporter (known as the monocarboxylate transporter) which can take up BHB.7

BHB is a “more reliable” source of transportable energy. AcAc, on the other hand, can undergo a spontaneous reaction, where it’s converted to another ketone: acetone.8 Acetone can be excreted, with only a small amount (if any) oxidized for energy.

Exogenous Ketosis

Remember: ketosis simply means that blood ketone levels are elevated about 0.5mM.

Exogenous ketosis is achieved using external means—often taking the form of exogenous ketone supplements or ketone body precursors like medium-chain triglycerides (MCTs). Exogenous ketones eliminate the need for fatty acids to be broken down, instead directly elevating blood ketones upon ingestion.

Exogenous ketones can come in several forms including ketone salts and ketone esters. Of the ketone esters, the AcAc diester and BHB monoester (present in our ketone ester) are the most widely used.

MCTs, while not ketones, are a type of fat that is highly ketogenic. Once ingested, MCTs can be rapidly broken down in the liver to produce ketone bodies. MCTs can have different carbon lengths and this can slightly dictate how ketogenic they are; MCTs with 8 carbons (C8) are 3 times more ketogenic than a 10-carbon MCT and about 6 times more ketogenic than a 12-carbon MCT.9 Coconut oil is a rich source of MCTs, but these precursors can also be consumed in the form of MCT Oil Powder.

Keto Diet 101

The hallmark of a ketogenic diet is rooted in an extremely low carb intake, which drastically minimizes any outside supply of glucose. The keto diet also calls for a less drastic reduction in protein consumption, sometimes due to the (perhaps false) belief that high-protein will convert to glucose in a process known as gluconeogenesis (GNG).10 This would (gasp!) kick you out of ketosis. However, this is a much-disputed topic. The more moderate protein approach to keto is what differentiates it from the atkins diet, which advocates high-protein consumption. 

On a strict keto diet, you’ll need to get about 70% - 80%+ of your total daily calories from fat, 10% - 15% from protein, and the minor remaining amount from carbohydrates (mostly non-starchy vegetables).

Exactly how many carbs can you eat? Traditionally, recommendations call for no more than 50g of carbs per day, with more severe restrictions limiting your intake to 20g - 30g. If you’re new to keto, the upper limit might be the best place to start before gradually weaning off carbs. 

How long does it take to get into ketosis

This will depend on multiple factors like activity, body type, and carbohydrate intake. It could take anywhere from 48 hours (on the quick end) to one week to get into ketosis, and a bit longer to fully “keto adapt.”

Ketone Metabolism

When just floating around your body’s circulation, a fuel source is relatively useless. To harvest the energetic benefits of ketones, our body must break them down.

Before talking about ketone metabolism, let’s review just exactly how ketones are created in the first place.

Ketogenesis: How Ketones are Made

We know you didn’t come here for a biochemistry lecture (or maybe you did?), so we’ll keep things brief.

Ketogenesis occurs in the liver, which can produce, but not use ketones.

There are 5 basic steps to how ketones are made.

1) Condensation - first, a free fatty acid (FFA) is broken down into two molecules of acetyl-coenzyme A (acetyl-CoA). Then those two molecules condense to form a molecule called acetoacetyl CoA, which is catalyzed by the enzyme thiolase.

2) Production of HMG CoA - Acetoacetyl CoA will combine with another molecule of acetyl CoA to produce 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction is catalyzed by the enzyme HMG-CoA synthase.

3) Breakdown - another enzyme known as HMG-CoA lyase then lysis (breaks down) HMG-CoA back into acetyl-CoA and a molecule called acetoacetate (AcAc), a ketone body.

4) Creation of BHB - once AcAc is formed, some of it will be reduced into BHB, another ketone, by the enzyme BHB-dehydrogenase. The amount of BHB produced is dictated by a ratio of NAD to NADH.

5) Acetone production - Some amount of AcAc undergoes a spontaneous decarboxylation reaction in which it is converted into a “waste product” known as acetone (another ketone body). While some evidence says acetone can be metabolized as a fuel,11 most of it is excreted in the breath (this is where the term “ketone breath” comes from, and why we can measure for ketones using a breath meter).


Ketolysis: How Ketones are Used for Energy

Now that we have our ketones (AcAc and BHB) inside the circulation and being dispersed to tissues, they can be used for energy.

For this to occur, our mitochondria (cell powerhouses) must break down ketones into their component molecules. When BHB enters the mitochondria through a monocarboxylate transporter, it’s then converted back into AcAc by BHB-dehydrogenase. Following this reaction, one coenzyme group is added to AcAc from succinyl-CoA. This reaction is catalyzed by an enzyme called 3-oxo-acid-transferase (AKA ketoacid coenzyme A transferase).

These steps leave us with a molecule called acetoacetyl-CoA, which then is converted into two molecules of acetyl-CoA by acetyl-CoA thiolase. Acetyl-CoA is our metabolic “end product.” Once it condenses with oxaloacetate, acetyl-CoA can enter an energy-yielding process called the Krebs cycle (a.k.a the TCA cycle or citric acid cycle).

From this, we get ATP, the energy currency of cells.

Are Ketones a Favorable Energy Source?

When the body uses fuel sources like ketones, carbohydrates, and fat, energy is created (stored) in a molecule called adenosine triphosphate (ATP).

How much energy is released during the oxidation of each fuel source determines how much energy it can store in ATP. This has a lot to do with what’s known as the Gibbs free energy number, which in turn is highly influenced by the amount of heat energy a substrate can generate. This heat is known as combustion enthalpy.

It turns out, ketones have a higher combustion enthalpy (and thus, heat production) than pyruvate, lactate, and glucose.12

This means ketones have the potential to transfer more energy to ATP per unit of oxygen than do other substrates. A 1995 study demonstrated that ketone metabolism resulted in a greater free energy per ATP molecule—basically more potential energy was provided by ketones compared to glucose for cells to “do work.”13

There are a few other factors that make ketones a more “favorable” energy source.

For one, the uptake of ketones doesn’t require insulin. Glucose, on the other hand, requires several well-coordinated steps (mediated in part by insulin) in order to be sucked up by the muscles and used for energy. Ketones enter cells through transporters (the monocarboxylate transporter) and are thus broken down more rapidly, without the need for a cascade of signaling events.

In addition, energy from ketone oxidation enters the electron transport chain at the beginning as a molecule known as NADH. The electron transport chain, as the name suggests, uses the transport of electrons across cell membranes to create a proton gradient, resulting in ATP production.

All of this is to say that cells are able to create a bit more energy from ketones than they can with other fuel sources.

How to Measure Ketosis (Am I in Ketosis?)

Endogenous ketosis produces AcAc and BHB, which are present at various concentrations in the blood (remember, BHB at a higher level). Exogenous ketosis directly elevates BHB and AcAc. 

Either way, a state of ketosis means you’ll have ketones in your blood as well as your urine, and perhaps in your breath. This means that ketones can be measured using devices tailored to each specific molecule, based on where it’s most likely to be present in detectable amounts.

Blood Ketone Measurement

Measurement of blood ketones is the gold standard method used to measure blood BHB in response to endogenous or exogenous ketosis. 

Blood ketone measurement requires a handheld device, in which a small amount of blood (obtained through a finger prick) is placed onto a test strip, which is then inserted into the ketone meter. The device provides a numerical measure of BHB (in mM) after a few seconds.

One advantage of blood ketone measurement: it’s the most accurate way to measure ketosis for at-home testing. If you want robust readings of BHB, a blood ketone device is the way to go.

But this method is invasive, requiring a finger prick for each reading. This can also get costly. On top of the device (usually running $30 or more), the test strips cost about $1 - $3 per strip. Depending on how often you’re checking ketones, this could add up.

Urine Test Strips

Number two on our list of measurement techniques involves going number one. Urine ketone test strips are another and less-invasive way to measure ketones. But how do ketones show up in the urine in the first place?

When ketones are in your body (endogenous or exogenously sourced), they will end up in the kidneys where some, but not all, of these ketones are reabsorbed and put back into circulation. The remaining ketones end up in the urine. Interestingly, if in a prolonged fasted state, your kidneys become more efficient at reabsorbing ketones.14,15

Specially-designed test strips are able to measure the presence of ketones due to certain chemicals present on the material. The strips change color to indicate the levels of ketones (acetoacetate) appearing in your urine. Typically, a dark purple color will indicate a higher amount of urine ketones. 

Urine test strips have disadvantages. Urine is a less-reliable measure compared to blood (which we discussed earlier with the kidneys’ ability to reabsorb them). 

When someone becomes keto-adapted their kidneys might be able to better reabsorb and utilize more of the ketones they produce—meaning less spills over into the urine. A study found that the kidneys were able to reabsorb more ketones as time progressed in individuals who were undergoing a long-term fast.14

To the best of our knowledge, this same type of study has not been repeated in individuals adhering to a keto diet but the findings of this study show that the kidneys to have the ability to reabsorb more ketones under certain conditions. Also, high ketone levels in the urine don’t necessarily indicate high levels in the blood16 or ketone levels achieved through exogenous ketone supplements.

The latter might be due to the fact that, in some cases where ketones are rapidly elevated (such as when you use exogenous ketones), ketones won’t appear in the urine. For instance, most of BHB from an exogenous source will be metabolized, and little will get excreted.15 

Urine strips are also influenced by hydration, so results could vary drastically. Overall, urine strips might best be used as a “guide” rather than a definitive reading of ketosis, especially since they give a ketosis measurement range, not an exact number. 

There are some advantages to urine testing. It’s usually less expensive than blood testing, the meters are widely available, and ketosis can be measured literally anywhere, at any time (almost). 

Breath Acetone Meter

As we’ve covered earlier, the breakdown of AcAc in the body leads to the production of acetone. Acetone is sometimes referred to as a metabolic “waste product,” since most of it can’t be used for anything (unlike BHB or AcAc). 

When the body is in a low level of ketosis, acetone in the breath correlates fairly well with blood ketones.17 For this reason, measuring the levels of acetone in the breath can give a snapshot of ketone levels in the body. You can do this by purchasing a handheld device that requires a huff, and a puff, until a numerical scale is produced that gives you a reading (in parts per million) of breath acetone. This non-numerical scale is less precise than blood ketones, however. 

A disadvantage is that, as blood ketone levels become more elevated or rise rapidly (if you ingest a ketone ester, for example), breath acetone no longer correlates well with blood ketones, and the meters become less accurate.18 

The breath meter is the cheapest way to measure ketones, as it only requires a one-time purchase of the device. It’s also non-invasive, portable, and convenient.

When to Measure Ketones

Measure ketones at the same time each day, both for consistency and to remove outside influencers that might affect your ketone levels or interfere with measurement accuracy. Some may wish to check ketones levels about 60 - 90 minutes following a meal, consuming exogenous ketones, or exercise.

What number should you look for? Is there an “optimal level” of ketones? This answer isn’t so cut-and-dry.

For weight loss, a blood BHB of 1.5mM - 3mM might be the best range to garner benefits. Most experts agree that nutritional ketosis occurs when blood ketone levels reach 0.5mM, with “light ketosis” falling somewhere between 0.5 and 1.0mM. This range might be sufficient for weight loss. However, “optimal” ketosis occurs anywhere from 1.0 - 3.0mM, and this might further benefit weight loss.19

Whatever ketone levels you find yield the best subjective and objective results is the level that’s probably best for you. Experiment away.

Keto for beginners

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Keto Adaptation and the “Keto Flu”

Diving right into the ketogenic diet without research, prior experience, or adequate knowledge of what to expect might lead to some unintended side-effects. 

This might be due to the fact that most people transitioning to keto will drastically be altering their metabolism. After years of relying on carbohydrates as a main source of fuel, you’re now retraining metabolic systems to rely primarily on fat stores.

A period of adaptation is required when starting a keto diet so all the requisite enzymes and energy systems can become “fat burners.”

In the first week or two of keto, symptoms might occur, commonly referred to as the “keto flu."20 

This is because you’ll have a low availability of carbohydrate to fuel your brain, muscles, and other organs. At the same time, your liver isn’t quite fully capable of ketone production, nor are you capable of fully utilizing ketone bodies. Symptoms will likely subside once you become more adapted to the ketogenic diet. 

Symptoms of keto flu might include: fatigue and low energy during the day, trouble sleeping, brain fog, muscle cramping, craving for sugar or carbohydrates, constipation, reduced exercise performance or poor recovery from exercise, moodiness, irritability, headaches, and “keto breath.”20 

Using exogenous ketones like a BHB monoester might make it easier to transition into ketosis.20 

Ketone monoesters provide a source of usable fuel in the form of ketones, before you’re endogenously producing any, helping make a switch to the keto diet a bit easier and perhaps a tad more symptom-free.

Applications for Ketosis

Keto has origins in the history of medicine. Ketogenic diets were long prescribed as a treatment for drug-resistant epilepsy in children, where results in the literature are astoundingly positive.21

Now, the uses for ketosis achieved through ketogenic diets seem to have potentially endless applications for health and disease.

Epilepsy

Remember, the brain can’t use fat for energy because fat can’t cross the blood-brain barrier; it can use glucose and ketone bodies.

Ketones, however, can access the brain. Once inside, ketones undergo metabolism through a process distinct from that of glucose metabolism.

This alternate pathway might offer several benefits, including reduced oxidative stress, lower inflammation, and an alteration of certain brain neurotransmitters involved in health and disease.22 It’s an enticing theory that a lower reliance on glucose metabolism (in favor of increased utilization of ketones) in the brain offers several advantages, especially in conditions where fuel metabolism and neurotransmitter release has become unbalanced.23

Such is the case in epilepsy, where abnormal and chaotic brain activity results in recurring seizures.24 A primary cause may be an imbalance of excitatory neurotransmitters like glutamate and inhibitory ones like GABA. Increased glutamate levels in the brain are associated with a variety of neurological disorders.

Where drugs have failed, the ketogenic diet has shown promise in delivering effective seizure control, in some studies reducing the frequency of seizures anywhere from 40% - 90%.25 But how does this happen?

Ketogenic diets increase levels of GABA in the brain,26 decrease glutamate,27 activate potassium ion channels,28 and reduce brain blood glucose—all of which may reduce the firing rate of neurons and reduce the potential of a seizure.

Ketogenic diets may increase mitochondrial biogenesis, which would allow more ATP to be produced and attenuate neuron excitability.21 A state of ketosis may interfere with pro-inflammatory cytokines associated with seizure activity. Lastly, ketogenic diets might inhibit DNA methylation (one process by which genes are regulated) while also increasing adenosine (an inhibitory neurotransmiter) activity in the brain.29

In terms of exogenous ketones, studies have shown that injection of ketone bodies into rats reduces convulsive activity.30 The AcAc diester has been shown to protect against oxygen toxicity seizures in rats.31

Alzheimer’s Disease

A buildup of plaques and tangles inside neurons in the brain is a characteristic aspect of Alzheimer’s Disease (AD). These changes negatively impact memory, judgement, behavior and language.

Normal day-to-day activities are impaired, and quality of life suffers in AD patients. It’s a disease commonly seen with aging, but disease progression may start in early life. Diet and lifestyle might play a huge role.

Impaired brain metabolism in AD means that brain insulin insensitivity deprives neurons of glucose.32

 In the case of an energy-starved brain, an alternative fuel source, such as ketone bodies, might provide a life-changing treatment for this condition.

Ketone metabolism appears to be preserved in patients with AD.33

As a brain fuel, ketones result in lower oxidative stress and mitochondrial damage compared to glucose.34 The implications for this have been demonstrated. Mice and humans treated with a BHB-butanediol ketone ester show improvements in cognitive and behavioral function along with structural changes in the brain.35,36

But what about diet? In one study, a six-week ketogenic diet improved symptoms of mild cognitive impairment, a less severe but nonetheless devastating form of AD.37 Foods that contain ketone precursors, like MCTs, can improve cognitive test scores in AD patients.38

Mean fasting insulin for these patients was also high at the beginning of the study, which is indicative of hyperinsulemia; however, this value decreased means the ketogenic diet was able to help ameliorate this disease risk factor as well.

“Let food be thy medicine,” has never rang more true.

Parkinson’s Disease

Another cognitive disease associated with aging, Parkinson’s disease (PD) is characterized by a buildup of misfolded proteins called “Lewy bodies.” These accumulate in the brain, leading to neuron death, inflammation, and mitochondrial dysfunction in centers involved in the regulation of movement. Shaking, rigidity, and poor movement control are common symptoms.39

As in the above disorders, energy metabolism in the brains of PD patients is severely impaired due to mitochondrial dysfunction. A decreased use of glucose,40 less mitochondrial energy production,41 and high levels of inflammation promote a cycle of more neuron death and more Lewy body formation.42

In animals, a ketogenic diet in PD leads to fewer symptoms of poor motor control, reduces inflammation, and attenuates the loss of neurons.43,44 In vitro (“cells in a dish” model), addition of the ketone body BHB protects against degeneration of neurons.34

There has been one study in patients with PD. In this trial, a ketogenic diet produced improvements in clinical scores of tremor, balance, and mood.45

Ketosis may provide an alternative energy source with anti-inflammatory benefits for those suffering from PD, but more human work needs to be done.

Mood and Migraines

Like many other neurological conditions, depression and anxiety are also linked to changes in the brain, including but not limited to: inflammation, altered gene expression, and an imbalance of neurotransmitters.46

The presence of ketone bodies might directly influence some of the causes of mood disorders.

Fed exogenously, ketones in the blood have been shown to reduce anxiety levels in rats.47 BHB (both endogenous and exogenous) alleviates depression-like behavior in stressed-out mice in part by increasing a beneficial hormone known as brain-derived neurotrophic factor (BDNF).48

Many case studies (n=1) provide some evidence that migraines improve on a ketogenic diet.49,50,51,52 In theory, this might be due to the presence of ketone bodies decreasing glutamate levels, which have been implicated in the manifestation of migraines.53

All in all, when it comes to the brain, ketones might be a “super fuel."

This is why many people swear by the ketogenic diet and exogenous ketones for enhancing their day-to-day cognitive function and productivity. We can’t disagree.

Ketosis for Weight Loss

The obesity epidemic seems to only be getting larger.

While the exact causes aren’t agreed upon, it’s probably a combination of low physical activity, poor diet, epigenetics, and an all-around society encouraging overconsumption.

Regular dieting has produced poor results for many. Restricting calories for a long time isn’t any fun, and many find this strategy unfeasible. For this reason, low-carbohydrate ketogenic diets (LCKD) have become more popular as a way to boost fat loss and improve health.

The high-fat and restricted-carbohydrate nature a KD causes a slew of hormonal and metabolic changes which directly and indirectly might contribute to weight loss and weight loss maintenance.

The high-fat and restricted-carbohydrate nature a KD causes a slew of hormonal and metabolic changes which directly and indirectly might contribute to weight loss and weight loss maintenance.

One the one hand, a low intake of carbohydrates means a lower secretion of insulin. This increases the release of fatty acids from adipose tissue, lowers fat synthesis (lipogenesis) and decreases fat storage.54,55 The result is a higher “fat burning” capacity, where your body starts to rely on fat oxidation for energy rather than glucose. On top of this, ketogenic diets may increase metabolic rate by decreasing mitochondrial efficiency. More heat is lost this way, and more calories are burned.56 This, along with the fact that low-carbohydrate diets often contain larger amounts of protein, contribute to what is known as the “metabolic advantage” of low-carb and ketogenic diets. This means that compared to traditional higher carbohydrate diets, they lead to increased metabolic rate and weight loss, when the two diets are matched for calories.57

Ketogenic diets are also satiating, making you feel full and satisfied rather than watching the clock for your next meal.

Ketone bodies might have a direct appetite-suppressing effect. The infusion of BHB has been shown to reduce food intake and body weight in animals,58,59 change levels of hunger regulating hormones in the brain,60 and reduce appetite.61,62

Ketone Ester drinks reduce appetite and ghrelin (the hunger hormone) more than the same amount of calories obtained through carbohydrates.60

Better regulation of appetite can lead to a reduced caloric intake, which might be one of the main reasons that ketogenic diets have shown such promise for weight loss. That’s also why, perhaps, they’re more effective at keeping weight off in the long term. Social media posts sure do support this claim, and so does some of the literature.

A meta-analysis of 13 studies revealed that people who ate a ketogenic diet showed greater reductions in body weight and an improvement in other metabolic variables compared to a low-fat diet group in the long term.63 This is true, of course, if you can stick to it.

Roads to weight loss are many, and vary for the individual. For some, the strong satiating properties of a high-fat ketogenic diet might make it easier to adhere to your diet. Eating high fat might make you less hungry, meaning you’ll snack less, and won’t be tempted to keep reaching for the potato chips.

Ketosis for Cancer

The “hallmarks of cancer” include: the loss of growth regulation, an ability to avoid destruction by immune cells, a near-infinite ability to divide and grow, promotion of inflammation, and activation of the spreading of tumors to other parts of the body.64

Once tumor cells start to grow and divide, it’s hard to stop them. Cancer cells accumulate damage, become dysfunctional, and ultimately alter energy metabolism.

One theory on cancer origins is known as the metabolic theory of cancer; this means that the root cause is a defect in mitochondrial energy production or a defect in cellular respiration.65,66,67

With compromised energy, cell death and damage accumulates, and normal cells become cancerous and mutate. Another theory is that cancer is the result of genetic defects related to tumor suppressor genes and oncogenes but there is some debate regarding the acceptance of this theory.67

A strategy to tackle the issues of aberrant glucose metabolism in cancer cells might be through application of the ketogenic diet. Metabolic therapies using KD have shown much promise in the treatment of tumor cells and the disease of cancer itself.

A vast majority of studies in animals have demonstrated anti-tumor effects of KD. In humans, several case studies have shown that ketogenic diets can stabilize tumor growth and alter tumor metabolism.68,69,70

The presence of BHB alone (exogenous) can change cell metabolism from that of glucose metabolism to ketone metabolism and lower blood glucose, both of which could alter the progression of cancer cells. Exogenous AcAc supplementation decreases the size of tumors and increased survival time in mice with cancer.71

While the data are promising, nutritional interventions are far from a “magic bullet” for cancer treatment.

It’s a complex disease, and the fight for a cure may mean tackling the disease from many sides. Nonetheless, ketones and ketogenic diets represent a promising area of research for cancer therapies, and the work being done in this area is exciting.

Ketosis for Diabetes and the Metabolic Syndrome

Insulin is a hormone that helps regulate blood glucose—it’s responsible for initiating a cascade of signalling events in which the end product is glucose uptake into cells. Insulin is usually released in response to a rise in blood glucose (like after a meal).

In the case of diabetes, the signals needed for insulin to be effective fail because the body doesn’t respond properly to insulin—this is termed “insulin resistance.” Type II diabetics are insulin resistant. Type I diabetics, on the other hand, don’t even produce insulin. Due to high levels of blood glucose, both diseases are harmful to blood vessels and organs in the body.

Ketogenic diets are a lifestyle approach being heavily advocated as a treatment for diabetes. Why are they so beneficial?

Ketogenic diets lead to reduced blood glucose and lipid levels, even in the absence of weight loss.72,73 However, many KD do lead to weight loss,74 and this may further improve insulin sensitivity and risks pertaining to other metabolic disorders like cardiovascular diseases.

Ketogenic diets also improve insulin sensitivity,75 and many studies have shown that lower fasting insulin levels occur in response to KD.75,76 Restricting carbohydrates seems to have many benefits for both type I and type II diabetics.

Exogenous ketones might play a small but important role in diabetes management.

When used strategically alongside lifestyle and diet interventions, exogenous ketones may help to control blood glucose. Ingestion or infusion of ketone esters and ketone salts have been shown to reduce blood glucose and lipids, and increase insulin sensitivity.77,78

Ketosis and the Microbiome

Of all the hot topics in health, the gut microbiome perhaps tops the list.

Our microbiome is the trillions of microscopic organisms inhabiting our intestines, sometimes referred to as an organ in and of itself. Each of us has a unique microbiome, which contributes to thousands of physiological processes in the body.79 Digesting food is just the tip of the iceberg.

Altered gut bacteria, essentially a change-up of the bacterial composition, can have big impacts on health, both positive and negative. In the case of a loss of balance between “good” and “bad” bacteria, disease risk might increase. This is termed “dysbiosis.” It’s currently unknown which comes first, disease or dysbiosis, but the two are highly correlated. This is perhaps due to the fact that gut bacteria are heavily influenced by what we consume.80 "You are what you eat."

The ketogenic diet has been shown to induce changes in the gut microbiome, and many of these changes have been linked to disease improvement.

The gut microbiomes of epileptic children change in response to a KD—there are fewer pathogens and more beneficial bacteria.81 Some research has indicated that this change in gut microbiome might be necessary for the benefits of a KD in epilepsy.82

Another study has shown that KD feeding triggered reduced gut microbial counts and a compositional remodeling of the gut in mice with autism spectrum disorder.83 This finding is supported by the data that ketogenic diets lead to improved neurological health.

Gut changes might be one reason that KD is so good for appetite regulation and satiation. Ketogenic diets lead to changes in hunger hormones like ghrelin, 84which has been shown to be inhibited by the ketone BHB.60

Changes to the gut biome don’t take long once you transition to a diet. One study has shown that after just five days of feeding a diet primarily of meats, eggs, and cheese (i.e. a ketogenic diet), drastic shifts in several gut biome species occurred—some taking place within just one day of starting the diet.85 A day or two after the diet ended, the microbes settled back to “normal”.

Ketosis and Athletic Performance 

Any training regimen requires proper nutrition and a recovery strategy. 

What you put in your body is just as (if not more) important than the training you put it through. For athletes, most guidelines like the guidelines created by the American College of Sports Medicine still support the idea that carbohydrates are king when it comes to fueling high-intensity performance.86 

However, a new interest is growing in the use of ketogenic diets for some aspects of sport performance, particularly those involving endurance exercise.

Why dismiss long-held nutritional dogma? Well, some sports requiring high endurance (think, ultramarathons) make the athlete likely to run out of stored muscle glycogen. In this case, a more metabollically efficient athlete, one whose body is adapted to burning fat and using ketones for fuel will have virtually “unlimited” fuel stores to call upon. 

In sports relying on body composition, such as martial arts, gymnastics, and competitive lifting, ketogenic diets might be a great way for some get lean. Others wishing to improve recovery or just eat healthier might also see substantial benefits and enjoyment from transitioning to a ketogenic diet. 

Ketogenic Diets and Performance

Is there any evidence that nutritional ketosis through a ketogenic diet can provide benefits above and beyond traditional sports nutrition diets? 

Improved fat burning ability has been reported in athletes consuming a ketogenic diet—one study reporting a near doubling of fat burning capacity in ketogenic runners compared to athletes eating a mixed diet.87 “Keto adapted” athletes could also use fat at a higher percentage (70% vs. 50%) of their maximal aerobic capacity (an intensity where many begin to burn mainly carbohydrates).87 

More fat burning theoretically means a higher endurance capacity in fuel-limited activities. Humans have around 150,000kcal of stored fat, while only 2,000kcal in the form of stored glycogen.

Ketogenic athletes have better access to their large cache of fat stores, with no evidence that their muscle glycogen stores are compromised.

Despite this fact, most studies show no benefit of a low-carb diet compared to a traditional diet for athletic performance, with only one actually showing performance improvements.88,89 For the most part, KD results in a decrease in anaerobic sprint performance.90 

This is because high-intensity exercise performance is determined in part by how well you can produce energy by breaking down glucose (glycolytic capacity). Glycolysis requires carbohydrates and the presence of certain mitochondrial enzymes efficient at breaking down glucose molecules—some of which are downregulated on a ketogenic diet;91 the body also has less readily available glucose on a low-carb diet.

Ketogenic diets do improve the power:weight ratio (primarily by reducing weight); this could benefit weight-conscious sports like gymnastics, cycling, and mixed martial arts. 

Ketogenic diets might also promote recovery by reducing exercise-induced inflammation.90

However, responses to a ketogenic diet and effects on performance will vary greatly from one individual to another, especially given the type of exercise. There are scientists on both sides of the debate—both for and against a blanket prescription of low-carb diets for performance. 

Exogenous Ketones for Performance

An alternative to consuming a ketogenic diet for athletes is to supplement with exogenous ketones

Maybe you’re a high-level athlete who wants the benefits of ketosis without making big changes in diet. Exogenous ketosis achieved through ketone supplements can provide the benefits of ketones without having to restrict dietary carbohydrates. This “abnormal” body state of ketosis plus, high carbohydrate availability might offer a performance advantage. While more research needs to be done, studies are promising.

Ketone Ester has been shown to improve endurance performance by 2 - 3% when taken before exercise.92 

The cyclist participants rode further after ingesting a ketone ester and carbohydrates compared to when they ingested only some pre-race carbs. In the same study, the group consuming the ketone ester had 30% lower blood lactic acid, lower muscle glycogen use, and a lower amount of muscle protein breakdown due to exercise.92 

These results are supported by the fact that ketone ester has a glycogen-sparing effect; it also attenuates muscle protein breakdown during exercise. This could mean less recovery required to bounce back after training or competition.92

More evidence for a recovery benefit of post-exercise ketosis comes from studies in which consumption of a ketone ester drink with post-exercise carbs and protein enhances activation of muscle protein synthesis.93 It also accelerates muscle glycogen replenishment, in one study by as much as 50% vs. carbohydrates alone.94 

However, a separate study indicated no extra benefit of post-exercise ketone ingestion on glycogen replenishment, so we need more work before definitive conclusions can be made.93 

While evidence for the BHB monoester is solid, other ketone supplements have consistently failed to show a benefit for athletic performance.

Ketone salts have been shown to reduce95 or otherwise not improve96 high-intensity exercise performance any more than carbohydrates alone. Ingestion of the AcAc ketone diester decreased performance by 2% in one study.97 The results of the latter study were a bit confounded by the fact that ketone diester ingestion induced severe gastrointestinal side effects in the participants, probably causing much of the performance drop.

Ketosis to Prevent Overtraining

A new theory has emerged that chronic supplementation with exogenous ketone esters might help prevent symptoms of overreaching

Overreaching, in a general sense, results when athletes train too hard and or don’t allow sufficient recovery. This leads to performance decrements and if severe, lots of down time. 

A recent study demonstrated that athletes who consumed the BHB monoester after every exercise session during an overload training regimen showed fewer signs of overtraining compared to a similar group who consumed identical post-workout nutrition minus the ketone ester.98

Lower stress hormones throughout the study were shown in the ketone ester group, and ultimately they improved exercise performance by the end of the study. In contrast, the control group suffered a performance loss after 3 weeks of hard training.98

Several variables in this study, like appetite and energy intake, make definitive conclusions about the direct effect of ketones difficult. Nevertheless, this study is great evidence that ketosis achieved through exogenous ketones might be a valuable addition to an athlete’s toolbox.

Ketosis, Aging, and Longevity

Besides the myriad of metabolic and energetic benefits provided by ketones, they are also signaling molecules. This means that ketones play a role in gene expression throughout the body, which might drive adaptations that benefit lifespan and healthspan in humans.

The ketone beta-hydroxybutyrate may play a role in how quickly you age. BHB has been shown to inhibit certain enzymes known as histone deacetylases (HDACS).22 HDACS are implicated in lifespan, with decreased HDAC function being associated with longevity.

It has been shown that ketogenic diets alter pathways associated with longevity and provide protection to a variety of cells. The “fasting mimicking” effects of a ketogenic diet are probably responsible for this, resulting in many beneficial changes including low insulin levels, reduced insulin-like growth factor signaling, AMPK activation, repression of mTOR, and upregulation of antioxidant genes.

Applying ketosis to aging is a sphere worth watching.

Final Thoughts on Ketosis

Whether you’re trying to lose weight, clean up your diet, or enhance your performance and productivity, exploring ketosis might be a worthwhile endeavor.

The evidence for ketogenic diets and exogenous ketones is strong for many health outcomes, and less concrete for other outcomes like performance. Nevertheless, the popularity of keto says something about how powerful this lifestyle may be.

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