Ketones were misunderstood, and perhaps underestimated, for ages. But scientists are now recognizing that these energy compounds are a special fuel source whose potential is just starting to be realized. “Ketones, also known as ‘ketone bodies,’ are molecules synthesized from body fat,” says Brianna Stubbs, PhD lead translational scientist at The Buck Institute for Research on Aging near San Francisco. Until recently, ketones were considered to be mostly a backup energy supply during carbohydrate restriction or starvation, and during special instances of potentially dangerous uncontrolled blood sugar in mostly Type 1 diabetics. But recent research has uncovered unexpected health benefits and the powerful role they may play in health and aging in healthy people, as well as in those with certain health conditions.1 Here’s the lowdown on ketones, aging, and health.
WHAT ARE KETONES?
Ketones, also called ketone bodies, are compounds that serve as a stealth energy source when the body’s primary fuel sources — glucose and fat — aren’t easily accessible. This can happen if glucose, the sugar found in foods that contain carbohydrates, is in short supply. Although there are around 100,000 calories (or more) of fat stored in even lean bodies, when glucose is not easily accessible, all that fat can’t be burned for fuel in the usual manner by some cells, leaving them short of the energy needed to enable them to do their thing.2
Cells all over the body use glucose and fat to function. But brain cells and red blood cells almost exclusively rely on glucose. So, what happens when the normal supply of carbs is curtailed? Protein comes to the rescue to become the next go-to fuel. Protein is broken down, and some amino acids undergo a process called gluconeogenesis, thereby creating glucose molecules that the brain, red blood cells, and other cells in the body, can use.3
But, the primary function of body proteins is to help create everything from antibodies and hormones to hair, skin, and muscle. So, using protein as an energy source is not ideal. Not only can muscle loss occur, but the functions of other important proteins in the body may be impaired.4,5
So, the body has a protective system to help avoid excess protein loss: it accesses the endless supply of fat. But in this situation, fat undergoes a different type of metabolism. Normally, when fat is “burned” or broken down for fuel, it needs glucose for that cycle to be completed. But, if sufficient amounts of glucose are not easily accessible, a type of “metabolic switch” occurs, where some of the fat is broken down and converted to ketone bodies. The ketones, or ketone bodies, then become what author Travis Christofferson refers to as ‘the fourth fuel’ in "Ketones, The Fourth Fuel: Warburg to Krebs to Veech, the 250 Year Journey to Find the Fountain of Youth."
During times of starvation (or fasting) ketones can supply a high proportion of the body’s basic energy needs, and up to 70 percent of the brain’s energy. Protein breakdown still occurs to some extent to provide some glucose to the brain and the red blood cells, since ketones alone cannot maintain their normal function. Still, during times when no food is available, ketone energy lengthens the time that a person can stay alive.1
Since the ketone system is a type of starvation response and a last-ditch fuel, relying on ketones for energy has often been assumed to be a sub-optimal, even dangerous, physiological state. The fact that people with diabetes sometimes develop life-threatening, diabetic ketoacidosis, where blood accumulates exponentially high levels of ketones, has caused some to warn against going into ketosis, for fear that ketones could rise too high.3
But varying levels of ketones in the blood seem to have vastly different effects on health. Concentrations where a person enters ketosis, but not ketoacidosis, can have health-enhancing and healthy-aging effects. “Cells all over the body can burn ketones,” says Dr. Stubbs. Might this indicate that we are designed to use ketones for energy in more ways than just during a starvation state? It has been suggested that prior to the establishment of widespread agriculture, some cultures, such as the Inuit of the Arctic, living in environments with low levels of dietary carbohydrates did exist in a “normal: state of mild ketosis.”4,6
DIFFERENT TYPES OF KETONES
Ketone bodies come in several forms and types. Acetoacetate (AcAc), 3-B-hydroxybutyrate (also known as beta-hydroxybutyrate or 3HB), and acetone are the three main types of ketones. AcAc accumulates when glucose is low. Beta hydroxybutyrate (3HB) is then formed from AcAc. Both AcAc and 3HB provide energy to tissues all over the body, including the brain, which normally relies on glucose for fuel. Acetone is generated from AcAc and is recognized by its alcohol-like fruity mouth odor which kicks in once you enter a state of ketosis.4
When ketones are generated within the body from acetyl coA, they are known as endogenous ketones (endo means “internal” or “within” and genous refers to “producing” or “generating”). When ketones are synthesized in a supplemental form, mimicking the molecular structure of endogenous ketones, they are known as exogenous ketones (exo means “from outside”).7,8
ENDOGENOUS KETONES MADE BY YOUR LIVER
What may be surprising is that ketones made in the body are present at low levels in healthy people. But certain triggers can kick ketone production into overdrive, causing amounts in the blood to rise, known as hyperketonemia. Although there is no universal definition of ketosis, one is considered to be in ketosis when ketones in the blood reach certain levels. After eating a meal, there may be trace levels of ketones, around 0.1 to 0.5 micromoles/liter (um/l). But in the morning, when one has not consumed food or drink since dinner the night before, ketone levels may reach 0.25 to 0.5 um/l. The “official” state of ketosis is said to occur when blood levels reach a point where ketones are considered to be mild or moderately elevated, somewhere above 0.5 to 1.0 and up to 3.0 millimoles/liter (mm/l).4,9
Ketones and their presence in the blood were misunderstood because for many years they were viewed in the lens of the emergency state of diabetic ketoacidosis. This potentially deadly condition can occur most commonly in people with Type 1 diabetes, but is also seen in those with Type 2 diabetes, gestational diabetes, and chronic alcoholics who binge drink. Ketone levels during diabetic ketoacidosis can start at 3 to 10 mmol/l and reach 25 mmol/l or much higher, although they tend to be paired with high blood glucose and low insulin levels.4,10,11,12
But simply the presence of ketones in the blood does not signify that a person is heading towards diabetic ketoacidosis. Ketones are present at low levels in healthy people. Levels during ketosis during an energy- or carb-restricted diet or following prolonged endurance exercise do not reach super-high levels.4,13,23
Is it normal to almost never enter true ketosis like most Americans eating the standard American diet, or are we better off being in ketosis periodically, or for most of the time?
“The looming question is, what ketone level is normal?” asks Christofferson. “Is it normal to almost never enter true ketosis like most Americans eating the standard American diet, or are we better off being in ketosis periodically, or for most of the time?” Typically, a person eating three meals per day, starting early in the morning and eating or snacking late in the evening, doesn’t have enough overnight fasting time to ramp up ketone production. “But many ketone scientists point out that humans most likely spent most of their tenure on the planet in ketosis much of the time when food was scarce, and with modern agriculture [and food readily available] we have essentially turned off ketosis,” says Christofferson.
WHAT TRIGGERS KETOSIS?
There are several ways to bump up ketone concentrations in the blood. The body accelerates ketone production when other energy sources are in short supply. So, if a person fasts — going for extended periods without eating or drinking anything but water, ketosis will occur. A very low calorie diet, or a very low carbohydrate diet, can also trigger ketosis. A ketogenic diet, which consists of 60 to 80 percent fat, and consequently, low levels of carbohydrates from food, by definition puts a person in ketosis. A “fasting-mimicking” diet such as Prolon, which is a plant-based ketogenic diet that is very low in calories, also leads to increases in blood ketones.4,10,14,15,16
EXOGENOUS KETONES IN SUPPLEMENTS
But energy deprivation is not the only way to enter ketosis. Nutritional supplements that allow you to ingest ketones will also raise blood levels of ketones. These exogenous ketones come in liquid, capsule, tablet, or powder form and allow a person to establish blood levels of ketosis, but without having to consume high amounts of fats or low amounts of carbohydrates, and without needing to “starve” or fast.
Two forms of exogenous ketones have been developed, ketone esters and ketone salts. Ketone salts appear to raise levels to about <1 mm/l, while the ketone ester versions appear to be able to enhance ketosis, with 3HB levels reaching 3-5 mm/l in healthy adults.17
One interesting aspect of exogenous ketones is that they can put you into ketosis, even while you continue to eat normally and get “normal” amounts of fat, protein, and, especially, carbs. More research is needed to see how this adequately nourished dietary environment might affect the body’s response to being in ketosis. “We’ve seen in studies that some exogenous ketones not only elevate levels of ketones, but increase ketogenesis, resulting in hyperketonemia and increased ketone oxidation. This means that exogenous ketones can mimic some (but not all) of the features of endogenous ketosis,” says Dr. Stubbs.
Even though a person may be consuming carbohydrates where normally, blood glucose levels would rise in response, when taking exogenous ketone supplements, blood glucose tends to go down. Plus, the fatty acids in the blood plasma that might be used for energy also decrease. “Proportionally, you shift the balance of what you're oxidizing from carbs and fat, towards ketones,” explains Dr. Stubbs. Supplementing with exogenous ketones seems to trigger the body to consent and allow the new fuel source to take over.
HOW CAN I MEASURE MY KETONE LEVELS?
You are considered to be in a state of ketosis once normal levels of blood ketones of < ~0.5 mm/l reach around 1.0 mm/l. You can measure your ketone levels in several ways, including a serum blood test in a lab or using a convenient hand-held, portable monitor. This device is similar to a glucometer that measures a person’s blood glucose. With a pinprick of blood, you can get a reading that has been shown to be highly correlated with laboratory blood tests. Both of these methods measure levels of betahydroxybutyrate. Urine tests are sometimes also used. A person applies a small amount of urine to a test strip and it changes colors to indicate the presence of ketones. This tests measures levels of a different ketone, acetoacetate. The quantities of this type of ketone in urine do not accurately reflect blood levels of BhB, however. So a handheld ketone meter is thought to be a more accurate instrument.24,25
|Ketone Blood Levels|
|Ketone levels after eating ("post-prandial")||< 50 um/l
< 0.1 mm/l
|Ketone levels in the morning after an overnight fast||0.25 to < 0.5 mm/l|
|Normal blood levels of ketones||< 0.5 mm/l|
|Nutritional ketosis ("Hyperketonemia")||> 1.0 mm/l|
|Ketones during exogenous ketone ester supplementation||> 1.0 mm/l|
|Ketones during and after prolonged endurance exercise||> 1.0 - 2.0 mm/l|
|Ketones during a keto diet||> 4.0 mm/l|
|Ketones during prolonged complete fasting||6.0 – 9.0 mm/l|
|Ketones levels at the start of ketoacidosis||> 3.0 mm/l|
|Ketone levels during diabetic ketoacidosis||> 10 - 25.0 mm/l|
|*um/l: micromole/liter; mm/l: millimole/liter
*Average ketones levels from 1, 4, 6, 9, 10, 13, 17
WHAT ARE THE BENEFITS OF KETONES?
Aside from their important role providing fuel, researchers are uncovering other aspects of ketone function that may benefit health and delay aging. For example, in healthy, non-diabetic people, inducing ketosis may help promote immune health. Some studies have found improvement in cognition and brain function.1,12,13,16,20,21,22
Sports performance studies have found that elite cyclists taking exogenous ketone esters boosted their performance. Dr. Stubbs also studied athletes. “We found that exogenous ketones could spare muscle glycogen and decrease blood lactate during cycling exercise. In 30-minute time trials, athletes went 2 percent further, which was a statistically significant increase,” she says. Some studies have found no ergogenic benefits in sports performance, however, and some athletes reported symptoms such as GI discomfort.17,18,19,23
The effects of ketones on aging are currently being studied, since fasting and caloric restriction — both of which may increase the production of ketones — have shown beneficial effects on aging. “To me, the most fascinating property of ketones is their ability to massively increase the antioxidant capacity of the cell,” says Christofferson.”
HOW CAN I LEVERAGE KETONES FOR WEIGHT LOSS?
Like other diets where calories are restricted, ketogenic diets have been shown to lead to weight loss. Some people find the “the keto diet” an easy way to lose weight since being in ketosis can suppress appetite. Restricting calories — which leads to weight loss — is easier if you are not hungry.
To trigger ketosis with endogenous ketones, daily energy intake should consist of ~60-80 percent fat, 10 percent or more of protein, and a percentage of carbohydrates low enough to drive ketogenesis. Traditionally, people choose to eat more animal-based foods to achieve this. However, choosing a plant-based version of a keto diet which is higher in unsaturated fats may avoid some of the negative health effects associated with consuming the higher levels of saturated fat found in animal-based foods.16
More research needs to be done to see whether exogenous ketones alone or when consumed with a variety of diet approaches might aid weight loss. “Exogenous ketones do seem to have an acute appetite-blunting response, although we don’t know if that lasts long term yet,” says Dr. Stubbs. “We haven’t seen weight loss from only using a ketone supplement yet, perhaps because there have not been long enough studies.”