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The Keto Diet

Ketones, Ketosis and Longevity

By Dr. Martica Heaner, PhD
Ketones—a backup energy source—may improve health and longevity. Studies on fasting, and low-carbohydrate diets have expanded our understanding of ketosis and the potentially-powerful effects of ketone molecules on health and aging.

The human body is an exquisite machine. When things get out of whack, defense mechanisms kick in to keep systems running smoothly.1 During an infection, killer immune cells battle pathogens. Got a fever? Or, are you pushing during a cardio workout? Your sweat rate accelerates to minimize overheating. When you have a wound, a cascade of healing steps are activated. And during times of low energy intake — whether that’s from starvation or deliberate fasting, or from very low calorie- or carbohydrate-restricted dieting — the body ramps up low-level production of special molecules called ketones to provide greater supplies of an alternate fuel source — these ketones can literally save your life.

Now, research is showing that ketones might also be the key to better long-term health. “High levels of blood ketones may be effective in maintaining healthy blood sugar levels, promoting heart health, and helping to maintain healthy body weight — which may optimize your longevity,” explains Kristine Clark PhD, RD, associate research professor and former director of sports nutrition at Penn State University in State College. Here’s how ketones, ketosis and longevity are connected.

WHAT IS KETOSIS?

The body needs energy — or calories from food — to survive. Normal metabolism relies on fuel mostly from calories that come from the fats and carbohydrates in the food you eat.2 Protein in foods can provide energy. But since protein is needed for other crucial functions in the body like creating hormones, enzymes and antibodies, as well as building skin, muscles and hair, it’s usually only used as fuel when carbohydrates are in short supply.3

That’s because our brain and red blood cells rely exclusively on glucose, or the "sugar" in carbohydrates for energy.4 When carb intake from foods is low or when overall calorie intake is low — such as when a person is starving, fasting or following a low-carb "ketogenic" diet — the body uses up its limited supply of stored carbs. As those get depleted, blood sugar is at risk of dropping precipitously low, potentially impairing brain function and even causing death.

But the body has a back-up plan: First, its go-to protective mechanism is to access other sources of glucose. So proteins are broken down to provide it. But protein structures like skeletal muscle are essential. It’s safer to spare them, rather than catabolize them for fuel. So, the body shifts to a different type of metabolism, using fat stores instead.

High levels of blood ketones may be effective in maintaining healthy blood sugar levels, promoting heart health, and helping to maintain healthy body weight — which may optimize your longevity.

Dr. Kristine Clark PhD, RD

Associate Research Professor and former Director of Sports Nutrition at Penn State University

During everyday metabolism, fat and glucose are metabolized for energy. But when glucose intake drops too low and stored glucose is depleted, normal fat oxidation is impaired because some glucose is needed to burn it. So the liver shifts and increases the breakdown and conversion of fat to produce greater levels of ketone bodies, also known as ketones. “Ketones are an alternative energy source that can be used by the brain, as well as by most cells in the body, barring the liver where they are produced,” explains Brianna Stubbs, PhD, lead translational scientist at the Buck Institute for Research on Aging in San Francisco.

The physiological state of ketosis signals that several different related actions are taking place. First comes the breakdown of fat, or lipolysis. The triglycerides gleaned from this process are then converted into ketones. The production of ketones is known as ketogenesis. As measurable levels of ketones build in the blood, a state of hyperketonemia is reached. The rising levels of ketones in the blood are then shuttled to all the cells that can use them, where they get “burned” or oxidized for fuel. “People use the term ketosis to encapsulate all these different processes,” says Dr. Stubbs, “There can be a lot of confusion around the term because it’s been poorly defined in the scientific literature.”

Most typically, reaching a state of ketosis is defined as occurring when certain levels of blood ketones are reached. If your ketones rise up to around 0.5 mmol/L, which can occur after doing a 24 to 36 hour fast, you are considered to have reached a state of ketosis, Dr. Stubbs explains. An overnight fast can induce ketosis naturally in the mornings, depending upon the length of time since a person ate the day or night before. So, lower levels of ketosis, at around 0.25 mmol/L can occur even without fasting or dieting per se.5

IS KETOSIS THE SAME AS KETOACIDOSIS?

Ketones were first measured in the urine of people who were experiencing complications from diabetes.6 This created a negative perception among some because of their relationship to a life-threatening condition called diabetic ketoacidosis (DKA). But ketosis is not the same process as DKA. In diabetic ketoacidosis, ketone levels reach 3.0 mmol/L or much higher, along with a highly elevated blood glucose and low bicarbonate levels in the blood and there is an increased risk of death.7 The ketones produced at lower blood levels under different physiological conditions not only appear to be safe, but seem to have real health benefits.

WHAT’S SPECIAL ABOUT KETONES?

Ketones are an energy compound produced by the liver when the body is in a state of ketosis. They can be burned for fuel in the absence of glucose from carbohydrates to power the body’s metabolism in a surprisingly efficient manner. “Ketones are generally utilized in proportion to their concentration in the blood,” says Dr. Stubbs. So, the higher the blood level, the more that are used. “Ketones don’t require a hormone to be absorbed, like glucose energy does, and the transporter that carries them to cells is ubiquitous — even people who are not on a ketogenic diet have some of this transporter present,” she explains.

There are 3 main types of ketones produced by the body: acetoacetate (AcAc), 3-β-hydroxybutyrate (3HB or BHB), and acetone.8 Beta-hydroxybutyrate (BHB) has been the most widely studied and seems to confer a host of health benefits such as protecting the body from oxidative stress and helping to promote a healthy inflammation response. Some concern has been expressed that other types of ketone bodies, such as AcAc, may be pro-inflammatory, according to a review in the journal Cell Metabolism .9

HOW DO YOU ACHIEVE KETOSIS?

Different methods of fasting can induce ketosis. You can completely forgo food (as with a water fast, which should be done with a physician’s supervision.) Or you can restrict how many calories you eat by simply eating less or by manipulating when you eat. Lengthening the time in between eating periods, such as with intermittent fasting, automatically results in fewer calories consumed and can drop glucose levels to a level where ketone production speeds up.

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A low-carbohydrate, high fat diet, also known as a ketogenic diet, can also starve the body of glucose and total calories to trigger ketosis. Even long periods of exercise that deplete the body's carbohydrate energy reserves can activate ketosis.10

WHAT IS A KETOGENIC DIET?

Everyone knows someone who has tried a keto diet, and there are a number of different ways to follow it. The conventional method focuses on eating animal-based foods like meats, eggs, dairy and butter along with some plant-based foods such as olives, avocados, oils and non-starchy vegetables. But plant-based versions of the keto diet high in avocados, coconut, olives, nuts and seeds are an optional approach, and may have more beneficial effects due to plant-specific ingredients.11 Whole plant foods contain health-boosting phytochemicals, along with fiber which feeds the microbiome. There is also a higher proportion of healthier unsaturated fats. One study in the Journal of Clinical Endocrinology & Metabolism found that study participants who ate more unsaturated fats compared to saturated fats while following a ketogenic diet reached greater levels of ketosis and avoided the adverse effects on total cholesterol and LDL cholesterol often seen with diets high in saturated fat.12 The higher fiber load and increased levels of phytochemicals may also play a role in making it less inflammatory: One commercially-prepared plant-based ketogenic diet has been shown to mimic the physiological conditions of a fast, triggering ketosis and resulting in improved biomarkers for inflammation like insulin-like growth factor 1 (IGF-1) and c-reactive protein (CRP), as well as helping promote healthy levels of blood pressure and body fat.13

HOW DO KETONES IMPROVE HEALTH?

Both fasting and ketogenic diets have long been used as a treatment for epilepsy since they were found to help minimize seizures, according to the Academy for Nutrition and Dietetics.14 Ketones have also been found to have the potential to affect other aspects of health such as dampening appetite. This results in people who follow a ketogenic diet being able to successfully lower the amount of calories they consume while still feeling satiated. Not only can this aid weight loss, but since the diet is very high in fat (from 65 to 90 percent of total calories consumed), the low carbohydrate and low protein levels mean less of the hormone, insulin, is released which could also have beneficial metabolic effects. And the low carbohydrate intake means that blood glucose stays low, which can help maintain healthy blood sugar levels. Other studies have found that ketones may be beneficial in cognitive health.15

Triglyceride levels in the blood can also lower on this diet, since they are used to produce the ketones.16 But, the high saturated fat intake means there can also be a concurrent rise in LDL cholesterol levels, which can have a negative effect on heart health. And while a ketogenic diet can be useful in keeping blood glucose levels low which is beneficial maintaining healthy blood sugar levels, some research shows that insulin resistance may worsen over time, making a person less able to tolerate glucose in foods, although improvements in insulin sensitivity have been shown as well.17

Richard Veech, MD, DPhil, a researcher at the National Institutes of Health (NIH), who passed away in early 2020, was a pioneer in the field and, along with colleagues, studied how ketones and the ketogenic diet could help support brain health.18 Other research has shown that therapeutic uses of exogenous ketones can help support circulation and healthy cell activity.19

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CAN KETONES IMPROVE LONGEVITY?

Ketosis has been linked to living longer, and a variety of mechanisms may play a role. Autophagy is a process in the body by which cells discard damaged components to repair or replenish cells and tissues. Biologist Yoshinori Ohsumi, PhD, based at the University of Tokyo, won the Nobel Prize in 2016 for discovering the mechanisms of how autophagy works.20 Fasting, or nutrient deprivation, can trigger autophagy and the process may contribute to rejuvenating tissues in a way that slows aging. 21 Fasting also induces ketosis, resulting in the increased production of ketones. Dr. Veech also found that supplements appear to have the potential to enhance lifespan.22 Fasting has been shown to increase lifespan, as has modified fasting in the form of caloric restriction.23 One long-term research project known as the CALERIE study had participants reduce their daily caloric intake by 25 percent and maintain that deficit for two years. Participants experienced improvements in measures such as inflammatory markers tumor necrosis factor (TNFα) and C-reactive protein (CRP), as well as decreases in T3 thyroid hormone, body weight and heart health. When the body’s inflammation response is enhanced and other risk factors associated with aging are mitigated, there appears to be the potential for extended lifespan.24 More and longer studies are needed to determine if being in ketosis will increase lifespan in humans. But many researchers believe there is potential in some effects of this metabolic state and are using isolated ketones to learn more.

ENTER THE EXOGENOUS KETONE ZONE

The ketones that arise from manipulating what you eat are endogenous ketones—or ketones the body makes from high fat intake during a caloric and/or carbohydrate restriction.

Recently, a new way to reach ketosis was developed. Dr Veech began researching the therapeutic properties of BHB ketones. Along with Kieran Clarke, PhD, at the University of Oxford in England, he developed an exogenous ketone ester. Exogenous ketone are compounds made outside of the body, synthesized by scientists in a supplemental form.

Exogenous ketones appear to work in a similar way: They induce ketosis by saturating the blood with ketones, but without having to follow a restrictive diet.25 Since many people find it tough to stick to a keto diet or a fasting regimen, exogenous ketones may be a way to get the benefits of ketosis without some of the hard work. “One study in the American Journal of Clinical Nutrition gave unhealthy people who were overweight a ketone supplement after being given a glucose load to ingest,” says Dr. Stubbs. “They showed a blunting of the normal spike in blood glucose”.26 She points out that this was an acute, short-term study, but the results suggest that ketone supplements can help stabilize blood glucose.

IS KETOSIS SAFE?

Some health experts and researchers worry about the potentially negative effects of ketosis when it’s achieved through a very high fat ketogenic diet. “Dietary carbohydrate restriction is becoming increasingly popular because of some proven metabolic benefits including helping to maintain healthy plasma glucose levels, and increased satiety,” says Eric Ravussin, PhD, the Associate Executive Director for Clinical Science and the director of the Nutrition Obesity Research Center (NORC) at the Pennington Biomedical Research Center in Baton Rouge. “But the benefits of carbohydrate restriction are probably outweighed by several metabolic risks of fat intake including reduced glucose tolerance, unhealthy cholesterol levels, and increased ectopic fat deposition (fat around the internal organs.) Whether ketone bodies are good for health and longevity remains to be determined.”

It might be that a plant-based form of the ketogenic diet or exogenous ketone supplements that can induce ketosis ameliorate some of the potential negative effects of the traditional keto diet. The exogenous ketone supplement may be a way to avoid heavy saturated fat intake since ketones can be consumed to reach desired blood levels without having to eat excess fat. And a plant-based ketogenic diet is naturally lower in saturated fat because no animal foods, which are high in saturated fat, are eaten. 27

“There’s no doubt that ketone compounds are very powerful,” says Dr. Stubbs. “The ketone supplements seem to provide benefits such as sparing protein breakdown and supporting brain health.” Ketone science is challenging the accepted picture of aging and pointing towards the possibility of fuller, longer lives. “There is so much more to learn about ketones, but the future looks promising,” says Dr. Stubbs.

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