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Your Health Exogenous Ketones: All You Need to Know
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The Keto Diet

Exogenous Ketones: All You Need to Know

By Brady Holmer
The health benefits of the ketogenic diet have been well documented. Exogenous ketones present a novel way to achieve ketosis. Research shows they are safe, and may provide support for metabolism, cognitive performance, and healthspan.

You eat right, exercise consistently, and (try) to keep stress levels low and positive thoughts high. These are all things that have been shown to improve health, and likely have benefits for living a vital and longer life.

These more traditional strategies for improving health and wellness are being superseded by modern science-backed ways to optimize physical and cognitive function throughout life. Many of these strategies target evolutionary or “ancient” biological programs that once ensured survival in times of hardship, but in modern times, could be leveraged to promote increases in health and perhaps, lifespan — at least that’s what many are hoping for. The longevity market is booming, and there has never been a better time to take full control of your health.

KETOSIS: A PATH TO HEALTHY AGING?

One such longevity strategy involves putting the body into a state of ketosis. Ketosis is a metabolic state where instead of utilizing glucose to produce energy, the body is using fat and producing ketone bodies. This happens for a few reasons, but is mainly a response to low levels of insulin resulting from a lack of dietary carbohydrate and low blood glucose. In this case, the body needs a source of fuel, and calls upon stored adipose (fat tissue) to meet this need. Ketone bodies are produced following the oxidation (breakdown) of this fat tissue.1 When this happens, breakdown products including acetyl-coenzyme A (acetyl-CoA) are taken to the liver and used to produce the ketone bodies acetoacetate (AcAc) and beta-hydroxybutyrate (β-HB). These ketone bodies can then be delivered to and metabolized by tissues including muscles, the brain, and the kidneys.1

Since ketosis occurs due to a lack of dietary carbohydrate and glucose, it was typically our body’s response to starvation, and can also occur during prolonged fasting. Another way to achieve ketosis is by eating a low-carbohydrate/high-fat diet, also known as a ketogenic diet. Keto diets are typically characterized by including <50g of carbohydrates per day, though this may vary depending on your activity levels.

Why would anyone want to be in ketosis? There are several benefits — both well-documented and speculative — of being in ketosis. Recent reviews about the benefits of the ketogenic diet show that there is strong evidence to support the keto diet’s effectiveness for weight loss and reducing mid-life mortality (i.e. improving healthspan) in mice, and ketone bodies alone are beneficial for fine-tuning blood glucose and fat metabolism.2,3,4 Another popular use of nutritional ketosis is for optimizing cognition, brain health, and focus — but studies on these benefits have not been conducted.

Benefits of the ketogenic diet may be due to reduced blood glucose levels and the utilization of fat for fuel, which some say is a “cleaner” source of energy because it’s metabolism produces fewer oxygen free radicals than glucose.4 However, ketone bodies may have beneficial effects by themselves — even if you’re not fasting or eating a ketogenic diet. Research now shows that ketone bodies, primarily β-HB, act as “signaling metabolites” in the body — activating a variety of genetic programs and pathways that may play a role in healthy human aging.4

You heard that right — these tiny little ketone molecules might play a direct role in activating pro-longevity pathways in the body, along with exerting other effects on metabolism and health.

For this reason, scientists doing research in this area think that being in ketosis at least occasionally is likely a longevity and healthspan strategy for everyone.

However, the ketogenic diet isn’t for everyone, and some individuals aren’t ready or willing to engage in a dedicated intermittent fasting (IF) regimen. For this reason, other routes to achieve ketosis could provide an alternative way to gain the health benefits of ketosis without adhering to a particular dietary regimen.

WHAT ARE EXOGENOUS KETONES?

Exogenous ketones are an emerging area in nutrition and healthspan research, and are becoming a big player in the consumer health and longevity market.

What are exogenous ketones? Exogenous ketones are external sources of ketones that deliver ketones directly, rather than the body producing them on its own. By using exogenous ketones, one can enter ketosis without fasting or eating a low-carb/high-fat or ketogenic diet. Even though the body is not ketogenic (producing ketones), you’re still in ketosis. This is referred to as exogenous ketosis.

While it’s a different route to achieving ketosis, the molecules of ketones ingested through exogenous ketones are exactly the same, meaning the health benefits are likely very similar to some of those observed with ketogenic diets or fasting.

Exogenous ketones have been researched heavily and are described as a “practical, efficacious way to achieve ketosis”.5 They are just as effective, and maybe even more effective, than a keto diet or fasting. Studies have shown that ketone esters can elevate levels of blood ketones to around 1.0 - 3.0 millimolar (mM) within just 30-60 minutes.6 On the other hand, it could take 2 - 4 days of a ketogenic diet or 48 hours of fasting to get your ketones this high.7

The consumer market for exogenous ketones is growing, and there are many different formulations available. What are the best exogenous ketones, and what are the potential benefits and risks associated with the different types?

TYPES OF EXOGENOUS KETONES
KETONE SALTS

Ketone salts were some of the “original” exogenous ketones. Ketone salts are composed of a ketone molecule, typically β-HB, bound to a mineral such as sodium, potassium, calcium, or magnesium. These types of exogenous ketones typically come in a powder form that can be mixed with a liquid.

In terms of their effectiveness, ketone salts may not elevate ketones to levels as high as other exogenous ketones like ketone esters. Studies on ketone salts find that they can elevate blood ketones to around 0.6 - 1.0mM — a relatively low level of ketosis.6,8

Ketone salts may not be the most desirable form of exogenous ketone due to the human body’s limit on mineral tolerance. Achieving ketosis using a ketone intake of ~50g using a ketone salt would require you to also consume an abnormally high amount of sodium, potassium, calcium, or magnesium that fall well above the recommended daily intakes.9

Furthermore, many ketone salts contain two different forms (known as isomers) of β-HB — one known as the “L” isomer and the other known as the “D” isomer. Most scientists consider the D isomer to be responsible for the benefits of β-HB. Unfortunately, some ketone salts contain only about half of the D isomer, with the other half of β-HB delivered being of the L variety.9

So, while they’ve been around the longest, ketone salts may not be the ideal way to achieve ketosis using exogenous ketones. Fortunately, the development of new ketone esters has allowed more research to be done, with promising results.

KETONE MONOESTER

Ketone monoesters are one type of exogenous ketone ester that has been studied and are now commercially available.

Ketone monoesters contain the ketone molecule β-HB bound (by an ester bond, hence the name) to an alcohol such as butanediol or glycerol. β-HB esters are a ketone precursor, meaning that after they’re ingested, the bond between β-HB and butanediol is broken. This gives one molecule of β-HB and one molecule of butanediol — which can then be converted to β-HB in the liver — delivering two molecules of β-HB into the circulation.5,8

Ketone monoesters come in liquid form, with the added benefit that 100% of the β-HB provided using these exogenous ketones is of the more beneficial D isomer.9,11

Ketone monoesters raise blood ketones rapidly and effectively. Studies on these exogenous ketones have found that blood levels of β-HB can reach 3 - 5mM within 30-60 minutes and stay elevated for several hours post ingestion.5,6,8 For this reason, monoesters are being studied for their potential applications to maintain healthy blood glucose levels and promote cognitive health, and even as a performance-boosting strategy for athletes.

One of the main reasons for consuming exogenous ketones, outside of a potential benefit for athletic performance, is to mimic the health-benefiting effects of ketogenic diets and intermittent fasting.

C6 KETONE DI-ESTER: A NEW WAY TO “SWITCH UP” METABOLISM

Juvenescence has entered the exogenous ketone market with an all-new type of ketone ester — a C6 ketone Di-ester. The C6 Di-ester, also known as Metabolic Switch, is formulated a bit differently than other ketone esters. The C6 Di-ester contains a molecule of β-HB bound to a medium chain triglyceride (MCT) called caproic acid.

Inclusion of an MCT in the ketone di-ester makes it a powerful inducer of ketosis. That is because the β-HB provided rapidly elevates blood ketones. In addition, C6 is transported to the liver, where the process of ketogenesis converts this MCT into ketone bodies. This is unique because although you’ve consumed an exogenous ketone, the body is also participating in endogenous ketone production.

Dr. Brianna Stubbs, a researcher working with Juvenescence on studying the effects of the C6 Di-ester, believes that this aspect differentiates it from other ketone esters. When the body actually produces ketones, certain genetic and metabolic effects may take place that can’t be recapitulated with some exogenous ketones. Furthermore, metabolism of the C6 Di-ester produces β-HB and the other primary ketone body, acetoacetate (AcAc) in a physiological ratio that might be “preferred” by our biology.

While these claims are somewhat speculative and more research needs to be done, the theory is rooted in sound science and there is no doubt that future studies will help elucidate the exact mechanisms of how the C6 Di-ester benefits human health.

There is no doubt, however, that not all ketone esters are the same, and the C6 Di-ester may prove to be one the more unique and highly beneficial compounds synthesized to date.

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HEALTH BENEFITS OF EXOGENOUS KETONES

One of the main reasons for consuming exogenous ketones, outside of a potential benefit for athletic performance, is to mimic the health-benefiting effects of ketogenic diets and intermittent fasting. What does the research say on the effectiveness of the different types of exogenous ketones to improve health and metabolism?

RESEARCH ON KETONE SALTS

A lot of the research on ketone salts has focused on athletic performance, with little data to support their use for endurance exercise at the moment.7

Some research in rodent models has shown that ketone salts may help to maintain cholesterol and blood glucose levels within the normal range and reduce adipose tissue and fat mass.10 However, the dose of ketone salts needed to achieve these benefits may require a mineral intake above what many humans should be consuming.9

RESEARCH ON KETONE ESTER

Research on the beneficial effects of ketone esters for health is much more available, and quite promising.

In nematode worms, supplementation with β-HB extended average lifespan by 20%.11 In rodents, β-HB monoester supplementation has been shown to induce many of the healthspan- and lifespan-extending properties achieved using genetic manipulation.12 This animal research tells us that ketone bodies act through some of the same longevity pathways as caloric restriction and prolonged fasting — some of the most well-known ways to increase lifespan in animals. Healthspan-enhancing effects have also been observed in rodents on a ketogenic diet — suggesting that ketone bodies may act to slow the aging process.3

While much more research is still being done, there are other benefits for health and longevity that might be provided by β-HB obtained using exogenous ketones. For instance, a recent-review by Dr. Eric Verdin, MD and colleagues conducting research at the Buck Institute for Research on Aging are working on the theory that β-HB ketone esters have the potential to benefit several aspects of human health including metabolism and cognitive health — processes that all may show a decline with aging. Furthermore, since β-HB acts on many longevity-related pathways, it is possible that exogenous ketones that provide β-HB may hold the potential to enhance healthspan and improve resilience throughout the lifespan.4

Juvenescence partnered with scientists on Metabolic Switch for this very reason. While more human and animal research is needed and currently underway, the C6 Di-ester is designed to target many pathways related to human healthspan and lifespan. The exciting research being done at the Buck Institute for Research on Aging holds much promise for the C6 Di-ester to be an innovative longevity and resilience-building strategy that anyone can access.

SHOULD YOU USE EXOGENOUS KETONES?

You might be wondering whether exogenous ketone supplementation makes sense for you. Since ketosis is a perfectly natural physiological state and ketones in and of themselves are not harmful, exogenous ketones likely pose no harm to health, but hold a definite upside for those who might choose to use them.

While there are some potential side effects of ketone salts, including gastro-intestinal symptoms, many studies on ketone esters have found them to be well-tolerated, even when consumed intermittently for a period of around 9 hours.6,8,13 While the taste of many ketone esters is something that may need to be acquired, a little bit of bitterness seems a worthwhile tradeoff for the health benefits of exogenous ketones.

As for when you should take exogenous ketones, this might be a personal preference. Some people may like to take them before sleep to reap the improved sleep quality noted by some anecdotal reports. Some people like to use them during a prolonged fast to help with mental and physical energy. At Juvenescence, work with researchers on the C6 diester has led to the recommendation of taking a daily or every-other-day serving of Metabolic Switch. This way you’ll maintain a constant, even if low, level of ketosis and allow your body to achieve the namesake “metabolic switch” — where it can turn to using ketones for an energy source instead of glucose.

YOUR HEALTHY AGING SOLUTION

Exogenous ketones, in addition to or as an alternative to a ketogenic diet and fasting, are proven to provide many of the same benefits shown for these dietary interventions. There is much work to be done, including studies on long-term exogenous ketone use in humans and how this may affect different outcomes of health and longevity. However, the science on β-HB from leading experts suggests that this “ancient” molecule likely has potent benefits in the modern world. At Juvenescence, we are determined to support your journey to optimal health and wellness. Exogenous ketones, including the C6 ketone Di-ester, are one tool at your disposal that holds the promise of improving healthspan and letting you be resilient throughout life, allowing you to live your best at any age.

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