Ketogenic (low-carb/high-fat) diets are popular largely due to their well-evidenced yet still-controversial effects on weight loss and body composition. Some individuals go “keto” for mental and cognitive benefits, to increase energy levels, or to enhance some aspect of physical performance (another debatable area of research).
New avenues for the application of ketosis are focusing on more understudied areas such as longevity (lifespan-extension) and cardiovascular health. This is where things get interesting, because rather than just a weight-loss tool, ketones might have a role for preventing disease and extending lifespan and healthspan in humans. Therefore, ketones could have benefits for people suffering from or at risk for CVD, but also exert salubrious effects for healthy individuals who might want to use ketones as a supplement.
A new article published in the Journal of the American College of Cardiology (JACC) expertly reviewed recent evidence on the potential of ketone bodies to reduce CVD risk, including plausible biological mechanisms and clinical/basic science evidence in support of those mechanisms. In this post, I’ll synthesize some of the talking points and provide my own bit of commentary along the way.
Ketone Supplements Primer
When we fast for long periods of time or eat a very low-carbohydrate (i.e. ketogenic) diet, our body “switches” its primary fuel source from glucose to fatty-acids, which the liver can convert to ketone bodies including acetone, acetoacetate (AcAc), and beta-hydroxybutyrate (BHB). When you’re measuring ketones using one of the myriad devices available, you’re either measuring acetone (in breath), acetoacetate (in urine), or beta-hydroxybutyrate (in blood). All three can indicate whether or not you’re in ketosis, which is usually defined as a blood ketone concentration greater than or equal to 5 millimolar (mM).
A ketogenic diet is one way to induce ketosis, but this post will focus not on dietary-induced ketosis but rather, ketosis achieved by using exogenous ketones. Exogenous ketones, or “ketone supplements” can put you into ketosis absent extended fasting or carbohydrate restriction. If you’re looking for an in-depth discussion on exogenous ketones, you can listen to episode 6 of my podcast where I talk with exogenous ketone expert Dr. Brianna Stubbs about the health and performance benefits of exogenous ketones.
There are several types of exogenous ketones, and 3 popular variations include medium-chain triglycerides (MCTs and MCT oil), ketone salts, and ketones esters. While I’ve tried only MCTs and ketone esters, I believe a majority of the research is now favoring the use of ketone esters both as an “anti-aging” intervention and a physical/mental performance-enhancing agent due to the greater tolerability of this exogenous ketone over ketone salts and MCTs (which aren’t even ketones, but must be converted into ketones once ingested).
Long story short — there is a heightened interest in using exogenous ketones to treat a variety of metabolic diseases, CVDs, and to enhance healthspan and lifespan. The research is pretty interesting, and many studies have shown how ketone bodies may positively affect cardiovascular health and performance.
How the Heart Utilizes Ketones
As it turns out, our heart really loves to use fat (fatty acids) as a fuel to produce ATP, with almost 40–60% of cardiac energy production coming from fatty acid oxidation. The heart can also utilize amino acids, lactate, and relevant to our discussion, ketone bodies, for ATP production.
Interestingly, it seems that our heart oxides ketones for energy in proportion to their concentration in our blood. In others words — increasing ketone body concentrations will increase the heart’s utilization of ketones.
In CVD, the heart loses its ability to switch between fuel sources, and may actually develop a preference for ketone bodies as a source of energy. Evidence has shown that heart failure is associated with a greater amount of ketone utilization by the heart.
If this is the case, then strategically increasing ketone levels in patients with heart failure and other CVDs should provide a source of energy for the heart and counteract many of the adverse functional and structural changes associated with these diseases. This could be done by providing ketone esters to boost blood ketones, or “supplementing” with ketones like you would a daily multivitamin.
Some ketone supplements are more effective than others. Here is a general overview of how different ketone “supplements” can affect levels of blood ketones.
1,3 butanediol: elevates blood BHB to 0.3–0.8mM (“light” ketosis)
MCTs: elevate blood BHB to 0.3–1.0mM (“light to moderate” ketosis)
Ketone salts: elevate blood BHB to 1.0–3.0mM (“optimal” levels of ketosis)
Ketone esters: elevate blood BHB to 2.0–6.0mM (“optimal” levels of ketosis)
Again — elevating ketones using any of the above methods will induce ketosis which could have a range of cardiovascular benefits, one of which we discussed already being improved energetic function of the heart. But beyond the energetic effects, studies show that ketones may provide an array of cardioprotective benefits.
Benefits of Ketones on Cardiovascular Function
Ketone bodies are not only sources of energy, but also powerful signaling metabolites in the body that can generate effects including the transcription of genes related to longevity, health, and cardiovascular function.
There are several areas where ketone supplementation or the infusion of ketone bodies has been shown to improve cardiovascular health in animals and humans.
Endothelial function: ketones may boost the body’s production of the potent vasodilator nitric oxide (NO) and improve vasodilation and blood flow in a variety of arterial beds including the coronary (heart) and cerebral (brain) circulation.
Mitochondrial function: ketones may reduce mitochondrial production of reactive oxygen species (ROS) which can lead to oxidative stress in the body. Ketones may also improve mitochondrial energy production.
Inflammation: ketones have anti-inflammatory effects that may reduce the production of pro-inflammatory cytokines.
Cardiac structural remodeling: ketones may reduce CVD-associated molecular and cellular changes that alter the heart’s structure, size, shape, and function — ultimately which may lead to heart failure.
In addition to these direct cardioprotective actions, there is some evidence that ketone bodies and/or ketogenic diets can reduce CVD risk factors like blood glucose, blood pressure, body weight, body fat, and abnormal lipid profiles. Evidence here is more scarce (especially in humans) and we will need more long-term studies to determine how ketone supplements may affect traditional CVD risk factors.
As a CVD-prevention strategy, ketone supplementation is definitely novel, theoretical, and underexplored as of yet. There are a variety of exogenous ketone ester supplements available or soon to be available online including the H.V.M.N. ketone ester, Metabolic Switch (Juvenescence), and Ketone Aid. At this point, it seems like the main barrier to the adoption of ketone supplementation may be taste (they’re quite bitter) and the prohibitively high cost of most ketone esters (though this is changing).
Exercise is clearly the best and most well-evidenced intervention we know to boost cardiovascular health and function or reduce/reverse CVD burden. What is interesting is that many of the benefits of ketones are shared by exercise — improved blood vessel function, reduced inflammation/oxidative stress, “metabolic flexibility” of the heart and other energetically-active tissues, and reduced CVD risk factors including body fat, blood glucose, and blood pressure.
This leads to the question of whether combining ketone supplementation with exercise could really pack a cardiovascular punch — for healthy and diseased individuals. I’m interested in the concept of using ketones as a longevity strategy but also as a daily performance-optimizer. Supplementing ketones before exercise, or using ketones as a post-exercise recovery tool are both options being explored and hypothesized about. What’s intriguing about ketones is that, other than intolerance at high doses, there may be no potential downside.
But back to disease.
Since some people are unable/unwilling to exercise, and many more are unwilling to alter their dietary patterns (especially if it means adopting a keto diet or introducing intermittent fasting), ketone esters could actually be a pretty remarkable tool at our disposal to help prevent or delay the onset of CVD.
Ketones activate many of the same beneficial pathways that exercise, dieting, and fasting do, without the need to undergo any of these interventions.
While we must be careful not to prematurely declare ketones an elixir of life, research is showing some pretty remarkable health benefits that, if extended to humans and proven clinically, may change our understanding of health, aging, and optimal human performance.
Yurista SR, Chong C-R, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD. Therapeutic potential of ketone bodies for patients with cardiovascular disease. Journal of the American College of Cardiology. Published online February 2021:S0735109721001947. doi:10.1016/j.jacc.2020.12.065