The Wild, Uncertain Science of Post-Exercise Ketones

A new review study points toward post-exercise ketone supplementation as a way to improve adaptation and performance. What does the uncertain science mean for endurance athletes?

I heard about athletes supplementing with ketones sometime in the mid-2010s. A company reached out, promising the next big breakthrough in endurance performance from this liquid supplement composed of a molecule naturally produced in the body from the breakdown of free fatty acids. They told me that the top cyclists in the world were already using ketones and that it was destined to take over running, too. They sent a few boxes…and they collected dust in the pantry. It felt like a biohack, and I wasn’t comfortable with it.

Over the years, more studies on ketone ingestion emerged, and I started to get more and more intrigued. Rumors came out that about 70 percent of the cycling peloton used the stuff. But they cost a ton, and it was hard to discern what was actual practice and what was just marketing.

It wasn’t until 2023, though, that I embraced that ketones were here to stay, whether I liked it or not. A 2023 study in the American Journal of Physiology-Endocrine and Metabolism had nine men complete two cycling trials, both with one hour consisting of two minutes at 90 percent of aerobic capacity (moderately hard), followed by two minutes at 50 percent of aerobic capacity (very easy). In both trials, the cyclists consumed a carb-protein drink immediately after exercise and at one, two, and three hours later. Here’s the study intervention: in just one trial, participants ingested 0.29 g/kg ketone monoester immediately after exercise and at one and two hours later.

The ketone trial led to 20 percent higher levels of natural erythropoietin (EPO) in the bloodstream.

For comparison, a 2005 study in the British Journal of Sports Medicine found that the initial exposure to altitude training increased EPO by an average of around 50 percent in swimmers, with large individual variability (returning to baseline after a couple of weeks of altitude training), with lots of variation across studies. Given that our bodies produce EPO to increase red blood cell production, and red blood cells transport oxygen that power endurance performance, the ketone study indicated that we could be seeing a supplement that supercharges adaptation and performance.

Context for Ketones

To be 100 percent honest, I was sad when I saw this study. I love performance physiology, but I don’t want to think about a new biohack. Maybe it’s a sign that I’m getting old when a study on cutting-edge science just makes me tired. Get these research protocols off my lawn!

But I also couldn’t bury my head in the sand (though that would probably increase EPO concentrations via hypoxia). Instead of giving into my old-coach fatigue, maybe I can help publicize the emerging science so fewer athletes have an information disadvantage. My final push was last week when a fantastic review article was published in the American Journal of Physiology-Cell Physiology by Ruben Robberechts and Chiel Poffé. If ketone supplementation has the potential that some think it may, the article could be a key step in the future of exercise physiology.

Before getting to the science, I think it’s important to lay out the stakes. Based on the articles (mixed with a heaping dose of gossip), I can see three different scenarios unfolding over the next 10 years.

One, post-exercise ketones don’t live up to their promise, and this is all a nothingburger. That outcome would please me the most, and we all know that what’s most important in science is my pleasure. If researchers did this type of theoretical analysis on other interventions (i.e. heat training, Vitamin D, lifting, ashwagandha, strides, beta-alanine, doubles, creatine), they could come back with similar findings. We are only talking about a few intervention studies and lots of theory, and future research could have different results. Plus, some critics would already be confident making their judgments as the Supreme Court of Nothingburgerland.

Two, ketones could become a more commonly used supplement with benefits for performance and health (like iron). They are expensive, which isn’t great, but maybe they will help athletes be healthier and faster, with limited side effects. On the flip side, maybe more research indicates tradeoffs that lead to benefit:risk calculations with performance or health. Over email, Dr. Poffé–an author of the review study and a key researcher in this field–says that “studies have shown divergent effects on performance depending on the exercise context and whether you take them before, during or after exercise.” Even if they are beneficial in some contexts, it’s not a simple equation of take ketones = get faster.

The third possibility is that they are banned as an illegal performance enhancer. I have no inside info on whether that’s a possibility, and at first blush, it doesn’t seem likely without some health risks. Dr. Poffé says “I honestly don’t see much of a reason to ban ketones while allowing other ergogenic supplements.”

So, yeah, we’re talking about a wide range of possibilities, which makes sense given the uncertain mechanisms and effects at play. Let’s dig in. (We got even deeper into the nuance on our podcast this week, which you can listen to here.)

Introduction to Ketones

As stated by the review study, ketone bodies “are molecules that are continuously produced from the breakdown of free fatty acids,” primarily in the liver. Ketone body production is upregulated during periods of low carbohydrate availability—that’s why you have heard “ketosis” thrown around for ultrarunners who practice low carbohydrate, high-fat nutrition, aiming to improve fat oxidation and avoid bonking. Ketosis via nutritional interventions comes with way too many downsides for endurance athletes, though, including everything from reduced bone density to diminished high-intensity performance. That makes sense intuitively because low carbohydrate availability is extremely stressful on most body functions, especially the endocrine system.

Ketone esters, enter stage left. Researchers figured out how to create an ester bond between a ketone body precursor and a ketone body (first in 1978 in rats, but not undergoing human testing until 2012). These ketone esters cause a “rapid and transient increase in ketone bodies,” possibly inducing ketosis. It was as if this evolutionary mechanism honed over millions of years now had a dimmer switch. For the chemistry nerds out there, you can probably guess what oral ingestion of an ester is like—not fun. Companies like HVMN honed the taste over time, and now I’d say that ketone esters taste like a robot’s ass. We can only imagine what they tasted like before.

Ketones have mostly been marketed as a before-and-during-exercise supplement, at least in the podcast ads I have heard. Take ketones, burn more fat at higher intensities, win the Tour de France, etc. However, a bunch of studies have shown limited to no acute benefit. For example, a 2017 study in Frontiers of Physiology found that pre-exercise ketone supplementation caused around a two percent performance decrease in 10 male professional cyclists doing a 50-minute time trial.

Perhaps there’s some protocol being used in the cycling peloton that improves acute performance, as the marketing claims indicate. Heck, Tom Evans reportedly took ketone esters on his way to winning Western States, so there must be some benefit for some athletes (or at least neutral impacts), possibly related to perceived effort. Anecdotally, when I tried ketones on a fatigued long run, the lights went out. Thankfully, I had my phone to call the Wuber (when my wife Megan drives to pick me up).

So perhaps it’s something else. Maybe all this ketone hype is because taking them improves recovery and hematological variables, confounding variables that are actually the driving force behind their use (maybe that even explains some of the success stories behind low carb, high fat nutrition approaches. I’d love to see the blood work!).

According to the review, after exercise, circulating ketone bodies are increased. However, any benefits athletes may see from a sustained increase are blunted in advanced athletes practicing good recovery nutrition. Ketone esters “may induce a unique physiological milieu to enhance post-exercise recovery and exercise adaptation as it allows to benefit from the potential beneficial effect of post-exercise ketosis in combination with other nutritional exercise recovery strategies (e.g., carbohydrate-protein recovery drink).” They had me at physiological milieu. Dr. Poffé says that his lab started ketone work in 2016 when “there was already some preliminary data showing that it could help riders during the Tour de France as a recovery aid.”

Mechanisms of Post-Exercise Ketones

I can’t emphasize enough how great this review article is, summarizing extremely uncertain science and studies. Before getting to the EPO mechanisms, let’s briefly touch on a bunch of other considerations. First, ketone bodies may cause epigenetic changes. For example, histone lysine β-hydroxybutylation could increase with ketone body increases, which may “increase transcription of genes involved in the adaptive response to exercise.” Across several different epigenetic mechanisms, it’s possible that ketone bodies could be a signal to the body to adapt to stimuli (which makes sense given their evolutionary role in exercise in energy-limited environments).

Second, ketones could “enhance the restoration of cellular energy status after exercise” while also blunting AMPK phosphorylation, which could enhance recovery due to its role in cellular stress or decrease adaptation due to its role in mitochondrial biogenesis. I love this one because that maybe-good, maybe-bad uncertainty regarding downregulation of AMPK points out just how little is known about the long-term consequences of post-exercise ketones, particularly in conjunction with other impacts.

Third, ketones alter g-receptor signaling, which “mediate cellular responses to a wide variety of external agents.” Fourth, ketones show anti-inflammation and anti-oxidation properties, which seems good at first glance but could theoretically cause long-term reductions in training adaptations since the inflammation response can spur adaptation. Fifth, ketones may influence neurotransmitter concentrations in the brain, which could profoundly impact perceived exertion (and possibly even mental health, though that’s a topic for another day).

The next cohort of potential adaptations are at the cutting edge of science but still theoretical. Ketones could increase muscle glycogen resynthesis, reduce protein degradation and enhance protein synthesis, spur angiogenesis that leads to more capillaries to supply blood to working muscles, induce favorable changes in muscle mitochondria, and improve sleep quality in athletes who are training hard. You can put those variables together with a 2019 study in the Journal of Physiology, where male athletes completed a three-week overload training block with six days a week of two-a-day training sessions, with one group having post-exercise ketones. That study found higher tolerated training load in the ketone group and improved performance. (The study was the subject of a Letter to the Editor disputing some of the conclusions.)

A 2023 study looked at a similar three-week overload block, validating the findings. They had 18 male athletes complete 10 training sessions per week, with one group taking post-exercise and pre-sleep ketones and the other taking a placebo. The ketone group “increased the number of capillary contacts and the capillary-to-fibre perimeter exchange index by 44 percent and 42 percent,” plus “substantially increased vascular endothelial growth factor and endothelial nitric oxide synthase expression both at the protein and at the mRNA level.” And the money finding: EPO concentrations in the ketone group increased by 26 percent. That study was eye-opening for the possible recovery and adaptation benefits of ketones, and it brings us back to the elephant in the room: potential hematological changes from increased EPO production.

Hematological Changes

In 2018, a study in the Diabetes Care journal found increasing levels of EPO after a ketone body infusion. The authors of the 2023 study that started this article cited this study as part of the impetus for their investigation (read their amazing summary here). We’re seeing similar findings in athletes in the 2023 studies, which found 20 percent and 26 percent increases in EPO production in the ketone groups relative to controls. But the science is not there to make a definitive conclusion.

In the title of this article, I promised uncertain science, and now we are deep in it. First, we don’t know how much this EPO change may impact performance. “Currently,” the review says, “it has not been identified if the observed changes in EPO post-exercise are indeed sufficient to induce an improvement in hemoglobin mass and oxygen transport capacity in humans, and whether these effects are additive to stimuli that are frequently used by athletes to increases EPO such as hypoxia.” It’s possible that these changes don’t correspond to performance benefits.

And get a load of this: “The precise physiological mechanism underlying ketone body-induced upregulation of EPO is currently unknown.” However, based on mouse models, the researchers theorize that it relates to H39K acetylation in kidney cells.

Are Ketones the Future?

There are tons of unanswered questions. How do these types of adaptations change over time? The longest study right now is a few weeks.

Do the processes change in female athletes? That’s one of my big concerns in making any recommendations since metabolic processes can vary based on gender. While more research is needed, Dr. Poffé indicates that past studies likely show that the results can be extrapolated to female athletes. “In a recent, unpublished study,” he says, “we observed that some effects are even more pronounced in females.”

How about aging athletes? Athletes of different levels, with different goals and backgrounds? What’s the right dosage and timing? Would the same responses happen at altitude? Should consumption be periodized? With similar studies, would other interventions lead to similar findings? Should ketones be banned altogether?

I don’t know the answers to those questions, and a lot more studies are needed before I make coaching recommendations other than “be careful” and “keep it simple.”

“Similar to most nutritional supplements,” Dr. Poffé says, “the long term effects (e.g. what occurs if you supplement for multiple years) are not known.” When athletes take ketones, he says instead of taking them chronically, to supplement “during periods of limited recovery opportunities,” like training camps. From a performance perspective, he advises to consider ketones when everything else is sorted out around training, nutrition, and recovery. They are “the final step,” not the first one.

In September, after reading the research, I dusted off that old package of ketones and opened up a serving for myself. Then I threw it in the trash because it seemed like a health hazard after all those years. I ordered a new package and started experimenting with them a couple days a week post-exercise. In October, at the Blue Sky Marathon, I closed the final four miles two minutes faster than last year to set a course record.

That probably had nothing to do with ketones, right? I’m no Olympian, but I train hard. And when looking back on the race and why I could finish so fast while feeling so good, I would be burying my head in the sand not to consider one of the only variables that changed.

I’m not sure what the future holds with post-exercise ketone supplementation. Maybe it’s all snake oil and placebo, with some studies that find physiological anomalies without a demonstration that it fundamentally alters performance trajectories, destined to be covering dust in the pantry of exercise physiology history.

Or maybe we’re seeing the dawn of a revolution in endurance training and performance.

posted Sunday January 14th
by David Roche (Trail Runner Magazine)