Do ketone esters increase EPO?

Ketone esters have received a lot of attention amongst elite athletes but also in the media. We covered the potential role of ketones in...

Do ketone esters increase EPO?

Ketone esters have received a lot of attention amongst elite athletes but also in the media. We covered the potential role of ketones in these previous blogs (effects on glycogen and performance and ketone bodies: fuel or hype?). Athletes have used ketones for the fuel they can provide, but there is increasing evidence that ketones act as signalling molecules as well as fuel. In fact, the role of ketones as a fuel during exercise has been questioned, since the amount of ingested ketone that can be used as fuel during exercise has been measured and is relatively low (1).

The ingestion of ketone esters can increase serum ketone body concentrations and serum EPO

In what ways might ketone bodies act as signals?

Ketone bodies could have wide ranging effects in a variety of tissues. We were interested to understand if ketones might affect aspects of red blood cell production. The idea came from an observation in people with diabetes treated with specific drugs that have a side effect of increasing ketone bodies. This treatment has been shown to increased markers of red blood cell mass (haematocrit and haemoglobin). In addition, athletes on a low-carbohydrate, ketogenic diet also show increases in these markers of red blood cell mass (2).

This prior evidence provided some hints, but because drugs and ketogenic diets have wide-ranging effects over and above simply increasing ketone body levels, and because these markers of red blood cell mass can also be influenced by other factors (such as plasma volume), the role of ketone bodies in red blood cell production was still unclear. If ketone bodies could alter red blood cell mass, then this could provide a benefit to both athletes and clinical populations, as the oxygen carrying capacity of the blood can be increased, in turn, potentially improve endurance performance.

Why study EPO with ketone esters?

Increasing red blood cell mass can take several weeks, and ketone supplements are not cheap. Therefore, before investing time and resource into a longer-term study, we wanted to understand the proof-of-principle: do ketone esters have the potential to increase red blood cell mass? The main hormone which regulates red blood cell production is erythropoietin (EPO).

The main hormone which regulates red blood cell production is erythropoietin (EPO).

EPO is of course known as a banned drug for this reason, but it can also be stimulated in natural ways such as altitude training. Being at altitude can stimulate the body to produce EPO. Therefore, if ketone esters can increase EPO in the short term, this suggests they have potential to alter red blood cell mass in the longer term. Longer-term studies with measures of red blood cell mass would still be needed to understand if ketone esters do increase the oxygen carrying capacity of the blood, but if ketone esters do not increase EPO in the short-term, then longer-term studies on red blood cell mass make less sense to invest in.

So do ketone esters increase EPO?

One prior study had provided people with an infusion of ketone bodies directly into a vein, and found increased EPO levels in the blood, and increase bone marrow activity (indicating increased red blood cell production) (3). However, the levels of ketone bodies in the blood were very high, and these people were studied in the fasting state and at rest. These factors mean that this might not translate to athletes, as exercise itself can stimulate EPO production, and ketone esters do not achieve the blood levels of ketones seen with infusion into a vein. Therefore, these factors might mean that ketone esters do not increase EPO in athletes. To answer this question, we asked 9 healthy males to complete a 1-hour bout of cycling intervals to mimic a training session with the aim of increasing the natural production of EPO with exercise (4). After exercise, these people drank recovery drinks containing carbohydrate and protein, with and without ketone esters (290 mg ketone monoester per kg body weight per hour for 3 hours).

This proof of principle study showed that ketone esters (in high doses) can increase EPO. Whether this will also have effects on RBC mass and performance remains to be determined.

Summary

We found that peak EPO levels after exercise were ~20% higher with ketone esters compared to the carbohydrate and protein alone. This increase is roughly similar to what has been observed with exposure to ~2000 m altitude. Of course, this is a high dose of about 20 grams for a 70kg person and this would have to be repeated daily for long periods of time, so it will also be expensive. This study showed that ketone esters can increase EPO. Whether ketone esters actually increase EPO enough, and also long enough, to cause changes in RBC over time, remains to be determined.

This study showed that ketone esters can increase EPO. Whether ketone esters actually increase EPO enough, and also long enough, to cause changes in RBC over time, remains to be determined.

What next?

There are many remaining questions to be answered. For example, what is the minimum (or optimal) dose of ketone esters for EPO production? What is the mechanism by which ketone esters increase EPO? Does supplementing with ketone esters increase red blood cell mass and longer-term performance? All these questions will require more research, but this initial study at least provides the proof-of-concept on which to build on, and the future of research on ketone esters for human health and performance looks interesting.

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References

  1. Dearlove DJ, Harrison OK, Hodson L, Jefferson A, Clarke K, and Cox PJ. The Effect of Blood Ketone Concentration and Exercise Intensity on Exogenous Ketone Oxidation Rates in Athletes. Medicine and science in sports and exercise 53: 505-516, 2021.
  2. McKay AK, Peeling P, Pyne DB, Welvaert M, Tee N, Leckey JJ, Sharma AP, Ross ML, Garvican-Lewis L, and Swinkels DW. Chronic adherence to a ketogenic diet modifies iron metabolism in elite athletes. Medicine and science in sports and exercise 51: 548-555, 2019.
  3. Lauritsen KM, Sondergaard E, Svart M, Moller N, and Gormsen LC. Ketone Body Infusion Increases Circulating Erythropoietin and Bone Marrow Glucose Uptake. Diabetes Care 41: e152-e154, 2018.
  4. Evans E, Walhin J-P, Hengist A, Betts JA, Dearlove DJ, and Gonzalez JT. Ketone monoester ingestion increases post-exercise serum erythropoietin concentrations in healthy men. American Journal of Physiology-Endocrinology and Metabolism 2022. DOI: 10.1152/ajpendo.00264.2022