Exogenous ketones have generated a lot of buzz in the endurance sports community over the last few years. Exogenous ketones are not to be confused with the ketones that circulate in the blood after adaptation to a very low carbohydrate, high fat, ketogenic diet; exogenous ketones are instead ingested in a supplement like a sports drink in much the same way that carbohydrates might be. There are a number of different types of exogenous ketones (6), with ketone monoesters seeing the most attention.

It was initially thought that, again like carbohydrates in sports drinks, taking on exogenous ketones during exercise might provide us with an alternative fuel source to help power long duration exercise and reduce use of our finite glycogen stores. There has been some indication that exogenous ketones do help us reduce glycogen use during exercise (2), although probably not via direct burning of the ketones to supply energy; the effect instead likely relates to some kind of signalling response (3). In 2019, data emerged suggesting exogenous ketones may aid in the recovery from demanding exercise (5). Now there is data suggesting exogenous ketones may promote important cardiovascular adaptations to exercise training, via effects on the important hormone erythropoietin, or EPO (4). That’s the data we’re going to focus on in this blog. 

Erythropoietin – EPO – what is it?

Erythropoietin, or EPO, is a hormone produced by the kidneys that plays a crucial role in the production of red blood cells. It signals to bone marrow to produce more red blood cells, which are responsible for carrying oxygen throughout the body. Increasing your overall red blood cell count is one of the key goals of endurance training, as more red blood cells mean more ability to carry oxygen to the muscles to support aerobic metabolism. Increasing your red blood cell count and oxygen carrying capacity will increase important endurance-related variables like V̇O₂max.

If you follow professional cycling, you may have heard of EPO. Use of artificial EPO was widely used as a performance-enhancing drug, particularly in the 1990s. The dopers injected EPO to stimulate red blood cell production and improve their performance. Research studies have shown that even small doses of EPO enhance endurance performance (1). Clearly, injecting artificial EPO to improve performance is both illegal and potentially dangerous; but the point I am making here is that stimulating EPO production naturally will likely improve performance in endurance events.

What did the new study show?

The exciting, headline finding of the new study was that including a ketone monoester in post-exercise recovery nutrition stimulated greater EPO concentrations. The study, which was conducted by researchers from the University of Bath in the UK, had nine male participants undertake a one-hour cycling session that involved high-intensity intervals interspersed with periods at lower intensities. The participants did this on two occasions; once with ingestion of carbohydrate and protein during the recovery period, and once with ketones added to the carbohydrate and protein.

The researchers took blood samples during the four hours that followed the exercise, and measured the concentration of EPO in those samples. In the control condition – i.e. without ketones – there was a small elevation in EPO, particularly in the 2-4-hour post-exercise period. When ketones were ingested, the elevation in circulating EPO concentration was larger, with the peak EPO concentration about 20% higher than in the control condition. The overall exposure to EPO above resting values – known as the integrated area under the curve – was also about three-fold greater in the ketone condition.

Practical applications

These results are, as you can imagine, generating a fair bit of excitement in the sports nutrition world, as finding a safe, legal means of elevate EPO has the potential to stimulate red blood cell production and improve performance. The authors were, however, cautious to note that they only assessed the acute EPO response, and we should exercise some caution in interpreting these findings. We don’t know if elevating EPO in this manner actually results in greater red blood cell production – it is likely, but we need longer-term trials to show this before we can be confident. Still, exciting!

What should we do? Well, the results do seem to add to the literature suggesting ingesting ketones during recovery might be something we should consider as endurance athletes. The precise dosage we should take is still to be determined. That said, watch this space!

Figure: It is rumoured that exogenous Ketones are a very popular ergogenic aid is professional cycling pelotons used by many high profile teams.

#EndureOn

References

1. Breenfeldt Andersen A, Graae J, Bejder J, Bonne TC, Seier S, Debertin M, Eibye K, Hostrup M, Nordsborg NB. Microdoses of recombinant human erythropoietin enhance time trial performance in trained males and females. Med Sci Sports Exerc 55: 311–321, 2023. doi: 10.1249/MSS.0000000000003052.
2. Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, King MT, Dodd MS, Holloway C, Neubauer S, Drawer S, Veech RL, Griffin JL, Clarke K. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab 24: 256–268, 2016. doi: 10.1016/j.cmet.2016.07.010.
3. Dearlove DJ, Harrison OK, Hodson L, Jefferson A, Clarke K, Cox PJ. The effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates in athletes. Med Sci Sports Exerc 53: 505–516, 2021. doi: 10.1249/mss.0000000000002502.
4. Evans E, Walhin JP, Hengist A, Betrts JA, Dearlove DJ, Gonzalez JT. Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men [Online]. Am J Physiol - Endocrinol Metab 324: E56–E61, 2023. https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders.
5. Poffé C, Hogan M, Mittendorfer B. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol 597: 3009–3027, 2019. doi: 10.1113/JP277831.
6. Shaw DM, Merien F, Braakhuis A, Maunder E, Dulson DK. Exogenous ketone supplementation and keto-adaptation for endurance performance: Disentangling the effects of two distinct metabolic states. Sports Med 50: 641–656, 2020. doi: 10.1007/s40279-019-01246-y.