"We injected the mice with cancer. Without ketones, they were running 5-7km a day. With ketones, 10-15km. The placebo group were wiped out by day 45. The ketones group? Around 30 per cent longer. The evidence suggests ketones work but not as many suspect.
It's a July Wednesday and Procycling is in Brussels for the annual Science and Cycling Conference. The question is being asked, in the unofficial keynote speech: do ketones improve the performance of cyclists?
The presenter is Peter Hespel, a professor in exercise physiology and sports nutrition at Leuven University. He also works with Deceuninck–QuickStep and has done for years. The Bakala Academy is based at Leuven University. It's a hotbed of sports-science research: VO2max gas analysers, static trainers, altitude rooms and more. Its major donor, Zdeněek Bakala, also owns Deceuninck-QuickStep.
So Hespel's in a privileged position. He can refine and either reject or apply results from the controlled labs to the chaotic setting of WorldTour racing. It's why the audience of WorldTour support staff and global academics are hanging off his every word. And the 58-year-old is loving it, a typically mischievous Belgian twinkle in his bespectacled eyes.
"From our research, ketones can improve the performance of Grand Tour riders," Hespel continues.
We ask if Deceuninck are using them at the Tour de France. The answer seems obvious but there's no confirmation – and with it, Hespel's raising of the eyebrows encapsulates the mysterious air around the wonder supplement that's drifted over the peloton for years.
Every Tour, one news organisation or another insinuates that ketones complement energy gels and rice cakes in a rider's larder; every year, teams refuse to confirm or deny either its use or benefits. It's carved a reputation as the nutritional omertà, a fuelling Macbeth never uttered by the sporting actors.
That all changed at the 2019 Tour.
Jumbo go public
Few journalists attend the Science and Cycling Conference, so Hespel's revelation echoed briefly and quietly in the small academic chamber of VU Brussels University. Unlike Jumbo-Visma managing director Richard Plugge's interview with De Telegraaf halfway through the Tour, where he confirmed that ketone use is widespread among Tour riders.
"Ketones are a dietary supplement – you can use them just like vitamins. The substance is not on the prohibited list, and it's also known that other teams use ketones," he said.
It was reported that seven teams used them at the 2019 race. But why?
Ketones are an energy source produced by the liver during fasting or periods of low carbohydrate intake. That's important for survival but not necessarily tuned into high performance. The same, according to many, isn't true for ketones that aren't produced by the body, the idea being that by orally consuming ketones, you'll spare precious glycogen reserves for intense efforts like climbing a hill or sprinting to the line.
That purported preservation of carbs received a marketing boost from Jumbo-Visma as not only did Steven Kruijswijk finish third, but the Dutch team also won four stages of last year's Tour: the team time trial, plus individual victories for Mike Teunissen, Dylan Groenewegen and Wout Van Aert. Deceuninck-QuickStep added further possible ketonic support with three stage wins plus Julian Alaphilippe's 14 days in the yellow jersey.
So there you have it – ketones save the high-intensity nectar (glycogen) and so the riders ride faster? Not quite.
"We haven't published the study but we simulated a road race by having cyclists ride for 180 minutes at different speeds and intensities before a final 15-minute time trial, both with and without ketones," Hespel says.
"We noted that glycogen concentration in both groups was the same, as were the time trial results. In all honesty, I've never understood the physiological mechanism behind ketones improving intense efforts. And actually, arguably ketones could harm the rider if taken during hard efforts."
That harm is performance-related, not physical. Ketones are acidic. High-intensity efforts generate high levels of lactic acid and hydrogen ions, which lower the blood's pH levels and, eventually, cause a drop in power output and speed.
"If I was racing, I wouldn't want a lower buffer capacity when it comes to the final climb," says Hespel.
In the world of sports nutrition, this is ground-breaking. It's also disputed by ketones – to be exact, ketones ester – inventor Kieran Clarke, professor of physiological biochemistry at Oxford University, who cites her own research, including a 2016 study published in the journal Cell Metabolism, that ketone drinks alter the metabolic state to improve performance during the race. Clarke supports her assertions with anecdotal as well as empirical evidence.
"They were first used in 2012 at the Tour de France and then the London Olympics," explains Clarke. "We'd bottle them up and hand deliver them. The team who used them at the Tour drank one bottle before, during and straight after the stage, plus in the evening."
Client confidentiality means Clarke can't reveal who, though it's widely presumed the British-created drink was utilised by a successful British team. Sky, now Ineos, have never confirmed this; Chris Froome reportedly had to Google 'ketones' when questioned by a journalist. We asked James Morton, Sky's nutritionist between 2015 and April 2019, and he told us the team never used ketones in his time there. What about before? "No, the team never used them as far as I know," Morton replied.
Returning to the glycogen-sparing issue, Morton recommended contacting Brendan Egan, associate professor of sport and exercise physiology at Dublin City University. Egan has undertaken numerous studies around ketones and exercise. One of Egan's ketone studies saw no difference in performance in well-trained middle- to long-distance runners, while shuttle-run performance actually deteriorated in footballers.
"It's why I think that the major applications of exogenous ketones will be in supporting training and recovery, not performance," says Egan. "I've been consistently on the record about that, but we don't have the answers yet to say for sure."
Hespel thinks he does have the answers and it stems from those mice experiments.
"Our studies show that ketones increase anabolic signalling," he explains. Essentially, when a muscle is under strain, it cries out for protein to repair and rebuild. Ketones, Hespel, says, amplify this call to arms. "The mice received a very aggressive form of cancer that leads to accelerated muscle wastage. The ketones attenuated this breakdown."
Hespel took these findings into the sporting sphere, hypothesising that ketones would slow down – and ideally prevent – potential muscle breakdown during extreme exercise, namely a three-week Grand Tour. Alaphilippe, Viviani and co are no guinea pigs, so Hespel got creative, recruiting a group of well-trained student cyclists who'd broadly endure a three-week Tour of their own, with the châteaux and cornfields replaced by test tubes and white coats.
"We cranked up the training load from weeks one to three and, as time passed, the programme took its toll," Hespel says. "The atmosphere by the end of that third week mimicked that of a Tour team who'd won no stages and had four riders remaining. It wasn't a happy place."
But it was slightly happier in the ketone group who, on average, could maintain a higher training load than the placebo group. Yes, they still showed the classic signs of overtraining – a reduction in resting, submaximal and maximal heart rate – but not to the extent of those in the non-ketones group. "To be precise, there was a 90 per cent chance of increasing endurance performance somewhere between three and 17 per cent," Hespel says.
Perhaps the most telling difference between the groups was what they ate. Other than a post-workout protein-carbohydrate recovery drink, the subjects were free to eat whatever they wanted to. Initially, both groups averaged around 3,500 calories a day. But things diverged as training load cranked up. The control group maintained that calorie intake, resulting in an 800-calorie deficit each day; the ketone group ramped things up, averaging 4,200 calories in the final week and roughly remaining in caloric balance.
This is important as insufficient calorie intake and extreme exercise aren't happy bedfellows, widening the open window of infection, reducing power output and affecting mood. Key to this calorie difference were the respective hormonal profiles of the subjects, specifically the stress-induced hormone GDF-15. Relatively recent studies show this is a key hormone involved in appetite regulation. In an event like the Tour, the general pattern is a gradual increase in GDF-15 concentration that blunts the desire to eat. With ketones however, this increase was suppressed. Cue the greater calorie intake.
"That adds up," says Clarke. "The body goes to considerable lengths to maintain homeostasis. If you look at Hespel's study, ketone levels in the blood rise as normal during the non-ketone group as it's a protective mechanism against all the training. Increasing those levels raises it further, which eases stress and maintains hunger."
And that is arguably ketones' USP, according to former professional rider Greg Henderson. The New Zealander had a 60 per cent finish rate at Grand Tours, completing three Tours, one Giro and two Vueltas, and DNFing four times.
"Come the final week, you're truly sick of eating," the 43-year-old says. "You have a big breakfast, snack transferring to the start, have to keep on top of nutrition throughout the stage, pack in the calories on the bus to your new hotel and then more calories at the hotel. You know you have a good chef, who makes meals interesting, if you get through a Grand Tour and you haven't lost any weight."
Henderson has a keen interest in sports nutrition – so much so he's currently studying advanced human nutrition at Otago University. That interest saw Henderson dabble with ketones, albeit not at any of his high-profile teams – T-Mobile, Team Sky or Lotto Soudal.
"I'd heard [ketone] rumours for a long time but only tried it in my last year  when I was in the USA racing for UnitedHealthcare. There was something in it, albeit at a low-intensity aerobic level. But mate, if I'm racing a crit, it's not a worthwhile investment."
The price is not right
That investment is not a small one. HVMN, the American start-up who linked up with Clarke to commercialise the product, sell a day's worth of product (three bottles) for $99. Ignoring any trade discount and, for a full team of eight riders, over 21 stages that would amount to $16,632 or around £13,500. Still, according to HVMN, by the time the Tour came around last year, they'd already sold $200,000 worth of stock to WorldTour teams.
"It's not as cheap as we'd like but it's down from £2,000 per litre when we first started making it in the lab," says Clarke. "The problem is, it's expensive to make. Each bottle costs around $8 compared to around two cents for the glucose in an energy drink. That price will drop through volume but never to glucose levels."
Still, even at the price, demand is growing and not just in cycling. Clarke tells us professional football and gridiron teams are using it. The US Special Forces consume it, too, which brings it around to where the product derived from. Back in 2003, the US Army laid down a $10 million challenge for an efficient food source that soldiers could take out onto the battlefield.
"I'm a biochemist and had been working on ketone metabolism," Clarke explains, picking up the story. "Ketones aren't that well understood but you can't survive without them, so I knew if you could invent a drink, they'd be a satiating food source; you'd be able to go days without 'proper food'."
Clarke and her team created the ketone ester relatively quickly but rigorous Food and Drug Administration standards – "We had to prove they didn't kill anybody," says Clarke – saw a near 10-year delay from research to administered product. Currently, the pure ester is manufactured in Northumberland, from where it's shipped to America to be bottled by HVMN at a factory in Utah as the Food Standards Agency have yet to approve it in the UK.
HVMN aren't the only product on the market, of course. A quick Google search and you'll find an increasing number of ketone products, albeit in salt rather than ester form. This is an important difference, says Egan: "Though salts are cheaper, they can cause gastro-intestinal stress."
Studies show they also don't raise blood-ketone levels to the degree that Clarke's more expensive option does, and so reducing any potential performance improvement.
Sleep better, race faster
Hespel says those improvements stretch to improved sleep quantity and quality, too, via reducing night-time levels of adrenaline. Clarke says ketone-using riders at the 2012 Tour reported feeling fresher, both in the legs and in the mind. And it's in the mind where Egan cites another gain they have. Those footballers we mentioned earlier, the ones whose shuttle-run performance deteriorated when consuming ketones - it wasn't all bad.
"The footballers also performed a series of cognitive tests before and after the exercise challenge," says Egan. "This declined in the carbohydrate-only condition, but was maintained when exogenous ketones were added.
"This could be because one of the main roles of ketones is as food source for the brain when glucose levels are low," Egan continues. "Free fatty acids [FFAs] can't cross the blood brain barrier. Instead, FFAs are converted to ketones by the liver, which then fuel the brain.
"So it's easy to say they'd be 'brain fuel' when supplemented, but we need further research to say for sure. My guess would be that in a fuel-compromised state and when decision-making processes are prolonged [like in the third week of a Grand Tour], there may prove to be a benefit of supplementation."
Egan is at pains to highlight that ketones are more about slowing the rate of decline in periods of intense exercise rather than improvement per se.
"Even after 40 years, we're still making discoveries about carbohydrate products, so I'd urge people to refrain from making wild claims either for or against exogenous ketones until more research comes to light."
Clarke is less restrained. "When the price comes down, it'll become commonplace. People will use it as an anti-ageing drink, while little old ladies will drink it to make them feel better."
She also suggests it'll also be used as an everyday tonic to lose weight because it suppresses hunger. This, we suggest, clashes with Hespel's findings that it increases appetite. Clarke responds that's the versatility of the product – when sedentary it satiates appetite; in a catabolic state, like during the Tour, it increases appetite.
We put this to Professor Asker Jeukendrup, nutrition scientist at Jumbo-Visma, who questions its Jekyll and Hyde properties. "If you want to know that your results are caused by ketones, you need to make sure everything else stays constant and it wasn't," he says. "There was a difference in carbohydrate intake, so how do you know it was related to ketones and not the fact that they had more carbohydrate and more energy?"
Further, Jeukendrup argues any supplement is pointless if you don't have a meticulous fuelling strategy. But he doesn't deny that Jumbo-Visma riders use it, and he doesn't admit it, either. Why the secrecy? Competitive edge, surely, but perhaps restraint, too. In a sport tainted by illegal supplements and strategies, who wants to guarantee a packed inbox and singular press conference by explicitly saying which riders use ketones and what their individual protocol is, even if ketones are WADA approved?
Ultimately, it's reductionist to say that ketones come into their own during Grand Tours due to their recovery benefits; it's also speculative to say they lay behind Alaphilippe hanging around in that third week. Where did that endurance come from? Only Alaphilippe knows if he enjoyed the most suppressed GDF-15 levels in the peloton.