RONALD EVANS never intended to kick off a performance-enhancing drug craze, but that is what happened. Despite a ban on its use in sports, the substance he has long been studying has now been detected in doping tests of cyclists and boxers, while runners and bodybuilders share stories online about how it makes them leaner and stronger nonetheless.
The story begins in 2002, when Evans, a biologist at the Salk Institute in La Jolla, California, performed some experiments involving mice and exercise wheels. He fed a drug known as GW1516 to unfit mice, expecting to see modest effects on their fat metabolism. But tests showed that mice which had been given the drug could run twice as far on their wheels as ones that hadn’t. “It was an amazing moment,” says Evans. Couch-potato mice had been transformed into endurance runners. Ever since, he has been chasing a dream with ramifications not just for elite athletes, but all of us.
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We know that exercise truly is the best medicine. Get your body moving, even a modest amount, and the rewards range from stronger bones to a sharper mind. But what if you could use a pill to mimic those benefits without having to do any training at all? That question – and Evans’s promising work – have sparked a drug-discovery movement. As the first fruits of this work edge closer to the clinic, there is an increasingly heated debate about how these kinds of therapies should be used. All agree, however, that a healthcare revolution is on the way.
Many of us turn to exercise as a means of losing weight, but the benefits go way beyond that. Working out challenges virtually every organ in the body, stimulating growth and repair. It also causes a broad shift in the body’s metabolism that protects against obesity, metabolic disorders such as diabetes, and cancer. Other upsides include a more efficient cardiovascular system, boosted cognition, memory and mood, and even a longer life.
“We’re designed to move,” says Evans. Yet most of us don’t move nearly enough. One study of adults in more than 100 countries found that . The World Health Organization recommends a minimum of 2.5 hours of moderate exercise a week, yet worldwide more than a quarter of us don’t manage that.
No one has come up with a good remedy for this. Simply telling people to eat more healthily and exercise more doesn’t work, says Evans. We may be designed to move, but evolution has also programmed us to store fat to survive winter and famine. So it isn’t entirely your fault if you don’t exercise as much as you should. On top of that, plenty of us have physical limits on how active we can be. Putting exercise in a pill, says Evans, “is going to allow people who can’t exercise to get some of the benefits”.
The first step is to work out how physical activity elicits its effects. Most of what we know is about aerobic endurance training. This is because experiments designed to probe the physiology of exercise are mostly done on mice and rats, animals that take easily to running on wheels. It is trickier to persuade them to lift weights.
These studies have taught us that muscles act as control centres, hosting proteins that sense the body’s increased activity and drive widespread changes to deal with the challenge. Signals, such as falling energy levels or a flood of calcium ions generated by contracting muscles, trigger the release of messenger molecules. These stream to various organs, where they initiate a range of responses. They might ask the brain to grow fresh neurons, for example, or stimulate bones to get stronger.
A pill that sought to replicate all this – an “exercise mimetic”, as Evans calls it – would have to be very different from the majority of common medicines. Many of these are based on small molecules that target proteins responsible for a specific job in the body, either helping the protein do its job more quickly or stopping it working. Statins, for example, inhibit a protein that is needed to make cholesterol, and so help lower our blood cholesterol level.
The drug that Evans was using, GW1516, targets a different sort of protein called PPAR-delta. He describes it as a master switch that, when flicked, activates a wide-ranging genetic programme. The effects that follow include shifting the composition of muscles – reducing the amount of “fast twitch” fibres, built for explosive bursts of energy, and increasing the proportion of “slow twitch” ones that favour endurance. It also prompts our bodies to switch from burning sugar to fat.
Flipping this particular switch isn’t the only way to create sedentary supermice. In 2012, at the Dana-Farber Cancer Center in Boston a hormone released by muscles during exercise, which he named irisin. It is a messenger chemical that helps tell various parts of the body to engage exercise mode. In obese mice, boosting irisin levels converted inactive white fat into energy-burning brown fat, and caused the animals to lose weight even on a high-fat diet. In 2018, Spiegelman and his colleagues also pinned down the mechanism by which .
Meanwhile, at the University of Southampton, UK, has found a , which indirectly activates a metabolic sensor called AMPK. To see if compound 14 might be a good treatment for metabolic disorders, he and his colleagues fed mice a high-fat diet so they became obese and developed diabetes-like symptoms, then gave them compound 14.
“The results floored us,” says Tavassoli. After just seven daily doses of the drug, the mice lost weight and their diabetes symptoms disappeared. By comparison, people whose diabetes is treated with metformin, which works through a similar pathway to compound 14, tend to gain weight. In more recent, unpublished work, Tavassoli and his team showed that patterns of gene expression in the animals’ fat cells no longer reflect obesity, but resemble those of normal-weight mice. Compound 14, says Tavassoli, appears to be “profoundly reprogramming” the metabolism of these mice.
So far, these substances have mostly been tested in non-human animals. But the relevant metabolic pathways are similar in people, which makes Evans optimistic that activating PPAR-delta or similar master switches could “reboot physiology” in us too. He says pressing such switches could be all it takes to go from sluggish and overweight to fit and athletic.
A workout for your brain
Other researchers hate the idea, though, including some of those who have identified promising exercise-related compounds. “To say ‘exercise mimetic’ as though you can capture exercise in a pill is absurd,” says Spiegelman. He has two big objections. The first is that there are many types of exercise that each have different physiological effects. The molecular pathways involved are too diverse and complex, he says, to hit them all with one pill. John Hawley, who studies the physiology of exercise at the Australian Catholic University in Melbourne, agrees. “There will never be a drug that mimics all the effects of exercise,” he says. “It is impossible.”
Take the mental health benefits of exercise. It is fair to say that biochemical mechanisms play a role here. There is evidence, for example, that exercising the muscles prompts them to , which has been linked to depression and mental illness. Even so, Hawley argues that the mood boost from cycling around a beautiful lake or playing with a close-knit team can’t be captured in a pill. “I don’t think there is any drug that is going to do that,” he says.
Spiegelman’s second concern is the risk of side effects. Studies of GW1516 were abandoned because high doses, given long-term, caused tumours in mice. Tavassoli fears cancer could be a risk of using drugs to boost metabolism in this way without fully understanding the effects. “You can’t have these pathways on all the time without there being some sort of downstream consequence,” he says.
A one-stop exercise pill may be too blunt an instrument. When neuroscientist at Florida Atlantic University gave mice a compound that activates AMPK through the same pathway as compound 14, she saw that, after a week, muscle and brain had both benefited. But after two weeks, although the muscles of the mice still looked good, the cognitive effects were “horrible”. The animals had increased inflammation in their brains and performed worse in a maze. When you exercise, your body distributes the benefits over time in a way that’s tailored to your own physiology, says van Praag. “That’s a tall order for a pill.”
Rather than using drugs as a long-term pass for inactivity, van Praag and Tavassoli suggest that they might give a short-term boost. They could protect people who can’t exercise properly for short periods, such as those recovering from surgery or even astronauts living in microgravity. Maybe they could help highly obese people get to a weight where they can begin to exercise. “The ideal would be to take it short term to get over the hump,” says Tavassoli, “then exercise hard and stop taking the compound.”
What excites Spiegelman, though, is something else. He envisions a whole new generation of treatments for specific medical conditions from osteoporosis to liver disease. The idea wouldn’t be to trigger the entire metabolic programme associated with exercise, but to go for a switch further down the line, where the effects are still powerful, but more targeted. You might say that Spiegelman isn’t dreaming of one exercise pill but multiple pills, each harnessing different benefits. The term “exercise mimetic” isn’t just misleading, he says, but “not ambitious enough”.
He sees particular promise for neurodegenerative disorders, including Alzheimer’s disease. Aerobic endurance exercise has a big effect on the brain, increasing blood flow and improving the health and connectivity of neurons. It even triggers the birth of new neurons in the hippocampus, a brain area associated with memory. It is virtually the only thing known to do this. Spiegelman has found that a precursor of irisin reaches the brain and influences the expression of genes related to neurogenesis. With Christiane Wrann, now at Massachusetts General Hospital on neurogenesis and cognition, and has set up a small company with the aim of moving irisin-based drugs into clinical trials.
Exercise itself doesn’t have a dramatic effect on patients with Alzheimer’s disease, which might make you wonder what Spiegelman hopes to achieve. But this is precisely the point. “Why should we limit ourselves to the effects of endurance exercise?” he says. He thinks that drugs such as his can go “beyond exercise”. Giving the compounds to patients in higher doses than they would naturally appear in the body might have an effect on conditions that are currently seen as untreatable.
Beyond exercise
Van Praag is now investigating another molecule, cathepsin b, which she has shown in mice, primates and humans to be . She suggests the research might lead to tailored treatments for people with cognitive issues, for example by monitoring levels of exercise-regulated biomolecules, and where necessary boosting them.
For now, Evans is following the same approach as Spiegelman: that of developing drugs to treat specific conditions. This is because there is no pathway to regulatory approval for a drug that promotes general health. “The only way that you can get a pill approved is to treat a disease,” says Evans.
He advises a Boston-based company, Mitobridge, which is developing two drugs to target PPAR-delta, in order to treat acute kidney disease and Duchenne muscular dystrophy (DMD), a muscle-wasting disease that affects boys. These drugs work in a similar way to GW1516. Tests in mice suggest they can help DMD and phase I clinical trials in humans suggest they are safe. Both drugs are now in phase II trials to evaluate if they can treat the diseases in humans.
Evans reckons this could act as a bridge to a broader, health-promoting pill for people who are inactive for whatever reason. Once a drug that targets PPAR-delta is approved for one condition, doctors will be free to prescribe it “off-label” for other conditions, at least in the US. That could open the door to using them for prevention of ill health too. This is similar to the way statins developed. The drugs were initially approved to treat heart disease; now they’re prescribed to reduce the risk of developing it. Evans admits that no drug will ever capture the full benefits of every type of exercise, but sees no reason why we shouldn’t get a broad sweep of those benefits from pills.
For some, that is a horrifying vision. Van Praag reckons the way to combat inactivity is to redesign society to support exercise, from building more cycle paths to better education about the pros of activity. Hawley fears that even talking about an “exercise pill” is counterproductive, because it might give people an excuse not to be active.
Evans thinks this is missing the point. “I love exercise!” he says. He sees the root of the inactivity problem not as personal weakness, but the powerful forces that profit when we eat more and move less. Cheap junk food and soft drinks loaded with calories drive our metabolism towards obesity. Tech companies use sophisticated machine-learning techniques to keep us glued to our screens. Trying to dismantle those influences is a worthy fight, says Evans, but one that is ultimately doomed to fail.
Exercise pills in some form are now inevitable, insists Evans. Once they are approved, we will face a dilemma. Instead of waiting for chronic diseases and wastage to take hold, should we medicate ourselves in advance, to offset the inevitable health damage done by modern life? “I think it’s an important debate to have,” he says. “Is society ready to have it?”
