The Zero-Minute Workout
There is strong evidence that exercise is wildly beneficial. There is even stronger evidence that most people hate to exercise. So if a pill could mimic the effects of working out, why wouldn’t we want to take it?
We all know that exercise is good for us. We also know that most people don’t get nearly enough. Thirty-four percent of U.S. adults are “physically inactive”; another 20% are “insufficiently active.” And, not surprisingly, almost 40% of U.S. adults are classified as obese. To be reductive: many of us eat too much and exercise too little.
The cost of physical inactivity is massive — not just in illness and death but in dollars, too: researchers from the Centers for Disease Control and Emory University say the U.S. spends around $117 billion a year on health care due to inadequate physical activity. And those are just the direct costs from treating cardiovascular disease, diabetes, and so on. It doesn’t even include things like loss of productivity.
A lot of smart people have spent a lot of time and effort trying to get people to exercise more. Mostly, they’ve failed. On this week’s episode of Freakonomics Radio: what happens next?
Obesity started out as a problem in wealthier countries, but now it’s spread to middle- and low-income countries. The contributing factors are not in dispute: we consume too many calories, especially low-quality calories; and we don’t burn off nearly enough calories with physical activity. To be fair, burning calories through exercise is a pretty inefficient process; it takes a lot more exercise than you’d think to burn off one cheeseburger. In that regard, it’d be better to just eat less.
“[P]eople who are physically active, especially if they get somewhere between 150 and 300 minutes per week of moderately vigorous physical activity, have a large reduction in their all-cause mortality — typically about a 50% or maybe 40% reduction in their all-cause mortality,” Joyner says. “And typically, they live… depending on the study, between about four and seven years longer.”
But how can we be sure it’s the exercise that’s actually causing better health outcomes? The most famous evidence for this claim is from a study, conducted in London after World War II, comparing sedentary bus drivers to more active bus conductors. The drivers had higher rates of both heart attacks and coronary-artery disease. Joyner says this finding has been replicated over the years in studies of other cohorts as well. What’s more, researchers have found that exercise can blunt the negative effects of other risk factors — high blood pressure, high cholesterol, obesity, etc.
The type of cohort studies that Joyner is describing, however, are not the randomized, controlled trials that scientists consider their gold standard. How do we know that there aren’t other reasons that people with high levels of physical activity enjoy good health? Maybe the kind of people who are more likely to exercise are the same people who are more likely to eat better, or sleep better; maybe they’re the same people who don’t smoke, or who face less stress in their lives — stressors like poverty or difficult work or home environments. But Joyner points to studies of individuals demonstrating that brief periods of exercise training can improve glucose tolerance, blood vessel function, and other biomarkers associated with health.
Much of Joyner’s research is about one of the major mechanisms behind these improvements — the increased blood flow to skeletal muscles that accompanies physical activity. During exercise, a person’s heart rate increases from around 60 or 70 beats per minute to approximately 200. Blood flow to the muscles also increases — from maybe 500 milliliters at rest, to up to 16 or 17 liters during intense exercise.
The longer-term benefits of that increased blood flow are significant. Large blood vessels throughout the body, as well as the capillaries in small blood vessels around the skeletal muscles, grow. The lining of the blood vessels becomes, in Joyner’s words, “more prone to relax versus constrict,” which reduces blood pressure. The skeletal muscles also secrete hormone-type substances that scientists believe positively affect everything from the liver to the brain, improving metabolism and brain growth.
So given the massive and widespread benefits of exercise, we would all be idiots to not do a lot of exercise, or at least enough exercise. Yet surveys suggest that, at best, only about 20% of Americans actually get enough exercise. Joyner is not hopeful that change is in the future.
“[U]ntil we have a wholesale change in transportation and food policy and just the way things are, I don’t see a whole lot changing,” he says. “Most of the population’s behavior aligns with various overt and covert incentives, and I think we have a whole lot of incentives to be physically inactive and eat a lot… I think we have a built-environment problem. I think we’ve got an incentive problem… I think we’ve also got a transportation-policy problem.”
Many of us are familiar with institutional attempts to improve our fitness. For example, more than 80% of large companies in the U.S., offer programs that encourage, and often incentivize, exercise and weight control. A randomized study of one such company, BJ’s Wholesale Club, was recently published in the Journal of the American Medical Association. It found that employees in the wellness program did self-report that they were more likely to exercise and manage their weight. But the data revealed there were no significant differences in actual health markers, including weight loss. And as we heard on last week’s live show, a world-class team of behavioral scientists recently did an experiment over 28 days, with 53 different interventions, to try to increase the exercise activity of people who were already members of a gym. All 53 versions of the intervention failed to create lasting change.
Ronald Evans, director of the Gene Expression Laboratory at the Salk Institute for Biological Studies, is a big believer in the benefits of exercise. But he is also a realist, and this has turned him into a futurist.
Evans’ lab is developing a pill that would mimic the effects of exercise in the absence of actual exercise (other labs around the world are working on similar exercise mimetics, as they’re called, with various mechanisms).
Evans is well-known for having discovered a family of hormone receptors that act as genetic switches. Years ago, Glaxo Wellcome (now known as GlaxoSmithKline) licensed a technology that Evans had developed and used it to build a drug called GW1516. It was not originally built as an exercise pill; it was designed to increase HDL cholesterol levels. But the drug never received FDA approval; it caused tumors in the mice it was tested on.
Evans eventually began working with a less powerful version of the drug, with the assumption it would be less toxic. Another difference: he wasn’t looking at its effect on cholesterol. He found something surprising. In both sedentary and obese mice who received the compound for about 30 days, their physiology seemed to indicate the mice had been exercising, even though they hadn’t been.
“[I]n terms of metabolic fitness in, let’s say, the brain, it does exactly the same things,” Evans says. “It gives you this increased energy expenditure, you burn more lipids, you burn more sugar, and you correct your insulin. Your adipose depot starts to shrink, so you lose weight. And the drug, by itself, gives you adult neurogenesis.”
The drug also seems to boost endurance, at least in mice. After 30 days of giving them the drug, Evans and his team put the sedentary mice on a treadmill, and compared the mice that got the drug to those that did not. They found that the mice that got the drug could run about an hour longer.
So this sounds pretty much like a miracle drug, right? Others thought so, too. Right before the 2008 Beijing Olympics, Evans reached out to the World Anti-Doping Agency, or WADA, about the potential for athlete abuse; he eventually helped develop a test for it. Soon after, WADA banned the drug. But in 2013, a bunch of pro cyclists were caught using it. Fast-forward to today: Ronald Evans and a pharmaceutical firm he co-founded, Mitobridge, are working on a new form of the drug that’s meant to minimize side effects. He estimates that in two to three years, it will be clear whether the pill appears to be effective enough to receive FDA approval.
Moving toward that goal, Mitobridge is targeting patients with Duchenne muscular dystrophy, a genetic disorder that typically strikes young boys, who rarely survive into their twenties. But Evans clearly sees a much wider potential use for this drug.
“There is absolutely no way that the potential here is going to be limited to one or two diseases,” Evans says. “It will be very high, from metabolic to neuro to vascular to aging. We can think of the potential here in different ways, and maybe… can it be used preventatively in some cases just to maintain health, as opposed to just treating disease.”
Tens of millions of Americans take statins every day to forestall heart disease; millions more take metformin to treat diabetes, or even the onset of diabetes. We put fluoride in our water supply to prevent tooth decay. But just because a drug may soon exist that could mimic the effects of exercise does not necessarily mean we should immediately spike our water supply with it. So Evans’ drug, if it does make it through FDA approval, will surely have its philosophical and ethical skeptics.
Even now, it’s got its physiological skeptics, including the Mayo Clinic’s Michael Joyner. “I think you can find a mimetic for things that sort of look like exercise, but I don’t think you’re going to find the big-picture drug or compound that can do the 10 or 15 main things that exercise does for people.”
And experts in behavior change warn of unintended consequences. Katherine Milkman of the University of Pennsylvania, for example, worries that Evans’ pill may give people a license not to exercise.
“He may not intend for it to replace fitness, but will people take it and then feel that they’re licensed to skip workouts?” Milkman asks. “Whether that’s the intent of the medication doesn’t mean it won’t be a nasty side effect.”
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