It was late summer, and the gray towers of the Salk Institute, in San Diego, shaded seamlessly into ocean fog. The austere, marble-paved central courtyard was silent and deserted. The south lawn, a peaceful retreat often used for Tai Chi and yoga classes, was likewise devoid of life, but through vents built into its concrete border one could detect a slight ammoniac whiff from more than two thousand cages of laboratory rodents below. In a teak-lined office overlooking the ocean, the biologist Ron Evans introduced me to two specimens: Couch Potato Mouse and Lance Armstrong Mouse.
Couch Potato Mouse had been raised to serve as a proxy for the average American. Its daily exercise was limited to an occasional waddle toward a bowl brimming with pellets of laboratory standard “Western Diet,” which consists almost entirely of fat and sugar and is said to taste like cookie dough. The mouse was lethargic, lolling in a fresh layer of bedding, rolls of fat visible beneath thinning, greasy-looking fur. Lance Armstrong Mouse had been raised under exactly the same conditions, yet, despite its poor diet and lack of exercise, it was lean and taut, its eyes and coat shiny as it snuffled around its cage. The secret to its healthy appearance and youthful energy, Evans explained, lay in a daily dose of GW501516: a drug that confers the beneficial effects of exercise without the need to move a muscle.
Exercise has its discomforts, after all: as we sat down to talk, Evans, a trim sixtysomething in a striped polo shirt, removed a knee brace from a coffee table, making room for a mug of peppermint tea; he was trying to soothe his stomach, having picked up a bug while hiking in the Andes. Evans began experimenting with 516, as the drug is commonly known, in 2007. He hoped that it might offer clues about how the genes that control human metabolism are switched on and off, a question that has occupied him for most of his career.
Mice love to run, Evans told me, and when he puts an exercise wheel in their cage they typically log several miles a night. These nocturnal drills are not simply a way of dealing with the stress of laboratory life, as scientists from Leiden University, in the Netherlands, demonstrated in a charming experiment conducted a few years ago. They left a small cagelike structure containing a training wheel in a quiet corner of an urban park, under the surveillance of a motion-activated night-vision camera. The resulting footage showed that the wheel was in near-constant use by wild mice. Despite the fact that their daily activities—foraging for food, searching for mates, avoiding predators—provided a more than adequate workout, the mice voluntarily chose to run, spending up to eighteen minutes at a time on the wheel, and returning for repeat sessions. (Several frogs and slugs also made use of the amenity, possibly by accident.)
Still, as the example of Lance Armstrong Human makes clear, sometimes exercise alone is not enough. When Evans began giving 516 to laboratory mice that regularly used an exercise wheel, he found that, after just four weeks on the drug, they had increased their endurance—how far they could run, and for how long—by as much as seventy-five per cent. Meanwhile, their waistlines (“the cross-sectional area,” in scientific parlance) and their body-fat percentage shrank; their insulin resistance came down; and their muscle-composition ratio shifted toward so-called slow-twitch fibres, which tire slowly and burn fat, and which predominate in long-distance runners. In human terms, this would be like a Fun-Run jogger waking up with the body of Mo Farah. Evans published his initial results in the journal Cell, in 2008. This year, he showed that, if his cookie-dough-scarfing mice were allowed to exercise, the ones that had been given 516 for eight weeks could run for nearly an hour and half longer than their drug-free peers. “We can replace training with a drug,” he said.
The drug works by mimicking the effect of endurance exercise on one particular gene: PPAR-delta. Like all genes, PPAR-delta issues instructions in the form of chemicals—protein-based signals that tell cells what to be, what to burn for fuel, which waste products to excrete, and so on. By binding itself to the receptor for this gene, 516 reconfigures it in a way that alters the messages the gene sends—boosting the signal to break down and burn fat and simultaneously suppressing instructions related to breaking down and burning sugar. Evans’s doped mice ran farther, in part because their muscles had been told to burn fat and save carbohydrates, which meant that they took longer to “hit the wall”—the painful sensation encountered when muscles exhaust their glucose store.
In dozens of other ways, 516 triggers biochemical changes that take place when people train for a marathon—changes that have substantial health benefits. Evans refers to the compound as “exercise in a pill.” But although Evans understands the mechanism behind 516’s effects at the most minute level, he doesn’t know what molecule triggers that process naturally during exercise. Indeed, one of the most significant challenges facing anyone who wants to develop an exercise pill is that the biological processes unleashed by physical activity are still relatively mysterious. For all the known benefits of a short loop around the park, scientists are, for the most part, incapable of explaining how exercise does what it does.
The compound 516 was developed in the late nineties, in the laboratories of GlaxoSmithKline. Its creator, a chemical biologist named Tim Willson, was in charge of a research group tasked with prospecting for chemicals that could bind to the PPAR-delta receptor. The search had been prompted by an earlier discovery: compounds that bound to a similar gene receptor were highly effective in treating diabetics, the pharmaceutical industry’s most lucrative market. Willson’s team tested 516, first in a test tube and then on middle-aged, obese monkeys, and the results were exciting. “We got this dramatic increase in good cholesterol, and a commensurate decrease in the bad kind,” he told me recently, noting that 516 also lowered insulin levels and triglycerides. The combination of effects made 516 seem like a promising treatment for what’s known as “metabolic syndrome,” a cluster of symptoms—including obesity, high blood pressure, and high blood sugar—that is a precursor to heart disease and diabetes. More than a third of adult Americans are estimated to have metabolic syndrome, which made 516’s potential profits seem rather attractive. GlaxoSmithKline took the drug all the way through Phase II clinical trials in humans, successfully demonstrating that it lowered cholesterol levels without any problematic side effects.
But, in 2007, GlaxoSmithKline decided to shelve 516. The company was about to embark on Phase III trials—the large, expensive, double-blind, placebo-controlled trials that are required for F.D.A. approval—when the results of a long-term-toxicity test came in. Mice that had been given large doses of the drug over the course of two years (a lifetime for a lab rodent) developed cancer at a higher rate than their dope-free peers. Tumors appeared all over their bodies, from the tongue to the testes. The results made GlaxoSmithKline’s decision all but inevitable. If a large dose of the drug seemed to increase the risk of cancer at the end of a mouse lifespan, the only way to conclusively prove that even a lower dose would not have a similar effect on humans would be to run a seventy-year trial. Without that proof, the F.D.A. would likely judge the potential risks of taking the drug to be greater than the actual dangers of high cholesterol.
Elsewhere, however, work on 516 persisted. Because Willson, in 2001, had published his description of the chemical’s structure and clinical effects, other labs were able to synthesize the chemical for research use. Ron Evans began his work on 516 at Salk the same year that GlaxoSmithKline’s researchers abandoned theirs. Since then, he has developed a less potent version that he hopes will also be less toxic.
And 516 is not the only “exercise pill” in development. At the University of Southampton, on England’s south coast, I met with a chemical biologist named Ali Tavassoli, a lanky, youthful forty-two-year-old with a chilled-out demeanor, which gives way to geeky enthusiasm when he starts explaining the particulars of protein interactions. Tavassoli came across his drug, Compound 14, more or less by chance, while designing a way to screen a new class of cancer drug, and he still seems somewhat bemused by the fact that his lab is now a front-runner in the race to develop an exercise pill. In a recent paper, he and his colleagues showed that Compound 14 caused the blood-glucose levels of obese, sedentary mice on a high-fat diet to approach normal levels in just a week, while melting away five per cent of their body weight. It works, he explained, by fooling cells into thinking that they are running out of energy, causing them to burn through more of the body’s fuel reserves.
Meanwhile, in Boston, Bruce Spiegelman, a Harvard cell biologist, has discovered two potent exercise hormones. One of them, irisin, turns metabolically inert white fat in mice into mitochondria-packed, energy-burning brown fat, and Spiegelman said that he’s seen evidence that it may also boost levels of healthy proteins in the area of the brain associated with learning and memory. He is now researching a third compound, and when I visited his lab he invited me to look through a microscope at a petri dish of sleek, round muscle fibres—a kind of mouse tartare—awaiting treatment with the chemical. They were twitching spasmodically. “It’s spontaneous,” Spiegelman said, as I recoiled. “The membranes are electrically active, and it’s almost like static on a radio. They just fire occasionally.” The experiment—effectively, exercise in a dish—is an efficient way of screening a large number of chemicals before selecting the most promising candidates for trials on intact mice.
I noticed that the fibres were a deep red, almost like raw tuna, and Spiegelman explained that this is a familiar property of slow-twitch muscle, the fat-burning, fatigue-resistant kind called upon during endurance training. Fast-twitch muscle, which is more powerful but tires quickly, and which runs on carbohydrate, is pinker. The piscine comparison is not incidental. During his research, Spiegelman discovered that tuna have a mutation in a gene that plays an important role in determining muscle-fibre ratios. As a result, all the muscle in tuna is slow-twitch, which is the reason for the distinctive color and meaty texture of a tuna steak. Spiegelman is now collaborating with other researchers with the goal of inserting the tuna version of that gene into easily farmed fish, such as carp or salmon, in order to “tunafy” them and thus ease demand for wild bluefin.
Although Spiegelman, Evans, and Tavassoli study different compounds, they have all followed what could be described as the metal-detector method of exercise-pill development: scanning thousands of chemicals in order to find one or two that convey some of the benefits of exercise. Other researchers are tackling the problem from the opposite direction—attempting to document all the biochemical reactions that exercise unleashes, which will create a sort of road map for drug development. Next year, the National Institutes of Health will embark on an ambitious five-year study to measure every major molecule changed by exercise in approximately three thousand people of both sexes and all age groups, and with a variety of preëxisting fitness levels. Maren Laughlin, who is leading the program, explained that the technology to create a molecular snapshot of the human body in motion has only become available in the past decade. “We’ve studied human metabolism for many, many years, but almost always at rest,” she said. It is as if our knowledge of how the brain works had come from observing only people who were asleep.
In Australia, a biologist named David James recently took the first step in this direction, studying muscle biopsied from four young, healthy men before and after ten minutes of flat-out cycling on an exercise bike. James and his colleagues itemized every measurable difference in protein structure between the before and after samples. They found more than a thousand changes, of which only ten per cent can be explained by current medical science. For anyone wanting to develop an exercise pill, these new data are both promising and daunting. “You know, people talk about exercise mimetics,” James said. “But what are you going to mimic?”
The red double-decker buses of London are famous around the world. Less well known is the fact that the first quantitative, systematic medical study of exercise took place aboard them. In the late nineteen-forties, a young British epidemiologist named Jerry Morris was looking through the postmortem folios of a hospital in the East End when he noticed an alarming increase in the frequency of heart attacks during the first half of the twentieth century. Others had seen the same trend but nobody had an explanation. Morris, however, suspected that the frequency of heart attack might correlate with sedentary occupations, and so he turned to the double-decker bus. “If you’ve been to London, then you know,” Bill Hayes, a writer and photographer who is at work on a history of exercise, told me. “The driver sits at the front and drives the bus, and the conductor hops on and off the bus and climbs up and down the stairs taking tickets and getting people to their seats.” Of the thousands of drivers and conductors working on London’s buses at the time, the vast majority were men, and most came from a similar social background. The only substantial difference between them, in aggregate, was their daily activity levels.
Morris spent hours on buses, monitoring how much time the drivers spent sitting (ninety per cent of their shift, on average) and counting the numbers of steps the conductors climbed each day (between five hundred and seven hundred and fifty). Then, with the help of Britain’s newly established National Health Service, he went through the busmen’s medical records. Morris was stunned by how powerfully the data bore out his initial hypothesis: the sedentary drivers were almost twice as likely as the mobile conductors to drop dead of a sudden heart attack. He followed up with what he described as an “epidemiology of uniforms”—a painstaking comparison of the waist size of trousers issued to both groups, at every age—which established that drivers were significantly bulkier around the midsection than their conductor peers. Morris later confirmed a similar correlation in postal workers, with sedentary counter clerks showing a much higher incidence of cardiovascular disease than postmen, who did their rounds on foot or by bike.
When the papers presenting these findings appeared in The Lancet, Morris’s conclusion—that exercise was medically important and that its absence resulted in death and disease—was met with surprise and even disbelief. “Puzzling,” the Aberdeen Evening Express declared, noting that Morris’s studies failed to take into account what were then generally accepted risk factors for heart attack, such as a temperamental propensity toward “nervous strain.” Mainstream medical wisdom held that heart attacks were most likely the result of high blood pressure, and that physical activity had nothing to do with either.
Up to this point, historical attitudes toward exercise had varied, according to Hayes. The Ancient Greeks were fans. Plato, a former competitive wrestler, praised the mental-health benefits of physical exertion, and Hippocrates wrote, “Eating alone will not keep a man well, he must also take exercise.” By contrast, medieval Europeans tended to regard the body as a vessel for sin, and exercise as a distraction from the more important work of improving the soul. “The spirit flourishes more strongly and more actively in an infirm and weakly body,” the twelfth-century French abbot St. Bernard of Clairvaux assured his followers. Avicenna, a Persian scientist whose view of bodily health was substantially more enlightened than that of his European contemporaries, took an intermediate view—advocating moderate exercise but warning of the dangers posed by its heating effects and its capacity to spread preëxisting impurities throughout the body.
There also seemed to be some confusion about what exercise actually was. Hayes mentioned “De Arte Gymnastica,” a 1569 treatise by an Italian nobleman named Girolamo Mercuriale, which is considered the first book on sports medicine. The forms of exercise Mercuriale discussed included being a passenger in a boat rowed by someone else. “It’s kind of sweet,” Hayes said. “He believed that because it causes movement and movement had an effect on the humors within the body, it would be a good thing.” Until the Victorian era, when sporting activity came to be regarded as a moral safeguard against dissipation, vigorous exercise was still cautioned against, particularly in the case of women. It was thought to lead to strain, fatigue, and even untimely death.
Of course, for most people, through most of human history, not moving has not been an option. The illustrated exercises in “De Arte Gymnastica” were aimed at Renaissance princelings; the feudal peasants laboring on the nobility’s vast estates could hardly avoid sustained and strenuous activity. Only since industrialization, which made physical exertion a choice rather than a necessity, have scientists begun to quantify its virtues—and, in the process, to increase the burden of guilt on those who fail to squeeze in enough of it around the constraints of their sedentary jobs.
In the sixty years following Morris’s pioneering work, the benefits of exercise have been measured in study after study. Researchers soon silenced any remaining doubts over Morris’s findings, repeatedly demonstrating that physical activity helped reduce deaths from heart disease and stroke. Subsequent studies—examining, variously, twins, the Amish, Danish workers forced to take the elevator, and Dallas students prescribed bed rest—showed that a lack of exercise was tied to the early onset of more than forty chronic diseases or conditions, from constipation and colon cancer to depression and diabetes. Today, more than a hundred thousand published papers testify to the connection between exercise and health. Barely a week goes past without a headline linking exercise to stronger bones, a reduced risk of dementia, the ability to learn new languages, and, of course, better sex. Countless institutions, including the World Health Organization and the Centers for Disease Control, recommend at least a hundred and fifty minutes of exercise a week. Such is the weight of medical evidence that, if something could be developed to safely mimic the benefits of exercise, it would likely be the most valuable pharmaceutical in the world. Yet, at the same time, the sheer range of those benefits suggests that it is unlikely that any single drug could have such wide-ranging effects.
The real problem, according to Ron Evans, lies in the term “exercise,” which is too general to be useful. “You have to be more granular about it,” he told me. He suspects that a mere handful of biochemical pathways will prove to be responsible for the majority of exercise’s benefits. Among the current field of exercise-pill competitors, Evans is the closest to the finish line. He has set up a company, Mitobridge, to take his improved version of 516 to market; this summer, it launched Phase I trials in humans.
The F.D.A. doesn’t currently recognize metabolic syndrome, let alone lack of exercise, as a disease. Anyone who wants to market an exercise pill must therefore get it approved as a treatment for a disease that does meet the F.D.A.’s criteria, in the hope that, once it is on the market, its use will spread to encompass a wider range of conditions. Evans pointed out that statins were initially approved, in the late eighties, specifically for people who had had a heart attack; three decades later, they’re routinely prescribed for tens of millions of people who have only high cholesterol. With this example in mind, Mitobridge is testing its drug as a treatment for Duchenne Muscular Dystrophy, an incurable genetic disease that affects one in five thousand males, causing their muscles to break down and leading inexorably to death at an average age of twenty-six. “The economics of getting a drug approved make Duchenne a good target,” Evans said. “It’s a disease for which there are no good drugs, and the kids who have it will all die young. That’s an easier sell to the F.D.A.”
Even if everything goes smoothly, however, 516 is multiple trials and several years away from reaching the market. And although Evans is convinced that his improved version of the drug is safe, any molecule that affects metabolic processes is necessarily interacting with a variety of other molecules throughout the body, in ways that we don’t yet understand. Nonetheless, Evans, James, and Spiegelman are all confident that legal drugs mimicking some of the effects of exercise are on their way, sometime within the next ten to fifteen years. Ali Tavassoli, the Southampton researcher, is more skeptical. “Newspapers, the media—they always get me in to be the cynical Brit on this one,” he said, laughing at the gung-ho attitude of his American colleagues. His main work lies in cancer research, and he is all too aware that dramatic changes in cell metabolism are linked to the growth of tumors. His fear is that artificially increasing the rate at which muscle cells burn energy cannot help but have long-term consequences elsewhere in the body. “Not all of them are going to be good news,” he said.
All drugs have risks: the issue is whether the possible benefits make the risks worthwhile. For someone with Duchenne, taking 516 would make perfect sense. There are a handful of other contexts where a short course of an exercise pill could be extremely useful. Astronauts, for example, routinely spend two hours a day exercising on equipment designed to mitigate muscle atrophy and bone loss caused by low gravity, but they still return to Earth after a six-month space-station stint with mild osteoporosis and significantly weakened muscles. Other people for whom an exercise pill might be a gamble worth taking include patients recovering from surgery or attached to a ventilator. Then, there are the elderly. After the age of forty, all of us, even the athletic, lose about eight per cent of our muscle mass each decade, with a further fifteen-per-cent decline between the ages of seventy and eighty. The resulting frailty can be lethal: nearly half of seniors hospitalized for a hip fracture never go home.
The cost-benefit analysis becomes murkier in the case of the estimated eighty per cent of American adults who do not get their recommended hundred and fifty minutes of exercise each week. From a public-health perspective, physical inactivity is one of the most significant problems of the twenty-first century. One recent study found that, of all the deaths in Europe in 2008, seven per cent could be attributed to inactivity—more than twice as many as were caused by obesity. “So which is better for those people?” Willson, the original developer of 516, asked me. “Being told—again—to exercise for thirty minutes a day, or taking a pill?”
One could respond with another question: Why can’t humans just be more like mice? Why do so many of us choose to skip exercise in favor of watching TV or catching up on e-mail? I talked to Theodore Garland, a biologist at the University of California, Riverside, who has studied variations in voluntary physical activity between species. He pointed to theories that much of human development has been motivated by the imperative to conserve energy, and suggested that, over evolutionary time, different species tend to develop neurochemical reward systems that make movement more appealing, or less, based on their survival needs. Instead of designing a pill to replace exercise in humans, Garland favors a different pharmaceutical solution. “Personally, I’ve been more interested in the possibility of drugs that would make us more motivated to exercise,” he said.
A taste for exercise, I gradually realized, was something that all the pill researchers had in common. Spiegelman follows a strict regimen of kickboxing, running, and lifting weights. Tavassoli is a surfer and rock climber; Evans and James are cyclists. Willson is a triathlete, who recently completed his eleventh Half Ironman. “I train because that’s part of the way I live,” he said “It’s part of my personality. I love that discipline of having to exercise regularly.” Taking a pill, he said, would feel like cheating.
“In a lot of people’s eyes, the development of an exercise pill is a bad thing,” Evans said. “They say we’re trying to undermine exercise in America.” The more accurate charge is that Evans’s research may redefine exercise—for better and for worse—in much the same way that other fields of metabolic research have gradually redefined food. During the nineteenth and twentieth centuries, as scientists discovered vitamins, minerals, and phytochemicals, “food” was transformed into “nutrients.” That conceptual shift paved the way for dietary pyramids, labelling laws, the rise of so-called superfoods, and even wholesale food replacements such as Soylent. In the coming years, as research provides us with new ways of understanding and quantifying physical activity, our relationship with exercise will surely change. A morning jog will be reclassified as a good source of beneficial chemicals; sports may be redesigned to optimize their molecular outcomes. A scientific understanding of the parts may well come at the expense of appreciating the immeasurable whole.
Although 516 has not been approved as a drug, plenty of people are taking it. Once the structure of a new compound has been published, chemical-supply laboratories are free to synthesize it for sale, “for research purposes only.” 516 is easy and relatively cheap to make, and it is readily available online. The earliest adopters were élite athletes looking for an edge. The World Anti-Doping Agency added 516 to its list of prohibited substances in 2009, and testing for it is now routine. Since then, at least six professional cyclists have been suspended after being caught taking the drug. More recently, 516 has become popular among the kind of men—and they are almost all men—who frequent messages boards with names like “Think Steroids,” “Swol HQ,” and “Juiced Muscle.” All across this peculiar corner of the Internet, guys whose avatars typically feature headless selfies in body-building poses are dosing themselves with 516 and sharing their reactions—usually anonymously, using such screen names as Macho313, nofatchix, and Big Beef.
I joined a couple of forums to ask these men about their experiences using 516. Most were unwilling to talk, let alone be identified, but eventually a member of the MuscleChemistry.com forum agreed to correspond with me, on the condition that I refer to him only by his online handle, Iron Julius. He told me that he lived in a small town in the South and was a father of three. He began taking the drug sometime in 2012, having heard about it on another board. “It wasn’t yet very popular but the little info there was made it sound like something I might like,” he wrote. Iron Julius’s wife had been nagging him to start running with her, but his bulk made him hesitate. Still, he signed up for a five-kilometre race, mostly to support her. He started taking 516 five days before the race. “I was just planning to walk a good bit,” he wrote. “But I actually ran with her the entire time. It blew my mind how good I felt.”
Iron Julius still takes 516, although lately he has noticed a decrease in the drug’s quality. “I’m a volunteer firefighter so stamina at times is very important,” he explained. “If you research, many police and firefighters are on some form of performance-enhancing substance as the jobs are sometimes physically demanding.” Iron Julius told me that around a third of the people he sees at the gym are using 516, without any side effects that he’s heard about. When I asked whether he would recommend it, his response was, “Hell yeah man, try it. It don’t mess with hormones and it increases performance.”
So I ordered some. A few weeks later, a twenty-milligram bottle of 516 arrived, taped into a sealed Tyvek envelope. It was about the size of the complimentary shampoo you get in hotels and contained a cloudy white liquid with a faint smell of nail-polish remover. A label instructed me to “see accompanying information”—there wasn’t any—for dosage instructions. Below that were two contradictory phrases: “Rx only” and “Not for human consumption.”
I called Tim Willson, the drug’s designer, to ask whether he would take it. “No,” he said, without hesitation. I contacted the other researchers and found that none of them had ever taken an exercise pill, in any form. I put the bottle to one side of my desk while I pondered not only the advisability of ingesting a likely carcinogen but also the fact that I actually enjoy exercise and get plenty of it. Since then, the bottle has sat on my desk, undisturbed. During the past month, its contents appear to have developed a faint, yellowish tinge. ♦