This article surveys some of the research groups working on exercise mimetic drugs, potential ways to artificially induce some of the beneficial metabolic reaction to exercise. This proceeds in much the same way as the past few decades of calorie restriction research that also aims for pharmaceutical methods of inducing metabolic change, which is to say that it is slow going, very expensive, there are ever a slate of potential candidate drugs, but none result in practical outcomes for clinical medicine. The main output is increased knowledge of narrow slices of the operation of metabolism, rather than drug candidates on their way to the clinic.
The operation of metabolism is fantastically complex and still poorly understood at the detailed level needed to adjust it safely and successfully. Even though both calorie restriction and exercise are highly reliable ways to beneficially adjust the operation of metabolism, that doesn't mean it is easy to reverse engineer the relevant mechanisms and points of intervention. Tinkering with metabolism has so far proven to be an expensive, low-yield line of research. That will change at some point in the future, but one could have said that at any time since the turn of the century, and been wrong about significant progress being imminent.
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.
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. 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.
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.
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. 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.
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 an improved version of 516 to market; this summer, it launched Phase I trials in humans.