Not everyone can exercise. People with muscle-wasting diseases and movement disorders, the frail, the very obese and post-surgical patients are among those who face a significant challenge when it comes to working out.
This can be frustrating, considering the well-established benefits of exercise.
But what if a drug could stimulate the body into producing some of the same effects of exercise - more endurance and weight control, for example - without the need to run a single step?
Such a pill may be on the way. Several scientists are testing compounds that apparently can do this - and people wouldn't even have to move at all to benefit.
"Our goal is to understand these circuits," says Ronald Evans, director of the gene expression laboratory at the Salk Institute for Biological Studies in La Jolla, California.
"We are taking this concept and trying to develop a drug that can help us game the system that is naturally activated during exercise."
Salk scientists have been working since 2007 on a chemical compound, known as 516, that mimics the effects produced by exercise by triggering a specific genetic circuit, "a back door into the exercise genetic network," Evans says.
The researchers built upon earlier work that identified a gene mechanism that encourages the muscles to burn fat, rather than carbohydrates, much as highly trained elite athletes do.
"There are many reasons why people cannot run or walk or exercise," Evans says. "If you can bring them a small molecule that can convey the benefits of training, you can really help a lot of people."
Several other scientists are studying compounds that work differently from 516, but with the same aim: to give the benefits of exercise to people who aren't able to do it.
Ali Tavassoli, a professor of chemical biology at Britain's University of Southampton, has discovered a drug known as compound 14 that works "by fooling cells into thinking they have run out of energy," Tavassoli says.
It does this through a series of molecular actions that spur cells into metabolizing sugar, which produces energy, he says.
(Harvard cell biologist Bruce Spiegelman, who is working on an approach using exercise hormones, declined an interview, saying it wouldn't be "wise" when "this area has been hyped so much.")
Any such drug would require licensing by the Food and Drug Administration, yet the FDA doesn't recognize "the inability to exercise" as an illness in need of a drug.
So Evans has targeted 516 for young people with Duchenne muscular dystrophy, an approach that he believes offers the best chance for FDA approval.
"This [disease] afflicts kids who can't exercise and ultimately die of muscle wasting, often at a relatively early age, at 15 or 16," Evans says. "It's a disease with a large unmet medical need."
But the drug, now undergoing a small human safety study, has "a potentially wide application," he says, including for amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease, and for "people in wheelchairs."
He says he also thinks it could be a lifesaver for those rare individuals who develop acute kidney injury, or AKI, a potentially fatal side effect of cardio-bypass surgery that results in often irreversible organ damage.
"The organ or tissue changes its metabolic properties and begins to burn sugar, and because it happens quickly, it's very hard to stop," Evans says.
"Our drug helps to draw the tissue back to a more healthy state, returning it from a chronic inflammatory damaged state. It soaks up sugar. If you do this carefully and quickly, you can override the damage response."
Because Tavassoli's compound breaks down sugar, he says he sees it as a potential treatment for diabetes or metabolic syndrome, a cluster of conditions that include obesity, hypertension, high blood sugar, high triglycerides and elevated LDL, the "bad" cholesterol.
"The most startling results have been the effect of the molecule on glucose tolerance and body weight in a mouse model of diet-induced obesity," he says.
"It improves glucose tolerance and reduces body mass."
Compound 14 has not yet been tested in humans. "While our results are promising, we are quite a way from anything going into the clinic," Tavassoli says.
Any of these drugs would have the potential for abuse. Amateur athletes might want them to get faster or stronger. Elite athletes might seek them out to cheat the system.
Even the sedentary might look for an easy way to "exercise" without having to really do it. The experimental 516 already is banned by the World Anti-Doping Agency, according to Evans, and "I'm sure any [future] version of it will be, too."
Evans acknowledges that once a drug is licensed, "people who aren't sick will want it," he says.
"Everyone knows that whatever exercise they get probably isn't enough. But we are not developing a drug like this to make someone run faster."
Tavassoli agrees. "Unfortunately, as with all other pharmaceuticals, there is no way to prevent abuse, but the potential benefit to millions of people suffering from disease outweighs any concern about abuse by athletes," he says.
Evans - who hikes and plays tennis - has never taken 516. "I like exercising, and that's good enough for me," he says, adding: "People are designed to move."
"But if they can't, it's not healthy to be sedentary. That's why we are developing this drug. We are trying to take science out of the laboratory and bring it into the clinic in a way that can change people's lives. If we can do that, it would be a game-changer."
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