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August 4, 2008, Howard Hughes Medical Institute — Trying to reap the health benefits of exercise? Forget treadmills and spin classes, researchers at the Salk Institute for Biological Studies may have found a way around the sweat and pain. They identified two signaling pathways that are activated in response to exercise and converge to dramatically increase endurance.

The team of scientists, led by Howard Hughes Medical Investigator Ronald M. Evans, Ph.D., a professor in the Salk Institute’s Gene Expression Laboratory report in the July 31 advance online edition of the journal Cell that simultaneously triggering both pathways with oral drugs turned laboratory mice into long-distance runners and conferred many of exercise’s other benefits.

In addition to their allure for endurance athletes, drugs that mimic the effects of exercise have therapeutic potential in treating certain muscle diseases, such as wasting and frailty, hospital patients unable to exercise, veterans and others with disabilities as well as obesity and a slew of associated metabolic disorders where exercise is known to be beneficial.

Previous work with genetically engineered mice in the Evans lab had revealed that permanently activating a genetic switch known as PPAR delta turned mice into indefatigable marathon runners. In addition to their super-endurance, the altered mice were resistant to weight gain, even when fed a high-fat diet that caused obesity in ordinary mice. On top of their lean and mean physique, their response to insulin improved, lowering levels of circulating glucose.

“We wanted to know whether a drug specific for PPAR delta would have the same beneficial effects,” says Evans. “Genetic engineering in humans, commonly known as gene doping when mentioned in connection with athletic performance, is certainly feasible but very impractical.”

An investigational drug, identified only as GW1516 (and not commercially available), fit the bill. When postdoctoral researcher and lead author Vihang A. Narkar, Ph.D., fed the substance to laboratory mice over a period of four weeks, the researchers were in for a surprise.

“We got the expected benefits in lowering fatty acids and blood glucose levels but no effect, absolutely none, on exercise performance,” says Narkar. Undeterred, he put mice treated with GW1516 on a regular exercise regimen and every day had them run up to 50 minutes on a treadmill.

Now the exact same drug that had shown no effect in sedentary animals improved endurance by 77 percent over exercise alone and increased the portion of “non-fatiguing” or “slow twitch” muscle fibers by 38 percent. The result, while very dramatic, gave rise to a vexing question: Why is exercise so important?

First and foremost, exercise depletes muscles’ energy store, a chemical known as ATP. In times of high demand, ATP releases all its energy and forms AMP. Rising AMP levels alert AMPK, a metabolic master regulator, which acts like a gas gauge that the cell is running on empty and revs up the production of ATP. “That led us to consider whether AMPK activation was the critical trigger that allowed PPAR delta to work,” recalls Narkar.

Usually, AMPK can be found in the cytoplasm, the compartment that surrounds the nucleus, but the Salk researchers’ experiment revealed that some exercise-activated AMPK molecules slip into the nucleus. There they physically interact with PPAR delta and increase its ability to turn on the genetic network that increases endurance.

“It essentially puts a turbo charge on PPAR delta, which explains why exercise is so important,” says Evans.

Then came the ultimate couch potato experiment. The researchers fed untrained mice AICAR, a synthetic AMP analog that directly activates AMPK. After only four weeks and without any prior training, these mice got up and ran 44 percent longer than untreated, untrained mice. “That’s as much improvement as we get with regular exercise,” says Narkar.

“Exercise in a pill” might sound tempting to couch potatoes and Olympic contenders alike, but the dreams of the latter might be cut short. Evans developed a test that can readily detect GW1516 and its metabolites as well as AICAR in blood and urine and is already working with officials at the World Anti-Doping Association, who are racing to have a test in place in time for this year’s Summer Olympics.

By Jeremy Laurance, August 7, 2008, Independent UK – A pill which may “lock in” the benefits of dieting, allowing dieters to return to normal eating without putting on weight, has been discovered by scientists.

The inventors also claim that the pill, a dietary supplement called alpha-lipoic acid and widely sold in health food shops, also slows ageing, which is a known effect of low-calorie diets.

But the finding has triggered a dispute between two of the scientists who carried out the research, conducted in rats, over whether it can be applied to humans.

Malcolm Goyns, director of Immorgene Concepts, a scientific research company in Stockton-on-Tees, who led the research, said he was sufficiently convinced to follow the approach himself.

Evidence from the tropical Okinawan islands in Japan’s extreme south-west, which has the highest proportion of centenarians in the world, demonstrated the life-prolonging effects of calorie restriction, he said.

Their traditional diet is high in vegetables and fish and low in fat, but they also have a cultural habit known as hara hachi bu – or “eat until you are 80 per cent full”.

This is based on the notion that it takes the stomach’s stretch receptors 20 minutes to tell the brain how full it really is, preventing overeating – and Okinawans are among the leanest and fittest people in Japan as a result.

Dr Goyns said: “While calorie restriction diets are followed as a matter of course in communities like Okinawa, the diet can be difficult to follow for most people. Our discovery indicates that by following a calorie restriction diet for six months and then taking alpha-lipoic acid while eating normally, the same life extension effects will be experienced.”

He added: “Simply adding the supplement to the diet has no effect. It seems that alpha-lipoic acid fools the body into behaving as if it was still on whatever diet it was following before the supplement was added. We found there was an anti-obesity effect as well. Although weight does rise when you come off the restricted diet, if you take alpha-lipoic acid, even though you are eating normally again you still have a reduced weight.”

The study, published in Mechanisms of Ageing and Development, was carried out by Dr Goyns with colleagues from the University of Liverpool. The researchers investigated the effect of alpha-lipoic acid when given to rats on normal and low calorie diets.

Experiments have shown that curbing the amount of food rats eat can extend their lives by 25 to 40 per cent. However, anti-ageing benefits are lost when the rats return to a normal diet. In the study, researchers found the benefits of the low calorie diet were extended by giving the rats the supplement when they returned to normal eating.

Brian Merry of the School of Biological Sciences at the University of Liverpool, who carried out the study, said: “If you put the animals on to a restricted diet they would normally go on to an extended survival trajectory. When they were switched to a normal diet, this compound seemed to lock them into the benefits of their pre-existing diet.”

“It is an unusual and interesting finding and it needs repeating in further research. That was as far as I was prepared to go, but Malcolm [Goyns] wanted to apply it to humans. I said I didn’t agree with his interpretation and we had to wait for further studies.”

He added: “People have been buying this stuff and taking it for years as a dietary supplement. I don’t think anyone knows what its effect is. There have only been two studies in rats and mice [before our study].

“It is also sometimes used in stroke patients to treat re-perfusion injury. What happens as the blood supply is restored after a stroke is oxidative damage to the cells. Alpha-lipoic acid is an antioxidant and can help reduce the damage. It is also used to treat diabetics and oxidative damage to the liver in people who have eaten poisoned mushrooms.”

Alpha-lipoic acid is sold as an anti-oxidant supplement and is also used in the treatment of certain conditions including stroke and liver damage.

A recent ruling by a Federal judge mandated that an experimental drug treatment should be given despite objections from the drug manufacturer. We would like our reader’s opinions on this ruling. Let us know if we can use your name, affiliations or you want to reply anonymously.

According to a federal judge in Newark, NJ, a 16-year-old patient, terminally ill with a rare form of muscular dystrophy, should be allowed to use an experimental drug treatment despite objections from the drug’s developer. The case, which touches on major ethical issues, is being closely watched by the pharmaceutical industry. Under the ruling, the patient would be able to start taking a drug intended to treat Duchene muscular dystrophy, a rare and fatal disease that strikes boys and young men. The developer, PTC Therapeutics of South Plainfield, N.J., contends that the patient does not meet the criteria to be a part of the drug’s clinical trial, and is planning to appeal. The FDA must also approve the patient’s application to use the drug. According to the NY Times, it was not immediately clear what implications the ruling would have for other patients seeking access to clinical trials of experimental treatments since drug developers tightly enforce parameters concerning who can participate in these trials. Those who do not meet the guidelines are excluded, often because their cases might alter the results, even if the patients consider the trial a final hope in the face of a devastating illness. In the ruling, Judge William J. Martini, of the United States District Court in Newark, said that Jacob should be allowed to take the experimental drug even though he does not meet the criteria for eligibility. The CEO of PTC Therapeutics, Stuart W. Peltz, said he was concerned the decision could encourage patients to sue to gain access to clinical trials. He stated that “To have the courts decide who gets the drug, it’s something we should all be concerned about and that it’s not the way clinical trials should be thought of, in our opinion.” According to the patient’s family, the lawsuit was not intended as a challenge to widespread practices at drug companies, rather, it’s circumstances were unique, complicated by allegations of deception by the patient’s mother. According to the lawsuit, the mother said that officials at PTC Therapeutics led her to believe that her son would be allowed to take part in a clinical trial, only to ultimately say his disease had advanced to a point where the patient no longer met the proper criteria for the study. She said she helped the company obtain federal grants to research the disease, and that the company discouraged her from enrolling Jacob in an earlier study with the understanding that he would be allowed to take the drug in a later trial. PTC Therapeutics has denied those claims. While drug developers occasionally allow exceptions for patients who do not meet a study’s criteria, some companies fear overuse of this process could discourage patients from volunteering for trials, where many participants receive placebo.