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NOVA ScienceNOW

Marathon Mouse: Expert Q&A

  • Posted 07.21.09
  • NOVA scienceNOW

On July 21, 2009, molecular biologists Ron Evans and Vihang Narkar answered questions about their research into "exercise pills," the science of metabolism, performance-enhancing drugs, and more. 

Ron Evans

Ron Evans

Ron Evans is a Professor in the Gene Expression Laboratory and the March of Dimes Chair in Developmental and Molecular Biology at the Salk Institute for Biological Studies in La Jolla, California. Full Bio

Photo credit: Courtesy of the Salk Institute for Biological Studies

Vihang Narkar

Vihang Narkar

Vihang Narkar has been a post-doctoral research fellow in Ron Evans' Gene Expression Laboratory at the Salk Institute since 2004.  Full Bio

Photo credit: Courtesy of the Salk Institute for Biological Studies

Ron Evans

Ron Evans is a Professor in the Gene Expression Laboratory and the March of Dimes Chair in Developmental and Molecular Biology at the Salk Institute for Biological Studies in La Jolla, California. His lab studies the activity of a family of genes that control the storage and burning of fat and appear to play a critical role in what distinguishes the proverbial couch potato from an endurance athlete. The research holds potential implications for improving health and treating diseases, including obesity, diabetes, and heart disease. Evans earned his Ph.D. in microbiology at UCLA. Among many honors, Evans has received the Albert Lasker Basic Medical Research Award and the Harvey Prize in Human Health, and he has served as a Howard Hughes Medical Institute Investigator since 1985. Outside the lab, Evans is a fan of the La Jolla 500, and he has even taken a turn driving Formula One cars himself.

Vihang Narkar

Vihang Narkar has been a post-doctoral research fellow in Ron Evans' Gene Expression Laboratory at the Salk Institute since 2004. He was the lead author of a 2008 paper published in the journal Cell and quickly picked up in the popular press, reporting on his research with pharmacological agents that appear to serve as exercise "mimetics," or, as the lay press reported, "exercise in a pill." Narkar earned his B.S. at the University of Bombay, India and his Ph.D. in pharmacology at the University of Houston.

Q: When will this research result in something we can purchase? Randy Still, Birmingham, Alabama

Q: So when do you anticipate seeing GW1516 and AICAR available for prescription? Would this be available for elderly people who have had heart problems? Anonymous

Q: I just watched the show on the drug, AICAR. Then I looked it up on the Internet and found a company supposedly selling it at 99% pure. Is this drug actually on the market? Have any tests been done on humans? And if so, does it work? Joseph Orr, N. Hollywood, California

Ron Evans and Vihang Narkar: Currently, neither of these drugs are approved or tested for use in humans for weight control or exercise-related benefits.

Q: Are there any natural foods that can give the same affects as GW1516 and AICAR? Jeff Morrow, Charlotte, North Carolina

Evans and Narkar: Resveratrol, derived from Japanese knotweed, grapes or a component of red wine, is proposed to have similar effects as the above synthetic drugs.

Q: What can endurance athletes, both pros/elites and amateurs, learn from your research about improved, natural, and safe ways to increase mitochondria and fat-metabolism efficiency? Adam Feerst, Denver, Colorado

Evans and Narkar: While some aspects of exercise seem to be mimicked by drugs, the use of these drugs should be restricted to aliments or conditions in which exercise or physical activity is impeded. For example, we do not yet know the benefits, if any, in highly trained "fit" mice. Thus, professional or amateur athletes should continue to reap the benefits of exercise.

Q: Once there is a cure for paralysis, do you believe these drugs could help rejuvenate the extreme muscle atrophy that the lack of use creates? Christopher Janney, Hollywood, California

Q: I have been paralyzed below my second cervical vertebrae for 23 years, and I require a ventilator for breathing. I gain weight easily, and currently, consume approximately 800 calories per day to lose, sometimes, one pound per week. Could your drug help me? Anonymous

Evans and Narkar: The drugs, if approved, may have potential benefits in preventing weight loss in people who are unable to exercise. The potential of these drugs to slow or reverse muscle atrophy has not yet been tested.

Q: Was there a change/improvement in thyroid function in relation to body composition? In other words, did the drugs and/or exercise signal the thyroid, contributing to the outcome? (IF a mouse even HAS a thyroid!) Thanks. Grant Shatek, Minneapolis, Minnesota

Evans and Narkar: Great question! We haven't tested the effect on thyroid function. And yes, mice have thyroid.

Q: I'd like to know if there is a possibility that a drug could help MS patients who are limited in their exercise needs and abilities by the progress of their disease. The vicious circle of MS symptoms cause lack of energy, general fatigue, and depression—which by their nature discourage patients from even simple exercise. The decreased mobility adds to the problem by making it almost impossible to do even simple exercises. Any help here? Thank you for your interest. Jeanne Elmes, Morgantown, West Virginia

Evans and Narkar: The hope in the future is that the drugs will be useful in conditions such as MS. In terms of muscle enhancement, the drugs have only yet been tested in rodents.

Q: How can I become a test subject? Catherine, Morro Bay, California

Q: Hello! Are clinical trials being conducted yet? I am very interested in taking part in them. After a full hysterectomy in my late 20's due to an infection at the birth of my third child, my once runner's body of 105 lbs. skyrocketed to now 200 lbs. This was eight years ago, and I have tried everything to lose the weight. We eat organic, healthy, and mostly raw foods. Exercise is now extremely hard due to the weight it puts on my knees and ankles. I have been checked for thyroid conditions, and I am clear. Please consider using a mom, wife, educator such as myself for this. I am so intrigued and hopeful for what the future could mean for a former runner like myself who dreams of the day I will be running again!

Thank you. Julie Johnson, Westfield, Indiana

Evans and Narkar:These drugs are currently not in clinical trial for exercise mimetic effects.

Q: My mom and I like to go for walks, but she doesn't walk very fast because she has really bad arthritis. Do you think the exercise pills could help her be in better shape? Rachel, Shelley, Idaho

Evans and Narkar: At least one drug (GW1516) in combination with mild exercise worked wonders in mice. It remains to be seen if these drugs have similar effects in humans.

Q: Would these types of drugs pose greater problems in the ethics of sports, specifically "cheating" with drugs to gain an advantage over competitors? And if so, is there research into any signs to test for when screening? UC Santa Cruz - Sophmore, Santa Cruz, California

Q: Drs. Evans and Narkar,
The NOVA scienceNOW piece on your research left open the possibility that human athletes may attempt to use AICAR and/or GW1516 to attempt to get a competitive edge. Have you done any experiments in mice to determine to what extent the drugs are complementary to normal exercise? If you have, what results are you willing to share? Thomas Traub, Fairfax, Virginia

Evans and Narkar: One serious concern for any performance-enhancing drug is the potential abuse of these drugs by athletes. Keeping this in mind, we have developed assays to detect the circulating levels of these compounds in the blood. The assay has been provided to the World Anti-Doping Association (WADA) and both AICAR and GW1516 have been placed on the list of banned substances.

Q: If this works at DNA levels, does it affect the turning on of some genes or the turning off? Can it repair damaged genes that no longer aid in burning calories? How would it affect food intake and digestion? What about the energy level? If you are always tired, will this work for people with illnesses that render them exhausted all the time? Does it aid in not needing more sleep? Can it help more than just lazy people? Wibs, Richmond, Virginia

Evans and Narkar: The drugs have a combined effect of turning on and off genes. They do not necessarily repair damage genes, but rather increase the expression of genes that are involved in regulating calorie burning and muscle repair. We have not tested the effect of the drugs on sleep, though they appear not to affect sleep in mice.

Q: Dear Dr. Evans:
Can you demonstrate the changes in the muscle morphology using non-invasive scanning technologies, and what would they be? Thank you! Bill Riley, Northern Virginia Community College, Alexandria, Virginia

Evans and Narkar: We are not aware of such technology. The changes need to be demonstrated by traditional muscle biopsies. However, scanners for visualizing lean body mass as well as muscle blood flow (Doppler imagers) are available.

Q: How might this pill help people with Mitochondrial diseases, like Mitochondrial Myopathy? Anonymous

Q: Is there any possibility that this research can be used to treat ALS (Lou Gehrig's Disease)? Gayalyn Wojtowicz, Clifton Park, New York

Q: Since your drug improved production of mitochondria in muscle and the energy production of mitochondria, do you think it could help those with mitochondrial diseases and those with muscular dystrophy? Anisa, Chattanooga, Tennessee

Evans and Narkar: As a first step, we have only tested the effects of the drugs in healthy mice. The good news is that they work. Future research will be directed towards specific diseases (e.g. muscle wasting, muscle dystrophy) where muscle function or exercise capacity is compromised, keeping in mind the beneficial effects of the drugs on promoting mitochondrial function and stimulating fat metabolism.

Q: My daughter has LCHADD, the inability to metabolize long-chain fatty acids, along with hypotonia. Her diet is restricted to 15 grams of fats per day, most (we try) as medium-chain. We need information on how to help her and other patients like her build muscle.

Has your research been linked to any other ongoing research into fatty acid oxidation disorders (FODs) such as LCHADD, MCAD, VLCAD or the mitochondrial disorders that often accompany them? Expanded newborn screening will be identifying infants with these FODs, and many more patients will be needing care in the future. There is an organized group of FOD/mitochondrial patients who will be very interested in the response to this query.

Many thanks,
Janet (mother of a 17-year-old with LCHAD) Janet

Evans and Narkar: Both AICAR and GW1516 target fat-metabolizing pathways and have anti-diabetic effects, and GW1516 has excellent cholesterol-lowering effects. Therefore, these pathways can be potentially targeted in a variety of metabolic disorders.

Q: When did the two of you become involved in this research? A.V. High, Lancaster, California

Evans and Narkar: Dr. Evans has been involved in studying the biology of nuclear hormone receptors for the past 30 years! We became interested in identifying drugs that mimic exercise for the last five years. Our early studies of the genes that control endurance began nearly 10 years ago!

Q: What would be the byproducts of the excess mitochondrial activity when the energy is produced in reaction to the drug and not actually consumed by true physical activity? Is there a difference? Mandy O'Brien, Kernersville, North Carolina

Evans and Narkar: This is a good question. We believe a significant amount of the energy produced in response to AICAR helps to build-up and maintain new mitochondria. Some additional amounts of energy could be lost as heat.

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