Muscle DNA Damage Initiates Physical Aging

Researchers found that cumulative damage to muscle DNA and reduction of the DNA contained in an organelle called the mitochondria are the cause. The findings appear in the online version of the April 12 edition of the Proceedings of the National Academy of Sciences (http://www.pnas.org/cgi/reprint/0501559102v1).

"Nobody believes you can reverse the aging process completely -- but we can improve the quality of life," says Mayo Clinic endocrinologist and lead investigator K. Sreekumaran Nair, M.D. "What we've shown here is an important first step to understanding aging in a specific organ in humans," explains Dr. Nair.

Mitochondrial DNA is critical for the production of a form of chemical energy known as ATP (adenosine triphosphate), which is needed by all cells for all bodily functions. When ATP is reduced, so is muscle endurance -- and thus begins the slide toward age-related muscle weakness, loss of muscle mass and onset of many diseases of old age.

Researchers examined muscle samples from 148 healthy men and women ages 18 to 87. They discovered that older people have significantly higher damage to DNA, as well as reduced mitochondrial DNA abundance. As a result of the damage and reduced mitochondrial DNA levels, both gene expression and mitochondrial protein content diminish with age -- thus explaining the reduced ATP production and loss of muscle endurance the investigators found.

Significance of the Mayo Clinic Research

Despite the growing concern over age-related conditions as more people live longer, no one knew where the process of physical decline began. As a result, scientists lacked a way of designing therapies to intervene in the process to improve quality of life. The new findings offer a focal point for development of preventative therapies.

"In humans, aging and changes in the mitochondrial DNA occur in parallel," explains Dr. Nair. "This suggests that the mitochondrial changes contribute to the aging process -- and will now guide us in our research to focus on these changes to reverse or prevent them perhaps. Previous studies in our laboratory and others have shown that exercise enhances mitochondrial functions. What remains to be determined: Does exercise prevent the decay of muscle mitochondria that occurs with age? That is the focus of our continued research."

Background Biology

These findings build on previous research that shows loss of muscle fiber and reduced ability to produce many proteins necessary for muscle functions and endurance lead to reduced muscle mass. These changes in muscle mass tend to lead to a lifestyle marked by reduced physical activities -- which further changes body composition by replacing lean tissue with accumulating fat. Common results from these changes in aging muscles are increased incidence of diabetes and related disorders, such as hypertension and the onset of heart disease. In addition, reduced muscle mass and strength among the elderly are the basis of many disabilities that result in fractures.

Scientists have known that lowered muscle function contributes to the aging process because it signals the start of the deteriorating condition sarcopenia (muscle wasting disease). Onset of sarcopenia, in turn, starts a cycle of decline in old age including inactivity, loss of muscle mass and sedentary lifestyle -- all of which can contribute to the onset of many diseases of aging such as heart disease and diabetes.

Collaboration and Support

In addition to Dr. Nair, other Mayo Clinic research team members are: Kevin Short, Ph.D.; Maureen Bigelow; Jane Kahl; Ravinder Singh, Ph.D.; Jill Coenen-Schimke; and Sreekumar Raghavakaimal, Ph.D. Their work was supported by a National Institute of Aging Grant and was conducted by Mayo Clinic General Clinical Research Center, which is supported by the National Institutes of Health.