Promising New Research Sheds Light On Human Muscle Aging

In findings reported in the Sept. 30 issue of the journal EMBO Molecular Medicine¹, researchers at the University of California, Berkeley, have identified critical biochemical pathways linked to the aging of human muscle. They were able to manipulate these pathways and restore the ability of aging human muscle to repair and rebuild itself.

Previous research revealed that molecular signals from surrounding muscle tissue governs the ability of adult stem cells to repair and replace damaged tissue. The signals change with age in ways that inhibit tissue repair. The earlier research also showed that the regenerative function in old stem cells can be revived by sending them the correct biochemical signals, in effect, reversing the aging of the muscles. However, the earlier studies used laboratory mice that are bred to have identical genes and are raised in similar environments. They typically have a lifespan of around two years, versus the average seventy to eighty years that humans live. The new research confirms that the same mechanisms and effects occur in humans.

The UC Berkeley researchers compared samples of muscle tissue from nearly 30 healthy young (aged 21 to 24) and senior (aged 68 to 74) men who participated in an exercise physiology study. The researchers conducted the following sequence of actions:

1. Muscle biopsies were taken from the quadriceps of all the subjects at the beginning of the study.
2. The leg from which the muscle tissue was taken was then immobilized in a cast for two weeks to simulate muscle atrophy.
3. After the cast was removed, the study participants exercised with weights to regain muscle mass in their legs.
4. Two additional samples of muscle tissue were taken at three days and four weeks after cast removal.
5. The before and after muscle tissue samples were then analyzed and compared at UC Berkeley. They determined the levels of the adult stem cells that are responsible for muscle repair and regeneration.

The researchers found that, before the legs were immobilized, young muscle had double the number of adult stem cells found in the same volume of old tissue. That difference increased to a factor of four during the exercise phase, in which the old muscle stem cells remained inactive. The researchers also found that old muscle showed signs of inflammatory response and scar formation both during immobility and four weeks after removing the cast.

Morgan Carlson, a UC Berkeley post-doctoral scholar and one of the authors² said – “Two weeks of immobilization only mildly affected young muscle, in terms of tissue maintenance and functionality, whereas old muscle began to atrophy and manifest signs of rapid tissue deterioration. The old muscle also didn’t recover as well with exercise. This emphasizes the importance of older populations staying active because the evidence is that, for their muscle, long periods of disuse may irrevocably worsen the stem cells’ regenerative environment.” The authors also warned that, in the elderly, too rigorous an exercise program after immobility may also cause replacement of functional muscle by scarring and inflammation. “It’s like a Catch-22,” said Michael Conboy, another author of the study.

The researchers also looked at the response of the human muscle to biochemical signals. Previous studies (on mice) found that adult muscle stem cells have a receptor called Notch, which triggers growth when activated. They also have a receptor for the protein TGF-beta. If the receptors become overloaded they set off a chain reaction that eventually inhibits a cell’s ability to divide. As the body ages, the Notch progressively declines and the levels of TGF-beta increase. The stem cells gradually lose their ability to rebuild the body.

The new study revealed that the same pathways are at play in human muscle. It discovered that mitogen-activated protein kinase (MAPK) was an important positive regulator of Notch activity. It is essential for human muscle repair, but it is rendered inactive in old tissue. MAPK is known to be an important enzyme for organ formation in such diverse species as nematodes (microscopic roundworms), fruit flies and mice. The MAPK levels are low in old human muscle, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly.

Experimentally inhibiting MAPK prevents young human muscle from regenerating. Conversely, when old human muscle was cultured in a solution where activation of MAPK had been forced, the regenerative ability of the old muscle was significantly enhanced. “The fact that this MAPK pathway has been conserved throughout evolution, from worms to flies to humans, shows that it is important,” said Conboy. “Now we know that it plays a key role in regulation and aging of human tissue regeneration. In practical terms, we now know that to enhance regeneration of old human muscle and restore tissue health, we can either target the MAPK or the Notch pathways. The ultimate goal, of course, is to move this research toward clinical trials.”

As the researchers noted, it’s important not to exercise too vigorously after a muscle injury. It’s also important to exercise regularly to help prevent muscle degeneration. Please take a look at the Physical Therapy Aids in the Silver Buzz cafe Store. If you’re a new reader of Silver Buzz Cafe, you may also be interested in the series of articles on the effect of aging on the human senses that started on July 20, 2009. You can find all of them, covering hearing, smell, taste, touch and vision, by clicking the “Aging” tag in the tag cloud diagram in the left hand panel of this page.

 ¹ EMBO Molecular Medicine, a peer-reviewed, scientific publication of the European Molecular Biology Organization.
 ¹ The National Institutes of Health, the California Institute of Regenerative Medicine, the Danish Medical Research Council and the Glenn Foundation for Medical Research helped support this research. Other co-authors of the research paper include: Abigail Mackey at the University of Copenhagen in Denmark; Per Aagaard at the University of Southern Denmark; Dr. Michael Kjaer at the Institute of Sports Medicine and Centre of Healthy Aging at the University of Copenhagen in Denmark; and Dr. Charlotte Suetta, a post-doctoral researcher in Kjaer’s lab,