Manipulating stem cells in old muscle can restore youth to aging tissue, according to research from the University of California, Berkeley. Scientists altered the activity of a molecular pathway to make stem cells in older tissue produce new muscle fibers at levels comparable to young stem cells. They say that their findings may one day lead to novel therapies for age-related diseases such as Alzheimer’s and Parkinson’s, as well as possibly to the reversal of the atrophying effect of aging.
“When we exert ourselves, like going to the gym or running after the bus, we always damage muscles which are being replaced over time [by] muscle stem cells,” says Irina Conboy, assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center. “But when we get older, cell death is faster than cell replacement.”
Muscle wasting–loss of muscle mass–occurs both during aging and in a number of diseases, such as cancer and muscular dystrophy. Because muscle loss often correlates with poor health outcomes, pharmaceutical companies have been striving to find new treatments that boost muscle mass without the harmful side effects of anabolic steroids.
In previous research, Conboy’s team found that old stem cells, placed in culture with young blood and muscle tissue, were able to churn out new cells at a speedier rate. Conversely, young stem cells exposed to old tissue grew prematurely old, significantly scaling back new-cell production. Conboy reasoned that stem cells must receive different chemical cues in youth versus in old age, and identifying and manipulating those cues may successfully restore youth to old muscle.
In their current study, published in the online edition of the journal Nature, Conboy and her team found that old muscle produces elevated levels of a molecule called TGF-beta, which is known to inhibit muscle growth. The researchers then showed that the muscle-deteriorating effects of TGF-beta can be reversed by blocking its pathway in old mice.
In the experiments, the researchers used RNA interference, which can silence specific genes, to inhibit the molecules that act downstream of TGF-beta to prevent cells from multiplying. They then locally injured the muscles of treated mice, as well as untreated old and young mice, by injecting a small amount of snake venom, which killed muscle tissue in the immediate vicinity.
After five days, the team found that the young mice were able to produce healthy cells to replace damaged tissue. The treated older mice, whose inhibitory pathways were suppressed, were able to regenerate new cells in much the same way. Not surprisingly, old untreated mice did not recover as well and developed fibroblasts and scar tissue around the injured site.
Conboy says that regulating the TGF-beta pathway may provide a therapeutic possibility for treating age-related muscle disorders. However, she adds that shutting down the pathway altogether may lead to unwanted consequences, such as tumor growth and other side effects. She says that the team’s next goal is to find an appropriate balance between TGF-beta activity and another protein, called Notch, which has previously been shown to successfully rejuvenate old tissue.
Both proteins bind to the same receptors on the surface of stem cells and therefore naturally compete with each other. “In physiologically young animals, Notch is high and TGF-beta is low, and in old animals, it’s the opposite,” says Conboy. “These levels are definitely regulated by the aging process, but we don’t yet know what is the cause.”
Conboy says that this relationship reflects an unfortunate cycle in aging: as levels of Notch drop off with age, TGF-beta is left with ample room to inhibit stem cells, further suppressing the body’s ability to repair damaged tissue. “It’s a self-imposed inhibition of regeneration,” says Conboy.
Michael Rudnicki, director of the Regenerative Medicine Program and the Sprott Centre for Stem Cell Research at the Ottawa Health Research Institute, says that while finding appropriate calibrations may prove challenging, identifying the relationship between Notch and TGF-beta pathways may be a first step in developing therapies for a range of diseases.
Notch and TGF-beta are present in the stem cells of other organs, including the brain, so a similar approach may be a way of repairing tissue in these other organs. “One can think about targets for drug development to reverse or ameliorate many phenomena,” says Rudnicki. “Whether it will reverse aging, I don’t know, but it would be helpful for soft tissue damage or following a stroke.”