Biochemical pathways that could reverse aging of human muscle
5 October 2009
Critical biochemical pathways linked to the aging of human muscle
have been discovered by researchers at the University of California,
Berkeley and the University of Copenhagen. By manipulating these
pathways, the researchers were able to turn back the clock on old human
muscle, restoring its ability to repair and rebuild itself.
The findings are reported in the Sept. 30 issue of the journal
EMBO Molecular Medicine. 
"Our study shows that the ability of old human muscle to be
maintained and repaired by muscle stem cells can be restored to youthful
vigour given the right mix of biochemical signals," said Professor Irina
Conboy, a faculty member in the graduate bioengineering program that is
run jointly by UC Berkeley and UC San Francisco, and head of the
research team conducting the study.
"This provides promising new targets for forestalling the
debilitating muscle atrophy that accompanies aging and perhaps other
tissue degenerative disorders as well."
Previous research in animal models led by Conboy, who is also an
investigator at the Berkeley Stem Cell Center and at the California
Institute for Quantitative Biosciences (QB3), revealed that the ability
of adult stem cells to do their job of repairing and replacing damaged
tissue is governed by the molecular signals they get from surrounding
muscle tissue, and that those signals change with age in ways that
preclude productive tissue repair.
Those studies have also shown that the regenerative function in old
stem cells can be revived given the appropriate biochemical signals.
What was not clear until this new study was whether similar rules
applied for humans.
Unlike humans, laboratory animals are bred to have identical genes
and are raised in similar environments, noted Conboy, who received a New
Faculty Award from the California Institute of Regenerative Medicine
(CIRM) that helped fund this research. Moreover, the typical human
lifespan lasts seven to eight decades, while lab mice are reaching the
end of their lives by age 2.
Working in collaboration with Dr. Michael Kjaer and his research
group at the Institute of Sports Medicine and Centre of Healthy Aging at
the University of Copenhagen in Denmark, the UC Berkeley researchers
compared samples of muscle tissue from nearly 30 healthy men who
participated in an exercise physiology study. The young subjects ranged
from age 21 to 24 and averaged 22.6 years of age, while the old study
participants averaged 71.3 years, with a span of 68 to 74 years of age.
In experiments conducted by Dr. Charlotte Suetta, a post-doctoral
researcher in Kjaer's lab, muscle biopsies were taken from the
quadriceps of all the subjects at the beginning of the study. The men
then had the leg from which the muscle tissue was taken immobilized in a
cast for two weeks to simulate muscle atrophy.
After the cast was removed, the study participants exercised with
weights to regain muscle mass in their newly freed legs. Additional
samples of muscle tissue for each subject were taken at three days and
again at four weeks after cast removal, and then sent to UC Berkeley for
Morgan Carlson and Michael Conboy, researchers at UC Berkeley, found
that before the legs were immobilized, the adult stem cells responsible
for muscle repair and regeneration were only half as numerous in the old
muscle as they were in young tissue.
That difference increased even more during the exercise phase, with
younger tissue having four times more regenerative cells that were
actively repairing worn tissue compared with the old muscle, in which
muscle stem cells remained inactive. The researchers also observed that
old muscle showed signs of inflammatory response and scar formation
during immobility and again four weeks after the cast was removed.
"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," said
Carlson, the study's first author and a UC Berkeley post-doctoral
scholar funded in part by CIRM. "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
At the same time, the researchers 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 Conboy.
The researchers further examined the response of the human muscle to
biochemical signals. They learned from previous studies that adult
muscle stem cells have a receptor called Notch, which triggers growth
when activated. Those stem cells also have a receptor for the protein
TGF-beta that, when excessively activated, sets off a chain reaction
that ultimately inhibits a cell's ability to divide.
The researchers said that aging in mice is associated in part with
the progressive decline of Notch and increased levels of TGF-beta,
ultimately blocking the stem cells' capacity to effectively rebuild the
This study revealed that the same pathways are at play in human
muscle, but also showed for the first time that mitogen-activated
protein (MAP) kinase was an important positive regulator of Notch
activity essential for human muscle repair, and that it was rendered
inactive in old tissue. MAP kinase (MAPK) is familiar to developmental
biologists since it is an important enzyme for organ formation in such
diverse species as nematodes, fruit flies and mice.
For old human muscle, MAPK levels are low, so the Notch pathway is
not activated and the stem cells no longer perform their muscle
regeneration jobs properly, the researchers said.
When levels of MAPK were experimentally inhibited, young human muscle
was no longer able to regenerate. The reverse was true when the
researchers cultured old human muscle in a solution where activation of
MAPK had been forced. In that case, 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."
Other co-authors of the EMBO Molecular Medicine paper include Abigail
Mackey at the University of Copenhagen in Denmark, and Per Aagaard at
the University of Southern Denmark.
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.
1. Carlson M, Suetta C, Conboy M, Aagaard P, Mackey A, Kjaer M,
Conboy I. ‘Molecular aging and rejuvenation of human muscle stem cells’,
EMBO, Wiley-Blackwell, 2009, DOI 10.1002/emmm.200900045
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