For decades, scientists have sought to understand the anti-ageing
effects of parabiosis, a technique in which researchers sew a young
mouse and an old mouse together so that they share a circulatory system.
The hunt for the fountain of youth is back to square one—at least for
those seeking it in blood. New findings cast doubt on research that
attempted to explain why the muscles of an old animal can be rejuvenated
with a dose of blood from a young animal.
For decades, scientists have sought to understand the anti-ageing
effects of parabiosis, a technique in which researchers sew a young
mouse and an old mouse together so that they share a circulatory system. The young mouse’s blood seems to rejuvenate the old mouse, regenerating
its wasting muscles and restoring its cognitive abilities. On the basis
of those results, at least one company is attempting to replicate the effect in humans using blood plasma from healthy young people to treat patients with Alzheimer’s disease.
In 2013, a team led by Amy Wagers, a stem-cell researcher at Harvard
University in Cambridge, Massachusetts, seemed to offer an explanation
for this blood-doping effect. The scientists found that levels of a
protein called GDF11 decreased in the blood of mice as they grew older.
When the researchers injected the protein into the heart muscle of old
mice, it became ‘younger’—thinner and better able to pump blood.
Two
subsequent studies by Wagers and her colleagues found that GDF11 boosted
the growth of new blood vessels and neurons in the brain and spurred
stem cells to regenerate skeletal muscle at the sites of injuries.
Rejuvenation riddle
Those results quickly made GDF11 the leading explanation for the
rejuvenating effects of transfusing young blood into old animals.
But
that idea was confusing to many because GDF11 is very similar to the
protein myostatin, which prevents muscle stem cells from differentiating
into mature muscle—the opposite effect to that seen by Wagers and her
team.
For GDF11, “You could imagine that when it came out last year that it
helped muscle, it was quite a surprise,” says David Glass, executive
director of the muscle diseases group at the Novartis Institutes for
Biomedical Research in Cambridge, Massachusetts. “Did we miss
something?”
Glass and his colleagues set out to determine why GDF11 had this apparent effect. First, they tested the antibodies and
other reagents that Wagers’ group had used to measure GDF11 levels, and
found that these chemicals could not distinguish between myostatin and
GDF11.
When the Novartis team used a more specific reagent to measure
GDF11 levels in the blood of both rats and humans, they found that GDF11
levels actually increased with age—just as levels of myostatin do.
That
contradicts what Wagers’ group had found.
Glass’s team next used a combination of chemicals to injure a mouse’s
skeletal muscles, and then regularly injected the animal with three
times as much GDF11 as Wagers and her team had used. Rather than
regenerating the muscle, Glass found, GDF11 seemed to make the damage
worse by inhibiting the muscles’ ability to repair themselves.
He and
his colleagues report their results on 19 May in Cell Metabolism.
Glass says that although his group’s results do not explain why
parabiosis works, they could help to explain the mechanism behind
bimagrumab, an experimental Novartis treatment for muscle weakness and
wasting.
The drug, which is currently in clinical trials, blocks
myostatin—and perhaps GDF11 as well.
Meticulous methods
Thomas Rando, a stem-cell biologist at Stanford University in
California, praises the attention to detail in the methods used by Glass
and his team. “They did a very thorough and rigorous job,” he says.
He
does not see the findings as a setback for the field, because they
confirmed what researchers had expected before the studies by Wagers and
her colleagues. “If this paper was published first, it would not have
been surprising,” he says.
Wagers, however, stands by her findings. She says that although at
first glance the Novartis group’s data seem to conflict with her team’s
results, there could be multiple forms of GDF11 and that perhaps only
one decreases with age.
Both papers suggest that having either too much
or too little GDF11 could be harmful, she says. She adds that the
Novartis group injured the muscle more extensively and then treated it
with more GDF11 than her group had done, so the results may not be
directly comparable.
“We look forward to addressing the differences in the studies with additional data very soon,” Wagers says.
Rando expects that researchers will now investigate the finding that
GDF11 affects the growth of neurons and blood vessels in the brain. “I’m
not sure which result is going to stand the test of time,” he says.
See subsequent posting on: Peptides Follistatin a Myostatin precursor
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