This
is a stunner. It effectively reverses aging effects in the heart
muscle. Most likely though, the diastolic effect is unique to the
heart and is an effect of a developing age related deficiency that
this protein resolves. The sure promise here is that we can restore
youthfulness to the heart itself. It may not end heart disease but
it certainly will also strengthen a damaged heart at least. This is
very good news.
Obviously
restoration of heart function and strength will also restore blood
flow and eliminate illness brought on by such limitations.
Again
this is pleasant surprise.
Making old hearts
younger
Researchers at Harvard Stem Cell
Institute find protein that reverses some effects of aging in mice
13 may 2013
Two Harvard
Stem Cell Institute (HSCI) researchers —
a stem cell biologist and a practicing cardiologist at Brigham
and Women’s Hospital — have identified
a protein in the blood of mice and humans that may prove to be the
first effective treatment for the form of age-related heart failure
that affects millions of Americans.
When
the protein, called GDF-11,
was injected into old mice, which develop thickened heart walls in a
manner similar to aging humans, the hearts were reduced in size and
thickness, resembling the healthy hearts of younger mice.
Even more important
than the implications for the treatment of diastolic heart failure,
the finding by Richard
T. Lee, a Harvard
Medical School professor at the hospital, and
Amy
Wagers, a professor in Harvard’s Department
of Stem Cell and Regenerative Biology,
ultimately may rewrite our understanding of aging.
A report on Lee and
Wagers’ findings was published today by the journal Cell.
“The most common
form of heart failure [in the elderly] is actually a form that’s
not caused by heart attacks but is very much related to the heart
aging,” said Lee, who, like Wagers, is a principal faculty member
at HSCI.
“In this study, we
were able to show that a protein that circulates in the blood is
related to this aging process, and if we gave older mice this
protein, we could reverse the heart aging in a very short period of
time,” Lee said. “We are very excited about it because it opens a
new window on the most common form of heart failure.”
He added, “This is
the coolest thing I’ve ever been a part of.”
Doug
Melton, HSCI co-director and Harvard’s Xander
University Professor, called the discovery
“huge. It’s going to change the way we think about aging.”
“I have 300 patients
right now, and I think I have about 20 who are suffering from this
type of heart failure, which we sometimes call diastolic
heart failure,” said Lee. “They come into
the hospital, have a lot of fluid taken off, then they’ll go home.
Then they come back again. It’s really frustrating because we don’t
have any drugs to treat this. We need to work as hard as we can to
figure out if this discovery can be turned into a treatment for heart
failure in our aging patients.”
The Lee and Wagers
labs now are focused on moving GDF-11 toward clinical trials —
which Lee predicts could begin in four to five years — and learning
what other tissue types the protein might affect.
Wagers, who since her
postdoctoral days at Stanford has been working with what is called
the parabiotic mouse system — in which mice share a circulatory
system — previously showed that factors in the blood of young
animals, which until now had been unidentified, have a rejuvenating
effect on various tissues in older animals, particularly in the
spinal cord and musculature.
“As we age, there
are many changes that occur in different parts of the body,” Wagers
said, “and those changes are often associated with a decline in the
function of our bodies. One of the interests of my laboratory is in
understanding why this happens and whether it is an inevitable
consequence of aging, or if it might be reversible.
“In this study, we
compared young and old animals and identified a substance in the
blood that is present at high levels when you’re young, and lower
levels when you’re old. We further found that when we supplemented
the low levels of this substance that were present in old animals to
the levels normally seen in youth, this could have a dramatic effect
on the heart.
“It’s been
observed for many, many years that when aging occurs it affects
multiple body systems sort of in a semi-synchronous way,” Wagers
said, “and this suggests that there may be some common signal that
drives the body’s response to getting older. We hypothesized that
this common signal might be a substance that was traveling in the
bloodstream, because the bloodstream accesses organs throughout the
body.”
“I think Amy and I
started thinking about something like this almost five years ago,”
said Lee, who added that he and Wagers were brought together by HSCI.
“Without the Harvard Stem Cell Institute, this never would have
happened,” he said.
The researchers
conducted their first experiment about four years ago, and the
results were startling, Lee said. “A fellow named Francesco
Loffredo was examining the hearts of the
aging mice. He came to me and said, ‘You don’t have to analyze
it; you can see it with the naked eye.’ I couldn’t believe that,
and I said ‘Go back, analyze it, and do it blinded.’ Then I
looked at the hearts, and I could see he was correct,” Lee
recalled.
“When we started
these experiments, I actually was thinking that there would not be a
response,” Wagers said. “We had been using similar kinds of
approaches in other tissues, regenerative tissues, tissues that we
know have the capacity to heal themselves after they’ve been
injured. But the heart is not well known for doing that, and so I
was quite convinced that there would be no response. When I saw the
dramatic difference in heart size that was very apparent after this
exposure of an old animal to young blood, it was very clear that we
had to figure out what was going on,” she said.
“The blood is full
of all kinds of things,” the biologist said, “and trying to
narrow down what might be the responsible factor was going to be a
big challenge. I think that’s where the collaboration was so
wonderful, in that we could take advantage of the expertise in both
of our laboratories to really home in on what might be the
responsible substance.”
Lee explained, “We
thought it was interesting right away, and we repeated it right away.
But we had to show that this was not a blood pressure effect, that
the young mice didn’t just cause the old mice to have lower blood
pressure. We had to build a custom device to measure blood pressures
off their tails. It took a year to do the analysis to show that it
was not a blood pressure effect.
“After about 2½
years we were convinced, and said, ‘We really have to identify this
factor.’ It took about six months to find something, and another
year to be convinced that it was real,” Lee said. “We looked at
lipids; we looked at metabolites. Then we set up a collaboration with
a startup company in Colorado, called SomaLogic,
that had an interesting technology for analyzing factors in blood.
And by working closely with SomaLogic, we found the likely factor.”
What the researchers
found was that at least one of the factors causing the rejuvenation
of the hearts was GDF-11, “a member of a very important
family of proteins called TGF-beta proteins, for transforming growth
factor. There are around 35 members of the family,” Lee said. “Some
have been very well studied, and this is one that is relatively
obscure.”
Over the course of her
still-early career, Wagers has celebrated the publication of
important papers by going skydiving. This coming weekend, she plans
to take the plunge again, this time accompanied by postdoc Loffredo.
The work was supported
in part by HSCI, the National Institutes of Health, and the American
Heart Association.
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