Harvard finds protein that reverses aging in the heart and target human clinical trials in 2018

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.

It ultimately may rewrite our understanding of aging.

Journal Cell – Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

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B. D. Colen/Harvard Staff

A finding by Richard T. Lee (left), a Harvard Medical School professor at Brigham and Women’s Hospital, and Amy Wagers (right), a professor in Harvard’s Department of Stem Cell and Regenerative Biology, ultimately may rewrite our understanding of aging.

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.

“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.”

ABSTRACT – The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-β superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

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