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In Study Blood Protein Reversed Heart Aging in Old Mice

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By Anette Breindl
Science Editor

Researchers have identified a protein that can reverse cardiac hypertrophy, the thickening of the heart muscle that is one of the key features of diastolic heart failure.

More generally, though the researchers have not specifically looked at life span yet, they said they believe that the protein in question may turn out to be a whole-body regulator of the aging process.

The team published its findings in the May 10, 2013, issue of Cell.

The authors identified the factor, GDF-11, with so-called parabiosis experiments, where two animals share a blood supply. The study began as an attempt to identify factors in the bloodstream of young mice that could rejuvenate older animals, and co-corresponding author Amy Wagers, of Brigham & Women's Hospital, told BioWorld Today that when the studies started, she thought that any such factors would target stem cells and control regenerating tissue.

"I actually suggested [the heart] as a negative control," she said, because "I thought the heart" – which does not regenerate – "wouldn't show an effect." But the effect on the heart was not only there – it was pronounced.

"Usually we do quite sophisticated quantitative analysis. . . . This was one of those things where you just looked at the hearts and you knew that something had happened," said co-corresponding author Richard Lee. "There are a lot of things in science that are subtle. This was not one of them."

But though the effect was not subtle, identifying its causal agent turned out not to be trivial, either.

Parabiosis experiments can show the existence of a circulating molecule that can affect aged tissue. But "you then create a situation where you have to identify where the effect is coming from," Wagers said.

And in that, Lee said, "we were unsuccessful for quite a while." Success came when the team reached out to biotech company SomaLogic, whose aptamer technology was able to identify GDF-11 as the protein responsible for the effects seen in the parabiosis experiments. When aged mice were treated with recombinant GDF-11, both the size of their hearts overall and of individual heart cells was reduced compared to mice on placebo. The levels of several proteins that are affected in humans with cardiac hypertrophy also were affected.

The researchers said they hope their findings will ultimately translate into therapies for heart failure. Lee, who is a practicing cardiologist, told BioWorld Today that diastolic heart failure is "one of the most frustrating diseases that cardiologists face."

In diastolic heart failure, the heart is still able to pump, but the thickening of the heart muscle means that its pumping volume is reduced, which ultimately leads to blood backing up in the lungs. While there are treatments for some types of heart failure, none of them work in elderly patients with diastolic heart failure, which affects about 1 percent of those who are older than 50.

From a recombinant protein to an approved therapeutic is a long road in the best case, and a dead end more often than a long road. But Lee pointed out that "this is a case where the mechanism is the same as the treatment." In other words, if the protein is effective, clinical development might be more rapid than in cases where a drug candidate has to be identified to recapitulate an effect.

Scientifically, the authors also plan to see whether GDF-11 is a more general regulator of aging. Studies of aging have tended to look at individual cells rather than global regulators of aging. But just last week, researchers reported that proinflammatory signaling in the hypothalamus is a key driver of aging. (See BioWorld Today, May 2, 2013.)

The results now reported in Cell showed that the inverse phenomenon also influences an organism's age. Factors like GDF-11 may be general anti-aging factors. Wagers said the researchers "don't know at a precise molecular level" how the factors her team has identified work, but that classical regulators of aging such as the sirtuins "are definite candidates."

The authors also consider it likely that GDF-11 has broader anti-aging effects throughout the body. "How far does this go?" Lee said. "We're working hard to see what other organs it plays a role in."