Not many messages, so here is another age article. Still a long way from a real treatment of course.
In step forward for rejuvenation field, researchers turn back the clock on mice hearts
When Thomas Braun was starting out as a young professor at Germany’s University of Würzburg in 1997, he decided to try his hand at a new field: heart regeneration, a sci-fi-esque premise that could offer a way to treat patients recovering from a heart attack. He thought it would take a few years before they got results.
“We were,” he acknowledges now, “rather naïve.”
But on Thursday, after two and a half decades of fitful starts and abandoned leads, Braun and a team of researchers at the Max Planck Institute showed that they could reprogram heart cells in mice and get the animals to regenerate cardiac tissue after a heart attack. The breakthrough, published in Science, adds new evidence that it will eventually be possible to help patients recover muscle lost in heart attacks and gives another boon to anti-aging researchers who want to one day apply these rejuvenation techniques across much of the body.
It was not previously clear whether rejuvenation techniques Braun deployed would work in cardiac cells, which are among the least manipulatable in the body.
“It shows that it can be done in the heart,” said Payel Sen, a researcher at the National Institute on Aging who wasn’t involved in the work. “And we know that cardiovascular issues are one of the leading causes of mortality in aging, so if we are able to reprogram the heart, that would be impactful.”
Adults today have cholesterol-lowering treatments that can help stave off heart attacks. And patients who suffer such attacks can take beta-blockers and one of a couple new drugs to slow their decline.
But their decline is effectively inevitable; heart cells are some of the most inflexible in the body. Unlike, say, the liver or muscle, they don’t regenerate when injured. And that paints a grim prognosis for people with heart failure. Even in the pivotal study for Merck’s vericiguat, one of the new cardiovascular drugs on the market, 16% of patients who received the medicine died in less than a year.
Over the years, researchers have tried various approaches to induce heart cells, known as cardiomyocytes, to divide, rarely with luck. Engineered stem cells became a popular approach for a while, after a purported breakthrough, but those results largely vanished in a cloud of scandal.
“Cardiomyocytes are really, extremely reluctant to go into cell division,” said Braun, who now directs the Max Planck Institute for Heart and Lung Research.
About four years ago, Braun and a postdoc began trying a new strategy, called Yamanaka factors. Discovered in 2006, this cocktail of proteins can turn a specialized cell like a neuron back into a stem cell. Over the past decade, a handful of researchers have tried to give these factors to mice in a way that reverses the signs and symptoms of aging.
In 2016, Juan Carlos Izpisua Belmonte showed he could “rejuvenate” aging mice with the factors. Last year, Harvard’s David Sinclair used the approach to restore vision in old blind mice. Jeff Bezos and other big Silicon Valley names have recently raised hundreds of millions of dollars for a reprogramming startup called Altos Labs.
Braun similarly thought the approach could be his answer. And he had other evidence to back it up; if you injured the heart of a fetal mouse, the fetus has little difficulty regenerating the organ. So Braun didn’t want to reverse cells all the way to stem cell, just to their earlier, still-dividing fetal state.
“What if we turned back the clock?” he asked. “From an adult heart muscle cell to a younger one?”
That turned out to be painstaking work. It wasn’t clear how many of the Yamanaka factors the heart cells would need to revert back to fetal state. Too little and they wouldn’t regenerate. Too much and you could make the cells forget their identity and former tumors.
Cancer, a disease where cells proliferate beyond control, has been the constant thorn in reprogramming’s side. Many of Belmonte’s mice showed signs of age reversal but many of them died of cancer within days of treatment.
For the experiment, Braun bio-engineered mice so that they can express Yamanaka factors, but only when they’re fed a certain antibiotic. After four years of tinkering, he found one factor recipe that he believed would work.
To test the theory, he treated mice with the antibiotic to get them to express the factors before inducing in them a massive heart attack. He also tried inducing a massive heart attack one day after. In both cases, heart cells grew back and heart function improved.
“It’s exciting,” said James Martin, a Baylor College of Medicine researcher who’s developing a separate gene therapy to regenerate heart tissue. “It opens the door to further development of treatment.”
Martin, though, doesn’t expect that Braun’s approach itself will become a treatment. In addition to the difficulty of delivering these factors into a patient — viral vectors are a possible but imperfect solution — the regeneration they saw was limited.
A third group of mice who were treated just six days after the heart attack didn’t see any benefit, meaning the window for treating patients would be tiny.
“I don’t think this would work for most heart failure patients,” Martin said.
Still, the results provide further evidence that it will one day be feasible to regenerate heart tissue in patients, Martin said. And if heart cells can be reprogrammed, then likely other non-dividing tissues can be too, a boon to the broad rejuvenation field.
Researchers, for example, have spent decades trying to figure out how to regenerate spinal cords after injury.
Braun’s study, though, also points to the difficulty that the field will encounter. Heart cancer is one of the rarest malignancies, affecting less than 2 out of 100,000 people. But mice in the study who expressed Yamanaka factors for too long managed to develop tumors in the heart.
If heart cells can be reprogrammed, any cell probably can. And, Sen said, if reprogrammed heart cells can develop cancer, then probably any cell — if reprogrammed incorrectly — can too.
“One can’t hide,” said Braun. “It’s a dangerous game.”