Run-down cells, known as senescent cells, may make us old. A new study of mice suggests that they also drive another scourge of our advancing years—atherosclerosis, the buildup of fatty plaques in our arteries that can spur heart attacks and strokes. If scientists verify the findings, drugs that cull the cells could one day treat or even prevent one of the world’s biggest killers.
The contribution of senescent cells to atherosclerosis has remained murky, but the new study provides “the best evidence that they are important,” says cardiovascular pathologist Gary Owens of the University of Virginia School of Medicine in Charlottesville, who wasn’t connected to the research.
Senescent cells permanently stop reproducing, but they can linger in the body for a lifetime. Their inability to reproduce is a good thing, scientists say. Because they are stressed out or carry damaged DNA, they could spawn tumors if they continued to divide. Senescence has its downsides, however. As more cells in a tissue senesce, they can’t reproduce to furnish replacements for other cells that have died or been injured. In addition, senescent cells don’t completely shut down; they continue to leak enzymes and other molecules that can alter their environment.
Over the years, these run-down cells accumulate in our bodies, leading researchers to suspect that they are responsible for at least some of the physical decline of old age. Earlier this year, a team led by cancer biologist Jan van Deursen of the Mayo Clinic in Rochester, Minnesota, bolstered that notion, revealing that deleting senescent cells from mice increased their life spans by up to 20% and improved their health.
In their new study, Van Deursen and colleagues tried to determine the role of senescent cells in atherosclerosis. Previous studies have disagreed about the cells’ impact on plaque formation, with some suggesting that they promote it and others indicating that they help prevent it. To tackle the question, Van Deursen and his team used mice that had been genetically engineered to kill off many of their senescent cells in response to a particular drug. The researchers let the mice chow down on a fat-rich diet for 3 months and dosed some of them with the drug.
When the scientists measured the amount of fatty buildup in one of the animals’ major arteries, they found that mice purged of senescent cells carried 60% less plaque than did the other mice. Atherosclerosis developed rapidly in the animals that retained senescent cells. Within just 9 days of starting the high-fat diet, they sported streaks of fat in their arteries that are harbingers of the disease, the researchers report online today in Science. These lesions teemed with senescent cells. In the rodents that received the drug, however, the telltale streaks were much smaller, and harbored few senescent cells. Owens says that the speed at which senescent cells appeared is disturbing. “It makes you worry if you go on a fast food binge for a couple of days,” he says.
Plaques can become lethal if they fracture and trigger blood clots, which can block arteries and lead to a heart attack or stroke. In the mice that eliminated their senescent cells, Van Deursen and colleagues found, plaques carried thicker protective caps and thus were less likely to break. Several types of senescent cells lurk inside plaques, but the researchers’ results suggest that the wrongdoers that promote atherosclerosis are foam cells, a type of immune cell that has settled down in the artery lining and begun feasting on fats. “We think they have roles throughout the process of atherosclerosis,” Van Deursen says. Early on, senescent foam cells may promote the growth of lesions by inciting inflammation. In older lesions, the cells may cause trouble by releasing enzymes that weaken the plaque.
The study marks the first attempt to remove senescent cells from plaques and determine the effects, says vascular biologist Martin Bennett of the University of Cambridge in the United Kingdom, who wasn’t connected to the research. But the molecular markers the scientists used to recognize and remove senescent cells are not exclusive to those cells, he notes. “Thus, they need to be sure that what they have identified or ablated in atherosclerosis are just senescent cells.” Owens agrees that the researchers could have done more to confirm that the cells they targeted are senescent. If they can do that, he says, their technique could pave the way for atherosclerosis treatment. “This would be a whole new approach, and that’s pretty exciting.”
Several groups of researchers have developed so-called senolytic drugs that slay senescent cells, and clinical trials of one compound, developed by a company co-founded by Van Deursen, will start early next year in patients with a type of arthritis. Tests in atherosclerosis patients could be a way off, however. For one thing, Van Deursen says, researchers first need to show that targeting senescent cells works in animals whose arterial blockages more closely mimic human atherosclerosis, such as pigs. In the meantime, you might want to lay off the double cheeseburgers.