As we age, our bodies accumulate the cellular equivalent of clutter. Much of this clutter is made up of the remains of neutrophils, the most abundant white blood cells in the immune system. Neutrophils are plentiful because they have an important job — clearing pathogens like bacteria and viruses from the body.

In general, neutrophils don't stick around for very long, though. After 12 to 24 hours, most are cleared through the liver, spleen and bone marrow. Clearing out any remaining neutrophils is important because when they become old and stick around they become toxic, injuring nearby cells and eventually contributing to inflammation in organs and tissues.

This inflammation is one of the hallmarks of aging. “The clearing of senescent neutrophils is important for preventing chronic inflammation,” one of the researchers on a new study looking at the association between chronic inflammation and aging, Katrin Andreasson, told TheDoctor.

“We have been trying to figure out why we age. Now we know one big reason for it.”

The job of clearing neutrophils falls to immune cells called macrophages, including a type of macrophage found in every organ of the body. The body normally clears these aging neutrophils, but when prostaglandins, lipids with hormone-like actions that the body makes primarily at sites of tissue damage or infection, bind to certain receptors on the surface of these macrophages, it interferes with their ability to clear old, senescent neutrophils and causes inflammation.

To prevent this from happening and improve the removal of senescent neutrophils and reduce the effects of aging, researchers at Stanford University and the University of Münster in Germany developed a mouse model in which the gene that codes for the prostaglandin receptor on macrophages, EP2, was deleted.

The deletion, the researchers reported, prevented conditions such as heart disease and fat accumulation that are both driven by chronic inflammation and common in old age.

Deleting the gene also slowed cognitive decline.

The results made it clear that chronic inflammation plays an important role in these conditions and in the aging process. “We have been trying to figure out why we age,” Andreasson said. “Now we know one big reason for it.”

Deleting the gene that codes for the prostaglandin receptor on macrophages prevented conditions such as heart disease and fat accumulation that are both driven by chronic inflammation and common in old age.

The study compared younger normal mice (six to eight months old, the equivalent to late adolescence or young adulthood in humans) and older normal mice (about two years old, the equivalent to 60 to 70 years old) to other older mice who were identical except the gene for EP2 had been deleted when they were four to six months old, the equivalent of their teenage years.

What they found was the deletion of the EP2 gene rebooted the destruction of old neutrophils prevented by the binding of a prostaglandin to the EP2 receptor. As a result, worn-out, senescent neutrophils accumulated in the livers, spleens, bone marrow and other organs of older normal mice, but not in the organs of older mice lacking the EP2 gene.

The results on tests of multiple organs in mice lacking the EP2 gene were also similar to those of younger mice. The researchers found that levels of 71 proteins in the blood were significantly changed in older normal mice compared to younger normal mice. Fifty-nine of those proteins, however, stayed at levels similar to younger mice in the older mice without the EP2 gene. Many of those proteins are produced in the liver.

Deletion of the EP2 gene reduced inflammation in the blood, liver, colon, heart and kidneys of older mice. It also reduced inflammation in the hippocampus, the part of the brain responsible for memory and navigation ability. Older mice lacking the EP2 gene could navigate a maze and recall objects they had seen before almost as well as younger mice and better than older mice who did not lack the gene.

Older mice that lacked the EP2 gene looked younger, leaner and more physically fit than older mice with the gene. Their speed, balance and forelimb grip strength were like those of younger mice.

When the researchers treated normal 22-month-old mice with an experimental drug that inhibited EP2, they found it reduced total and senescent neutrophil levels to levels similar to those of younger mice.

These findings suggest a drug that blocks EP2 on tissue-resident macrophages could slow the aging process. No currently approved drugs block just the EP2 receptor, however, although several target the prostaglandin, Andreasson, the Edward F. and Irene Thiel Pimley professor of neurology and neurological sciences at Stanford, said. Nonsteroidal anti-inflammatory drugs, or NSAIDs, for example, block the production of the prostaglandin that connects to the EP2 receptor. Unfortunately, these drugs also block important prostaglandins.

When the researchers treated normal 22-month-old mice with an experimental drug that inhibited EP2, they found it reduced total and senescent neutrophil levels to levels similar to those of younger mice. In cell culture dishes, the drug restored the ability of tissue-resident macrophages in older mice to digest neutrophils.

The study and a related editorial are published in Science.