But the garbage collectors themselves age. Andreasson's team reported in a 2021 Nature study that tissue-resident macrophages grow increasingly vulnerable to inflammation as animals get older — and can start producing inflammation themselves.

How does one receptor gum up the works?

The key player is PGE2, one of five prostaglandins — hormone-like molecules produced by immune cells. PGE2 acts differently depending on which receptors sit on a cell's surface. One of those receptors, EP2, strongly promotes inflammation, and tissue-resident macrophages carry large amounts of it.

PGE2 levels rise substantially with age, responding to infection, injury and toxic compounds the aging body produces. At the same time, tissue-resident macrophages develop higher concentrations of EP2. The result is a harmful feedback loop: constant PGE2 stimulation of EP2 weakens the macrophages' ability to engulf worn-out neutrophils. Senescent neutrophils then accumulate in the bloodstream and tissues.

"Once that starts, there's a steady decline in a macrophage's performance," Andreasson said. "We've shown that when tissue-resident macrophages don't have EP2 on their surfaces anymore or when that receptor is plugged up by a drug, this decline doesn't happen."

What happened when scientists deleted EP2?

Lead author Jessy Tan, PhD, an instructor in neurology, and colleagues engineered mice whose EP2 gene could be deleted at a chosen time, specifically in tissue-resident macrophages. They compared three groups:

• Young normal mice, 6 to 8 months old (roughly late adolescence in humans)
• Old normal mice, 23 to 25 months old (comparable to humans in their 60s or 70s)
• Nearly identical old mice whose EP2 had been deleted at 4 to 6 months of age

Removing EP2 restored the macrophages' cleanup ability. Old mice without the receptor kept youthful, low neutrophil levels in the liver, spleen and bone marrow — organs where normal old mice accumulated senescent neutrophils. Effects appeared in the brain, heart, skeletal muscle, liver, spleen, bone marrow, kidney and colon.

These mice looked younger too. They carried less visceral fat, built more muscle, and matched young animals on tests of organ function, speed, balance and forelimb grip strength. Their memory held up: they navigated mazes and recognized previously seen objects nearly as well as young mice. Inflammation dropped in the blood, liver, colon, heart, kidney and hippocampus, a brain region central to memory.

Many of the protected proteins came from the liver. "The liver is one of the body's most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry," Andreasson said. "It's the central organ determining the body's metabolic rate."

Could a drug do the same thing?

No approved drug selectively blocks EP2. Aspirin and other nonsteroidal anti-inflammatory drugs work by cutting PGE2 production broadly — the mechanism behind their effects on pain, fever, swelling and redness, the "four horsemen" of inflammation. But that broad suppression also interferes with other prostaglandins that perform useful jobs, and PGE2 itself can be beneficial through receptors other than EP2.

As a proof of concept, the team gave normal 22-month-old mice an experimental EP2 inhibitor for two months. The treatment pulled both total and senescent neutrophil counts back toward youthful levels. In cell cultures, the drug significantly restored aging macrophages' ability to engulf and digest worn-out neutrophils.

What about humans?

Searching a large database of cell types from young, old and diseased human livers, the researchers found the same pattern seen in mice: more neutrophil accumulation, more senescence, weaker macrophage function and higher EP2 activity in older livers — with the changes even more pronounced in diseased ones. Andreasson said this was the first time these changes had been observed in human cells.

The caveats are real. The work relied on mice, cell cultures and observational human liver data, not clinical trials. "We need to develop a safe drug" that blocks EP2 without disrupting PGE2's other functions, Andreasson said. Still, if such a drug emerges, it could one day slow age-related deterioration in organs and extend the number of years people stay healthy.