Stanford Deleted One Receptor From Immune Cells. Fifty-Nine of 71 Aging Blood Proteins Stayed Young.

Stanford Medicine researchers have found a single receptor on a single class of immune cell that, when switched off, keeps mice from aging the way mice normally age — in the blood, the liver, the gut, the heart, the kidney and the brain at once.

The receptor is EP2. It sits on the surface of tissue-resident macrophages, the long-lived immune cells that live permanently inside organs and act as their cleanup crew, and it responds to prostaglandin E2, an inflammatory hormone. The study, from lead author Jessy Tan and senior author Katrin Andreasson, was published Thursday in Science with collaborators at the University of Munster.

The team engineered mice in which the EP2 gene could be deleted specifically in those macrophages, then compared three groups: young animals of 6 to 8 months, normal older animals of 23 to 25 months — roughly a human in their sixties or seventies — and older animals whose EP2 had been removed at 4 to 6 months.

The blood told the clearest story. In normal old mice, 71 blood proteins had shifted significantly with age. In the EP2-deficient old mice, 59 of them had stayed at youthful levels. The animals had less visceral fat, more muscle, better physical performance, and less inflammation measured in blood, liver, colon, heart, kidney and hippocampus. Cognitive decline was substantially reduced; on maze navigation and object recognition, the old modified mice performed like the young ones.

The mechanism runs through a kind of cell the field has been circling for years. Senescent neutrophils are worn-out immune cells that stop functioning but refuse to die, and they accumulate in tissue as animals age while leaking inflammatory signals. Macrophages are supposed to clear them. When EP2 was missing, they did — the older modified mice accumulated far fewer senescent neutrophils in liver, spleen and bone marrow. "Senescent neutrophils are killing our tissues," Andreasson said. "Clearance of these cells is essential for preventing chronic inflammation."

The result that matters most for anyone hoping this becomes a drug is the last experiment. Genetic deletion at 4 to 6 months is prevention, and no human gets that option. So the team gave an experimental EP2-blocking compound to 22-month-old mice — already old — for two months. "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," Andreasson said.

The lab has been working this seam since a 2021 Nature paper on the same signaling pathway and brain aging. The distance from a mouse to a person remains the usual distance, and inflammation-blocking drugs have a long history of doing less in humans than they promise in rodents. The work was funded by the NIH, the American Heart Association, the Phil and Penny Knight Initiative for Brain Resilience, Stanford, the Arc Institute and the Chan-Zuckerberg Biohub.