Stanford Study Finds One Immune Switch May Help Drive Aging Across the Body

New research from Stanford Medicine, conducted in mice and human cells, points to a specific failure in the immune system that may help explain why the body ages. Tissue-resident macrophages — immune cells that live permanently within organs — become less able with age to dispose of neutrophils, the most abundant white blood cells, once those neutrophils become dysfunctional. When the researchers blocked a single receptor on these macrophages, multiple organs in mice, including the brain, heart, muscle, liver, spleen, bone marrow, kidney and colon, retained more youthful characteristics. The findings are described in a paper published in the journal Science.

Neutrophils patrol the blood for pathogens and typically survive only 12 to 24 hours; in aging animals, most neutrophils that never encounter a pathogen quickly enter a dysfunctional state called senescence, releasing chemicals that damage nearby cells and promote inflammation. About 100 billion neutrophils must be cleared from the body every day, a job largely done by tissue-resident macrophages. "Senescent neutrophils are killing our tissues," said senior author Katrin Andreasson, a professor of neurology at Stanford. "Clearance of these cells is essential for preventing chronic inflammation."

The researchers found that a receptor called EP2, which responds to the inflammatory hormone PGE2 and is abundant on tissue-resident macrophages, weakens the macrophages' ability to engulf neutrophils as PGE2 levels rise with age. Disabling EP2 specifically in these macrophages protected mice from frailty, excess fat accumulation and heart trouble linked to chronic inflammation, and substantially reduced cognitive decline.

"We've been trying to figure out why we age," Andreasson said. "Now we know at least one big reason for it." The results point toward a potential drug strategy that could slow age-related deterioration in organs and possibly extend the number of years people remain healthy.