Stanford Medicine researchers announced on July 16 that they have identified a key immune cell receptor involved in the aging process of organs, based on studies conducted in mice and human cells. The study found that tissue-resident macrophages, a type of immune cell, play a central role in age-related organ decline due to their decreased ability to clear senescent neutrophils as organisms age.
The research demonstrated that blocking a single receptor, known as EP2, on tissue-resident macrophages preserved the youthfulness of multiple organs in mice. These included the brain, heart, skeletal muscle, liver, spleen, bone marrow, kidney, and colon. The EP2 receptor binds specifically to PGE2—a hormone associated with inflammation and pain. In experiments where this receptor was selectively disabled on tissue-resident macrophages in mice, chronic-inflammation-driven disorders such as frailty and heart trouble were prevented; cognitive decline was also substantially slowed.
Katrin Andreasson said, "Senescent neutrophils are killing our tissues. Clearance of these cells is essential for preventing chronic inflammation." She added that tissue-resident macrophages serve as the body's garbage collection crew by removing defunct cells like neutrophils—up to 100 billion per day.
The study also highlighted that with age both PGE2 production and EP2 concentration increase on tissue-resident macrophages. This combination reduces the ability of these cells to clear senescent neutrophils from tissues and blood. Mice lacking EP2 receptors maintained lower numbers of senescent neutrophils across organs and showed physical characteristics more typical of younger animals—including less visceral fat and greater muscle mass.
Experiments involving an experimental drug inhibiting EP2 activity further supported these findings by reducing total and senescent neutrophil counts toward youthful levels in older mice. Additionally, analysis using a large database showed similar patterns—age-related increases in neutrophil buildup and heightened EP2 activity—in human livers.
Andreasson said, "We need to develop a safe drug" targeting only EP2 without affecting other prostaglandins or upstream processes such as PGE2 production.
