Immune Cell Interaction Breakdown Drives Aging, New Study Finds

Aging is inevitable, but the mechanisms that accelerate it may be more immune-driven than previously appreciated. A new study from Stanford Medicine traces a key contribution to organ decline to an age-worsening failure of the immune system to remove senescent cells. Using mouse experiments and analyses of human liver data, the researchers show that tissue-resident macrophages lose an essential “cleanup” function as they age, allowing damaged immune cells to accumulate.

The work focuses on neutrophils, short-lived first responders best known for rapid, destructive pathogen-killing. After spending about a day in circulation, most neutrophils are normally cleared by macrophages in organs such as the liver, spleen, and bone marrow. With advancing age, however, many neutrophils enter senescence instead of being efficiently removed, transitioning into a harmful state that promotes inflammation and tissue dysfunction.

Central to the mechanism is a pro-inflammatory prostaglandin signaling pathway. As mice age, production of prostaglandin E2 (PGE2) rises, and macrophages become enriched with the PGE2 receptor EP2. The study demonstrates that sustained EP2 signaling reduces macrophages’ ability to engulf and digest senescent neutrophils, creating a feedback loop in which immune debris fuels chronic inflammation throughout the body.

To test causality, the team engineered mice in which EP2 could be deleted selectively in tissue-resident macrophages at a chosen time point. When EP2 was absent from these macrophages, aged mice maintained more youthful neutrophil clearance, with fewer senescent neutrophils accumulating in multiple organs. This preservation correlated with improved physiological outcomes spanning brain, heart and skeletal muscle, liver, kidney, and gut-related tissues.

The protective effects were not limited to peripheral tissues. Cognitive decline also slowed in EP2-deleted animals, including performance in memory- and navigation-like behavioral tasks. Inflammatory signatures in relevant tissues and circulating protein profiles shifted toward youthful patterns, particularly in liver-related pathways, aligning with the liver’s role in systemic metabolic regulation.

Beyond genetic deletion, the researchers evaluated an experimental EP2-inhibiting drug. Administering the compound to older mice for two months reduced both total and senescent neutrophil counts toward youthful levels. In cell-based assays, macrophages from treated mice regained robust capacity to clear damaged neutrophils that otherwise accumulated with age.

The team further connected the findings to human biology by leveraging a large dataset of cell-state changes across young, old, and diseased livers. Human samples showed the same broad pattern: increased neutrophil senescence, macrophage decline, and heightened EP2-related activity with age and disease, supporting the translational relevance of the mechanism.

Overall, the study reframes aging-associated organ decline as partly driven by immune cell interaction failure—specifically, macrophage impairment in clearing senescent neutrophils. By blocking a single receptor on tissue-resident macrophages, researchers preserved youthfulness across multiple organs in mice, suggesting a potential pharmaceutical strategy to extend health span.