Tissue-Resident Macrophages Emerge as Master Regulators of Aging Through EP2-Driven Neutrophil Clearance
Key Insights
A Stanford-led study published in Science identifies tissue-resident macrophages as central coordinators of age-related decline across multiple organs, rather than passive bystanders.
Researchers found that EP2 receptor (search) signaling increases in aged macrophages, suppressing their metabolism and ability to clear senescent neutrophils from tissues.
Blocking EP2 in aged mice restored macrophage cleanup function, leading to healthier heart function, reduced frailty, less muscle loss, and improved cognitive performance.
Aging has long been viewed as the gradual, inevitable accumulation of cellular damage. But a landmark study published in Science now points toward a different explanation: aging may result substantially from the body's growing inability to remove harmful immune cells before they begin damaging surrounding tissue. At the center of this discovery are tissue-resident macrophages, long-lived immune cells that act as permanent maintenance crews in organs throughout the body.
Led by Jessy Tan Yuting at the Stanford University School of Medicine, the research team demonstrated that these macrophages become less effective with age due to heightened signaling through a receptor called EP2. This receptor responds to the inflammatory molecule prostaglandin E2, and its activity increases markedly in older tissue-resident macrophages. The consequence is profound: macrophages lose their capacity to engulf aging neutrophils, allowing these short-lived cells to accumulate in tissues where they adopt characteristics of cellular senescence.
A Cleanup System That Begins to Fail
Neutrophils are produced at an astonishing rate—more than 100 billion per day in humans—and normally survive only a short time before being cleared by macrophages. When this clearance mechanism falters, aging neutrophils persist and become far from harmless. The researchers found that these lingering neutrophils display DNA damage, resist normal cell death, produce inflammatory signals, and release damaging neutrophil extracellular traps (NETs).
Rather than remaining isolated, these senescent neutrophils place neighboring healthy cells under stress. Imaging of mouse liver tissue showed that nearby liver cells experienced harmful effects simply because of their proximity to aging immune cells. The liver also emerged as a major source of age-related immune changes throughout the body, suggesting that dysfunction in one organ can influence aging elsewhere.
Restoring the Body's Natural Defenses
The research team tested two distinct approaches to reducing EP2 signaling in aged mice: genetic techniques that selectively removed EP2 from tissue-resident macrophages, and pharmacological agents designed to block the receptor. Both strategies produced remarkably consistent results.
Macrophages regained their ability to efficiently remove senescent neutrophils. Their mitochondria—the energy-generating structures inside cells—functioned more like those found in younger animals. Immune balance improved across multiple organs, and the benefits extended well beyond the immune system itself.
Older mice maintained healthier heart function, developed less body fat, experienced less muscle loss, and showed reduced frailty. The animals also performed better on cognitive tests, and markers of chronic inflammation declined across the board.
Evidence Beyond Mice
To determine whether the same process might operate in humans, the researchers analyzed existing datasets from human liver and heart tissue. The human samples mirrored many of the patterns observed in mice: older tissues contained higher levels of EP2 in tissue-resident macrophages, more senescent neutrophils, and fewer interactions between macrophages and neutrophils that would normally allow damaged cells to be removed.
These findings do not prove that blocking EP2 would slow aging in humans, but they strongly suggest the underlying biology is shared across species.
A Parallel Discovery: Macrophage Aging Across Tissues
Complementing the Stanford findings, a separate study published in BMC Biology from the USC Leonard Davis School of Gerontology (search) mapped how macrophages age across different body tissues. Led by senior author Bérénice Benayoun, associate professor at the USC Leonard Davis School, the research analyzed data from macrophages collected from mouse brain, lungs, liver, and other organs.
"We know that aging affects immune cells like macrophages, but most studies focus on a single tissue or organ, so there is little known on how local tissue environment can impact immune cell aging," said Benayoun. "We wanted to understand whether immune cells age in the same way throughout the body or whether each tissue has its own aging story."
The answer was both. Aging macrophages across many tissues become more focused on responding to stress and cellular damage while losing molecular programs involved in maintaining healthy tissue structure. Yet macrophages in different organs age differently—brain macrophages showed distinct age-related changes compared with those in the lungs—and aging can affect macrophages differently in males and females across tissues.
"There's an incredible wealth of publicly available, underutilized sequencing data for studying immune aging," said Ella Schwab, the study's lead author and PhD student at the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences. "By analyzing data from dozens of pre-existing studies, we could examine how macrophages age across tissues and between sexes—something no single study had the power to do alone."
Toward a Unified View of Immune Aging
Both studies converge on a critical insight: tissue-resident macrophages are not passive bystanders in the aging process but central coordinators of age-related decline. The USC study identified a set of genes and molecular pathways that changed consistently across many types of macrophages, representing potential core features of immune aging and targets for future treatments. The Stanford study went further, demonstrating that restoring macrophage function through EP2 blockade can reverse multiple signs of aging in animal models.
Scientists caution that these findings remain based primarily on animal research, and much more work will be needed before EP2-blocking drugs can be tested as treatments for healthy aging or age-related diseases. Nevertheless, the results reframe aging not as passive wear and tear alone, but as a process driven in part by the immune system's declining ability to remove harmful cells before they damage surrounding tissue. If that cleanup process can be restored, at least some aspects of aging might be slowed.