Blocking a single inflammatory receptor protected mice from many of aging’s most damaging effects.
Aging may be driven in part by a breakdown in the body’s cleanup system. New research suggests that as specialized immune cells lose their ability to remove worn-out cells, inflammatory debris begins to accumulate, damaging organs throughout the body.
In experiments involving mice and human cells, Stanford Medicine researchers traced much of this failure to tissue-resident macrophages, long-lived immune cells that live inside organs and dispose of dead, damaged, and aging cells.
The scientists found that blocking a single receptor on these macrophages preserved youthful function across a striking range of tissues in mice, including the brain, heart, liver, kidneys, colon, spleen, bone marrow, and skeletal muscle.
Mice in which the receptor was selectively disabled developed less frailty, accumulated less fat, retained more muscle, and performed better on tests of memory, balance, strength, and organ function. They also showed fewer signs of the persistent inflammation associated with aging.
“We’ve been trying to figure out why we age,” said Katrin Andreasson, MD, the Edward F. and Irene Thiel Pimley Professor in Neurology and Neurological Sciences. “Now we know at least one big reason for it.”
How Immune Waste May Drive Aging
The findings were published in Science.
The work points to a possible explanation for why aging affects so many organs at once. Rather than arising independently in the brain, heart, liver, and other tissues, some forms of age-related decline may share a common source: immune cells that can no longer keep up with the body’s daily waste.
That waste includes enormous numbers of neutrophils, the most abundant white blood cells in the immune system.
Neutrophils Become Toxic With Age
Neutrophils are built for speed and destruction. Produced in bone marrow, they enter the bloodstream and rush toward infections, where they attack bacteria, viruses, and fungi by releasing toxic chemicals. Some also rupture themselves, casting out long strands of molecular material that form web-like traps around pathogens.
This aggressive strategy makes neutrophils effective first responders, but it also makes them short-lived. Most survive for only about 12 hours, and few last longer than a day.
Roughly 100 billion neutrophils must be removed from the body every 24 hours. Most are cleared in the liver, spleen, and bone marrow before they can cause trouble.
When Aging Cells Escape Disposal
As animals age, however, this disposal system becomes less efficient.
Neutrophils that remain in circulation too long can enter senescence, a damaged state in which cells stop functioning normally but remain biologically active. Instead of quietly dying, they release inflammatory substances that injure nearby tissue and encourage other cells to age.
“The older we get, the more our neutrophil counts rise, with senescent neutrophils constituting an ever higher percentage.”
“Senescent neutrophils are killing our tissues,” Andreasson said. “Clearance of these cells is essential for preventing chronic inflammation.”
Macrophages Keep Tissues Clean
That clearance is normally handled by macrophages.
Macrophages perform several essential jobs. They attack pathogens, coordinate immune responses, support tissue repair, and swallow cellular debris. Andreasson describes them primarily as the body’s waste management system.
“They’re the body’s garbage collection crew. A lot of that garbage is defunct cells.”
The Body’s Long-Lived Waste Collectors
Tissue-resident macrophages are a particularly important subtype. Many enter organs during fetal development and remain there for life, adapting to the needs of the tissue around them. Macrophages in the brain, liver, heart, and other organs perform different specialized tasks, but all help maintain the local environment.
One of those tasks is removing aging neutrophils.
Within 8 to 12 hours of entering the bloodstream, neutrophils begin showing signs of age. Even before they become fully senescent, some display molecular signals on their surfaces that mark them for destruction. (Neutrophils that haven’t arrived at senescence yet but have lived long enough and seen enough to put out “kill me now” flags of surrender on their cell surfaces are fair game.)
Aging Weakens the Cleanup Crew
The problem is that tissue-resident macrophages age too.
In a 2021 Nature study, Andreasson and her colleagues showed that these cells gradually lose metabolic energy and become more responsive to inflammation. Their declining performance may allow damaged cells to persist, which generates still more inflammation and places additional strain on the immune system.
The new study identifies a signaling pathway that appears to drive this collapse.
EP2 Drives an Inflammatory Breakdown
Immune cells produce signaling molecules called prostaglandins. One of them, PGE2, can either help or harm tissues depending on the receptor it activates.
The receptor examined in the study, known as EP2, strongly promotes inflammation. Tissue-resident macrophages carry large amounts of it.
PGE2 production rises in response to infection, injury, and toxic substances released by damaged tissue. It also increases with age. At the same time, tissue-resident macrophages develop more EP2 receptors, making them increasingly sensitive to the inflammatory signal.
A Self-Reinforcing Cycle of Damage
The result is a biological double hit.
As PGE2 levels climb and EP2 receptors multiply, macrophages are exposed to stronger and more persistent inflammatory stimulation. The new research suggests that this weakens their metabolism and reduces their ability to engulf aging neutrophils.
Senescent neutrophils then accumulate in the blood and organs, where they release damaging chemicals and fuel further inflammation. This creates a self-reinforcing cycle that may help drive widespread age-related decline.
Blocking EP2 Restores Macrophage Function
Andreasson and her colleagues had previously shown that aging gradually erodes the energy metabolism of tissue-resident macrophages.
“Once that starts, there’s a steady decline in a macrophage’s performance,” she said.
The new work suggests that EP2 is a key trigger.
“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.”
Testing EP2 Removal in Aging Mice
To test the receptor’s role, Andreasson’s team engineered mice whose EP2 gene could be deleted at a chosen time, but only in tissue-resident macrophages.
Removing the receptor restored the cells’ ability to consume neutrophils, reversing the failure caused by excessive PGE2 signaling.
The researchers compared three groups: younger normal mice (age 6 to 8 months) corresponding to late adolescence or early adulthood in humans; older normal mice (23 to 25 months), whose human counterparts would be in their 60s or 70s; and nearly identical older mice whose EP2 gene had been deleted at 4 to 6 months of age (their “teenage” years).
The differences extended far beyond individual immune cells.
Youthful Blood Chemistry and Liver Function
The team identified 71 blood proteins whose levels changed significantly in older normal mice. In animals whose tissue-resident macrophages lacked EP2, 59 of those proteins remained at youthful levels.
Many of the proteins originated in the liver, an organ that plays a central role in metabolism, detoxification, nutrient processing, and blood chemistry.
“The liver is one of the body’s most tissue-resident-macrophage-enriched organs and a major contributor to aging-related changes in blood chemistry,” Andreasson said. “It’s the central organ determining the body’s metabolic rate.”
Older Mice Regain Strength and Fitness
In normal older mice, senescent neutrophils accumulated heavily in the liver, spleen, and bone marrow. Smaller increases were detected throughout the other organs examined.
Older mice without EP2 on their tissue-resident macrophages maintained neutrophil levels closer to those of young animals.
Their outward appearance reflected the internal changes. They were leaner, more muscular, and more physically capable than normal mice of the same age. They carried less visceral fat, retained more muscle mass, and performed like young mice on several measures of organ function.
Removing EP2 also reduced inflammation in the blood, liver, colon, heart, kidneys, and hippocampus (a brain region tightly tied to memory and navigation ability).
The treated animals moved faster and showed better balance and forelimb grip strength. Their performance resembled that of much younger mice.
Memory Benefits Reach the Brain
The benefits also extended to the brain.
Older animals lacking EP2 navigated mazes and recognized familiar objects almost as well as young mice. Their memory was substantially better than that of equally old mice whose macrophages still carried the receptor.
Together, the findings suggest that restoring immune cleanup may protect organs not by targeting each disease separately, but by removing one source of chronic damage shared across the body.
Why Existing Anti-Inflammatory Drugs Fall Short
No approved medication currently blocks EP2 without affecting other parts of the prostaglandin system.
Some widely used painkillers reduce inflammation by suppressing PGE2 production. Non-steroidal anti-inflammatory drugs, including aspirin, can therefore reduce pain, fever, swelling and redness, the “four horsemen” of inflammation.
But PGE2 is not universally harmful. Its effects depend on which receptor it binds to, and some of those pathways perform useful or essential functions.
Broadly blocking prostaglandin production can therefore interfere with beneficial processes as well as damaging ones. A drug aimed only at EP2 could offer a more precise approach by weakening the inflammatory signal while leaving other prostaglandin functions intact.
An Experimental Drug Reverses Immune Decline
To explore that possibility, the researchers treated otherwise normal 22-month-old mice for two months with an experimental drug that inhibits EP2.
The treatment lowered both total and senescent neutrophil numbers toward levels seen in younger mice.
In laboratory dishes, macrophages from older animals were far less effective at consuming worn-out neutrophils. The EP2-blocking drug significantly restored that ability.
Human Liver Cells Show the Same Pattern
The researchers then examined a large database containing detailed information about every major cell type in young, old, and diseased human livers.
Human cells showed the same pattern seen in mice. Older livers contained more neutrophils, more signs of neutrophil senescence, weaker tissue-resident macrophage activity, and stronger EP2 signaling. The changes were even more pronounced in diseased livers.
According to Andreasson, this was the first time the full pattern had been identified in human cells.
A More Precise Strategy Against Aging
The study does not show that blocking EP2 can slow aging in people, and a drug safe enough for long-term human use has not yet been developed. But the similarities between mouse and human liver cells suggest that the pathway may be biologically relevant beyond laboratory animals.
Rather than attempting to suppress inflammation everywhere, the research points toward a narrower goal: restore the immune system’s ability to remove the cells that produce it.
“We need to develop a safe drug” that disables EP2 without interfering with earlier processes such as PGE2 production, Andreasson said.
References:
“Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging” by Yuting Jessy Tan, Travis E. Conley, Fuwen Yao, Fernando J. García-Marqués, Damilola E. Akinyemi, Van Vuong Dinh, Qian Wang, Abel Bermudez, Jieun Kim, Julia A. Belk, Oliver Soehnlein, Sharon J. Pitteri and Katrin I. Andreasson, 16 July 2026, Science.
DOI: 10.1126/science.aea3075
“Tidying up aging organs” by Garret A. FitzGerald, 16 July 2026, Science.
DOI: 10.1126/science.aei9816
The study was funded by the National Institutes of Health (grants 1RF1AG080742, 1RF1AG070839 and P30AG066515), the American Heart Association, the Phil and Penny Knight Initiative for Brain Resilience (at the Wu Tsai Neurosciences Institute), Stanford University, the Arc Institute, and the Chan-Zuckerberg Biohub. The research was conducted in part at the Neurosciences Preclinical Imaging Community Laboratory at the Wu Tsai Neurosciences Institute.
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