We may age at different rates, but none of us escapes aging . A study in mice and in human cells by Stanford Medicine researchers pins much of the blame on a particular type of immune cell’s increased inability, with advancing age, to gobble up another immune cell type.
So-called tissue-resident macrophages appear to be central coordinators of age-related organ decline. Blocking a single receptor on these cells preserved the youthfulness of multiple organs in mice including the brain, heart, skeletal and heart muscle, liver, spleen, bone marrow, kidney, and colon. The receptor binds specifically to a hormone known to cause inflammation and pain in humans as well as mice.
In mice, selectively disabling this receptor exclusively on tissue-resident macrophages prevented chronic-inflammation-driven disorders of age including frailty, excessive fat accumulation and heart trouble; it also substantially slowed cognitive decline, said Katrin Andreasson , MD, the Edward F. and Irene Thiel Pimley Professor in Neurology and Neurological Sciences.
“We’ve been trying to figure out why we age,” Andreasson said. “Now we know at least one big reason for it.”
The study’s findings are described in a paper to be published online July 16 in Science . Andreasson is the senior author, and the lead author is Jessy Tan, PhD, an instructor in neurology.
This discovery clarifies systemic inflammation’s outsized contribution to aging and the debilities that accompany it. And it suggests a pharmaceutical approach that could restrain our organs’ ineluctable march to senescence, extending our overall health spans.
A tale of two cell types
The most abundant white blood cells in our immune system are neutrophils, our bodies’ main first responders. Born in the bone marrow, new neutrophils hop into the bloodstream, where they circulate and, if they come across a bacterial, viral or fungal pathogen, go all medieval on it: They squirt out poison and perform a hara-kiri horror act, spilling their guts out and unloading long, stringy macromolecules that form weblike nets and trap the pathogen.
Perhaps unsurprisingly, neutrophils are extremely short-lived: They’re lucky to survive 24 hours (12 hours is more typical). Some 90% of circulating neutrophils end up in the liver, spleen and bone marrow, awaiting execution and riddance by another batch of immune cells.
This neutrophil clearance is critical. In aged animals, the vast bulk of neutrophils that never see combat undergo a fast transition to senescence, a zombie-like state in which they injure, age and inflame neighboring cells by vomiting toxic chemicals and otherwise behaving like an addled rock star punching holes in a hotel room wall.
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.”
That’s a job for another type of immune cell called a macrophage. These cells are by turns soldiers, builders, medics and garbage collectors. They comb the tissues for pathogens, chew them up, spurt signaling substances that summon other cells to lend a hand, and pump out growth factors that help repair damaged tissue.
First and foremost, Andreasson said, “They’re the body’s garbage collection crew. A lot of that garbage is defunct cells.” And a lot of those cells are neutrophils — to the tune of 100 billion a day.
Macrophages come in several subtypes. Tissue-resident macrophages are long-lived and ubiquitous. They take up residence in each of the body’s organs during fetal development and remain for their lifetimes in whatever organ they’ve inhabited, adapting their roles to fit that organ.
One of tissue-resident macrophages’ prime responsibilities is to swallow senescent cells. Especially important targets for this operation, the study showed, are some 100 billion neutrophils, produced daily, which start showing signs of senescence within 8 to 12 hours after entering the bloodstream. (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.)
But tissue-resident macrophages also grow old and tired and dyspeptic. As Andreasson and associates showed in a 2021 Nature paper , over the advancing years these long-lived cells become ever more prone to succumb to aging-associated inflammation and to propagate it.
A distress signal
Immune cells produce hormones called prostaglandins. One of the five varieties of prostaglandin, called PGE 2 , can exert diverse effects on a cell, depending on which type of surface receptor is expressed on that cell’s surface.
Of the various subtypes of receptors for PGE 2 , one designated EP2 is highly pro-inflammatory. Tissue-resident macrophages are loaded with EP2.
Infection, injury and toxic chemicals including the ones produced by our aging bodies increase PGE 2 output. As the 2021 Nature paper showed, that output grows substantially as we grow older. So does the concentration of EP2 on tissue-resident macrophages.
It’s a one-two punch: PGE 2 ’s pro-inflammatory influence increases with age. The resulting unrelenting inflammatory PGE 2 stimulation on tissue-resident macrophages, the new study showed, downshifts these voracious cells’ ability to wolf down neutrophils. Senescent neutrophils then accumulate in tissues and blood.
Andreasson and her colleagues have previously shown that with aging, tissue-resident macrophages undergo a slow decay in their energy metabolism. “Once that starts, there’s a steady decline in a macrophage’s performance,” she said.
In the new study, she continued, “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.”
Block one receptor, rejuvenate many organs
Andreasson’s lab has bioengineered a mouse in which, at a time of the scientists’ choosing, the gene that’s a recipe for EP2 gets deleted — but only in tissue-resident macrophages. The subsequent disappearance of EP2 from these cells, the new study proves, reinvigorated the neutrophil-devouring process that PGE 2 undermines.
For their experiments, the Stanford Medicine researchers studied 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 otherwise virtually identical older mice whose EP2-encoding gene had been deleted at 4 to 6 months of age (their “teenage” years).
The scientists identified 71 proteins, found in blood, whose levels were significantly altered in older normal mice. Of those proteins, 59 stayed at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Many of these proteins originated in the liver.
“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.”
Smoldering senescent neutrophils, the study showed, accumulated in normal old mice’s livers, spleens and bone marrow — and, to a lesser extent, in all the many other bodily organs the researchers looked at.
But the organs of older mice lacking EP2 on their tissue-resident macrophages retained the lower neutrophil numbers of youth. These mice looked younger, leaner and more physically fit compared with control littermates. They evidenced less visceral fat and greater muscle mass. Their performance on tests of multiple organs’ function equaled that of young mice.
EP2 deletion reduced inflammation in the blood, liver, colon, heart, kidney and hippocampus (a brain region tightly tied to memory and navigation ability) in the older mice. Their speed, balance and forelimb grip strength resembled that of young animals.
Reducing EP2 action in older mice also preserved their memory capabilities. They could thread their way through a maze or recall previously encountered objects almost as well as younger mice — and far better than similarly old mice in whose tissue-resident macrophages EP2 remained functional.
Seeking drugs to target EP2
There are, today, no approved drugs that selectively shut down EP2 activity, although there are several that target PGE 2 . Non-steroidal anti-inflammatory painkillers work by blocking PGE 2 production, Andreasson said. (That’s how aspirin and similar drugs reduce pain, fever, swelling and redness, the “four horsemen” of inflammation.) But to greater or lesser degrees they all block other vital prostaglandins. Even PGE 2 has beneficial properties when it binds to receptors other than EP2, rather than the detrimental inflammatory one examined in this study.
The investigators treated otherwise normal 22-month-old mice for two months with an EP2-inhibiting experimental drug.
This drug reduced total and senescent neutrophil counts in old mice toward youthful levels. In culture dishes, old age diminished — but the EP2-blocking drug likewise significantly restored — the mice’s tissue-resident macrophages’ ability to engulf and digest burnt-out neutrophils.
Finally, the team turned to a large database characterizing goings-on in all cell types in young, old and diseased human livers. This database revealed the same age-related neutrophil buildup, increased neutrophil senescence, tissue-resident-macrophage decline and heightened EP2 activity in older — and even more so, diseased — livers that the Stanford Medicine researchers had seen in mice. It was a first-time observation in human cells, according to Andreasson.
Targeting neutrophil clearance may yield big therapeutic benefits, she said: “We need to develop a safe drug” that incapacitates EP2 without disrupting upstream events such as PGE 2 production.
A researcher from the University of Munster in Germany contributed to the work.
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.
# # #
About Stanford Medicine
Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .
Science
Experimental study
Animals
Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging
16-Jul-2026
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.