We all age at different rates, and no one is immune to aging. A study by researchers at Stanford Medicine using mouse and human cells found that the main culprit is that as we age, certain types of immune cells become less able to engulf other types of immune cells.
So-called tissue-resident macrophages are thought to be central regulators of age-related organ deterioration. Blocking a single receptor on these cells preserved the youth of multiple organs in mice, including the brain, heart, skeletal and cardiac muscle, liver, spleen, bone marrow, kidney, and colon. This receptor specifically binds to a hormone known to cause inflammation and pain in humans as well as mice.
In mice, selectively disabling this receptor only in tissue-resident macrophages prevented age-related diseases caused by chronic inflammation, such as frailty, excess fat accumulation, and heart disease. It also significantly slowed cognitive decline, said Katrin Andreasson, MD, Edward F. Pimley and Eileen Thiel Pimley Professor of Neurology and Neuroscience.
We have been trying to understand why we age. Now we know at least one big reason. ”
Katrin Andreasson, MD, Edward F. Pimley Professor of Neurology and Neuroscience and Eileen Thiel Pimley Professor
The findings are described in a paper published online July 16. science. Andreasson is the senior author, and the first author is Dr. Jessy Tan, lecturer in neurology.
This discovery reveals that systemic inflammation significantly contributes to aging and its associated deterioration. And it suggests pharmaceutical approaches that have the potential to curb the inevitable march toward aging of our organs and extend our overall healthspan.
A story of two types of cells
The most abundant white blood cells in our immune system are neutrophils, which are our bodies’ main first responders. New neutrophils born in the bone marrow jump into the bloodstream, where they circulate and behave in a totally medieval manner when they encounter bacterial, viral, or fungal pathogens. They perform the terrifying act of hara-kiri, spitting out venom, spitting out internal organs, and unloading long thread-like polymers that form webs that trap pathogens.
Perhaps not surprisingly, neutrophils are extremely short-lived. You’re lucky to survive for 24 hours (12 hours is more common). Approximately 90% of circulating neutrophils end up in the liver, spleen, and bone marrow, awaiting execution and elimination by another batch of immune cells.
This removal of neutrophils is very important. In older animals, large numbers of neutrophils that have never experienced combat rapidly enter senescence. In their zombie-like state, they vomit toxic chemicals and act like deranged rock stars punching holes in hotel room walls, causing damage to adjacent cells, causing them to age and become inflamed.
The number of neutrophils increases with age, and the proportion of senescent neutrophils becomes higher and higher.
“Aging neutrophils are killing our tissues,” Andreasson said. “Removal of these cells is essential to prevent chronic inflammation.”
That’s the job of another type of immune cell called a macrophage. These cells take turns to be soldiers, builders, medics, and garbage collectors. They comb the tissue for pathogens, chew them up, release signaling substances that recruit other cells to help, and pump out growth factors that help repair damaged tissue.
First and foremost, Dr. Andreasson said, “They are the body’s garbage collection squad, and much of that garbage is malfunctioning cells.” Many of these cells are neutrophils, and their number reaches 100 billion per day.
There are several subtypes of macrophages. Tissue-resident macrophages are long-lived and ubiquitous. They take up residence in various organs of the body during the development of the fetus and remain in that organ for the rest of their lives, adapting their role to suit that organ.
One of the main roles of macrophages present in tissues is to engulf senescent cells. A particularly important target of this surgery are the approximately 100 billion neutrophils that are produced every day, and studies have shown that they begin to show signs of aging within eight to 12 hours after entering the bloodstream. (Neutrophils that have not yet reached senescence but have lived long enough and have enough vision to plant a flag of surrender on their cell surface that says “kill me now” are fair game.)
However, the macrophages present in tissues also age, become tired, and experience indigestion. As Andreasson and associates showed in their 2021 report: nature As the years pass, these long-lived cells become more prone to succumb to age-related inflammation and proliferate, according to the paper.
distress signal
Immune cells produce hormones called prostaglandins. One of five types of prostaglandins, called PGE2, has different effects on cells depending on which types of surface receptors are expressed on the cell’s surface.
Of the different subtypes of receptors for PGE2, one, called EP2, is more pro-inflammatory. Tissue-resident macrophages incorporate EP2.
Toxic chemicals, such as infections, injuries, and those produced by the aging body, increase the production of PGE2. For 2021 nature The paper shows that production increases significantly with increasing age. The concentration of EP2 on macrophages present in tissues is similar.
This is a one-two punch. The proinflammatory effects of PGE2 increase with age. As a result, a new study shows that relentless inflammatory PGE2 stimulation of tissue-resident macrophages downshifts the ability of these voracious cells to devour neutrophils. Aged neutrophils then accumulate in tissues and blood.
Andreasson and her colleagues previously showed that with aging, the energy metabolism of tissue-resident macrophages slowly decays. “Once that starts, macrophage performance steadily declines,” she says.
In the new study, she continued, “we showed that this reduction does not occur when EP2 is no longer present on the surface of macrophages present in the tissue or when its receptors are blocked by drugs.”
Block one receptor, rejuvenate many organs
Andreasson’s lab bioengineered mice to delete the gene that was the recipe for EP2, at the time the scientists selected. However, only macrophages present within the tissue are deleted. The new study demonstrated that the subsequent loss of EP2 from these cells reactivated the neutrophil phagocytic process that PGE2 weakens.
For the experiment, the Stanford Medicine researchers studied younger normal mice (6 to 8 months old), which corresponds to late adolescence or early adulthood in humans. Older normal mice (23 to 25 months old), comparable to human mice, are in their 60s or 70s. Otherwise virtually identical older mice in which the gene encoding EP2 is deleted at 4 to 6 months of age (the “teenage” age).
The researchers identified 71 different proteins present in the blood, but their levels varied significantly in older, normal mice. Of these proteins, 59 remained at youthful levels in older mice, where tissue-resident macrophages lacked EP2. Many of these proteins originate from the liver.
“The liver is one of the most macrophage-rich organs in the body, and is a major source of age-related changes in blood chemistry,” Professor Andreasson said. “It is the central organ that determines the body’s metabolic rate.”
Smoldering aged neutrophils accumulate in the liver, spleen, bone marrow, and, to a lesser extent, in many other body organs the researchers examined, the study showed.
However, organs from older mice, where tissue-resident macrophages lacked EP2, retained lower neutrophil counts than those of younger mice. These mice appeared younger, leaner, and more fit compared to their control littermates. They demonstrated less visceral fat and more muscle mass. Performance on tests of multiple organ function was comparable to that of young mice.
Deleting EP2 reduced inflammation in the blood, liver, colon, heart, kidneys, and hippocampus (brain regions closely associated with memory and navigational abilities) in old mice. Their speed, balance, and forelimb grip strength were similar to young animals.
Reducing EP2 action in aged mice also preserved memory performance. They were able to navigate mazes and recall previously encountered objects almost as well as young mice, and far better than similar older mice whose tissue-resident macrophages, EP2, continued to function.
Searching for drugs that target EP2
Currently, there are no approved drugs that selectively block EP2 activity, but there are several drugs that target PGE2. Nonsteroidal anti-inflammatory painkillers work by inhibiting the production of PGE2, Andreasson said. (This is how aspirin and similar drugs reduce the “four horsemen” of inflammation: pain, fever, swelling, and redness.) But they also block other important prostaglandins to a greater or lesser degree. Even PGE2 has beneficial properties when binding to receptors other than EP2, rather than the harmful inflammatory receptors examined in this study.
The researchers treated otherwise normal 22-month-old mice with an experimental drug that inhibits EP2 for two months.
The drug reduced total neutrophil counts and senescent neutrophil counts in old mice to youthful levels. Although senescence was reduced in culture dishes, the EP2 inhibitor similarly significantly restored the ability of macrophages present in the mice’s tissues to engulf and digest burnt-out neutrophils.
Finally, the research team turned to a large database characterizing the status of all cell types in the liver of young, old, and sick people. This database revealed the same age-related neutrophil accumulation, increased neutrophil senescence, decreased tissue-resident macrophages, and increased EP2 activity in diseased livers that the Stanford Medicine researchers observed in mice. This is the first time this has been observed in human cells, Andreasson said.
Targeting neutrophil removal could have significant therapeutic benefits, she said, adding that “we need to develop safe drugs” that neutralize EP2 without interfering with upstream events such as PGE2 production.
Researchers from the University of Münster in Germany contributed to the study.
This research was funded by the National Institutes of Health (grants 1RF1AG080742, 1RF1AG070839, P30AG066515), the American Heart Association, the Phil and Penny Knight Brain Recovery Initiative (Wu Tsai Neuroscience Institute), Stanford University, ARK Research Institute, and the Chan Zuckerberg Biohub. Part of the research was conducted at the Neurosciences Preclinical Imaging Community Laboratory at the Wu Tsai Neurosciences Institute.
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Reference magazines:
Tan, Y.J. others. (2026) Restoration of clearance of senescent neutrophils by tissue-resident macrophages limits organ aging. science. DOI: 10.1126/science.aea3075. https://www.science.org/doi/10.1126/science.aea3075
