Aging affects everyone, but it does not progress at the same rate in every person. New research from Stanford Medicine, based on studies of mouse and human cells, identifies a decline in the immune system that may help explain why the body ages and why chronic inflammation increases over time.
Researchers found that tissue-resident macrophages—immune cells that permanently live inside organs—become less effective at removing other immune cells as the body ages. This decline may contribute to aging throughout the body.
When scientists blocked a single receptor on these macrophages, multiple organs in mice retained more youthful characteristics. The benefits were observed in the brain, heart, skeletal and cardiac muscles, liver, spleen, bone marrow, kidneys, and colon. The receptor, known as EP2, responds to prostaglandin E2 (PGE2), a hormone involved in inflammation and pain in both mice and humans.
Disabling EP2 receptors specifically on tissue-resident macrophages also protected mice from several age-related problems linked to chronic inflammation, including frailty, excess fat accumulation, and heart disease. The treatment significantly reduced cognitive decline, according to Katrin Andreasson, MD, Edward F. Pimley and Eileen Thiel Pimley Professor of Neurology and Neuroscience.
“We’ve been trying to figure out why we age,” Andreasson said. “We now know at least one big reason why.”
The study, published in Science, was led by Andreasson and Dr. Jessy Tan, a lecturer in neurology.
The findings provide new insight into the role chronic, body-wide inflammation plays in aging and age-related disease. They also point to potential drug strategies that could slow the deterioration of organs and help extend healthy lifespan.
How the immune system removes aging cells
Neutrophils are the most abundant white blood cells and serve as some of the immune system’s most important first responders. Produced in the bone marrow, they enter the bloodstream to monitor for bacterial, viral, and fungal threats.
When neutrophils encounter pathogens, they can release toxic substances or destroy themselves by releasing long strands of biological material that form a web-like trap around invading microorganisms.
Neutrophils have short lifespans. Although they can survive for up to 24 hours, about 12 hours is more typical. Approximately 90% of circulating neutrophils eventually travel to the liver, spleen, and bone marrow, where other immune cells remove them.
This cleanup process becomes especially important with age. In older animals, many neutrophils that have never encountered a pathogen quickly enter a senescent, or dysfunctional, state. These aging cells can release harmful chemicals that damage nearby tissue and promote inflammation.
Neutrophil numbers increase with age, as does the proportion of neutrophils that become senescent.
“Aging neutrophils are killing our tissues,” Andreasson said. “Removal of these cells is essential to prevent chronic inflammation.”
Macrophages act as the body’s cellular cleanup crew
Macrophages perform much of this immune-system cleanup. These versatile cells fight pathogens, coordinate immune responses, and release growth factors that help damaged tissues repair themselves.
They also remove dead, damaged, and dysfunctional cells.
“They are the body’s garbage collection squad, and much of that garbage is malfunctioning cells,” Andreasson said.
Much of this cellular waste consists of neutrophils. Approximately 100 billion neutrophils are produced and removed from the body each day.
Several types of macrophages exist. Tissue-resident macrophages are unusually long-lived cells that colonize organs during fetal development. Once established, they remain in those organs throughout life and adapt to perform specialized functions in each location.
One of their most important roles is engulfing and digesting senescent cells. The new findings indicate that aging neutrophils are particularly important targets. Neutrophils begin to show signs of aging just 8 to 12 hours after entering the bloodstream. Cells that display signals indicating they should be removed can then be identified and engulfed by macrophages.
The problem is that tissue-resident macrophages also deteriorate with age. In a 2021 study published in Nature, Andreasson and her colleagues reported that these long-lived immune cells become increasingly vulnerable to inflammation as animals grow older. The macrophages can then contribute to inflammation themselves.
Inflammatory signals become stronger with age
Prostaglandins, hormone-like substances produced by immune cells, play an important role in this process. One of the five major prostaglandins is prostaglandin E2, or PGE2. It affects cells differently depending on which receptors are present on their surfaces.
One PGE2 receptor, called EP2, strongly promotes inflammation. Tissue-resident macrophages contain high levels of EP2.
PGE2 production increases in response to infections, injuries, toxic substances, and compounds produced as the body ages. Previous research by the team showed that PGE2 levels rise significantly over time. At the same time, tissue-resident macrophages produce higher levels of EP2.
These changes create a harmful inflammatory feedback loop. Increased PGE2 repeatedly stimulates EP2 receptors on tissue-resident macrophages. The new study found that this stimulation weakens the macrophages’ ability to engulf and digest neutrophils.
As a result, senescent neutrophils accumulate in the bloodstream and tissues.
Earlier research from Andreasson’s group also showed that the energy metabolism of tissue-resident macrophages gradually declines with age.
“Once that starts, macrophage performance steadily declines,” she said.
The new research suggests that EP2 plays a key role in this deterioration.
“We showed that this reduction does not occur if EP2 is not present on the surface of tissue-resident macrophages, or if the receptor is blocked with a drug.”
Blocking EP2 protects multiple organs
To investigate EP2’s role, Andreasson’s laboratory engineered mice in which the EP2 gene could be deleted at a specific point in time and only in tissue-resident macrophages.
Removing EP2 restored the macrophages’ ability to process neutrophils and prevented the damage caused by excessive PGE2 signaling.
The researchers compared young normal mice, 6 to 8 months old—roughly equivalent to late adolescence or early adulthood in humans—with older normal mice, 23 to 25 months old, approximately comparable to people in their 60s and 70s. They also studied older mice in which the EP2 gene had been deleted when the animals were 4 to 6 months old.
The team identified 71 blood proteins whose levels changed significantly in normal aged mice. Remarkably, 59 of these proteins remained at youthful levels in older mice whose tissue-resident macrophages lacked EP2. Much of the protein production associated with these changes occurred in 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,” Andreasson said. “It is the central organ that determines the body’s metabolic rate.”
Normal older mice accumulated senescent neutrophils in the liver, spleen, and bone marrow. Smaller increases were also found in many of the other organs examined.
In contrast, older mice whose tissue-resident macrophages lacked EP2 had lower neutrophil levels in their organs—similar to those normally seen in young animals.
The mice also appeared younger, leaner, and healthier than age-matched control animals. They had less visceral fat, more muscle, and performance scores on several organ-function tests that were comparable to those of younger mice.
EP2 blockade improves memory, muscle strength, and inflammation
Removing EP2 from tissue-resident macrophages reduced inflammation in the blood, liver, colon, heart, kidneys, and hippocampus—the brain region strongly associated with memory and navigation.
Older mice without EP2 performed similarly to young mice on tests of speed, balance, and forelimb grip strength.
Their memory also remained stronger. They navigated mazes and recognized previously encountered objects almost as well as young mice, outperforming mice of the same age whose EP2 receptors remained active.
Researchers search for drugs that target EP2
No approved drugs currently block EP2 selectively, although several medications affect PGE2 signaling.
Nonsteroidal anti-inflammatory drugs reduce PGE2 production. Andreasson explained that this is how aspirin and related medications help reduce pain, fever, swelling, and redness—the four classic signs of inflammation.
However, these medications can also interfere with other prostaglandins that perform important functions. PGE2 itself can produce beneficial effects when it interacts with receptors other than EP2.
For this reason, the researchers hope to target the specific EP2 receptors responsible for harmful inflammatory activity rather than broadly suppressing PGE2 production.
To test this approach, scientists treated otherwise healthy 22-month-old mice with an experimental drug that inhibits EP2 for two months.
The treatment reduced total neutrophil levels and senescent neutrophil counts in older mice, bringing them closer to levels seen in younger animals. Cell-culture experiments also showed that EP2 inhibitors significantly restored the ability of tissue-resident macrophages to engulf and digest aging neutrophils—a function that declines with age.
Similar immune changes occur in human liver cells
The researchers next analyzed a large database containing information about different cell types in the livers of young, older, and diseased humans.
They found a pattern similar to the one observed in mice. Liver cells from older adults showed greater neutrophil accumulation, progressive neutrophil senescence, reduced tissue-resident macrophage function, and increased EP2 activity. These changes were even more pronounced in diseased livers.
Andreasson said this is the first time these changes have been identified in human cells.
Improving the body’s ability to remove aging neutrophils could ultimately provide important therapeutic benefits for age-related inflammation and disease.
“We need to develop safe drugs” that inhibit EP2 without interfering with earlier processes such as PGE2 production, Andreasson said.
Researchers from the University of Münster in Germany also contributed to the study.
This research was funded by the National Institutes of Health (grants 1RF1AG080742, 1RF1AG070839, and P30AG066515), the American Heart Association, the Phil and Penny Knight Brain Recovery Initiative at the Wu Tsai Neuroscience Institute, Stanford University, the ARK Research Institute, and the Chan Zuckerberg Biohub. Part of the research was conducted at the Wu Tsai Neurosciences Institute’s Neurosciences Preclinical Imaging Community Laboratory.
Source: www.sciencedaily.com