Stanford Finds Blocking Single Receptor Restores Youth in Mice
Stanford Medicine researchers discovered that blocking a single pro-inflammatory receptor on specific immune cells reverses multi-organ aging in mice. The study, published in the journal Science, targets tissue-resident macrophages—immune cells that act as cellular clean-up crews. These cells lose their ability to clear expiring white blood cells as the body grows older, triggering systemic chronic inflammation.
The research team focused on the interaction between tissue-resident macrophages and neutrophils, which are short-lived immune cells. Under normal conditions, the body produces approximately 100 billion neutrophils each day to fight off infections. When these neutrophils reach the end of their lifespan, macrophages consume and digest them.
As mice and humans age, a hormone called prostaglandin E2 (PGE2) binds to a receptor named EP2 on the surface of macrophages. This constant binding disables the macrophages' ability to clear out dying neutrophils. The uncleared neutrophils then transition into an inflammatory state, releasing toxic chemicals that damage surrounding healthy tissues and accelerate organ aging.
Katrin Andreasson, a neurologist at Stanford University and senior author of the study, described the impact of these uncleared neutrophils:
"Senescent neutrophils are killing our tissues."
"Clearance of these cells is essential for preventing chronic inflammation."
The study team demonstrated a method to prevent this cellular decline, according to Andreasson:
"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 [in macrophage performance] doesn't happen."
"We've been trying to figure out why we age," Andreasson said. "Now we know at least one big reason for it."
To test this pathway, the researchers genetically modified mice to lack the EP2 receptor exclusively on their tissue-resident macrophages once they reached old age. They compared these older modified mice, aged 23 to 25 months, to normal older mice and young adult mice. The genetically modified older mice showed lower inflammation levels across multiple major organs, including the brain, heart, liver, kidney, spleen, colon, and skeletal muscle.
These modified mice performed as well as young mice in tests measuring speed, balance, and grip strength. They also demonstrated sharper spatial memory and cognitive speeds, finding their way through mazes with the proficiency of young adult cohorts. Unmodified older mice struggled with physical performance and suffered from cognitive decline.
The researchers also tested an experimental drug that inhibits EP2 in normal, unmodified 22-month-old mice for two months. The drug treatment successfully lowered senescent neutrophil counts and restored the macrophages' ability to engulf and clear the aging cells. The treated older mice showed physical and cognitive improvements similar to the genetically modified mice.
To see if these findings apply to humans, the researchers analyzed databases of human liver tissues. The human data mirrored the mouse models, showing a build-up of neutrophils, increased neutrophil senescence, and high EP2 receptor activity in older and diseased livers. This suggests that targeting the same EP2 pathway could slow organ aging in humans.
Even with the positive results in mice, human therapies based on this discovery face obstacles. No approved drugs currently target the EP2 receptor specifically. Existing anti-inflammatory medications block PGE2 production globally, which can cause severe side effects because PGE2 performs beneficial functions in other parts of the body.
EP2 remains a difficult target because it regulates broader metabolic pathways in the body. The research team stated that developing a safe drug to inhibit EP2 without disrupting upstream biological processes requires more work before clinical trials in humans can begin.
