Researchers at Stanford University have identified what could be a crucial factor in biological aging according to a published study in Science: the gradual accumulation of wear and tear involving cells getting damaged and certain troublesome cells not being properly cleared away. According to neurologist Katrin Andreasson, age-related declines in the clearance of tissue-resident macrophages (TRMs) allow senescent neutrophils to linger and damage organs, pointing toward potential new therapeutic targets for age-related decline.
Stanford Study Identifies Neutrophil Clearance Failure as Driver of Organ Aging
As bodies age, wear and tear mounts across major organ systems, increasing susceptibility to age-related diseases such as dementia. According to the research led by a team from Stanford University and published in Science by Tan and colleagues, a key mechanism behind this decline involves tissue-resident macrophages becoming less effective. These specialized immune cells are tasked with cleaning up waste in the body, including aging or senescent neutrophils.
Neutrophils act as the body’s first-responder white blood cells that kill pathogens as part of the immune system, and are very short-lived. When these short-lived cells reach the end of their lifecycle, failing to clear them properly as they age can start to become harmful to organs. According to neurologist Katrin Andreasson, senescent neutrophils are killing our tissues, and clearance of these cells is essential for preventing chronic inflammation.
Did you know? Our bodies produce around 100 billion neutrophils a day, making the daily cleanup job massive and critical for maintaining long-term health and preventing chronic inflammation.
Targeting the EP2 Receptor to Restore Macrophage Function
To test whether this can be addressed, the Stanford researchers reduced signaling through a cell receptor called EP2, using both drugs and genetic editing in tests on young and old mice. According to the study, this receptor sits on macrophages, immune cells that are tasked with cleaning up waste in the body, including neutrophils, and the pro-inflammatory EP2 receptor gets more active in later years, partly causing macrophages to become less efficient and start to cause inflammation themselves over time.
When EP2 was disabled or blocked in older mice, the changes were notable, showing more youthful patterns of inflammation alongside improvements in memory, frailty, muscle loss, and heart function. Furthermore, reducing EP2 activity meant senescent neutrophils were once again being properly cleared out, limiting the damage they could do by halting a slow decay in the energy metabolism of macrophage cells.
Liver Metabolism and Protein Restoration
During their analysis, the researchers were able to identify 71 proteins that changed in older mice. Removing EP2 from TRMs restored 59 of these proteins toward youthful levels. Tracing their cellular sources pointed to the liver as a major contributor.
“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,” according to Katrin Andreasson, who noted that it’s the central organ determining the body’s metabolic rate.
Translating Mouse Models to Human Biology and Future Therapies
While the primary findings stem from a mouse study, the research team also reanalyzed published data from human liver and heart tissue. According to the published findings, older human livers mirrored the mouse data, showing fewer TRMs, more neutrophils, higher expression of the EP2 gene in TRMs, and reduced macrophage function. Older human hearts similarly displayed fewer TRMs and higher EP2 expression, but not an increase in neutrophils.
Developing treatments presents substantial obstacles. According to the study authors, there are no approved drugs that selectively block EP2, and any treatment would need to do so safely without disrupting other beneficial effects. Designing a therapy capable of safely targeting EP2 in humans remains a formidable clinical challenge.
Frequently Asked Questions
What causes neutrophils to become harmful as we age?
Neutrophils are very short-lived white blood cells. According to Stanford University researchers, age-related declines in clearance of tissue-resident macrophages prevent these aging cells from being cleared properly, causing them to start becoming harmful to organs.
What is the EP2 receptor’s role in aging?
The EP2 receptor is a pro-inflammatory receptor located on the surface of macrophages. As the body ages, EP2 gets more active in later years, contributing to macrophages becoming less efficient and causing a slow decay in their energy metabolism.
Have these anti-aging findings been tested in humans?
The primary research is largely a mouse study. However, researchers also reanalyzed published data from human liver and heart tissue, finding similar patterns of fewer TRMs and higher EP2 expression in older humans.
Are there currently drugs available that block EP2?
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