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Aging involves the collective physiological, functional, and mental changes that accrue in a biological organism over time. A key driver of aging is inflammation, which affects multiple organs, including the brain. Findings from a new study demonstrate that altering prostaglandin E2 signaling in macrophages reduces inflammation and slows cognitive decline in mice.

Macrophages are a type of immune cell. They are key players in the initiation, maintenance, and resolution of inflammation.

Prostaglandin E2 is an important mediator of inflammation, angiogenesis, cell survival, and proliferation. It is produced via the enzymatic conversion of arachidonic acid, a type of fatty acid. Binding of prostaglandin E2 to its receptors on immune cells alters glucose metabolism in the cells and drives inflammation. Prostaglandin E2 levels increase with age and in the setting of neurodegenerative disease.

The investigators first studied peripheral blood mononuclear cells collected from young (less than 35 years) and old (greater than 65 years) human donors to better understand how prostaglandin E2 signaling affected macrophage energy production. They found that prostaglandin E2 reduced glycolysis (the breakdown of glucose) and impaired mitochondrial oxygen use. The primary receptor that mediated these effects was the EP2 receptor, which was present in higher quantities in the macrophages of old donors. Then they treated the cells with an inhibitor to block the EP2 receptor and found that the alterations in energy production reversed.

Next, the investigators studied mice that are predisposed to have Alzheimer’s disease. They treated the animals with EP2 receptor inhibitors or deactivated their EP2 gene. They found that in both situations the macrophages had better energy production, and the mice had lower levels of inflammation and cognitive decline.

These findings suggest that inhibition of immune-related processes that promote inflammation restores immune cell energy production and slows cognitive decline in mice. Learn more about the role of inflammation in cognitive decline in this episode featuring Dr. Dale Bredesen.

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