• Blocking a prostaglandin signaling pathway in aged immune cells reprograms their metabolism to a youthful state.
  • The metabolic rejuvenation of these immune cells restores aged mouse cognition.

Scientists have long considered that reversing age-related inflammation of the nervous system, or neuroinflammation, could slow cognitive aging processes and delay the onset of conditions like Alzheimer’s disease. Studies have shown that certain immune cells use a prostaglandin signaling pathway called PGE2-EP2 that may play a critical role in this age-associated neuroinflammation and cognitive decline. So, figuring out how to suppress this signaling pathway could provide a means to mitigate age-related cognitive impairments.

Andreasson and colleagues from Stanford University published a Nature article demonstrating that EP2 receptor inhibitors can reprogram myeloid cell metabolism to restore youthful immune function and aged mouse cognition. While the safety and efficacy of these drugs have yet to be tested in humans, their abilities to restore mouse age-related cognitive decline could pave the way for pharmaceutical developments to restore aged human cognition.

Aged Immune Cell Dependence on Glucose Intensifies Maladaptive Inflammatory Responses

We know that how and what cells metabolize to generate energy has an important role in regulating the activation and function of the immune system. Immune cells require robust metabolism based on glucose to meet their energetic demands. When immune cells do not meet their energy demand, this can lead to maladaptive inflammatory responses.

The way this works in an immune cell type called myeloid cells is through a pathway called PGE2-EP2 signaling. These cells produce the inflammatory modulator hormone PGE2 that stimulates a receptor present on their own surfaces called EP2. When PGE2-EP2 signaling is activated, it promotes the conversion of blood sugars (glucose) to the animal equivalent of starch (glycogen), diminishing cells’ glucose-dependent energy production. This results in immune cells that are in an energy-deficient state that drives inflammatory responses, which are intensified by aged myeloid cell dependence on glucose as a primary fuel source.

Interestingly, as we age, PGE2 levels increase and so does neuroinflammation, suggesting a link between increased PGE2-EP2 signaling and age-associated inflammation and cognitive decline. Figuring out how to suppress this signaling pathway could provide a means to mitigate age-related cognitive impairments.

Excessive PGE2-EP2 Signaling Drives Brain Aging

To determine how PGE2-EP2 modulates the metabolism of myeloid cells and age-related cognitive decline, Andreasson and colleagues produced evidence that PGE2-EP2 signaling drives brain aging. Using a class of human myeloid immune cells called monocyte-derived macrophages (MDMs), they first showed that aged human MDMs had a significantly increased presence of the EP2 receptor. Then, when these MDMs were exposed to EP2 inhibitors PF-04418948 and C52, the cells responded with an enhanced function of mitochondria — the cell’s power generator.

On top of that, the treatments with the EP2 inhibitors improved cellular use of glucose for energy production — glycolysis — and improved mitochondrial function. Overall, these findings indicated that the inhibition of PGE2-EP2 signaling enhanced aged myeloid cell metabolism based on glycolysis.

(Minhas et al., 2021 | Nature) Pharmacological EP2 inhibitors PF04418948 and C52 improve mitochondrial function and glucose-derived energy production. Increasing EP2 inhibitor treatment concentrations of immune cells facilitated increased mitochondrial function as measured with oxygen consumption rate (OCR) and cell energy derived from glucose as measured with extracellular acidification rate (ECAR). These results suggest EP2 blockade significantly improved immune cell metabolic function.

The team went on to find that partially eliminating EP2 function in aged mice also improved mitochondrial function and glycolysis. By genetically manipulating EP2 in aged mice, the researchers reduced the receptor’s cell presence by 50%, which significantly enhanced cellular utilization of glucose. Plus, it increased mitochondrial function, confirming EP2 inhibition’s role in improving mitochondrial metabolism not only in cells but also in animals.

Pharmacological EP2 Receptor Inhibition Restored Aged Mouse Cognition

The researchers then tested whether the EP2 inhibitors could improve memory function in aged mice with age-related cognitive decline. The Stanford University-led research team found that one month of oral administration with the brain-penetrant EP2 inhibitor C52 restored age-related spatial memory deficits. Interestingly, the C52 treatment also restored anti-inflammatory factors in the brain to youthful levels, which can reduce aged brain inflammation.

(Minhas et al., 2021 | Nature) Brain-penetrant EP2 inhibitor C52 oral administration reversed age-related mouse cognitive decline. The graph illustrates performance on a mouse maze requiring mice to remember an escape route. Treating aged mice with C52 enhanced performance on this task similar to young mice, indicating that C52 reversed mouse age-related cognitive decline.

Since the EP2 receptor is also highly expressed outside the brain, Andreasson and colleagues examined the effects of the brain impermeant EP-2 inhibitor PF-04418948. Following six weeks of oral administration, the team noted reduced proinflammatory factors responsible for inflammation in the blood and brain. Importantly, this treatment restored memory function. Since PF-04418948 does not enter the brain, the EP2 inhibitor could have changed blood composition to affect brain blood vessel function to improve cognition, although the mechanisms remain to be determined.

(Minhas et al., 2021 | Nature) Aged mice orally treated with the brain impermeant EP2 inhibitor PF-04418948 exhibited a reversal in cognitive decline. The graph shows performance time on a mouse maze where the mice had to remember an escape route. Aged mice administered PF-04418948 took significantly less time remembering the escape target hole, indicating that PF-04418948 reversed age-related cognitive impairment.

Pharmacological EP2 Blockade May Provide a Specific Means to Combat Age-Related Cognitive Decline

“If you adjust the immune system, you can de-age the brain,” said Andreasson in a press release.

“Our study suggests that the development of maladaptive inflammation and cognitive decline in ageing may not be a static or permanent condition, but rather that it can be reversed by inhibiting inflammatory PGE2 signaling through the myeloid EP2 receptor,” stated Andreasson and colleagues in their publication. Inhibition of EP2 receptors may offer a new approach to combat aging disorders with greater mechanistic specificity than drugs currently available.