Mental maladies that accompany aging have long been considered beyond redemption. But a new Stanford study has identified prostaglandin E2 (PGE2) signaling in immune cells as a key proinflammatory trigger that can be targeted to pacify unwanted inflammation and rejuvenate brain metabolism.

“Aging is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions,” the authors noted in Restoring metabolism of myeloid cells reverses cognitive decline in aging,” an article published in Nature.

If these experiments performed in aged mice and in human cell cultures can be replicated in humans, they will pave the way for new pharmaceuticals that recover mental abilities in older individuals.

That aging is egged on by inflammation is a long-standing theory in biology. Consequently, a therapeutic approach adopted to treat age-related pathologies such as heart disease, Alzheimer’s disease, cancer, frailty, and the loss of mental acuity, has been to somehow quash inflammation. A challenge in this approach, however, has been a lack of know-how on the exact trigger that kicks specific immune cells into inflammatory overdrive.

This new study zeroes in on the age-related functional inadequacies of a specific type of immune cell called myeloid cells that normally course through the body’s circulation, fighting off infections, cleaning up dead cells and protein clumps, providing nutrition to healthy cells, and keeping a lookout for pathogens. But with age, these cells lose their function focus, and incite unwanted inflammation, damaging healthy tissue in their misdirected warfare.

Andreasson
Katrin Andreasson, MD, professor of neurology and neurological sciences and senior author of a study that identified a particular set of immune cells that drive mental aging. (Source Steve Fisch, Stanford Medicine)

“If you adjust the immune system, you can de-age the brain,” said Katrin Andreasson, MD, professor of neurology and neurological sciences, and the study’s senior author.

The authors observed increased synthesis of the lipid hormone PGE2 in a type of myeloid immune cell—human monocyte-derived macrophages (MDMs)—in individuals over 65 years compared to those in individuals under 35.

Blocking the interaction of PGE2 with one of its common partnering receptors, EP2, restores a youthful metabolic profile, suppresses inflammation in mouse and human myeloid cell cultures and living mice, and reverses age-related mental decline in older mice, restoring their recall and navigation skills. The binding of PGE2 and EP2 receptors that are abundant on myeloid cells is a signal that normally provokes inflammatory activity.

Not only do older mice and human macrophages produce more PGE2 than their younger counterparts, but they also express more EP2 receptors on their cell surfaces, the study reported.

“It’s a double-whammy—a positive feedback loop,” said Andreasson. The increase in PGE2-EP2 binding amps up inflammation in the myeloid cells.

The increase in PGE2-EP2 binding also reroutes energy metabolism in myeloid cells, shifting cells from a state of energy consumption to energy storage. The authors showed PGE2-EP2 binding in aging macrophages and microglia increases the conversion of glucose to animal starch or glycogen (glycogenesis) and reduces the burning of glucose through respiration in the mitochondria, resulting in a chronic energy-depleted state. This lack of usable bioenergy further augments the already maladapted inflammatory machinery.

“This powerful pathway drives aging,” said Andreasson. “And it can be downshifted.”

Paras Minhas, an MD-PhD student and first author on the study, and his team showed inhibiting myeloid EP2 signaling shifts bioenergetic metabolism back to an energy-producing state, reduces inflammation in the brain and the organism, increases the ability of neurons in the hippocampus to establish fresh functional connections, and restores the performance of mice on spatial memory and cognitive tasks, such as navigating a maze and locating a novel object.

Despite not being able to penetrate the blood-brain barrier, one of the two experimental compounds the authors used to disrupt PGE2-EP2 binding was still effective in reversing aging-associated attributes, suggesting reprogramming myeloid cells outside the brain can still exert benefits within the brain.

The experimental compounds that the team used to block PGE2-EP2 binding, are not approved for human use and may have toxic side effects in humans that need to be tested, the authors noted, although none were observed in mice.