Study reveals immune factor in brain aging

Suppose Smokey the Bear breaks down in tears and starts lighting wildfires instead of putting them out. This roughly describes the behavior of certain cells in our immune system that become more and more irascible as we age. Instead of breaking down the embers, they stoke the flames of chronic inflammation.

Biologists have long hypothesized that reducing this inflammation could slow down the aging process and delay the onset of age-associated diseases, such as heart disease, Alzheimer’s disease, cancer, and frailty. , and maybe even prevent the gradual loss of mental acuity that happens to almost everyone. .

Yet the question of what, exactly, causes certain cells of the immune system to trigger inflammatory overdrive has lacked a definitive answer.

Now, researchers at Stanford Medicine believe they have one. If their findings in aged mice and in human cell cultures apply to real humans, they could portend the recovery of mental capacities in elderly people under pharmaceutical management.

In a study to be published on January 21 in Nature, investigators put the blame on a collection of immune cells called myeloid cells. Katrin Andreasson, MD, professor of neurology and neurological sciences, is the lead author of the study. Its main author is MD-Ph.D. student Paras Minhas.

Myeloid cells, which are found in the brain, circulatory system, and peripheral tissues of the body, are both soldier and ranger. When not fighting infectious intruders, they are busy cleaning up debris, such as dead cells and clumps of aggregated proteins; provide nutritious snacks to other cells; and serve as sentinels for signs of pathogen invasion.

But as we age, myeloid cells begin to neglect their normal health-protecting functions and engage in an endless program of warfare with a non-existent enemy, inflicting collateral damage to innocent tissue.

An effective blockade

In the study, blocking the interaction of a particular hormone and a receptor that abounds in myeloid cells was sufficient to restore the juvenile metabolism and placid temperament of mouse and human myeloid cells in a dish and in live mice. This blockade also reversed the age-related mental decline in older mice, restoring their recall and navigation skills to those of younger mice.

“If you adjust the immune system, you can reduce brain aging,” Andreasson said. Her team’s experiments in human cells suggest that similar rejuvenation may be possible in people, she said.

Myeloid cells are the main source of PGE2, a hormone belonging to the prostaglandin family. PGE2 does a lot of different things in the body – some good, some not always so good – for example, promoting inflammation. What PGE2 does depends on the cells and the different varieties of receptors on the surface of those cells that the hormone lands on.

One type of receiver for PGE2 is EP2. This receptor is found on immune cells and is particularly abundant on myeloid cells. It initiates inflammatory activity inside cells after binding to PGE2.

Andreasson’s team cultured macrophages, a class of myeloid cells found in tissues across the body, from people over 65 and compared them to macrophages from people under 35. They also looked at macrophages from young mice compared to old mice.

‘A double whammy’

They observed that older mouse and human macrophages not only produced significantly more PGE2 than younger ones, but also had significantly more EP2 on their surface. Andreasson and his colleagues also confirmed significant increases in PGE2 levels in the blood and brains of old mice.

“It’s a double whammy – a positive feedback loop,” Andreasson said. The resulting exponential increase in PGE2-EP2 binding amplifies intracellular processes associated with myeloid cell inflammation.

Researchers have shown, in human and murine myeloid cells, how this inflammatory hyperdrive sets in: Significantly increased PGE2-EP2 binding in myeloid cells in older adults alters energy production within these cells by redirecting glucose – which feeds the production of energy in the cell – from consumption to storage.

The researchers found that myeloid cells experience an increasing propensity, driven by an increase in PGE2-EP2 binding associated with age, to accumulate glucose by converting this energy source into long chains of glucose called glycogen (the animal equivalent of starch) instead of “spending” it on energy production. This hoarding, and the chronically depleted state of cells afterwards, drives them into an inflammatory rage, wreaking havoc on aging tissues.

“This powerful path leads to aging,” she said. “And he can be demoted.”

Stanford scientists have shown this by blocking the reaction of hormone receptors on the surfaces of myeloid cells in mice. They gave mice either of two experimental compounds known to interfere with the binding of PGE2-EP2 in animals. They also incubated cultured mouse and human macrophages with these substances. This caused the old myeloid cells to metabolize glucose just like the young myeloid cells, reversing the inflammatory nature of the old cells.

More strikingly, the compounds reversed the cognitive decline associated with the age of mice. The older mice that received them also performed recall and spatial navigation tests than young adult mice.

One of the two compounds used by the scientists at Stanford was effective even though it does not penetrate the blood-brain barrier. This suggests, Andreasson said, that even resetting myeloid cells outside the brain can have profound effects on what goes on inside the brain.

Neither compound is approved for human use, she noted, and it is possible that they have toxic side effects, although neither have been seen in mice. They provide a roadmap for drug makers to develop a compound that can be given to people.