Study reveals immune engine of brain aging

Suppose Smokey the Bear was crying and starting to start forest fires instead of putting them out. This roughly describes the behavior of certain cells in our immune system that become increasingly irascible as we age. Instead of extinguishing the embers, they fuel the flames of chronic inflammation.

Biologists have long theorized that reducing this inflammation can slow the aging process and delay the onset of age-related diseases, such as heart disease, Alzheimer’s disease, cancer and frailty, and perhaps even prevent the gradual loss of mental acuity that it happens to almost everyone.

However, the question of what, exactly, causes certain cells of the immune system to enter into inflammatory activity, lacks a definitive answer.

Now, Stanford Medicine researchers think they have one. If their findings in old mice and human cell cultures apply to real humans, they may portend the recovery of older people’s mental abilities, under pharmaceutical control.

In a study to be published on January 21 in Nature, the researchers blame a set of immune cells called myeloid cells. Katrin Andreasson, MD, professor of neurology and neurological sciences, is the senior 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 partly welded and partly forest guard. When they are not fighting infectious intruders, they keep busy cleaning up debris, such as dead cells and clusters of aggregated proteins; providing nutritious snacks to other cells; and serve as sentinels looking for signs of invading pathogens.

But as we age, myeloid cells begin to neglect their normal health protection functions and adopt an endless war agenda with a non-existent enemy, inflicting collateral damage on innocent tissues in the process.

An effective block

In the study, blocking the interaction of a specific hormone and an abundant receptor in myeloid cells was enough to restore the youthful metabolism and placid temperament of human and mouse myeloid cells in a dish and in live mice. This blockade also reversed the age-related mental decline in older mice, restoring their memory and navigation skills to those exhibited by young mice.

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

Myeloid cells are the main source of PGE2, a hormone that belongs to the prostaglandin family. PGE2 does many different things in the body – some good, others not always so good – for example, to promote inflammation. What PGE2 does depends on which cells, and on which of the several different varieties of receptors on the surfaces of these cells, the hormone lands.

One type of receptor for PGE2 is EP2. This receptor is found in immune cells and is especially abundant in myeloid cells. It initiates inflammatory activity within cells after binding to PGE2.

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

‘A double strike’

They observed that macrophages from mice and older humans not only produced much more PGE2 than the younger ones, but also had a much higher number of EP2 on their surfaces. Andreasson and his colleagues also confirmed significant increases in PGE2 levels in the blood and brain of old mice.

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

The researchers showed, in human and mouse myeloid cells, how this inflammatory hyperdrive installs: The vastly increased PGE2-EP2 binding in myeloid cells of older individuals alters the production of energy within these cells, redirecting glucose – which feeds glucose. energy production in the cell – from consumption to storage.

The researchers found that myeloid cells suffer an increasing propensity, driven by the increased age-associated PGE2-EP2 binding, to accumulate glucose, converting this energy source into long glucose chains called glycogen (the animal equivalent of starch) instead of “spend it” energy production. This accumulation, and the subsequent chronic state of energy depletion of the cells, leads to an inflammatory rage, wreaking havoc on aged tissues.

“This powerful path leads to aging,” she said. “And it can be reduced.”

Stanford scientists showed this by blocking the hormone receptor reaction on the surfaces of myeloid cells in mice. They gave mice one of two experimental compounds known to interfere with PGE2-EP2 binding in animals. They also incubated culture mice and human macrophages with these substances. This caused old myeloid cells to metabolize glucose in the same way as young myeloid cells, reversing the inflammatory character of old cells.

Most strikingly, the compounds reversed the age-related cognitive decline in mice. The older mice that received them performed as well on recall and space navigation tests as the young adult mice.

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

None of the compounds have been approved for human use, she noted, and it is possible that they have toxic side effects, although none have been observed in mice. They provide a roadmap for drug manufacturers to develop a compound that can be given to people.