Study shows the immune manager of aging of the brain

Suppose Smokey the Bear would go on a tear and start burning wildfires, instead of putting them out. It roughly describes the behavior of certain cells of our immune system that become increasingly angry as we age. Instead of stomping out glow, they ignite the flames of chronic inflammation.

Biologists have long argued that reducing this inflammation can slow down the aging process and delay the onset of age-related conditions, such as heart disease, Alzheimer’s disease, cancer, and weakness, and perhaps even prevent the gradual loss of mental acuity. .

The question of what exactly causes specific cells of the immune system to kick in inflammatory excess has lacked a definitive answer.

Now Stanford Medicine researchers think they have one. If their findings in old mice and in human cell cultures apply to real people, they can predict the pharmaceutically controlled recovery of mental capacity of older people.

In a study to be published on January 21 Earth, the researchers place the blame on 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 lead 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 part of the soldier and part of the ranger. If they do not fight infectious invaders, they continue to clean up debris, such as dead cells and clumps of composite proteins; provides nutritional snacks to other cells; and serve as sentries guarding for signs of invasive pathogens.

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

An effective blockade

In the study, blocking the interaction of a particular hormone and receptor abundant on myeloid cells was sufficient to restore the juvenile metabolism and calm temperament of mouse and human myeloid cells in a dish and in live mice. . This blockade also reversed age-related mental decline in older mice, which restored their recall and navigation skills than those displayed by young mice.

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

Myeloid cells are the body’s main source of PGE2, a hormone that belongs to the family known as prostaglandins. 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 what different types of receptors are on the cells’ surfaces, on which the hormone ends up.

One receptor type for PGE2 is EP2. This receptor is found in immune cells and is especially common in myeloid cells. It starts inflammatory activity in the cells after it is bound to PGE2.

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

‘A double blow’

Older macrophages of mouse and human, they observed, not only produced much more PGE2 than younger, but also much larger EP2 on their surfaces. Andreasson and her 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 enhances intracellular processes associated with inflammation in the myeloid cells.

The investigators showed, in both human and mouse myeloid cells, how this inflammatory hyperdrive occurs: The significantly increased PGE2-EP2 binding in myeloid cells of older individuals alters the energy production within these cells by converting glucose – which stimulates energy production in the cell – from consumption to storage.

The researchers found that myeloid cells are undergoing an increasing tendency, driven by increased PGE2-EP2 binding, which is associated with age, to store glucose by converting this energy source into long glucose chains called glycogen (the animal equivalent of starch) instead of giving it to energy production. That storage, and the subsequent chronic energy depletion of the cells, drives them to an inflammatory rage that destroys destructive tissues.

“This powerful road is driving aging,” she said. “And it can be turned off.”

Stanford scientists have shown this by blocking the hormone receptor response to myeloid cell surfaces in mice. They gave mice one of the two experimental compounds that are known to inhibit PGE2-EP2 binding in animals. They also incubated cultured mouse and human macrophages with these substances. Thus, old myeloid cells metabolized glucose, just as young myeloid cells do, reversing the inflammatory character of the old cells.

More strikingly, the compounds reversed mice’s age-related cognitive decline. Older mice that received it also performed on recall tests and spatial navigation as young adult mice.

One of the two compounds used by the Stanford scientists was effective, even if it did not penetrate the blood-brain barrier. Andreasson says this suggests that even the recovery of myeloid cells outside the brain can have profound effects on what goes on in 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 the mice. They provide a roadmap for drugmakers to develop a connection that can be given to people.