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Age-related cognitive decline may be reversible, study

Specific cells of our immune system become progressively irascible as we grow older. Rather than getting rid of embers, they stir up the flames of chronic inflammation.

It was believed that reducing this inflammation could slow the aging process and delay the onset of age-related conditions, for example, cardiovascular disease, Alzheimer’s disease, and so on. However, precisely, the topic of what makes specific cells of the immune system kick into inflammatory overdrive has lacked a definitive answer.

A breakthrough study from a team of neurologists at Stanford University claims to have discovered one-way immune cells become dysfunctional as we age, leading to the inflammatory hyperdrive that plays a role in most age-related diseases from cancer to cognitive decline.

They blamed a set of immune cells called myeloid cells. These cells are generally found in the brain, the circulatory system, and the body’s peripheral tissues. While not fighting off infectious intruders, these cells are busy cleaning debris, such as dead cells and clumps of aggregated proteins; provide nutrient snacks to other cells, and serve as sentinels watching for signs of invading pathogens.

As we grow older, the myeloid cells begin neglecting their normal, health-protecting functions and adopting a plan of endless warfare with a nonexistent enemy, inflicting collateral damage to innocent tissues in the process.

In the investigation, impeding the connection of a particular hormone and a receptor that abounds on myeloid cells was sufficient to reestablish the energetic digestion and peaceful demeanor of mouse and human myeloid cells in a dish and living mice. This blockade also reversed an age-related mental decline in older mice, restoring their recall and navigation skills to those showed by young mice.

Katrin Andreasson, MD, professor of neurology and neurological sciences, said, “If you adjust the immune system, you can de-age the brain. Our experiments in human cells suggest that similar rejuvenation may be possible in people.”

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, some not always so good — promoting inflammation. PGE2 depends on which cells, and which of several different receptor varieties on those cells’ surfaces, the hormone lands on.

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

Scientists compared their cultured macrophages, a class of myeloid cells situated in tissues throughout the body, from people older than 65 and compared them with macrophages from people younger than 35. They also looked at macrophages of young versus old mice.

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

The specialists found that myeloid cells go through an increasing propensity, driven by age-related increased PGE2-EP2 binding, to accumulate glucose by changing over this energy source into long glucose chains called glycogen (what might be compared to starch) rather than “spending” it on energy creation. That hoarding and the cell’s subsequent chronically energy-depleted state drives them into an inflammatory rage, wreaking havoc on aging tissues.

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

Scientists showed this by blocking the hormone-receptor reaction on myeloid-cell surfaces in the mice. They gave mice either of two experimental compounds known to interfere with PGE2-EP2 binding in the animals. They also incubated cultured mouse and human macrophages with these substances. Doing so caused old myeloid cells to metabolize glucose just as young myeloid cells do, reversing the old cells’ inflammatory character.

More striking, the compounds reversed mice’s age-related cognitive decline. Older mice who received them performed on tests of recall and spatial navigation as young adult mice.

One of the two compounds the scientists used was sufficient even though it doesn’t penetrate the blood-brain barrier. This suggests that even resetting myeloid cells outside the brain can profoundly affect what goes on inside the brain.

Andreasson said, “Neither compound is approved for human use, and they may have toxic side effects, although none were observed in the mice. They provide a road map for drugmakers to develop a compound that can be given to people.”

Journal Reference:
  1. Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R. et al. Restoring myeloid cells’ metabolism reverse cognitive decline in aging. Nature (2021). DOI: 10.1038/s41586-020-03160-0

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