Andreasson’s team 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.

‘A Double-Whammy’

Older mouse and human macrophages, they observed, not only produced much more PGE2 than younger ones but also had far greater numbers of EP2 on their surfaces. Andreasson and her colleagues also confirmed significant increases of 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 amps up intracellular processes associated with inflammation in the myeloid cells.

The investigators showed, in both human and mouse myeloid cells, how this inflammatory hyperdrive sets in: The vastly increased PGE2-EP2 binding in myeloid cells of older individuals alters energy production within these cells by rerouting glucose — which fuels energy production in the cell — from consumption to storage.

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

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

The Stanford 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 as well on tests of recall and spatial navigation as young adult mice.

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

Neither compound is approved for human use, she noted, and it’s possible they have toxic side effects, although none were observed in the mice. They provide a road map for drug makers to develop a compound that can be given to people.

Andreasson is a member of Stanford Bio-X, the Stanford Cardiovascular Institute and the Wu Tsai Neurosciences Institute at Stanford.

Other Stanford co-authors of the study are Amira Latif-Hernandez, Ph.D., instructor of neurology and neurological sciences; life science research professionals Aarooran Durairaj and Qian Wang, Ph.D.; postdoctoral scholars Amit Joshi, Ph.D., Esha Gauba, Ph.D., and Congcong Wang, Ph.D.; former graduate student Amanda Rubin, JD, Ph.D.; MD-PhD student Joy He; graduate student Miles Linde; medical student Peter Moon; Ravi Majeti, MD, Ph.D., professor and chief of hematology; Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology; Irving Weissman, MD, professor of pathology and of developmental biology and director of the Stanford Institute for Stem Cell Biology; and Frank Longo, MD, Ph.D., professor and chair of neurology and neurological sciences.

Researchers from Princeton University and the Keio University School of Medicine in Tokyo also contributed to the study.