Study hints at way to halt age-related function loss

22 Janvier, 2021, 05:56 | Auteur: Yves Courtet
  • Turn back time? Study hints at way to halt decline as we age

However, the preliminary study suggests that this immune dysfunction may be reversible.

Other Stanford co-authors of the study are Amira Latif-Hernandez, PhD, instructor of neurology and neurological sciences; life science research professionals Aarooran Durairaj and Qian Wang, PhD; postdoctoral scholars Amit Joshi, PhD, Esha Gauba, PhD, and Congcong Wang, PhD; former graduate student Amanda Rubin, JD, PhD; MD-PhD student Joy He; graduate student Miles Linde; medical student Peter Moon; Ravi Majeti, MD, PhD, professor and chief of hematology; Daria Mochly-Rosen, PhD, 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, PhD, professor and chair of neurology and neurological sciences.

New research published in the journal Nature on Monday begun by seeking the answer to what causes age-related immune dysfunction.

Scientists have long known that cognitive decline as we get older and specific age-related diseases including Alzheimer's are linked to inflammation, but they are still uncovering precisely why and how this is the case. For some of us, this means the immune system becomes slower in responding to infection, while for others, this means defective immune cells begin to attack healthy cells consistently.

Researchers focused on prostaglandin E2 (PGE2)- a hormone. The scientists also observed significant increases of PGE2 levels in the blood and brains of old mice.

In the study, researchers from Stanford Medicine studied myeloid cells in old mice, as well as myeloid cells in cultures from people older than 65 and under 35.

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.

What's more, the older counterparts also have greater surface numbers of EP2 receptors, which are responsible for binding PGE2.

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This process is "a double-whammy - a positive feedback loop", Katrin Andreasson, senior author on the new study, says in a press release.

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. In short, inflammatory characteristics disappeared, and the cells were rejuvenated. That hoarding, and the cells' subsequent chronically energy-depleted state, drives them into an inflammatory rage, wreaking havoc on aging tissues.

Andreasson said, "This powerful pathway drives aging". The experimental drug that inhibits PGE2-EP2 bindings is not ready for human clinical trials.

Whether chronic inflammatory activity played a crucial role in age-related cognitive decline and whether the cycle could be slowed or reversed. 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.

When the hormone was blocked in older mice, they performed as well as more youthful rodents in tests of their memory and navigation.

Of particular interest was one of the two compounds, which was found to be effective, even though it doesn't penetrate the blood-brain barrier.

According to the team, this suggests that resetting myeloid cells outside the brain could have a huge effect on what goes on inside the brain.

And neither of the experimental compounds have been tested in humans, so it is unclear whether they could be toxic, although no harmful side effects were seen in the mice tested. They provide a road map for drug makers to develop a compound that can be given to people.



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