A new study published Jan. 21 in Nature by Katrin Andreasson and Paras Minhas, suggests that cognitive aging is not irrevocable, but can be reversed by reprogramming glucose metabolism in myeloid cells.
Biologists have long hypothesized that reducing inflammation may slow down the aging process and delay the onset of age-associated diseases, such as heart disease, Alzheimer's disease, cancer and the frailty that concerns each of us during our aging.
Yet, the question of exactly what causes these inflammatory reactions of the immune system had not found a definitive answer.
A long-standing observation in epidemiological studies of aging populations has been that NSAIDs, which inhibit the production of cyclooxygenase-1 (COX-1) and COX-2 and prostaglandin (PG), prevent the development of the disease. Alzheimer's.
Model ALS mice and patients with sporadic ALS have increased levels of prostaglandin E2 (PGE2). In addition, levels of microsomal proteins PGE synthase-1 and cyclooxygenase-2, which catalyze PGE2 biosynthesis, are dramatically increased in the spinal cord mice model of ALS .
Preclinical studies suggest that prostaglandin E2 (PGE2) is an essential inflammatory mediator of brain damage via the activation of four G protein coupled receptors, namely EP1-EP4.
Transient inhibition of the EP2 receptor by antagonists permeable to the blood-brain barrier shows marked anti-inflammatory and neuroprotective effects in several rodent models of epilepsy, without, however, having a noticeable effect on seizures per se.
In the brain, microglia lose the ability to remove misfolded proteins associated with neurodegeneration.
Prostaglandin and myeloid cells
Prostaglandins are one of the main mediators of inflammation which play an important role in improving neuroinflammatory and neurodegenerative processes. Myeloid cells are the main source of PGE2, a hormone belonging to the prostaglandin family. Prostaglandins are a group of physiologically active lipid compounds derived from arachidonic acid.
Arachidonic acid is one of the most abundant fatty acids in the brain (10% of its fatty acid content). Among other things, it helps protect the brain from oxidative stress by activating the gamma receptor activated by peroxisome proliferators.
One type of receiver for PGE2 is EP2. This receptor is found on immune cells and is particularly abundant on myeloid cells. It initiates inflammatory activity inside cells after receiving PGE2.
Myeloid and macrophages
Myeloid cells are distinguished from lymphocytes.
Monocytes, a type of myeloid cell, and their macrophages and dendritic cell descendants perform three main functions in the immune system. These are phagocytosis, antigen presentation and cytokine production.
Macrophages engulf and digest cell debris, foreign substances, microbes, cancer cells, and anything that does not have the type of proteins specific to healthy cells in the body on its surface.
The first author of the study, Paras Minhas, initially isolated monocytes from blood donated by healthy people under the age of 35 or over 65. Scientists also looked at macrophages from young mice compared to old mice.
During aging, functional changes are due to macrophages. Microglia residing in the brains of aged mice increase their soma volume but reduce the length of their processes, limiting their ability to interact and support neuron survival.
Macrophages can undergo "training" after re-exposure to a stimulus.
Recent studies have described that the induced immunity in young mice leads to an increase in myeloid lineage cells and can occur in myeloid precursors in the bone marrow.
As we age, a similar shift towards a myeloid cell line occurs, and the aging microenvironment may also have a ripple effect.
Effects of a significant increase in PGE2 levels
The authors observed that older macrophages from mice and humans not only produced significantly more PGE2 than in younger subjects, but also had a much higher number of EP2 on their surface. Andreasson and his colleagues also confirmed significant increases significant levels of PGE2 in the blood and brain of old mice.
The researchers found that in aging macrophages and microglia, PGE2 signaling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flow and mitochondrial respiration.
The dramatically increased PGE2-EP2 binding in elderly myeloid cells alters energy production in these myeloid cells by inducing them to store glucose, rather than fueling energy production in the cell.
Cells store glucose by converting this energy source into long chains of glucose called glycogen (the animal equivalent of starch).
This build-up creates a state of chronic exhaustion (stress) in the cells, which leads them to express inflammatory signals.
Not only have aging macrophage cells found it difficult to burn glucose, they also don't use other sources of energy for respiration. Young macrophage cells were better able to utilize lactate and pyruvate.
An apparent rejuvenation?
The authors deleted EP2 in transgenic mice, which halved the amounts of receptors. Macrophages from 20 month old EP2-deficient mice maintained normal cellular respiration and glycolysis. In control animals of the same age, macrophage function deteriorated with age.
Cells from control animals secreted pro-inflammatory factors, were poorly phagocytosed, and had fewer and poorly formed mitochondria. Macrophages deficient in EP2, on the other hand, had none of these problems, behaving like those of young mice.
Scientists gave mice one or both of two experimental drugs known to interfere with PGE2-EP2 binding in animals for a month. They also incubated cultured mouse and human macrophages with these substances. In doing so, the old myeloid cells metabolized glucose just like the young myeloid cells, reversing the inflammatory character of the old cells.
More strikingly, the drugs reversed the cognitive decline associated with the age of mice. Indeed, the old mice who received them performed recall and spatial navigation tests as well as the young adult mice. Blocking peripheral myeloid EP2 signaling is therefore sufficient to restore cognition in aged mice.
The blood-brain barrier EP2 inhibitor C52 improved glycogen synthesis, improved glycolytic response and TCA cycling of myeloid cells (microglia and peripheral macrophages), and improved cognitive performance.
Surprisingly, mice reaped these cognitive benefits even when treated with an EP2 inhibitor (PF-04418948) that does not cross the blood-brain barrier.
Since activation of the EP2 receptor has been identified as a common culprit in several neurological conditions associated with inflammation, such as stroke and neurodegenerative disease, selective small molecule antagonists targeting EP2 are being developed. to suppress PGE2-mediated neuroinflammation.
Several companies manufacture selective EP2 antagonists, but none are approved for human use. Pfizer's PF-04418948 was tested for safety in a Phase 1 study in 2010, but the company has discontinued clinical development.
However, targeting EP2 could be complicated. The receptor is known to regulate blood flow and blood pressure, and has been shown to protect the brain during stroke.