How Scientists Reversed Aging, And What It Means For You
The Biology of Old Age
There are many suggested causes of old age. Telomere shortening, DNA damage, and depletion of stem cells are just a few of the proposed sources.
Recently, researchers found that a type of cell called a macrophage also plays a crucial role in aging. Macrophages are phagocytotic immune cells; they consume cells and other pathogens flagged by the immune system as dangerous. When macrophages need to consume a pathogen, their energy needs drastically go up.
Remember in biology when you were told that the mitochondria was the “powerhouse of the cell?” Cells produce energy through two main ways: glycolysis and oxidative phosphorylation. Both of these processes work inside the mitochondria by converting glucose into ATP, a molecule that acts as the cell’s “currency” on energy. Glycolysis converts glucose to ATP by degrading glucose into pyruvate. This reaction triggers the production of 2 ATP per molecule of glucose, which the cell can then use for other biological functions. Oxidative phosphorylation, on the other hand, is far more complicated, but also yields much more ATP. In a nutshell, it strips the electrons from hydrogen molecules so it can create an electrical gradient and produce up to 38 ATP per glucose molecule. Researchers found that as macrophages age, they tend to shut down these “metabolic pathways,” as they are called.
The way macrophages shut down these pathways is related to a crucial enzyme: PGE2. When PGE2 binds to its receptor EP2, it inhibits glycolysis and oxydative phosphorylation through a complex series of enzyme interactions. At the core of this is an enzyme called glycogen synthase. PGE2-EP2 interactions trigger the activation of glycogen synthase. Rather than convert the glucose to ATP, the activated glycogen synthase adds glucose to a glycogen chain, making it impossible for the cell’s many mitochondria to access the glucose when the cell needs energy. As a result, glycolysis and oxidative phosphorylation are inhibited, and the macrophage grows “exhausted,” since it no longer has the ATP needed to complete nearly every cellular task. Even worse, macrophages barely touched their massive glucose reserves in the form of glycogen.
These fatigued macrophages weren’t able to clear the “junk” in between cells, causing inflammation throughout the body. Specifically, in the case of brain cells, this inability to reduce buildup eventually led to cognitive decline we see as people grow older. One thing we see, is that as people grow older, their macrophages tend to have more EP2 receptors than in younger versions of cells, opening up the possibility that reducing the amount of PGE2-EP2 interaction could reduce symptoms of aging.
A Revolutionary New Treatment
Researchers decided to see if blocking PGE2 interaction with EP2 could “reactivate” glycolysis and oxidative phosphorylation and “reverse” symptoms associated with aging. By blocking off the receptor, so PGE2 could no longer interact with EP2 and would therefore be unable to activate glycogen synthase.
Researchers picked an inhibitor called C52 for the task. C52 was picked because it could infiltrate the blood-brain barrier, meaning it would be able to be able to inhibit EP2 not just in the body, but also in the brain. This was crucial, because without EP2 inhibition in the brain, the macrophages wouldn't be able to clean up debris and reverse cognitive decline. Mice were treated for one month with C52 in order to see if the EP2 inhibition had any significant changes.
The results were groundbreaking. Not only were improved cognitive ability and reduced inflammation noticed in mice treated with C52, but they also had healthier mitochondrial activity and far more ATP production, while decreased amounts of active glycogen synthase were observed.
How Does This Apply To Humans?
Humans, like mice, do have PGE2 and EP2. It is likely, that since mice, like humans, are mammals, that we share the same mechanism in regards to aging as well. If an inhibitor like C52 is tested in humans and shows promise, it could have revolutionary effects in reducing symptoms associated with aging.
However, the possibilities aren’t just limited to drugs. Resveratrol, flavonoids, and alkaloids are just a few of the many compounds that have been shown to inhibit EP2.
Resveratrol, for example, is a compound found in grapes and red wine. Resveratrol has been shown to inhibit EP2 and in some cases, reduce the production of PGE2. Resveratrol has actually been touted as an anti-aging supplement for quite some time now, so it would be very interesting to see if, should this be re-applied in humans successfully, their theory holds merit.
The same applies to blueberries. Blueberries have long been suggested as a “superfood.” They also have been shown to have large amounts of flavonoids, a group of compounds that have been seen to inhibit PGE2 production.
This theory could also have a lot of promise for Alzheimer’s disease patients. Alzheimer’s disease has been suspected to be caused by the buildup of misfolded proteins — it’s a macrophage’s job to remove these. If the macrophages are actually too exhausted to remove these misfolded proteins, a EP2 inhibitor might have significant effects in reducing Alzheimer’s symptoms.
This actually falls in line with previous research. Many patients on anti-inflammatory medicines have shown to have reduced risk for Alzheimer’s. This may be due to the fact that alkaloids, a group of compounds found in some painkillers and anti-inflammatory medicines, have been found to also reduce PGE2 production. Its important to keep in mind, however, that EP2 inhibition has currently only been found to work in mice. While the study does show promising results, its important to take this with a grain of salt. We don’t know how it works in humans, and red wine and blueberries could do wonders to anti-aging, but they could also have no effect. Frankly, we just don’t know yet whether this phenomenon will make us younger until it is tested in humans. On the bright side, if PGE2-EP2 interactions are found to effect aging in humans, not only could it help reduce inflammation and cognitive decline in humans, but it could also significantly those with diseases like Alzheimer’s.
References
https://www.frontiersin.org/articles/10.3389/fphar.2018.00976/full
https://www.nature.com/articles/s41586-020-03160-0
