cGAS-STING: Might Slowing this Necessary Immune Reponse Assist Aging Brains?
Studying inflammation caused by the cGAS-STING pathway and how to combat it
Background
When thinking about aging, inflammation is often a common issue that comes to mind. In order to reduce this painful side effect, scientists have begun studying if changing an existent human process (cGAS-STING) could be beneficial. cGAS-STING stands for Cyclic GMP-AMP Synthase — Stimulator of Interferon Genes. It is part of the human innate immune system that works to immediately identify and attack any antigen it comes across. The pathway functions in the following way: cGAS is an enzyme in a cell’s cytoplasm and detects when a pathogen is present. When a pathogen is found, the cGAS enzyme produces cyclic GMP-AMP, or cGAMP. This cGAMP molecule then binds to a STING protein in a cell’s endoplasmic reticulum, which signals the immune system to begin attacking the cell.
Because of the immune system work that cGAS-STING is involved with, it is also known to produce inflammation. In this article, the researchers were interested in studying the link between cGAS-STING and inflammation related to aging. If this inflammation was related to aging, then the scientists wanted to know if they would be able to reduce the effects of neurodegeneration (the loss of neurons in the brain, commonly found in older adults with diseases such as dementia or Alzheimer’s).
Summary
In order to study this linkage, researchers used two groups of mice with modified genes. One group of mice was STING-deficient, and the other was modified to express the cGAS gene. The mice went through several cognitive tasks so that the researcher’s could determine their brain health and inflammation levels.
The STING-deficient mice were created by the injection of H-151, which blocked STING function (the function that produces inflammation once a pathogen is detected by cGAS). After STING-deficient mice and non-deficient mice reached the age of 26 months, their inflammation levels were observed by looking at inflammation in various areas of the mice’s bodies. Mice with STING deficiency showed a significant reduction in inflammation in several areas, such as kidneys (low levels of creatinine and urea which are more prevalent when inflammation levels are high) and decreased amount of macrophages in the mice’s adipose (fat) tissue. In terms of cognitive health, mice treated with H-151 in order to be STING-deficient scored significantly higher in endurance time and strength abilities, as well as scored higher in both spatial (remembering locations and the space between objects) and associative memory (remembering relationships between objects that seem to have no correlation). These findings demonstrate how STING inhibition can serve as a means of prevention for issues with strength and memory during the aging process.
In addition, the scientists looked at the hippocampus (a major part of the brain that involves memory), and found that the adult mice without STING-deficiency were more prone to microgliosis (a condition that causes overactive immune cells in the brain). In those with the deficiency, the mice had significantly reduced microgliosis as well as increased healthy neurons throughout the hippocampus.
These results of the study suggest that the altering of this natural pathway may lead to better memory and brain health as a whole in the aging process. The next step in this research would likely be to continue to apply this to human trials and observe how the cGAS-STING process in the human body reacts to inflammation. The findings may one day prove to be effective in brain diseases such as Parkinson’s or Alzheimer’s and this fascinating study will hopefully be a launchpad to continued research trials.
