Inflammation is the body’s way of fighting off threats, but if it gets out of hand it can lead to painful chronic inflammation, and even contribute to diseases like Alzheimer’s and diabetes. Now, researchers at UC Berkeley have identified a molecular “switch” in mice that could effectively turn off that reaction, potentially reversing these conditions and possibly even aging itself.
At the heart of the study is what’s known as the NLRP3 inflammasome. This group of immune proteins keeps a watchful eye out for infections and other invaders to the body, and if it detects something it launches an inflammatory response to fight it off.
Normally this is an important function of the immune system, but sometimes the body stays in this heightened state for too long, causing chronic inflammation. This can not only cause pain and discomfort, but can lead to other chronic conditions like multiple sclerosis, cancer, diabetes, Alzheimer’s and Parkinson’s.
But on the new study, the researchers found a way to essentially switch off the NLRP3 inflammasome. This is done through a process called deacetylation, where a fragment of molecular matter is removed.
“This acetylation can serve as a switch,” says Danica Chen, senior author of the study. “So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off.”
Specifically, the team found that a protein called SIRT2 acted as the switch. They engineered mice that were unable to produce SIRT2, and over two years compared their health to a control group. They found that the test animals showed more signs of inflammation, and had higher insulin resistance – a problem that arises during type 2 diabetes.
In other tests, the team studied two groups of older mice that had had their immune systems effectively “rebooted.” The animals’ immune systems were reconstituted to have either the acetylated or deacetylated versions of the NLRP3 inflammasome. The differences were then compared after six weeks, and the researchers found that the deacetylated mice had better insulin resistance than the control group.
The team says that the study shows how drugs that effectively switch off NLRP3 could help treat conditions associated with inflammation, including diabetes, multiple sclerosis, Alzheimer’s, and Parkinson’s. Another molecule, dubbed MCC950, has already been fairly successful in trials as an NLRP3 blocker, and in the long run these kinds of drugs could even be applied to aging itself.
“My lab is very interested in understanding the reversibility of aging,” says Chen. “Now, we are asking: to what extent can aging be reversed? And we are doing that by looking at physiological conditions, like inflammation and insulin resistance, that have been associated with aging-related degeneration and diseases.”
The research was published in the journal Cell Metabolism.
Source: UC Berkeley
