While chronic inflammation is a natural result of getting old and experiencing stress and toxin exposure, it has been theorized to be the basis for a wide variety of chronic diseases. Scientists have now found a molecule that acts as a kind of switch that regulates the biological mechanisms that underlie chronic inflammation. The findings, which were reported in Cell Metabolism, may offer insight into treatments for many conditions including cancer, diabetes, and Alzheimer's.
"My lab is very interested in understanding the reversibility of aging," said the senior study author Danica Chen, an associate professor of metabolic biology, nutritional sciences and toxicology at the University of California Berkeley. "In the past, we showed that aged stem cells can be rejuvenated. 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."
A protein complex called the NLRP3 inflammasome helps sense and respond to potential threats against the body. Overactivation of this complex has been associated with chronic diseases including dementia, diabetes and cancer.
Chen's team has determined that this complex can be inactivated by deacetylating or deleting a chemical group from the NLRP3 inflammasome. It may be possible to treat age-related chronic inflammation and the diseases that come with it by using drugs that aim to deacetylate or turn off the NLRP3 inflammasome.
"This acetylation can serve as a switch," Chen explained. "So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off."
Investigating further, the researchers learned that a protein called SIRT2 normally acts to deacetylate the NLRP3 inflammasome. Using a mouse model, the scientists genetically deleted the SIRT2 protein, and found that the mice had a greater degree of inflammation at the age of two than normal mice. The inflamed mice also had higher resistance to insulin, which is connected to metabolic diseases.
In another mouse model, the immune systems of older mice were knocked out with radiation and then replenished with blood stem cells. One group was given stem cells that were made to generate a deacetylated NLRP3 inflammasome, the other group got acetylated NLRP3 inflammasome. After six weeks, insulin resistance went down in the mice that received the inactivated or deacetylated version. It may be possible, therefore, to reverse the progression of inflammation-related disease.
"I think this finding has very important implications in treating major human chronic diseases," Chen said. "It's also a timely question to ask because, in the past year, many promising Alzheimer's disease trials ended in failure. One possible explanation is that treatment starts too late, and it has gone to the point of no return. So, I think it's more urgent than ever to understand the reversibility of aging-related conditions and use that knowledge to aid a drug development for aging-related diseases."