Molecular Switch Reverses Chronic Inflammation & Aging

"My lab is very interested in understanding the reversibility of aging," said senior author Danica Chen, associate professor of metabolic biology, nutritional sciences and toxicology at UC 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 bulky collection of NLRP3 inflammasome immune proteins which are responsible for sensing potential threats to the body and launching an inflammatory response were shown to be essentially switched off by removing some molecular matter in a deacetylation process. Overactivation of NLRP3 inflammasomes is linked to a range of chronic conditions such as cancer, dementia, diabetes, and multiple sclerosis; this study suggests that drugs targeted towards deacetylation these NLRP3 inflammasomes may help to prevent and/or treat many age related conditions and even possibly age related degeneration itself in general. 

"This acetylation can serve as a switch," Chen said. "So, when it is acetylated, this inflammasome is on. When it is deacetylated, the inflammasome is off."

While studying macrophage immune cells and mice the SIRT2 protein was found to be responsible for deacetylating the NLRP3 inflammasomes. Animal bred with genetic mutations that prevent production of SIRT2 showed more signs of inflammation than their normal counterparts; these mice also exhibited higher insulin resistance which is associated with metabolic syndrome and type 2 diabetes. 

Older mice with immune systems that had been destroyed with radiation and then reconstituted with blood stems cells that produced either deacetylated or acetylated versions of NLRP3 inflammasomes were also studied; those given the off version of the inflammasomes were observed to have improved insulin resistance after 6 weeks, which indicates that switching off this immune machinery may reverse the course of metabolic 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."