New research demonstrates that it may be possible to turn back the clock on age-associated diseases linked to chronic inflammation.
A recent study, led by researchers at the University of California, Berkeley (USA), has discovered that dysregulation of the NLRP3 inflammasome can contribute to age-associated chronic inflammation. The findings, published in Cell Metabolism, highlight a molecular switch that could be exploited to reverse age-associated diseases.
The NLRP3 inflammasome is a protein complex that induces inflammation via the release of proinflammatory cytokines in response to potentially threatening stimuli.
Chronic inflammation has been shown to occur at a greater rate as individuals age and is caused by overactivation of the immune system. Chronic inflammation has been indicated as a factor in a variety of diseases, including Alzheimer’s, Parkinson’s, diabetes and cancer.
“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,” explained the study’s senior author, Danica Chen (University of California, Berkeley).
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Utilizing murine models and a cell-based system to model aging-associated inflammation, Chen and the team identified the NLRP3 inflammasome as a key mediator of chronic inflammation and found that deacetylation could be used to ‘switch it off’.
It was demonstrated that SIRT2, an NAD+-dependent deacetylase, regulates the NLRP3 inflammasome via deacetylation. Mice bred to not express the SIRT2 protein exhibited higher levels of inflammation at 2-years-old when compared with controls, as well as higher insulin resistance, a condition linked to type 2 diabetes and metabolic syndrome.
Irradiated older mice that produced the deacylated NLRP3 inflammasome demonstrated improved insulin resistance after 6 weeks, suggesting that reversal of age-associated conditions is possible via the control of this immune pathway.
“I think this finding has very important implications in treating major human chronic diseases,” Chen commented. “It’s also a timely question to ask, because in the past year, many promising Alzheimer’s disease trials ended in failure.”
These findings demonstrate the utility of deacetylation as a control for the NLRP3 inflammasome, revealing the potential for the development of drugs targeted towards switching off the inflammasome for the prevention or treatment of age-associated diseases.