Aging and Chronic Inflammation Reverse are Possible with ‘Molecular Switching.’

When our body's immune system starts to work harder than the usual pace because of stress, old age and environmental toxins, chronic inflammation occurs. Many dangerous diseases like diabetes, cancer, Alzheimer's, Parkinson's can have easy access to our bodies for chronic inflammation.

According to the new findings of the scientists from the University of California, Berkeley, there is a molecular "switch" controlling the immune machinery. So, it can control our bodies’ chronic inflammation. The study was published in the Cell Metabolism journal on Feb. 6. Scientists are in the opinion that this type of switching technologies can be used not only to halt but also alter many other age-related problems.

Danica Chen is the senior author of the study and an associate professor of nutritional sciences, metabolic biology, and toxicology at UC Berkeley. She says, "My lab is very interested in understanding the reversibility of aging. 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."

Chen and the team focused on a massive collection of NLRP3 inflammasome; a kind of immune protein in this research. They have invented a process that enables these proteins to sense any threat in our body and respond accordingly by launching an inflammation response. The deacetylation process can switch off the response by removing a small bit of molecular matter.

If the NLRP3 inflammasome becomes overactive, it can lead to many critical chronic conditions such as dementia, cancer, multiple sclerosis, and diabetes. The study by Chen and the team points out that the deacetylating process can stop and treat age-related conditions.

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

The team studied mice and macrophages, an immune cell. Scientists found that SIRT2 protein deacetylates the NLRP3 inflammasome. They used genetic mutation to breed a group of mice, and they lacked SIRT2 producing. As a result, this group of mice showed more inflammation signs in old age than the other normal group. The lack of SIRT2 is related to higher insulin resistance paving the way for type 2 diabetes attack.   

As a next step of the study, the team focused on the destroyed immune system of the old mice. Radiation destroyed their system. Researchers used the acetylated or deacetylated versions of the NLRP3 inflammasome for reconstituting the immune systems. The mice with the deacetylated versions showed better insulin resistance within six weeks. So, this switching can reverse many metabolic diseases. 

Chen says, "I think this finding has very important implications in treating major human chronic diseases. 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."

Co-authors of this research carried out their work in different institutes. Hou-Hsien Chiang, Hanzhi Luo, and Ming He worked on this previously at UC Berkeley. Mingdian Tan, Wei-Chieh Mu, Zhifang Zheng, and Rika Ohkubo are also from there. Hao Wu, Li Wang, and Qi Qiao continued their research from Harvard Medical School. Shimin Zhao did this from Fudan University.  

The National Institutes of Health supported the study with several grants having the serial number of R01DK101885, R01AG 063389, R01Al124491, R01DK117481, R01AG063404, and  DP1HD087988. The France-Berkeley Fund, the Dr and Mrs James C.Y. Soong Fellowship, the ITO Foundation Scholarship and the Honjo International Scholarship, the National Institute of Food and Agriculture, a Glenn/AFAR Scholarship, the Government Scholarship for Study Abroad (GSSA) from Taiwan also funded the research.