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Inflammation, Ageing and Molecular Switches By Mrs Vera West

     Here is another one of those “we have got the secret of life” articles, although in this case this seems literally to be so, with researchers claiming to have discovered a molecular switch that can turn off chronic inflammation:
  https://www.sciencedaily.com/releases/2020/02/200206144837.htm
  https://www.sciencedirect.com/science/article/pii/S1550413120300097?via%3Dihub

“It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD+-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.”

     No, I did not get all of that either. How about the common persons’ summary?

“Chronic inflammation, which results when old age, stress or environmental toxins keep the body's immune system in overdrive, can contribute to a variety of devastating diseases, from Alzheimer's and Parkinson's to diabetes and cancer. Now, scientists at the University of California, Berkeley, have identified a molecular "switch" that controls the immune machinery responsible for chronic inflammation in the body. The finding, which appears online Feb. 6 in the journal Cell Metabolism, could lead to new ways to halt or even reverse many of these age-related conditions. "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."

In the study, Chen and her team show that a bulky collection of immune proteins called the NLRP3 inflammasome -- responsible for sensing potential threats to the body and launching an inflammation response -- can be essentially switched off by removing a small bit of molecular matter in a process called deacetylation. Overactivation of the NLRP3 inflammasome has been linked to a variety of chronic conditions, including multiple sclerosis, cancer, diabetes and dementia. Chen's results suggest that drugs targeted toward deacetylating, or switching off, this NLRP3 inflammasome might help prevent or treat these conditions and possibly age-related degeneration 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."

By studying mice and immune cells called macrophages, the team found that a protein called SIRT2 is responsible for deacetylating the NLRP3 inflammasome. Mice that were bred with a genetic mutation that prevented them from producing SIRT2 showed more signs of inflammation at the ripe old age of two than their normal counterparts. These mice also exhibited higher insulin resistance, a condition associated with type 2 diabetes and metabolic syndrome. The team also studied older mice whose immune systems had been destroyed with radiation and then reconstituted with blood stem cells that produced either the deacetylated or the acetylated version of the NLRP3 inflammasome. Those who were given the deacetylated, or "off," version of the inflammasome had improved insulin resistance after six weeks, indicating that switching off this immune machinery might actually 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."

     That is all pretty spectacular, if it turns out to be true. So, make a mental note of all of this, and see if a few years, decades, or centuries down the track, this turns out to be right. But, by then we will all be long gone. Gone with the wind, in fact.

 

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Wednesday, 05 August 2020
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