Aging and Obesity's 'Significant Unresolved Problem' May Have Solution

Scientists may have figured out a way to prevent the development of fatty liver disease, a condition that often comes with age and obesity.

Nonalcoholic fatty liver disease affects millions of people worldwide—100 million in the U.S. alone—and is the most common liver disease, even leading to liver cirrhosis and liver failure over time. It can be caused by the accumulation of fat in the liver, which is in turn driven by aging and weight gain.

Now, scientists have identified the factors triggering the conversion of fat into the form that causes the disease, according to a new paper in the journal Science.

"While there is already effective and affordable medicine for diabetes, I see great potential for fatty liver, which remains one of the most significant unresolved medical problems today," said Simon Bekker-Jensen, a professor of cellular stress responses at the University of Copenhagen and a co-author of the paper, in a statement.

Fatty liver may develop as a result of aging and weight gain, as these cause the cells in the body to undergo "stress," leading to an overproduction of a chemical compound called reactive oxygen species. These can damage cells and also lead to the conversion of "brown" fat in the body into "white" fat, which increases the likelihood of the fat being stored in the liver.

The chemical mechanisms behind why stress is triggered—leading to the conversion of fat —were unclear until now. The authors found that the trigger is a protein called ZAK-alpha.

"There is a protein called ZAK-alpha that 'signals' the rest of the metabolism system about the cells being stressed. This triggers a chain reaction leading to, among other things, fatty liver," Bekker-Jensen said.

If the ZAK-alpha protein is stopped from acting, the signal triggering metabolic stress is disrupted. This may stall aging and obesity from advancing metabolic diseases such as fatty liver.

The paper describes how the researchers prevented the ZAK-alpha protein from working in mice and zebra fish and found that this slowed the development of metabolic diseases.

"Mice in which we deactivated the ZAK-alpha protein were much healthier than those with it. In old age, they were more active, had stronger muscles, and, importantly, did not develop various metabolic diseases," Bekker-Jensen said.

He continued: "Mice are a very good model for the human metabolism system. In the laboratory, we can closely simulate the modern human lifestyle, including a lack of exercise and an unhealthy, calorie-rich diet. When mice become overweight, they develop largely the same metabolic diseases as seen in humans."

The authors hope that these findings could help develop treatments and medicines that target diseases like fatty liver as well as others that stem from aging and obesity.

"ZAK-alpha is a well-established drug target that can be inhibited with small molecules," Bekker-Jensen said. "Therefore, we anticipate that this new knowledge will attract interest from numerous companies actively working on developing and testing drugs against metabolic diseases, including fatty liver."

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