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Researchers discover why older and overweight people develop metabolic diseases

[Jan. 12, 2024: JD Shavit, The Brighter Side of News]

Obesity and aging increase the risk of diabetes and fatty liver. Scientists have figured out what might help stop these problems. (CREDIT: Creative Commons)

As we age and gain excess weight, our bodies undergo a silent battle within their cells. This battle is marked by the overproduction of a chemical compound known as ROS, or reactive oxygen species.

This cellular stress, according to experts, has dire consequences, increasing the risk of diabetes and converting the body's 'brown' fat into the more harmful 'white' fat, which contributes to obesity. Additionally, it elevates the likelihood of accumulating excess fat in the liver, a condition known as fatty liver.


Alarmingly, approximately 25 percent of the Danish population currently grapples with fatty liver, a widespread issue that often leads to liver failure and even death in Western countries like Denmark.

Professor Simon Bekker-Jensen, a prominent researcher at the Department of Cellular and Molecular Medicine at the University of Copenhagen, recently delved into the factors triggering this adverse progression.


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"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," he explains.

Fatty liver, while initially not acutely dangerous, poses a significant threat. It can evolve into cirrhosis, a condition that can only be addressed through a liver transplant. In Denmark alone, around 700 people succumb to cirrhosis annually, highlighting the urgency of addressing this issue.


However, there is a glimmer of hope on the horizon. Professor Simon Bekker-Jensen and his colleagues have uncovered a potential breakthrough that could change the course of metabolic diseases caused by aging and obesity. Their research focuses on ZAK-alpha, a protein that plays a pivotal role in signaling cellular stress.

The most common metabolic disorders in the world. (CREDIT: Creative Commons)

The team demonstrated that by removing the ZAK-alpha protein, the negative progression from aging and obesity to metabolic diseases could be halted. Experiments conducted on mice and zebrafish yielded promising results. Bekker-Jensen elaborates, "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."


Addressing concerns about the applicability of mouse experiments to humans, Bekker-Jensen asserts, "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 ribotoxic stress response drives metabolic maladaptation in obesity and aging. (CREDIT: Science)

This groundbreaking research opens up new possibilities for the development of medicines that could treat and prevent metabolic diseases stemming from aging and obesity. While effective and affordable treatments already exist for diabetes, the discovery has profound implications for fatty liver, which remains a significant, unresolved medical challenge.


"ZAK-alpha is a well-established drug target that can be inhibited with small molecules. 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," Bekker-Jensen states.

ROS are a physiologically relevant source of translational impairment and activation of the stress kinases ZAKα, p38, and JNK. In obese and aging mice, this RSR drives metabolic maladaptation manifested by blood glucose intolerance, liver steatosis, and whitening of brown adipose tissue (BAT). (CREDIT: Science)

The path forward involves clinical studies, and there is already substantial interest from various clinicians eager to explore the potential of this breakthrough. With further research and development, this discovery could offer a lifeline to millions grappling with metabolic diseases worldwide, potentially transforming the landscape of medical interventions for the better.


In the fight against aging-related and obesity-related metabolic diseases, hope is on the horizon, and it's anchored in the remarkable potential of ZAK-alpha.

For more science news stories check out our New Discoveries section at The Brighter Side of News.


Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.


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