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Enzyme produced during exercise protects against aging

Worldwide, the proportion of people over the age of 60 is predicted to double in the next three decades. An aging population brings with it many attendant health issues, not least of which is type 2 diabetes. This disease is characterized by insulin resistance, or an inability of the body cells to respond to insulin, and its treatment places a burden on public health systems globally. 

Insulin resistance is often associated with reduced physical activity and so, as we age and become less active, we are more prone to developing type 2 diabetes. However, the precise mechanism whereby physical inactivity leads to the development of insulin resistance has not been demonstrated.

Now, in a study led by Professor Tony Tiganis of Monash University, researchers have discovered the metabolic mechanism whereby physical activity levels and insulin resistance are connected in laboratory mice. 

According to Professor Tiganis, skeletal muscle cells constantly produce reactive oxygen species (ROS) and this process increases during physical exercise. Moderate exposure to these oxygen-derived free radicals is essential for normal cellular function in our bodies, and also induces the body’s adaptive response to produce antioxidants in defense. Regular exercise benefits health by enhancing antioxidant defenses against high levels of ROS, and this is one of the ways in which doing exercise makes us feel better.

“Exercise-induced ROS drive adaptive responses that are integral to the health-promoting effects of exercise,” said Professor Tiganis. However, a reduction in generation of ROS in skeletal muscle, brought on by decreasing physical activity as we age, is instrumental in the development of insulin resistance. 

The research team found that, in mice, an enzyme called NOX-4 is essential for producing exercise-induced ROS and therefore for the adaptive responses that drive metabolic health. They found that levels of NOX-4 increased in skeletal muscle after the mice exercised and that this led to increased ROS, which elicited the adaptive responses that protect mice from the development of insulin resistance.

Importantly, the scientists have shown that the levels of NOX-4 in skeletal muscle are directly related to age-associated decline in insulin sensitivity. “In this study we have shown, in animal models, that skeletal muscle NOX-4 abundance is decreased with aging and that this leads to a reduction in insulin sensitivity,” said Professor Tiganis.

These findings help explain how physical activity actually enhances insulin responses and promotes metabolic health. In addition, the enzyme that is key in this mechanism has the potential to be targeted by drugs in order to promote its activity, thereby protecting against the consequences of aging, such as diabetes. 

“Triggering the activation of the adaptive mechanisms orchestrated by NOX-4 with drugs, might ameliorate key aspects of aging, including the development of insulin resistance and type 2 diabetes,” said Professor Tiganis. 

“One of these compounds is found naturally, for instance, in cruciferous vegetables, such as broccoli or cauliflower, though the amount needed for anti-aging effects might be more than many would be willing to consume.” 

The study is published today in the journal Science Advances.

By Alison Bosman, Staff Writer

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