A team of researchers from the National Institutes of Health (NIH) has identified an overactive enzyme that undermines health and promotes weight gain in middle-aged obese mice.
The prevalence of obesity is known to increase with age and to be associated with a higher risk for a number of cancers, cardiovascular disease – including stroke, myocardial infarction and heart failure – as well as type 2 diabetes.
Until now, the main contributing factors to this trend were thought to be purely environmental, led by an increased caloric intake and sedentary lifestyle around midlife.
However, Jay Chung, an endocrinologist at the National Heart, Lung, and Blood Institute (NHLBI), and colleagues have found that age-related weight gain is, at least partially, due to an active process driven by an enzyme regulating the expression of key genes involved in energy metabolism.
This enzyme is called DNA-dependent protein kinase (DNA-PK) and was shown in some of Chung’s earlier studies to increase in activity with age in middle-aged mice.
The new findings, presented in the journal Cell Metabolism, suggest that an overactive DNA-PK is associated with premature aging, defects in processes that reduce fat accumulatio, such as thermogenesis, and inflammation.
The NIH researchers tested whether suppressing DNA-PK expression and/or activity, thanks to a drug and without imposing calorie restrictio, in middle-aged mice caused weight loss or improved their health outcomes.
The experiment revealed that, in addition to preventing weight gain in the mice, inhibiting DNA-PK boosted the number of mitochondria in the animals by about two to three-fold, which is one known mechanism helping to reduce fat mass.
Between the two groups of mice being fed the same diet high in calories, those whose DNA-PK enzyme was blocked had a 40 per cent decrease in weight gain relative to those that retained normal DNA-PK activity.
Previous research published by Chung demonstrated other benefits linked with a decline in activity of DNA-PK, including increased insulin sensitivity, a reduction in blood sugar levels, and the activation of pathways controlling lifespan and longevity.
DNA-PK inhibitors have yet to be tested this way in humans. An increasing amount of research is also being done into the importance of daily calorie restriction or intermittent fasting to stay at a healthy weight and decrease disease risks.
A fasting-mimicking, low-carb diet can provide similar benefits to improve the cardiometabolic profile which deteriorates with age. For more information about eating a low-carb diet, visit our Low Carb Program.

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