NIH Study Finds Enzyme That Could Explain Weight Gain in Middle Age

The study may help explain a phenomenon noticed by researchers and primary care physicians alike: adults in their 40s may eat less and exercise more, but not see the results in weight loss.

The discovery of an enzyme that triggered mid-life weight gain in mice could lead to a new target for drug makers seeking ways to help middle-aged adults battle obesity, according to officials at the National Institutes of Health (NIH) who produced the study.

“Our society attributes the weight gain and lack of exercise at mid-life (approximately 30-60 years) primarily to poor lifestyle choices and lack of will power, but this study shows that there is a genetic program driven by an overactive enzyme that promotes weight gain and loss of exercise capacity at mid-life,” lead study author Jay H. Chung, MD, PhD, head of the Laboratory of Obesity and Aging Research at the National Heart, Lung, and Blood Institute (NHLBI), said in a statement. (The NHLBI is part of NIH.)

The NIH study is the first to show a link between the enzyme, known as DNA-PK, and obesity and exercise capacity. Researchers blocked DNA-PK with an inhibitor in a group of mice who consumed fatty foods, and withheld it in a control group. The group with the blocked enzyme showed a 40% drop in weight gain compared with the other group. Results were published in Cell Metabolism.

For years, researchers and primary physicians alike have seen that adults have a harder time losing weight as they age, particularly as they reach their 40s. Although new weight-loss pills have reached the market, not everyone benefits. The results of the new NIH study suggest there has been a basic lack of understanding about the changes in the body that cause people to gain weight at mid-life, particularly at the abdomen, which can increase cardiovascular risk.

As an endocrinologist, Chung said the mid-life “obesity paradox” always baffled him—he saw adults gain weight between ages 20 and 50 even though food intake decreased (the typical amount was about 30 pounds). For years, weight gain through adulthood has been blamed on sedentary lifestyles and unhealthy diets, but Chung and fellow researchers suspected there was something more at work.

Helping adults in their 40s and 50s avoid weight gain could help prevent a host of diseases—from diabetes to cancer to Alzheimer’s disease.

The researchers examined biochemical changes that occur in middle-aged animals, and discovered that DNA-dependent protein kinase, or DNA-PK, becomes more activity with age. This was important because DNA-PK works to convert food to fat and simultaneously reduces the body’s ability to convert food to fuel. Thus, this aligned with a frustration reported by middle-age patients: increasing amounts of exercise and declining amounts of food intake do not translate into weight loss.

Chung and his team speculated that curtailing DNA-PK activity may reduce fat accumulation and increase mitochondria, the parts of cells that turn fat into energy. They fed the intervention group of mice a drug that blocked the DNA-PK that raised mitochondria levels in skeletal muscle, boosted aerobic fitness, and helped the mice lose weight. The intervention also reduced type 2 diabetes.

“The study opens the door to the development of a new type of weight-loss medication that could work by inhibiting DNA-PK activity,” Chung said. He pointed out, however, that an FDA-approved drug is a long way off, because DNA-PK inhibitors have not been tested in humans.

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