The struggle to maintain a healthy weight is a lifelong challenge for many of us. In fact, the average American packs on an extra 30 pounds from early adulthood to age 50. What’s responsible for this tendency toward middle-age spread? For most of us, too many calories and too little exercise definitely play a role. But now comes word that another reason may lie in a strong—and previously unknown—biochemical mechanism related to the normal aging process.
An NIH-led team recently discovered that the normal process of aging causes levels of an enzyme called DNA-PK to rise in animals as they approach middle age. While the enzyme is known for its role in DNA repair, their studies show it also slows down metabolism, making it more difficult to burn fat. To see if reducing DNA-PK levels might rev up the metabolism, the researchers turned to middle-aged mice. They found that a drug-like compound that blocked DNA-PK activity cut weight gain in the mice by a whopping 40 percent!
Jay H. Chung, an intramural researcher with NIH’s National Heart, Lung, and Blood Institute, had always wondered why many middle-aged people and animals gain weight even when they eat less. To explain this paradox, his team looked to biochemical changes in the skeletal muscles of middle-aged mice and rhesus macaques, whose stage in life would be roughly equivalent to a 45-year-old person.
Their studies, published recently in Cell Metabolism, uncovered evidence in both species that DNA-PK increases in skeletal muscle with age . The discovery proved intriguing because the enzyme’s role in aging was completely unknown. DNA-PK was actually pretty famous for a totally different role in DNA repair, specifically its promotion of splicing the DNA of developing white blood cells called lymphocytes. In fact, lymphocytes fail to mature in mice without a working copy of the enzyme, causing a devastating immune disorder known as severe combined immunodeficiency (SCID).
Further study by Chung’s team showed that DNA-PK in the muscle acted as a brake that gradually slows down metabolism. The researchers found in these muscle cells that DNA-PK decreases the capacity of the mitochondria, the powerhouses that burn fat for energy. The enzyme also causes a decline in the number of mitochondria in these cells.
The researchers suspected that an increase in DNA-PK in middle age might lead directly to weight gain. If correct, then blocking the enzyme should have the opposite effect and help stop these mice from piling on the pounds.
Indeed, it did. When the researchers treated obese mice with a drug called a DNA-PK inhibitor, they gained considerably less weight while fed a high-fat diet. The treatment also protected the animals from developing early signs of diabetes, which is associated with obesity. Fortunately, there was no sign of trouble in the immune systems of middle-aged mice treated with the DNA-PK inhibitor, presumably because those essential DNA splicing events in lymphocytes had already occurred. Neither was there a sign of serious side effects, such as cancer.
As people age and their weight increases, they also tend to become less physically fit. The new evidence implicates DNA-PK in that process, too. Obese and middle-aged mice treated with the DNA-PK inhibitor showed increased running endurance. With treatment, they ran about twice as long on a tiny mouse treadmill than they would normally.
While the findings are in mice, they suggest that an increase in DNA-PK could explain why it becomes so frustratingly difficult for many of us to stay lean and fit as we age. It also paves the way for the development of a new kind of weight-loss medication designed to target this specific biochemical change that comes with middle age.
Chung says they are now looking for DNA-PK inhibitors that might work even better than the one in this study. But given the fact that DNA-PK has other roles, testing its safety and effectiveness will take time.
While we await the results, the best course to help fight that middle-age spread hasn’t changed. Eat right and follow an exercise plan that you know you can stick to—it will make you feel better. Take it from me, a guy who decided eight years ago that it was time to shape up, stopped eating honey buns, got into a regular exercise program with a trainer to keep me accountable, and lost those 30 pounds. You can do it, even without a DNA-PK inhibitor!
 DNA-PK promotes the mitochondrial, metabolic, and physical decline that occurs during aging. Park SJ, Gavrilova O, Brown AL, Soto JE, Bremner S, Kim J, Xu X, Yang S, Um JH, Koch LG, Britton SL, Lieber RL, Philp A, Baar K, Kohama SG, Abel ED, Kim MK, Chung JH. Cell Metab. 2017 May 2;25(5):1135-1146.
Overweight and Obesity (National Heart, Lung, and Blood Institute/NIH)
Health Tips for Older Adults (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Jay H. Chung (National Heart, Lung, and Blood Institute/NIH)
NIH Support: National Heart, Lung, and Blood Institute; Office of the Director