Mice genetically engineered to burn energy less efficiently live longer and are resistant to several age-related diseases, including cancer, hardening of the arteries, and obesity. The finding suggests that drugs based on this strategy could one day help stave off these age-related conditions in people, the researchers say.
Cells produce a molecule called ATP in their mitochondria that provides energy for the body. The weight loss drug 2,4-dinitrophenol (DNP) blocks this process, causing mitochondria to produce heat instead of ATP and forcing cells to metabolize stores of carbohydrates and fat for energy. Although popular in the 1930s, DNP use was discontinued in 1938 after several people died from overheating. More recent research in mice indicates that uncoupling proteins, which reside in the mitochondria and work like DNP, may offer an alternative strategy for weight reduction. Now, a team led by endocrinologist Clay Semenkovich of the Washington University School of Medicine in St. Louis, Missouri, has found that uncoupling protein 1 (UCP1) may also help ward off other conditions.
UCP1 is normally found in body fat, but the researchers genetically engineered mice to express low levels in their skeletal muscles. The mice had higher rates of metabolism but appeared healthy otherwise, and their core body temperature was only 0.5ºC higher than that of normal animals. The UCP1 mice lived longer on average, dying at 30 months compared to the 27-month life span of normal animals. Although cancer of the lymphatic system was the most common cause of death in the normal animals, killing 12 of 53, only four of the 51 UCP1 mice died from the disease.
That wasn't the only benefit. Mice that normally develop hardening of the arteries were protected from the condition after being bred to express UCP1 in their skeletal muscles. When UCP1 expression was triggered in the skeletal muscles of mice that were already obese, weight and blood pressure decreased, whereas weight increased in the normal obese animals, the researchers report in the December issue of Cell Metabolism.
Semenkovich's team speculates that the beneficial effects of UCP1 may be due to increased metabolism. Such activity can trigger molecular pathways that result in less of the chronic inflammation that has been associated with age-related diseases. Physiologist Kevin Conley of the University of Washington Medical Center in Seattle thinks something else is going on. The inefficient muscles may spur the genesis of more mitochondria, he says, which could lead to "a rebuilding of the cell that reverses cellular damage that occurs with age and age-related diseases."
Regardless of the mechanism, Semenkovich says the approach may be applicable to humans. "If we can figure out a way to target therapies to do this in skeletal muscles of people, it might be a way to treat age-related diseases," he says. Biologist Patrick Schrauwen of Maastricht University in the Netherlands agrees, but he adds that little is known about uncoupling proteins in humans and more investigation will be necessary before attempting to manipulate them to prevent disease.