In 1954, Denham Harman proposed the free radical theory of aging (FRTA), which posits that the accumulation of lipid, protein, and nucleic acid damage from free radicals results in a decline of function over time. Although the FRTA is one of the leading theories on aging today, it is still being modified. One major breakthrough was the identification of mitochondria as the major source of oxygen free radicals, such as superoxide and hydroxyl radical, and other reactive oxygen species (ROS), like hydrogen peroxide.

Support for the FRTA includes a decrease in ROS production in calorie restricted (CR) animals, a dietary strategy known to increase lifespan in a whole host of animals. A hot area of research is the search for calorie restriction mimetics, which mimic the lifespan extending effects of CR. By using CR mimetics therapeutically, we may be able to have lower cholesterol, blood glucose, and blood pressure, as well as lower instances of cancer, diabetes, neurodegeneration, and heart disease — and still be able to eat a hot fudge sundae every night.

Caldeira da Silva and Cerqueira suggest that mitochondrial uncoupling is an effective mimic of CR. In mitochondria, the electron transport chain uses electrons from glucose and lipids to pump protons across a membrane. This proton gradient can be used to make energy in the form of ATP through oxidative phosphorylation. The process is kind of like generating hydropower. Uncouplers work by putting a leak in the dam, which lets water through without going to the generator. They “uncouple” the electron transport chain from oxidative phosphorylation, thus reducing the efficiency of energy production. Although animals have uncoupling proteins (these proteins are important for thermogenesis, especially during hibernation), so far there are no known agonists. The researchers instead used low doses of the mitochondria uncoupler DNP. DNP was actually used as a diet pill because the body makes up for inefficient energy production by burning more fat. Unfortunately, all that potential energy in the proton gradient is released as heat, which can cause fatal fevers. (The FDA deemed DNP unfit for human consumption in 1938, although supplements are now sold online to bodybuilders).

Notably, the mice in the study had no change in body temperature. They were given doses 1000X below the lethal dose and plenty of space to let off any extra heat. The DNP treated mice ate the same amount of food as control mice but had lower body mass. The DNP treated mice showed many phenotypes observed in calorie restricted mice. Like CR mice, DNP treated mice had higher rates of respiration with lower production of ROS. These mice also had lower oxidative damage to their DNA and proteins, another hallmark of CR. They showed lowered blood glucose, lower triglycerides, and lower insulin. Most importantly, DNP treated mice showed an extended lifespan. This study suggests that mitochondrial uncouplers are an effective mimic of calorie restriction and might be a realistic therapeutic intervention for delaying aging and extending lifespan. Uncouplers may be even more effective than resveratrol, which may – or may not – only work on mice on a high fat diet.