Since 2003 scientists have known that warm-blooded animals on calorie-restricted diets had lower core body temperatures and could live longer lives. Now, researchers at Scripps Research Institute in La Jolla, Calif., report in tomorrow's issue of Science that solely by lowering the core body temperature of mice, they could extend the lives of their experimental subjects by as much as 20 percent. They accomplished this feat--conferring an extra three months of life to the animals, which typically live just over two years--without varying diet.

"Calorie restriction is not for everybody," says Tamas Bartfai, chair of Scripps' Molecular and Integrative Neurosciences Department and a co-author of the study. He adds that to benefit, calorie intake must be lowered by 25 to 30 percent. "If you drop it less than that," he says, "it's meaningless." So, he and colleague Bruno Conti attempted to determine if core body temperature could be dropped without taking in less food.

In cold-blooded animals, body cooling is easy--you merely drop the ambient temperature in their surroundings. But in warm-blooded species, which continuously regulate body temperature, the task is more difficult: The brain must be tricked into thinking the local temperature--which it senses through clues like blood flow--is too hot so that it lowers the body temperature a few fractions of a degree. "This is truly so childishly simple in concept," Bartfai explains. "You have a thermostat and you put a candle next to it and you fool it, and then the core body temperature drops a little bit."

To accomplish this deception biologically, Bartfai and Conti genetically engineered mice to overexpress uncoupling protein 2, which causes the mitochondria in cells to produce heat instead of ATP, the fuel source of cellular activity. They focused this effect on the hypocretin neurons, which are brain cells in the lateral hypothalamus. As the heat diffused through the brain, it reached the preoptic area, an anterior section of the hypothalamus and the specific region that regulates body temperature. Feeling the heat, the preoptic area caused core body temperatures in the mice to decrease by 0.3 degree Celsius to 0.5 degree C.

The mice in the study could consume whatever they pleased. The transgenic mice ate as heartily as the control group, and the females weighed at least the same across both groups. Transgenic males weighed 10 percent more than normal males, but Bartfai says that the heft indicates that the transgenic mice required less energy to maintain their core temperature. The researchers reported no other physical or behavioral differences between the transgenic and control populations. "Few people would choose a lifestyle that limits their caloric intake," wrote Clifford B. Saper, a neurologist at Harvard Medical School, in a commentary in Science. The study, he added, "raises the question of whether mild hypothermia of 0.3 degree C to 0.5 degree C might be easier to tolerate than a lifetime of starvation as a way to increase longevity."

Demonstrating that body temperature could be decreased without modulating diet has brought Bartfai and Conti a lot of attention. Bartfai says a number of high-tech firms in San Francisco have approached his team with an interest in developing a small, inductive device to be put in people's brains. "It would be very easy to put it in--from the mouth, through the palette," Bartfai explains. "It would not be some huge brain operation."