Two new studies led by scientists at The Scripps Research Institute (TSRI) could guide future therapies to improve health and lifespan. Together, the studies in animal models shed light on how reducing calorie intake directly influences lifespan by also reducing body temperature. Importantly, the researchers also identified a molecule that responds to lower body temperatures to regulate lifespan in fruit flies, giving scientists a target for future pharmaceuticals that may increase longevity.

“This exciting discovery demonstrated that the main biochemical pathway that regulates aging acts by lowering body temperature,” said TSRI Professor Bruno Conti, who led the first study.

“Flies also live longer in the cold and the mechanisms that regulate this response overlap with key aging pathways,” said TSRI Associate Professor William Ja, who led the second study on TSRI’s Florida campus.

The new research was published in the journal Proceedings of the National Academy of Sciences.

Scientists have long known that reducing calories - without causing malnutrition - can extend lifespan in animals.

“Researchers had found that mice that eat 40 percent less than normal live much longer - and they actually look younger,” said Conti.

Calorie restriction can also lead to a lower core body temperature. This just makes sense, Conti explained. “If there’s no food, it’s smart to reduce body temperature. You’re reducing your energy expenditure,” he said. “It’s fundamental for the survival of the organism.”

The new study finally shows how these two observations are related. Conti and his colleagues found that it all comes down to how the body uses a molecule called the IGF1 receptor. Previous studies had shown that lowering the activity of the IGF1 receptor can extend lifespan.

Using genetically engineered mouse models, Conti’s team found that calorie restriction provides the signal to lower body temperature, and that this occurs by reducing the activity of the IGF1 receptor in the brain.

“For the first time, we showed that calorie restriction, body temperature and the IGF1 receptor are part of the same pathway,” said study first author Rigo Cintron-Colon, a graduate student in the Conti Lab.

Inspired by observations that female mice seem more sensitive to calorie restriction, the researchers said their next step is to investigate whether male and female sex hormones affect the pathway.

The second study, led by Ja, drilled even deeper into the relationship between temperature and lifespan.

Using fruit flies as a model, Ja and his colleagues found that colder ambient temperatures result in a “metabolic brake” to slow down the production of new proteins in the cell. A molecule called 4E-BP responds to cold by sparing select proteins and regulating longevity.

Although the Conti and Ja studies were conducted independently, they reveal another intriguing parallel. The biochemical pathways implicated by the two publications are related and interact extensively. “Surprisingly, even though flies don’t maintain their body temperature like mammals do, organisms may use similar mechanisms to regulate lifespan in response to changes in temperature,” said Ja.

“Our results not only shed light on the temperature effect, but they also establish a parallel between temperature and diet, because 4E-BP is thought to play a role in diet-related life extension as well,” added Dr. Gil Carvalho who, along with Dr. Ilaria Drago, was a co-first author on the publication.

“We also show that the effects of diet on aging are cumulative,” Ja said. “Environmental factors such as temperature and diet seem to affect our health gradually over the years, so the sooner we implement healthy changes, the better off we're likely to be.” If the work in fruit flies holds true in humans, he noted, the research emphasizes the need to make healthy decisions f