Scientists have known for some time that restricting calorie intake in laboratory animals can extend their lifespan and reduce their risk of developing diseases of older age, such as cancer, heart disease, diabetes, and Alzheimer’s disease.
Some studies suggest that calorie restriction may have health benefits for humans, too. However, achieving and maintaining a calorie restricted diet is challenging for the vast majority of people.
Identifying a drug that can mimic the metabolic effects of calorie restriction has, therefore, been an important goal of research into life extension.
One of the striking effects of calorie restriction is that it leads to a fall in core body temperature. However, it has been unclear what contribution this makes to the diet’s health benefits.
“It’s not easy to discern what’s driving the beneficial changes of calorie restriction,” says Prof. Bruno Conti, Ph.D., of the Scripps Research Institute in La Jolla, CA. “Is it the reduced calories on their own or the change in body temperature that typically happens when one consumes fewer calories? Or is it a combination of both?”
Some research does suggest that the reduction in core temperature contributes to the diet’s beneficial effects and is not simply a side effect.
Mice engineered to have a lower core body temperature live longer than normal mice, for example, regardless of whether their calorie intake is restricted.
Other studies have found that people with a naturally low body temperature tend to live longer compared with those whose core temperature is closer to the norm for humans.
To identify chemicals that might contribute to these health benefits, Prof. Conti and his colleagues compared the metabolites — products of metabolism — of mice housed at 22°C with those living in 30°C conditions. The researchers fed all of the mice a calorie restricted diet.
At 30°C, the bodies of both mice and humans reach “thermoneutrality.” At this point, their internal temperature balances the ambient temperature, making it difficult to reduce body temperature.
Scientists believe that thermoneutral conditions reduce some of the health benefits of calorie restriction.
Therefore, Prof. Conti and his team reasoned that comparing calorie restricted mice housed at these different temperatures would reveal the metabolites responsible not only for reducing body temperature but also for extending lifespan.
Specifically, they analyzed levels of metabolites in the animals’ blood and their hypothalamus, which is the part of the brain responsible for regulating feeding behavior and body temperature.
In comparison with mice allowed to eat as much as they wanted, calorie restriction induced the hypothalamus to produce larger quantities of a range of metabolites when the ambient temperature was 22°C — but not when it was 30°C.
The researchers then used artificial intelligence to single out which of these metabolites were likely to be biologically relevant.
Two metabolites that stood out were nitric oxide, a signaling molecule that dilates blood vessels, and an opioid called leucine enkephalin.
In further experiments on calorie restricted mice, they demonstrated that both chemicals play a role in temperature control.
These metabolites, and others that the researchers identified, could provide pointers for developing drugs that offer people the life extending benefits of calorie restriction without the need to follow an arduous diet.
The study findings feature in the journal Science Signaling.
The authors note that their experiments involved reducing the calorie intake of mice to 50% of their usual intake over a period of 8 days. This restriction is more extreme than the usual calorie restriction that scientists use in lifespan experiments (60% of usual intake or more).
They write that further research will be necessary to confirm that milder, longer lasting diets have similar effects on metabolism.
