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Studies in mice led by scientists at the Scripps Research Institute have tied some of the biological effects of calorie restriction (CR)—which is known for its life-extending effects in animals—to metabolic molecules that are affected by changes in body temperature. The discovery helps to explain some of the elusive science behind the health benefits of calorie restriction, and indicates that targeting metabolic pathways could potentially mimic the effects of CR in humans. The findings may pave the way for developing compounds that reproduce the beneficial effects of reduced body temperature.

“The data we collected showed that temperature has an equal or greater effect than nutrients on metabolism during calorie restriction,” said Bruno Conti, PhD, whose team co-led the study alongside Scripps Research colleague Gary Siuzdak, PhD. The investigators reported on their findings in Science Signaling, in a paper titled, “Metabolic adaptation to calorie restriction.”

Cutting calories significantly may not be an easy task for most people, but it is tied to a host of health benefits ranging from longer lifespan to a much lower chance of developing cancer, heart disease, diabetes, and neurodegenerative conditions such as Alzheimer’s disease. Conti has spent years studying how and why calorie restriction leads to better health, with the ultimate goal of translating the findings into strategies for mimicking what happens naturally when a person eats less.

Animals—including mammals such as humans and mice—that are endothermic can maintain their core body temperature (Tb) by balancing heat production and heat dissipation. One consistent observation is that when mammals consume less food, their body temperature drops. It’s evolution’s way of helping us to conserve energy until food is available again, Conti explained. “This adaptive response is believed to have evolved to reduce energy expenditure when nutrients are scarce, effectively ‘gaining time’ to find food,” the researchers noted. It makes sense, considering that up to half of what we eat every day is turned into energy simply to maintain our core body temperature. But further than this, the researchers continued, “time is exactly what the organism gains when experimentally subjected to CR, because lifespan is prolonged.”

Research in rodents has also shown that reduced core body temperature isn’t just a consequence of CR, but also contributes to its beneficial effects. Conti’s previous work had shown that temperature reduction can increase lifespan independently of calorie restriction, and that these effects involve activation of certain cellular processes, most of which remain to be identified. Independent studies, such as the Baltimore Longitudinal Study of Aging, also found that reduced body temperature is associated with longevity.

On the flip side, studies have shown that preventing body temperature from dropping can actually counteract the positive effects of calorie restriction. Notably, in an experiment involving calorie-restricted mice, anticancer benefits were diminished when core body temperature remained the same. “It’s not easy to discern what’s driving the beneficial changes of calorie restriction,” Conti said. “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?”

 

For their newly reported research, Conti and his team designed an experiment that would allow them to independently evaluate the effects of reduced nutrients and those of body temperature. They compared one group of calorie-restricted mice housed at different ambient temperatures (Ta). One group of animals was housed at room temperature—about 68˚ F (22˚ C), and the other at 86˚ F (30˚ C). The temperature of the warmer environment is considered high enough to invoke thermoneutrality, a state at which most animals cannot easily reduce their body temperature. “The rationale for our study is that thermoneutrality exacerbates inflammatory and metabolic disorders, prevents the hypothermic response to CR, and antagonizes the beneficial effects that CR has on longevity,” the investigators noted.

Siuzdak and his team used a technology they developed called activity metabolomics to measure metabolites in the two groups of mice. This approach allowed them to look for molecules in the bloodstream and in the hypothalamus of the brain, which were changed by the reduction of either nutrients or body temperature. This approach provided the first comprehensive profiling of the metabolites that are changed by temperature reduction.

Through a computational analysis of results from both groups of mice, the scientists were able to prioritize those metabolites that were most responsible for triggering changes to core body temperature. They found that although calorie restriction altered many metabolic pathways involved in energy expenditure both systemically and in the hypothalamus in the 22° C group, fewer of these changes occurred in the group housed at thermoneutrality. “We found that thermoneutrality greatly affected the metabolic changes associated with CR, counteracting nearly 40% of changes in the plasma and up to 78% of changes in the hypothalamus,” they wrote. “Many of these metabolites affected by thermoneutrality play a pivotal role in energy exchange with the environment, as well as in fuel consumption and energy expenditure during CR.”

Further analysis attributed the metabolic effects of calorie restriction to the molecules nitric oxide and leucine enkephalin, which were produced in higher amounts in the hypothalami of the mice housed at 22° C. In a separate experiment, the investigators also showed it is possible to administer certain metabolites as a drug to affect body temperature.

Conti said further work to validate the changes induced by temperature during calorie restriction should provide novel targets for future medicines he calls “temperature mimetics,” which could offer the health-promoting effects without having to reduce body temperature. “In the future, it will be interesting to investigate whether the biochemical pathways that regulate physiology of the hypothermic response also affect healthspan and how this may be affected by Ta,” the authors concluded.

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