Evidence for the Calorie Restriction Response to be Triggered by Energy Imbalance

Calorie restriction, eating fewer calories while still obtaining needed levels of micronutrients, reliably extends life in mice. The metabolic response to calorie restriction is sweeping, changing near every aspect of cellular biochemistry. This makes it challenging to understand how calorie restriction works in detail to improve health and slow the aging process: when everything is changing, how to pick out the important changes? There is a good argument for the effects on life span to derive from upregulation of the cellular maintenance process of autophagy, but there are a great many other potentially contributing mechanisms. The calorie restriction response is triggered by nutrient sensing mechanisms, but even when only considering these triggers there is considerable room to debate how exactly this works, as the research here demonstrates.

Researchers have long debated why restricting a rodent's food intake increases its lifespan. One theory, he explains, suggests that rodents fed less food have fewer calories to metabolize and so produce less oxidants and other by-products of metabolism that damage cells. Another possibility is that the absolute number of calories matters less than the difference in calories consumed versus calories metabolized. Perhaps eating a massive number of calories is not detrimental to health as long as the animal is burning them off efficiently. But testing this theory by encouraging mice to exercise more, for example, can be tricky, because exercise comes with all sorts of other health benefits.

Researchers instead tested the impact of accelerated calorie burning by studying mice that were kept in cages at two different temperatures. Mice in the warmer cages were allowed to eat as much as they liked, and then mice in the cooler cages were given the same amount of food that their warmer-caged counterparts consumed. The key difference was that the cooler mice had to burn more energy to maintain their body temperatures.

In one experiment, researchers tracked biomarkers of health in mice kept at cooler temperatures for 11 weeks. Some mice were housed at 10 °C and fed the same diet as mice in 21 °C cages. Others were housed at 21 °C and fed the same diet as mice in 30 °C cages. In both cases, the cooler mice had lower levels of insulin. Their body weights also dropped and then stabilized at roughly 75% of the warmer-caged mice. A second experiment, which tracked mice over the course of their lifespans, revealed that mice housed at 22 °C lived about 20% longer, on average, than mice fed the same diet at 27 °C. The cooler mice also seemed to remain healthier as they aged, maintaining better balance and a more coordinated gait compared to those in warmer cages. "It's not simply the caloric intake or the macronutrient or protein intake or any one component. It is the interaction of those relative to the energy balance overall."

Link: https://www.pnas.org/post/journal-club/energy-mismatch-helps-mice-eat-less-live-longer

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