Researchers here make the point that calorie restriction studies in animals are also introducing a strong component of time restricted feeding, as animals tend to be fed once a day. Studies of intermittent fasting without calorie reduction have shown that this can produce a similar set of metabolic responses to a reduced calorie intake. Intermittent fasting and calorie restriction have been shown to improve health and extend healthy life spans via two overlapping sets of mechanisms, as assessed by various omics approaches. Thus the details of the approach to feeding animals any given fixed amount of calories (delivery of food per a day versus the same caloric intake split between several deliveries spaced over the day) will likely bias the results of any study.
Rodents are the most popular model to study caloric restriction (CR) in mammals. There are several ways to implement CR to rodents. One common method of food delivery is when a reduced amount of food (about 60%-80% of daily intake) is provided as a single meal once per day, usually, at the same time of the day. This type of CR induces strong food anticipation, and animals usually consume the food in a short (1-3 hr) period of time following a 21-hr period of fasting. Thus, CR is a self-imposed time-restricted (TR) feeding.
TR feeding, when an unlimited amount of food is provided for a limited time frame, significantly improves metabolic health of mice on high-fat (HF) or high-sugar diets, and this improvement in metabolism has been linked with restored or increased circadian rhythms in gene expression and signaling. Importantly, most TR studies were conducted in context of high-fat diet, obesity, or circadian rhythm disruption. Much less is known about the effect of TR on regular chow in healthy mammals.
Mealtime feeding (MTF) is another example of TR diet: 100% of daily food is provided once per day as a single meal; for unknown reasons, animals consume all food during a limited time frame in about 8-12 hr. Importantly, MTF increases longevity in mice independent of the caloric intake, suggesting that manipulation with the feeding schedule might have beneficial effects on longevity; however, the effect on lifespan is not as strong as the effect of CR. All three interventions: CR, TR, and MTF are periodic feeding/fasting diets. It was hypothesized that fasting can improve metabolism. Indeed, fasting mimicking diets such as ketogenic diet and intermittent fasting have positive effects on metabolism and, in some cases, on longevity which supports the potential importance of periodic fasting in health.
In order to understand the relative contribution of reduced food intake and periodic fasting to the health benefits of CR, we compared physiological and metabolic changes induced by CR and TR (without reduced food intake) in mice. CR significantly reduced blood glucose and insulin around the clock, improved glucose tolerance, and increased insulin sensitivity. TR reduced blood insulin and increased insulin sensitivity, but in contrast to CR, TR did not improve glucose homeostasis. Liver expression of circadian clock genes was affected by both diets while the mRNA expression of glucose metabolism genes was significantly induced by CR, and not by TR, which is in agreement with the minor effect of TR on glucose metabolism. Thus, periodic fasting contributes to some metabolic benefits of CR, but TR is metabolically different from CR. This difference might contribute to differential effects of CR and TR on longevity.