In 1935 Clive McCay published a paper demonstrating the pro-longevity effects of caloric restriction that would come to shape the future of longevity research. In McCay’s study, a simple 30% reduction of normal caloric intake was shown to impart robust gains in lifespan, becoming the accepted gold standard for lifespan-extending interventions. However, calorie restriction (CR) study designs continually incorporate one confounding factor. To achieve adequate beneficial caloric restriction, study animals are provided a daily, one-time meal, which they quickly consume in a matter of hours. This rapid consumption leads to a period of prolonged fasting between meals; therein lies the problem, as fasting has also been shown to provide benefits to both lifespan and healthspan. A study published in Nature Metabolism looks to address this long-standing issue and may lead to a complete rethinking of the calorie restriction model(CR).

In their recent publication, H. Pak et al. describe two novel feeding regimens designed with the intent of disentangling the once-per-day feeding behavior observed in typical CR studies. Diluted AL, a diet diluted with a non-digestible component providing 50% of the normal caloric density was made available to study animals continually; MF.cr, which provided the classic 30% caloric restriction, was provided in 3 meals per day. Through the use of these dietary regimens, researchers sought to gain insight into CR by eliminating both fasting and binging behaviors seen in previous experiments.

Similar to classic CR both of these non-fasting diets showed an improvement in body composition (reduced adiposity) and glucose metabolism (glucose tolerance). However, without a fasting component, these dietary interventions failed to achieve the increased insulin sensitivity and metabolic adaptions, such as increased fatty acid oxidation, typically seen in classic CR. Surprisingly, the chronic calorie restriction without fasting provided by the Diluted AL diet increased the frailty of experimental animals with age and was correlated to a decrease in quality of appearance, assessed by measuring standard factors such as coat appearance, kyphosis (skeletal posture), and distention of the abdomen. Moreover, without the benefit of a prolonged fast, calorie restriction alone was not only insufficient to extend but actually reduced lifespan when compared to animals given unlimited access to food, perhaps the most astounding finding of this study.

To further emphasize the role that fasting plays in classic CR, a third dietary regimen was created to discern if fasting alone was responsible for constituent metabolic adaptions. To provide an unrestricted amount of calories yet still maintain a prolonged fasting period, study animals were habituated to consume their full caloric intake within a 3-hour window and fast for the remaining 21 hours, what is referred to as a time-restricted diet (TR.al). This method resulted in a full recapitulation of the traditional CR diet with regard to body composition and metabolic adaptions (glucose metabolism, insulin sensitivity, and fatty acid oxidation) and further demonstrated that fasting is the critical component of classic CR.

This study makes clear that fasting is a potent means to achieve lifespan extension and, in the absence of fasting, chronic calorie restriction results in increased frailty and reduced lifespan, despite effectively reducing adiposity and circulating glucose. Taken together, these findings will compel further research to focus on the mechanisms involved in a fasting paradigm and reframe nearly a century of longevity research.