Age-related diseases, including cardiovascular disease, cancer, diabetes, and Alzheimer’s disease are a growing problem worldwide as global life expectancy increases. As many elderly individuals have multiple age-related diseases, treating these diseases individually has limited benefits to healthspan and lifespan. Finding ways to target the aging process directly may be a better way to treat or prevent multiple diseases simultaneously.
What is calorie restriction and why should we study it?
Calorie restriction (CR), in which calories are restricted by approximately 20-40%, extends lifespan and prevents or delays many age-associated diseases, including mice, rats, and non-human primates. Very few people are likely able to stick to a CR diet, so understanding how CR works is critical so that we can identify dietary strategies and/or new drugs that can mimic a CR diet and increase health in a wide population.
Is calorie restriction about how much we eat or when we eat it?
The beneficial effects of a CR diet have largely been thought to be due to the result of reduced caloric intake. However, in the lab, CR is typically implemented through once per day feeding. This not only restrict calories, but also impose a prolonged daily fast, as CR animals rapidly consume their entire daily meal within ~2-3 hours, and then fast for ~21-22 hours until their next meal. While CR researchers have always been aware of this, only recently have other groups shown that time-restricted or meal feeding that involve a fasting period are beneficial, improving metabolic health and even extending lifespan.
We realized that these results complicate the interpretation of CR studies, as the effects of CR might result from reduced caloric intake – per traditional assumption – and some may be attributable not to the reduction in calories, but to prolonged fasting between meals.
What our study adds
We examined the role of fasting in the response to a CR diet using a novel series of diet regimens. We tested how mice would respond to a reduction in calories when we shortened the fasting period using automated feeders, or when we eliminated imposed fasting by feeding mice a low-energy density diet packed with indigestible cellulose, reducing caloric intake without the imposition of fasting. We also tested fasting alone, training mice to eat a normal day’s portion of food in 3 hours. We examined physiological and metabolic outcomes in multiple strains and sexes of mice, and in one strain and sex – C57BL/6J male mice – we examined detailed molecular outcomes and tested the role of fasting in the ability of CR to extend health and lifespan.
What we found
First, we determined that fasting is necessary for many of the beneficial effects of a CR diet. A prolonged fast in a CR diet is required 1) to improve insulin sensitivity, 2) to reprogram the epigenome and metabolome of the liver, and 3) to reduce frailty, preserve cognitive function, and extend lifespan. Indeed, mice fed a diet reducing calories without fasting actually lived for less time than control-fed animals. Secondly, we found that fasting alone could mimic the effects of a CR diet. Mice fasted each day without a restriction in calories looked much like CR-fed mice, and had improved insulin sensitivity. Moreover, CR and fasting both induced similar changes in the transcriptional profile of multiple mouse tissues.
Our work, which finds that fasting is necessary and sufficient for the benefits of a CR diet, challenges long-standing assumptions about how and why CR diets promote health and longevity, and opens a new doorway into understanding the effects of CR. For example, our work may explain in part why different methods of dietary restriction in worms and flies that do not involve fasting rely on different molecular pathways. Our work may be the tip of an iceberg that, with further research, may at long-last allow us to understand the mechanisms by which CR promotes healthy aging.
Our results are broadly in line with previous work, which has shown that a prolonged inter-meal interval has significant health benefits for both rodents and humans. Fasting is incorporated in many fad diets and religious traditions, suggesting that if our results hold in humans, fasting alone may be able to recapitulate the benefits of a CR diet. In conclusion, we find that prolonged daily fasting has powerful health benefits and underlies many benefits of a CR diet in mice, and that perhaps in the future, we will say “you are when you eat.”