This open access paper provides a good high-level overview of what is known of the molecular mechanisms underpinning the beneficial response to calorie restriction and intermittent fasting. In short-lived species, quite sizable gains in life span are possible, though this is not the case for longer-lived species such as our own. The metabolic responses to calorie restriction and intermittent fasting are not the same; they appear to function through an overlapping set of mechanisms, such that intermittent fasting without reduction in overall calories can still improve health and extend life.

The ultimate goal for animal studies on calorie restriction (CR) and intermittent fasting (IF) is to identify the conserved molecular mechanisms that can extend the healthspan of humans. Healthspan, the period of life that is free from disease, is measured by examining declines of functional health parameters and disease states. Because healthspan is a multifactorial complex phenotype that is significantly affected by genotypes (G) and environmental factors (E) as well as complicated interactions between them (G × E), measuring healthspan often gets complicated.

Delayed functional aging in one parameter is not always necessarily linked to the extension of healthspan in different health parameters. In fact, by depending on the types of health parameters and experimental approaches, different healthspan results were observed from the studies that used the same long-lived mutant animals. Unlike healthspan, lifespan is unequivocally recorded by simply following the mortality of individual organisms. Lifespan extension in animal models is strongly correlated with a decrease in morbidity and an increase in health. Therefore, although we believe that results of health-related parameters from animal CR/IF studies are likely to be translatable to human healthspan, we will focus on the mechanisms of lifespan extension.

Although not complete, studies for the last two decades on CR have provided a great amount of details about the mechanisms of CR. Recent advances in omics and bioinformatic techniques followed by organism level genetic perturbation analyses significantly extended our knowledge on the molecular mechanisms that mediate lifespan extension by CR. A current understanding is that CR works through the key nutrient and stress-responsive metabolic signaling pathways including IIS/FOXO, TOR, AMPK, Sirtuins, NRF2, and autophagy. While these pathways regulate CR independently, cross-talks among these pathways as well as upstream master networks such as circadian clock were also suggested to regulate lifespan extension by CR.

Although the number of reports on IF is less than CR, recent studies clearly demonstrated that IF also extends lifespan in both vertebrate and invertebrate model organisms. However, there is still a lack of comprehensive understanding for the mechanisms responsible for lifespan extension by IF. As nutrient-dependent interventions, CR and IF were suggested to share a common strategy: the reduction of caloric intake and nutrients that limit longevity. In fact, CR and IF also result in common metabolic and physiological changes in multiple tissues and organs. For example, ketone bodies, insulin sensitivity, and adiponectin are increased while insulin, IGF-1, and leptin are decreased. Overall inflammatory response and oxidative stress are reduced by both regimens. They also cause similar behavioral changes such as increased hunger response and cognitive response.

Accordingly, it is widely accepted that common molecular mechanisms may mediate the lifespan extension by CR and IF. A proposed model for the mechanisms underlying the lifespan extension by CR and IF relatively follow the notion that both CR and IF alter the activity of common key metabolic pathways, namely, TOR, IIS, and sirtuin pathways. However, there must be independent mechanisms as well due to one major difference between CR and IF in that IF aims to extend lifespan without an overall reduction in caloric intake by taking advantage of the molecular pathways that respond to fasting.