Introduction

Life forms on our planet have evolved under the strong influence of a daily light/dark cycle. With sunlight as the primary source of energy for photosynthesis, the daily production of photosynthetic biomass has a predictable diurnal rhythm. The daily cyclical production of photosynthesized chemical energy is at the base of the food chain. Daily changes in light and darkness result in diurnal rhythms in other environmental parameters such as temperature and humidity. Such a predictable and robust daily rhythm in food availability and environmental factors has led to the evolution of an ∼24 hr internal timing mechanism or circadian rhythm to enable organisms to anticipate daily changes and to optimize fitness. Fundamental to this 24 hr rhythm is the ability to acquire food when it is available and to store a portion of these resources for utilization during the rest of the day (i.e., the fasting period) without compromising fitness and vitality. The fasting period also serves as a time for standby and repair so that the organism is fit and competent to harvest energy when light (for photosynthetic organisms) or food becomes available. While many non-photosynthetic lifeforms with short lifespan (< a few days) may not derive profound benefit from a circadian timing system, they share fundamental biochemical mechanisms for acquiring and storing food when it is available and then utilizing this stored energy during a quiescent period of fasting for repair, stress resistance, and vitality.

Inherent to this alternating cycle of feeding and fasting (irrespective of circadian rhythm-proficient or circadian rhythm-deficient organisms) is the theory that “fasting physiology” (biochemical processes associated with fasting) is triggered once stored energy is being utilized and therefore does not occur during the feeding period. This theory also highlights the notion that certain aspects of repair and rejuvenation that are integral to fasting-re-feeding physiology may be associated only with fasting. Hence, intermittent and periodic fasting may represent important factors in optimizing lifespan and healthspan. In circadian rhythm-deficient organisms, the optimal duration of fasting (i.e., one that avoids a low energy state that compromises viability) depends on the extent of stored nutrients and ambient conditions. These simple organisms have made tremendous contributions to the experimental dissection of molecules and mechanisms of cell-autonomous fasting physiology that is conserved across species. In circadian rhythm-proficient organisms, the inherent circadian oscillator has programmed a natural cycle of feeding and fasting that occurs with ∼24 hr periodicity. However, even oscillator-proficient organisms have retained mechanisms to adapt to a few days of reduced or no energy intake without substantial loss of vitality. As a result, the oscillator-proficient organisms can benefit from sustained daily rhythms as well as from periodic fasting of several hours. Reducing energy intake on a daily basis, as in caloric restriction, may allow the fasting physiology to be triggered sooner and to be sustained for longer periods of time than when consuming standard or excessive amounts of calories. Similarly, restricting the timing of food intake to a few hours without an overt attempt to reduce caloric intake, as in time-restricted feeding (TRF), may trigger the fasting physiology after a few hours of feeding cessation on a daily basis. In summary, these arguments highlight the relevance of fasting physiology within the energy-restriction or time-restriction paradigms.

Modern humans face complex health challenges and solutions. While prevention, vaccination, and treatment for infectious diseases have prolonged lifespan, the presence of artificial light enables human activity throughout the 24 hr day. This disrupted activity-rest cycle indirectly disrupts the natural daily cycle of feeding and fasting, and facilitates excessive caloric intake. Such chronically disrupted temporal regulation contributes to metabolic diseases and may also accelerate the aging process. Treating for metabolic diseases has been challenging, as the traditional pharmacological approach to disease management may not be sufficient. Long-term chronic pharmacological interventions have been particularly successful when the pharmacological molecule is a replacement of an essential biochemical agent, such as insulin (for type 1 diabetes), thyroid hormone, vitamins, or minerals, that is deficient. These replacement agents often have multiple modes of actions and exert pleiotropic effects. If daily, alternate daily, or periodic fasting can promote healthy lifespan by exerting pleiotropic effects, restoring a fasting period or switching to a diet that mimics fasting may be an effective treatment strategy for several chronic diseases.