Intermittent fasting (such as alternate day fasting) is not as effective as calorie restriction (consistent reduction in calories every day) in extending life span in animal models such as mice, but it does have many of the same effects on health and longevity. Even when total calorie intake is held consistent between intermittent fasting animals and controls, there are still benefits that accrue to the fasting animals. One might conclude that time spent in a state of hunger, with all of the signaling and changes in cell behavior that comes with it, is a meaningful component of the benefits derived from calorie restriction.
In contrast to the short and very frequent fasting periods of intermittent fasting (IF), periodic fasting (PF) or a fasting mimicking diet (FMD) last in most cases between 2 and 7 days (2-3 days in mice and 4-7 days in humans) and are followed by a high-nourishment refeeding period of at least 1 week. Another major difference from IF is that PF can be periodic and does not have to be carried out at a specific interval, but can be applied for one or several cycles either as a preventive measure or to treat a specific disease or condition. FMDs were developed to promote the effects of fasting while standardizing dietary composition, providing nourishment and minimizing the burden and side effects associated with water-only fasting. These steps are necessary for PF and possibly IF to move toward approval from the US Food and Drug Administration and standard-of-care applications.
Sixteen-month-old female C57BL/6 mice placed on a periodic 4-day FMD twice per month, alternating with a normal diet, display an 11% increase in their median lifespan, in addition to significant weight and visceral-fat loss, without loss of muscle mass. Moreover, FMD cycles reduce tumor incidence by 45% and delay tumor development. Notably, the FMD cycles also promote changes leading to an immune-system profile in 20.5-month-old mice more similar to that of younger mice (4 months old), in agreement with the effect of PF on hematopoietic stem cell (HSC)-dependent regeneration of immune cells.
In summary, similarly to the well-established effects of calorie restriction, FMD cycles delay the onset and reduce the incidence of age-related diseases, but achieve this with minimal or no long-term reduction in calorie intake and with positive effects on immunity and a targeted reduction in visceral fat. Thus, PF/FMD but potentially also certain dietary restrictions, including IF, may achieve many beneficial effects by mechanisms that are independent of reduced calorie intake.