Preclinical studies and clinical trials have shown that intermittent fasting has broad-spectrum benefits for many health conditions, such as obesity, diabetes mellitus, cardiovascular dis- ease, cancers, and neurologic disorders. Animal models show that intermittent fasting improves health throughout the life span, whereas clinical studies have mainly involved relatively short- term interventions, over a period of months. It remains to be determined whether people can maintain intermittent fasting for years and po- tentially accrue the benefits seen in animal models. Furthermore, clinical studies have focused mainly on overweight young and middle- age adults, and we cannot generalize to other age groups the benefits and safety of intermittent fasting that have been observed in these studies.
Although we do not fully understand the specific mechanisms, the beneficial effects of intermittent fasting involve metabolic switching and cellular stress resistance. However, some people are unable or unwilling to adhere to an intermittent-fasting regimen. By further under- standing the processes that link intermittent fasting with broad health benefits, we may be able to develop targeted pharmacologic therapies that mimic the effects of intermittent fasting without the need to substantially alter feeding habits.
Studies of the mechanisms of caloric restriction and intermittent fasting in animal models have led to the development and testing of pharmacologic interventions that mimic the health and disease-modifying benefits of intermittent fasting. Examples include agents that impose a mild metabolic challenge (2-deoxyglucose, metformin, and mitochondrial-uncoupling agents), bolster mitochondrial bioenergetics (ketone ester or nicotinamide riboside), or inhibit the mTOR pathway (sirolimus).12 However, the available data from animal models suggest that the safety and efficacy of such pharmacologic approaches are likely to be inferior to those of intermittent fasting.
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We thank Drs. Michel Bernier and Anne E. Burke for valuable input, Mr. Marc Raley for work on previous versions of the fig- ures, Dr. David G. Le Couteur for assistance with the prepara- tion of an earlier version of the manuscript, and the Intramural Research Program of the National Institute on Aging, National Institutes of Health, for its support.