A critical assessment of fasting to promote metabolic health and longevity

Abstract The adaptive starvation response allows us to survive periods of starvation – a characteristic of the environment in which humans evolved. We are now in an evolutionary transition from a global environment which was characterized by periods of famine to a world where obesity and caloric excess have become a new reality, but the mechanisms of fasting physiology remain relevant. First, many parts of the world are still plagued by famine with insufficient food resources and therefore the adaptive mechanisms required for survival during periods of decreased caloric intake are not simply relevant to our evolutionary past. Second, the obesity epidemic provides strong rationale for understanding the biology of fasting, as the same efficiencies that have evolved to allow us to survive periods of starvation also likely drive a genetic predisposition to obesity, and therefore some of the adaptive mechanisms may be maladaptive in the setting of food excess. A third compelling reason to explore the biology of fasting is that in model organisms, caloric restriction without overt starvation, is an intervention that prolongs lifespan. The purpose of this review is to provide an overview of the biology of fasting. We will highlight potential mechanisms of benefit from fasting as well as examine data from model organisms and humans that indicate potential health risks to fasting, particularly related to bone fragility. Finally, we will review clinical studies to date that have investigated the effects of fasting on metabolic outcomes and suggest signals of benefit.