Extended bouts of fasting are ingrained in the ecology of many organisms, characterizing aspects of reproduction, development, hibernation, estivation, migration, and infrequent feeding habits. The challenge of long fasting episodes is the need to maintain physiological homeostasis while relying solely on endogenous resources. To meet that challenge, animals utilize an integrated repertoire of behavioral, physiological, and biochemical responses that reduce metabolic rates, maintain tissue structure and function, and thus enhance survival. We have synthesized in this review the integrative physiological, morphological, and biochemical responses, and their stages, that characterize natural fasting bouts. Underlying the capacity to survive extended fasts are behaviors and mechanisms that reduce metabolic expenditure and shift the dependency to lipid utilization. Hormonal regulation and immune capacity are altered by fasting; hormones that trigger digestion, elevate metabolism, and support immune performance become depressed, whereas hormones that enhance the utilization of endogenous substrates are elevated. The negative energy budget that accompanies fasting leads to the loss of body mass as fat stores are depleted and tissues undergo atrophy (i.e., loss of mass). Absolute rates of body mass loss scale allometrically among vertebrates. Tissues and organs vary in the degree of atrophy and downregulation of function, depending on the degree to which they are used during the fast. Fasting affects the population dynamics and activities of the gut microbiota, an interplay that impacts the host's fasting biology. Fasting-induced gene expression programs underlie the broad spectrum of integrated physiological mechanisms responsible for an animal's ability to survive long episodes of natural fasting.
