Cellular Adaptations to Intermittent Fasting with Emphasis on the Brain

Animals living in their natural environments including our human ancestors prior to the agricultural revolution often experience periods of food scarcity during which their fat stores are utilized for production of the ketones that fuel cells in their nervous, musculoskeletal, and cardiovascular systems as they search for food. When initiated in young adulthood, intermittent fasting (IF) can double the life span of rats and mice. When rats or mice are maintained on IF feeding schedules (every other day food deprivation or daily time-restricted feeding), their brain function improves and their neuronal networks become relatively resistant to stress. Indeed, when animals are maintained on IF, fewer neurons degenerate, and functional deficits are reduced in models of Alzheimer’s disease, Parkinson’s disease, epilepsy, and ischemic stroke. Cellular adaptations of brain cells to IF include enhanced antioxidant defenses, mitochondrial stress resistance mediated by sirtuin 3, mitochondrial biogenesis, DNA repair, synaptic plasticity, and enhanced inhibitory tone. Regarding translatability to modern-day humans, it seems likely that the beneficial effects of IF on the brain will be most profound in overweight sedentary individuals. The latter conclusion is based on the facts that (1) the control animals in animal studies are fed ad libitum, are sedentary, and become obese as they age; (2) human studies have shown that obesity and insulin resistance adversely affect brain structure and function; and (3) recent studies of IF in normal-weight humans reveal significant improvements in health biomarkers. An increasing number of studies have shown that at least some of the beneficial effects of IF can be dissociated from an overall reduction in calories. Evolutionarily conserved adaptations to intermittent food availability explain the evidence that switching back and forth between fasting and fed states can optimize brain function and resilience.