Mark Mattson

Humans evolved in environments where food was not continuously available, and so possess robust adaptive physiological and behavioral responses to periods of food scarcity. Emerging research in this Laboratory and elsewhere has shown that intermittent energy restriction (IER; for example fasting for a period of 24 hours several times each week) and vigorous exercise can increase numbers and strength of synapses and can enhance brain function (cognitive and sensory – motor performance) and mood. We find that the general mechanism by which IER and exercise bene t neurons is by challenging them by increasing their activation state and energy demand, which results in a coordinated engagement of signaling pathways that promote neuroplasticity and cellular stress resistance. The pathways activated by exercise and IF include those involving brain-derived neurotrophic factor (BDNF), mitochondrial biogenesis, DNA repair and removal of oxidatively damaged proteins and organelles (autophagy). Peripheral changes in energy metabolism that occur during fasting and exercise may also contribute to their bene cial effects on the brain. In this regard, the depletion of glycogen stores in the liver triggers the mobilization of fatty acids from fat cells and the production of ketone bodies. Ketone bodies such as beta-hydroxybutyrate provide an alternative energy source for neurons and may also activate signaling pathways that enhance the ability of the brain to cope with stress. Our studies in animal models of chronic neurodegenerative disorders (Alzheimer’s and Parkinson’s diseases) and acute brain injury (stroke and severe epileptic seizures) demonstrate robust neuroprotective and neurorestorative effects ofIER. IER protects the brain by bolstering antioxidant defenses and protein chaperone levels,and by suppressing inflammation. The implications of these findings for strategies for optimizing brain function and reducing the risk of neurodegenerative disorders will be described.