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.
Dr. Mattson received his Ph.D from the University of Iowa in Biology and did his postdoctoral work in Neuroscience at Colorado State University. He is considered a leader in the area of cellular and molecular mechanisms underlying neuronal plasticity and neurodegenerative disorders, and has made major contributions to understanding the pathogenesis of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, and to their prevention and treatment. He has published more than 500 original research articles and numerous review articles in leading journals, and has edited 11 books in the areas of neuronal signal transduction, neurodegenerative disorders and mechanisms of aging. He is Editor-in-Chief of NeuroMolecular Medicine and Ageing Research Reviews, and has been/is a Managing or Associate Editor of the Journal of Neuroscience, Trends in Neurosciences, the Journal of Neurochemistry, the Neurobiology of Aging, and the Journal of Neuroscience Research. Dr. Mattson has served on several NIH study sections and on scientific advisory boards for many research foundations. He has trained more than 70 postdoctoral and predoctoral scientists, and has made major contributions to the education of undergraduate, graduate and medical students.
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