Caloric Restriction and the Aging Brain and Body

A chronic positive energy balance (excessive calorie intake and/or a sedentary lifestyle) increases the risk of diabetes, cardiovascular disease and cancers, and also adversely affects brain function and vulnerability to neurodegenerative disorders including Alzheimer’s disease.     Dietary energy restriction (DER) extends lifespan and protects the brain and cardiovascular system against age-related diseases in animal models.  We have found that DER, particularly when administered in intermittent bouts of major caloric restriction (e.g., alternate day fasting), activates adaptive cellular stress response pathways in neurons resulting in increased production of neurotrophic factors, protein chaperones, antioxidant enzymes and proteins involved in mitochondrial biogenesis.   As a result, the function of synapses is enhanced, neurogenesis (the production of new neurons from stem cells) is increased, and neurons are more resistant to oxidative and metabolic stress. DER exerts similar beneficial actions on cardiac myocytes.    Findings from our recent human studies have demonstrated a range of improvements of health indicators in asthma patients on alternate day DER and women at risk for breast cancer on a 2 day/week major caloric restriction diet.   In response to DER, brain-derived neurotrophic factor (BDNF), as an intercellular signal, and PGC-1alpha, as an intracellular signal, mediate enhanced function, improved energy metabolism, and resistance to degenerative diseases of aging in the brain and body.   DER has slowed the disease process and improved functional outcome in animal models of Alzheimer’s and Parkinson’s diseases, stroke and myocardical infarction.  DER can also accelerate recovery from traumatic injury and surgery in animals.  There is considerable potential for the application of DER to the practice of medicine, and for the development of novel therapeutic interventions that stimulate adaptive cellular stress responses in a manner similar to DER.