Figure 3.

Intermittent bioenergetic challenges forestall ILOD by stimulating adaptive stress response pathways. (a) As with other species, humans evolved in environments where there was competition for food, mates and other resources. Accordingly, selection favored individuals whose brains functioned best when they were hungry, physically active and under stress. In response to the challenges (exercise, dietary energy restriction/fasting, intellectual challenges and consumption of noxious phytochemicals) neurons experience mild bioenergetic and oxidative stress. The neurons respond adaptively by activating signaling pathways that improve their ability to cope with more severe stress and resist disease. These neuroprotective pathways are triggered by calcium, reactive oxygen species (ROS) and increased energy demand, and involve kinases such as AMP-activated kinase (AMPK), and transcription factors such as cyclic AMP response element binding protein (CREB). The latter pathways increase autophagy, and induce the expression of genes encoding neurotrophic factors, antioxidant enzymes and DNA repair enzymes. During the challenges there is a reduction of mTOR (mammalian target of rapamycin) activity and protein synthesis. Once the challenge is over (e.g., food has been acquired) there is a recovery period that involves eating, relaxing and sleeping. During the recovery period mTOR activity, protein synthesis and mitochondrial biogenesis increase, and the growth of axons and dendrites, formation of new synapses and neurogenesis (the production of new neurons from stem cells) occur. Because of the adaptive stress responses induced during the challenge period levels of oxidative stress, DNA damage and protein aggregation are reduced. This model predicts that individuals who regularly engage in cycles of challenges and recovery periods during their adult life will exhibit optimal brain function and will be relatively resistant to the development of ILOD. (b) An example of a lifestyle that includes intermittent challenges as a means of optimizing brain health. In this case the person fasts (water or non-caloric beverages only) on the first day, while engaging in intellectual challenges (light bulb) and physical exercise (running). On the next day the subject eats several meals, runs, relaxes and engages in critical thinking.