The central hypothesis examined in this issue is that insulin resistance promotes maladaptive brain function and contributes to reduced neuronal plasticity, potentially accelerating brain aging. Therefore, if we were to prevent or treat insulin resistance, through weight loss and exercise, cognitive function would be improved. In this article, we argue that successful interventions influencing these outcomes depend upon overriding maladaptive neurobiology. This maladaptation may have developed over the course of the lifespan through interaction with modern environments. Furthermore, we emphasize the need to take this emergent neurobiology into account when designing interventions.