Physical exercise, whether aerobic, endurance or resistance types, plays a central role in establishing and maintaining the integrity of the brain and central nervous system (CNS). When exercise is adhered to in conjunction with selective food/drink intake and dietary restriction, it promotes neurohealth. In this article, we review the interactions of age and gender, as well as insulin and diabetes, with exercise, individuals' cognitive-affective status and its interactions with exercise propensity, all of which modulate the eventual outcomes of the influence of exercise upon parameters of neurohealth. The combination of exercise with dietary restriction provides numerous factors pertaining to psychological, neurochemical and anti-pathological manifestations of neurophysiological resilience even through aging. The challenge evoked by the exercise-diet combination in the body mobilizes a multitude of adaptive cellular stress-response signaling pathways in neurons involving neurotrophic factors, anti-inflammatory cytokines, DNA-repair proteins, macroautophagy, and mitochondrial biogenesis.