Human organ systems evolved in the context of regular, low- to moderate-intensity endurance physical activity (PA); therefore, our physiology is adapted to relatively high levels of PA. Consequently, chronic inactivity may be a causative factor in the development of non-communicable diseases, including those associated with cognitive decline. Structured, planned exercise, a subcategory of PA, could offset the decline of activity levels in modern societies, however, neither the attributes of effective exercise regimens nor the underlying mechanisms are well determined. It has been suggested that regular, moderate-to-vigorous intensity aerobic exercise confers pro-cognitive, anti-inflammatory effects, which may be mediated by recurrent release of molecules from contracting skeletal muscle that act on the central nervous system (CNS). Here, we investigate the impact of long-term (12+ months) moderate intensity regular treadmill exercise, beginning in young adulthood, on the physiological function of C57/BL6J male and female mice, particularly the impact of long-term exercise on inflammaging and associated deterioration of hippocampus-dependent spatial memory. To investigate spatial memory over time, object displacement was performed bimonthly in both sedentary and exercising animals. Results indicate that, during the first 6 months of exercise, the pro-cognitive impact of exercise is modest in mice of both sexes. Investigations of longer-term impacts to help elucidate sex- and age-dependent dynamics and modulatory effects of exercise are ongoing and will be paralleled by analysis of the impacts of exercise on markers of inflammation in the brain and peripheral organs, along with an assessment of the role of muscle-derived lactate in the observed changes.