Physical exercise has always been one of the most promising methods aimed at brain wellbeing improvement, due to its distinct neuroprotective benefits. It has been illustrated that running rescues brain functions by boosting the expression levels of neurotrophic factors, including BDNF and IGF-1 [35,36]. Significantly, depletion of BDNF or IGF-1 through their specific antagonist eliminated exercise-induced improvements in cognition and hippocampus [36-38], showing that BDNF and IGF-1 are essential for exercise to promote neurogenesis in the hippocampus. Recently, treadmill running has been reveled to enhance neurogenesis, notably cell proliferation and neuroblast differentiation, in aged gerbil hippocampus following ischemic shock [39]. Later its effect on healthy ageing was confirmed in old Wister rats [40]. The study demonstrated that restoration of memory by treadmill exercise was correlated with enhanced expression of BDNF and IGF-1 [40]. Recent studies suggested that IGF-1 interfaces with BDNF to regulate exercise-dependent cognitive improvement [36]. IGF-1-induced protein synthesis is inhibited by central nervous system (CNS) inflammation [41], which is known to increase with age [42]. Chronic aerobic exercise, such as jogging, has been reported to reduce systematic inflammation that contributes to local inflammation in the brain [37]. Accordingly, chronic aerobic exercise recovers age-inhibited IGF-1 through reducing inflammation, which conduces to higher IGF-1 levels in the bloodstream and therefore increases neuronal IGF-1 uptake [37]. Neurons uptaking IGF-1 increase their CREB-mediated BDNF expression [38] and together contribute to neurogenesis enhancement. The effect of IGF-1 on BDNF expression during exercise was confirmed when intra-carotid injection of IGF-1 resulted in similar enhancement in BDNF expression to exercise [38]. Taken together these studies, Stimpson et al.proposed a model for the mechanism of exercise-induced cognitive improvement, in which IGF-1 increases BDNF expression, mediated by CREB [37]. Moreover, glutamate also involves in the upregulation of BDNF in response to exercise. It is well acknowledged that glutamate signaling triggers BDNF expression [16] and many studies indicate that exercise increase glutamate release [43]. In brief, physical activity exerts its beneficial effects on hippocampal neurogenesis and brain functioning through increasing IGF-1 and BDNF (Figure 2).