It has been proved that iron progressively accumulates in the brain with age.Calorie restriction (CR) may allay many of the adverse effects of aging on the brain, yet the underlying mechanisms, in particular in relation to brain iron metabolism, remain unclear.This study aimed to investigate the role of CR in the regulation of cerebral cellular iron homeostasis.C57BL/6 mice were randomly divided into four groups of eight.The control group was fed ad libitum a conventional diet, the CR group got 70% of the calories the control mouse intake per day, the D-galactose (D-gal) group received subcutaneous injection of D-gal at a dose of 100 mg/kg once daily to produce mouse model of aging, the D-gal plus CR group received both of the two interventions for 14 weeks.Then the Morris water maze (MWM) was employed to test the cognitive performance of all animals, and the expression of iron regulatory genes, ferroportin and hepcidin, in the cortex and hippocampus were detected by quantitative real-time PCR.Compared to the controls, the D-gal group mice showed significant spatial reference memory deficits in the MWM test, whereas D-gal-CR group mice exhibited almost normal cognitive function, indicating that CR protects against D-gal induced learning and memory impairment.The hepcidin mRNA expression was increased in D-gal group, decreased in CR group, and basically unchanged in D-gal-CR group.There was no statistical difference in the transmembrane iron exporter ferroportin expression between control and any of the experimental groups.The results suggest that the anti-aging effects of CR might partially lie in its capacity to reduce or avoid age-related iron acuumulation in the brain through down-regulating expression of brain hepcidin-the key negative regulator for intracellular iron efflux, and that to facilitate balance of brain iron metabolism may be an effective anti-aging measure.