Aging is a complicated multifactorial process in which a progressive decline in the physiologic function of organisms occurs. Oxidative stress and reactive oxygen species (ROS) have been proposed to be major cause of aging and other aging-related neurodegenerative conditions such as Alzheimer's disease.1,2) Aging-related oxidative damage in the brain and memory impairment mainly result from an imbalance between ROS generation and antioxidant enzyme activities. The overproduction of ROS or decrease in antioxidants in the brain can cause lipid peroxidation, nuclear and mitochondrial DNA damage, and protein oxidation and finally affect the normal functions of organisms. [3][4][5][6] D-Galactose (D-gal) is a reducing sugar normally present in the body. When present at levels greater than its normal content, it can be oxidized into aldehydes and hydrogen peroxide (H 2 O 2 ) by galactose oxidase. 7,8) It has been shown that D-galtreated animal models show aging-related changes including the impairment of spatial learning and memory, object novelty preference, and locomotor activity, 9,10) and increased production of ROS and lowered activities of antioxidant enzymes. 11,12) Other studies demonstrated that long-term subcutaneous injection of D-gal in mice induced decreased immune responses and increased cell karyopyknosis, apoptosis, and caspase-3 protein levels in hippocampal neurons.11,13) Therefore mice continuously injected with D-gal have been extensively used for pharmacologic research on brain aging.(Ϫ)-Epigallocatechin-3-gallate (EGCG) is a member of the catechin family and a major polyphenolic constituent of green tea.14) It was reported that EGCG has potent ironchelating, antioxidant, antiinflammatory, anticancer, and neuroprotective activities. [15][16][17][18][19] In particular, EGCG has been shown to have neuroprotective effects by elevating the a-secretase activity of amyloid precursor protein (APP) and conversion to soluble APP-alpha (sAPP-a) and reducing amyloid beta (Ab)-induced neurotoxicity in a 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) mouse model, the "Swedish" APP transgenic (Tg2576) mouse model of Alzheimer's disease, and N2a cells stably transfected with "Swedish" mutant human APP. 20,21) Furthermore, some studies have recently demonstrated that the neuroprotective mechanisms of EGCG are partly due to increasing activities of antioxidant enzymes and decreasing advanced glycation endproduct (AGE)-induced damage in aged rat brain or neuronal cells. 22,23) However, no study has been performed to evaluate whether EGCG has protective effects on aging mice induced by D-gal and its mechanisms of action. In the present study, we induced the aging mice model with D-gal (150 mg/kg/d, 6 weeks subcutaneously (s.c.)) and observed whether EGCG (2 mg/kg/d or 6 mg/kg/d, 4 weeks intragastrically (i.g.)) had potent antioxidant and antiapoptotic neuroprotective effects using behavioral testing and measurements of the activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), con...