Sesamin (SES), as one of the most abundant lignans in sesame seed and oil, exhibits multiple functions. The anti-aging effect of sesamin on D-galactose (D-gal)-induced senescent mice model and its mechanism of action were evaluated. The effects of sesamin (50 or 100 mg kg-1) on senescent mice were investigated by observing the changes of body weight, motor and memory ability, liver superoxide dismutase (SOD), glutathione peroxidase (GSHpx), reduced glutathione (GSH) and malondialdehyde (MDA). Moreover, the proliferative response and IL-2 production of splenocytes induced by ConA, the levels of macrophage proliferative response and IL-1, NO production by macrophage were observed. Results showed that age-related alternations of both motor and memory activity were ameliorated in the treatment group. Treatment with sesamin significantly increased the body weight, hepatic SOD and GSHpx activities, GSH content, the proliferative response and IL-2 production of splenocytes induced by ConA. Treatment with sesamin significantly decreased hepatic MDA content, the levels of macrophage proliferative response and IL-1 and NO production. In conclusion, sesamin has anti-aging effect on D-gal induced senescent mice, which might be related to its improvement of brain function, antioxidative activity and immunomodulatory effects.