Cordyceps sinensis is believed to be an anti-aging traditional Chinese herb. We previously reported that C. sinensis Cs-4 (a mycelia fermentation product of C. sinensis) improves glucose, lipid and energy metabolism and has antioxidant, anti-fatigue and endurance effects. In this study we examined gene expression (GE) profiles of neocortex and gastrocnemius from young (5 months of age), old (25 mo) and old Cs-4 treated (0.3 g/kg) C57Bl/6 mice. Age-related changes in GE were clustered. Cs-4 opposed GE of many changes that occurred with age (p210 days (both 0.5 and 1.0 g/kg). Kaplan-Meier analysis revealed the best extended lifespan and reduced the risk of death in mice receiving Cs-4 0.5 g/kg (p=0.03). In conclusion, C. sinensis Cs-4 reverses age-related changes in GE and extends the lifespan of mice, supporting the traditional belief that C. sinensis Cs-4 conveys anti-aging benefits to humans.