With increases in life expectancy, it is vital to understand the dynamics of aging, their interaction with lifestyle factors, and the connections to age-related disease processes. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel anticancer and anti-obesity phenotype mediated by a brain-fat axis: the hypothalamic-sympathoneural-adipocyte (HSA) axis in young animals. Here we investigated EE effects on healthspan and lifespan when initiated after middle age. Short-term EE for six weeks activated the HSA axis in 10-month-old mice. Long-term EE for twelve months reduced adiposity, improved glucose tolerance, decreased leptin levels, enhanced motor abilities, and inhibited anxiety. In addition to adipose remodeling, EE decreased age-related liver steatosis, reduced hepatic glucose production, and increased glucose uptake by liver and adipose tissue contributing to the improved glycemic control. The EE-induced liver modulation was associated with a suppression of protein kinase Cε. Moreover, EE down-regulated the expression of inflammatory genes in the brain, adipose, and liver. EE initiated at 18-month of age significantly improved glycemic control and showed a trend of positive impact on mean lifespan. These data suggest that EE induces metabolic and behavioral adaptations that are shared by factors known to increase healthspan and lifespan.