Short-term EE activated the hypothalamic-sympathoneural-adipocyte axis in 10-month-old mice. Long-term EE reduced adiposity, improved glucose tolerance, decreased leptin levels, enhanced motor abilities, and inhibited anxiety. EE decreased age-related liver steatosis, reduced hepatic glucose production, and increased hepatic glucose uptake and adipose tissue, improving glycemic control. EE-induced liver modulation was associated with a suppression of protein kinase Cε. EE down-regulated the expression of inflammatory genes in the brain, adipose tissue, and liver. Here, LEP is linked to age.