Musculoskeletal health is strongly influenced by regulatory interactions of bone and muscle. Recent discoveries have identified a number of key mechanisms through which soluble factors released during exercise by bone exert positive effects on muscle and by muscle on bone. Although exercise can delay the negative effects of aging, these beneficial effects are diminished with aging. The limited response of aged muscle and bone tissue to exercise are accompanied by a failure in bone and muscle communication. Here, we propose that exercise induced beneficial factors must battle changes in circulating endocrine and inflammatory factors that occur with aging. Furthermore, sedentary behavior results in the release of negative factors impacting the ability of bone and muscle to respond to physical activity especially with aging. In this review we report on exercise responsive factors and evidence of modification occurring with aging.