Aging is a fundamental biological process accompanied by a general decline in tissue function and an increased risk for age-related disease. The risk for cardiovascular, stroke, cancer, and neurodegenerative diseases significantly increases with aging, especially in people aged 60 years and older in the USA. Although the cellular and molecular mechanisms underlying aging and age-related disease are beginning to be unraveled, the role of the systemic milieu remains unknown. Recent studies have shown that systemic factors in young blood can revise age-related impairments and extend organismal lifespan, suggesting that the systemic milieu contains pro-aging and rejuvenating factors that play a critical role in the health and aging phenotype. In this review, we summarize the current knowledge of systemic milieu changes during the aging process and its link to age-related deterioration.