Aging is a biological process along with systemic and multiple organ dysfunction. It is more and more recognized that aging is a systemic disease instead of a single-organ functional disorder. Systemic aging plays a profound role in multiple diseases including neurodegenerative diseases, cardiovascular diseases, and malignant diseases. Aged organs communicate with other organs and accelerate aging. Skeletal muscle, heart, bone marrow, skin, and liver communicate with each other through organ-organ crosstalk. The crosstalk can be mediated by metabolites including lipids, glucose, short-chain fatty acids (SCFA), inflammatory cytokines, and exosomes. Metabolic disorders including hyperglycemia, hyperinsulinemia, and hypercholesterolemia caused by chronic diseases accelerate hallmarks of aging. Systemic aging leads to the destruction of systemic hemostasis, causes the release of inflammatory cytokines, senescence-associated secretory phenotype (SASP), and the imbalance of microbiota composition. Released inflammatory factors further aggregate senescence, which promotes the aging of multiple solid organs. Targeting senescence or delaying aging is emerging as a critical health strategy for solving age-related diseases, especially in the old population. In the current review, we will delineate the mechanisms of organ crosstalk in systemic aging and age-related diseases to provide therapeutic targets for delaying aging.