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The circulating milieu The influence of the circulating milieu (i.e., the collection of bioactive factors in systemic circulation) on physiological function has been studied using a variety of experimental approaches including heterochronic parabiosis (surgical joining of two circulatory systems) [66] , heterochronic blood exchange (administration of blood/blood factors of one organism into the circulating milieu of another organism) [67] , and in vitro or [68,69] or organ systems [13,70] , respectively, to distinct components of the circulation (e.g., blood/plasma/serum)