The capacity for physical activity is diminished with aging. Though largely attributed to sarcopenia (reduced mass and quality of skeletal muscle), little is known of how aging influences muscle blood flow and oxygen supply. Our working hypothesis is that the ability of the microcirculation to supply skeletal muscle fibers is impaired with aging, with adverse consequences on muscle function. Based upon the burgeoning development of genomic strategies in murine systems, the C57BL/6 mouse will be developed here as a model. Our goal is to define the changes that occur in the structure and function of the microcirculation in skeletal muscle that occur with aging. Vascular conductance in muscle appears diminished with aging; however, the underlying structural and functional adaptations are unresolved. Therefore, using vascular casting and histology, Aim 1 is to determine how micro vascular topology and morphology are altered by aging. Little is known of how aging influences the interaction between muscle fiber contraction, metabolic vasodilation, and oxygen delivery. Therefore, Aim 2 is to determine the effect of aging on arteriolar tone, reactivity and capillaty perfusion. Using the cremaster muscle preparation, intravital microscopy will determine whether responses to endothelium-dependent or -independent vasodilators are impaired and thereby define how microvascular responsiveness to muscle fiber contraction may be blunted. During exercise, both the redistribution of cardiac output to active skeletal muscle and the maintenance of microvascular perfusion pressure are governed through sympathetic nerve activity. Whereas changes in sympathetic neuroeffector pathways have been inferred, the effect of aging on the ability of sympathetic nerves to govern arterioles and venules is unknown. Therefore, Aim 3 is to determine the effect of aging on neural control of microvascular resistance and capacitance. We will test whether aging impairs sympathetic vasoconstriction, distinguish whether such changes are due to altered release of neurotransmitter vs. depressed responsiveness of microvascular smooth muscle cells, and determine whether the effects of aging on vasomotor responses to neurotransmitters are unique to catecholamines. Defining these key relationships in control (C57BL/6) mice will generate mechanistic hypotheses focused on how aging influences the cellular and molecular signaling pathways that dictate microvascular structure and function. Our long-term goal is to apply physiological genomics towards developing novel strategies for minimizing the adverse consequences of aging on muscle function and physical activity and to thereby preserve the quality of life.