Age related changes in connective tissue ECM will affect macromolecular transport and matrix fluid balance. However, there is little data on changes in protein and water transport during aging. This lack of data is a major gap in the aging data base which must be filled in order to test many modern theories of aging. Using new techniques, we have demonstrated that perivascular protein gradients exist, and are of sufficient magnitude to affect Starling equilibrium. Theoretical analyses show that these gradients are determined by transport parameters of the interstitial matrix. Possible age-related mechanisms for perivascular gradients are: (i) variations in protein mobility due to matrix, and (ii) opposition to anionic protein movement by the polyanionic matrix. Fischer 344 rats will be studied at ages of 100, 200, 300, 400, 500, and 600 days. Three experimental interventions will be used: volume loading, albumin loading, and salt loading. Two measurement protocols will quantify age-related ECM biochemical changes. First, In situ biochemical microscopy of rat mesenteric microvasculature is used to measure (i) perivascular protein, water and collagen distribution. Second, direct sampling and biochemical analysis of rat mesenteric buttons, gracilis muscle and skin will be used to measure: (i) tissue and plasma total protein, albumin, and globulin content; (ii) tissue hydration; (iii) total, soluble and insoluble collagen content, glycosaminoglycans and hyaluronan concentrations; (iv) Na+, K+, C1-, and Ca++. These measurements will test specific hypotheses and provide insight concerning the general hypothesis that aging is accompanied by changes in ECM structure and protein transport. There is extensive data showing that ECM changes are occurring during aging; there is abundant evidence indicating that macromolecular transport is determined by ECM; therefore, it is essential to determine whether protein distribution is changing with age.
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