Compositional changes in the extracellular matrix occur as a result of aging. This proposal examines the hypothesis that these changes cause a reduction in the hydrodynamic permeability of soft connective tissues, and that this decreased permeability may result in part from a progressive loss of glycosaminoglycans (GAGs) leading to decreased tissue hydration, increased tissue compaction and increased tissue hydrophobicity. Reduction in tissue permeability may affect a wide variety of transport phenomena. With aging, there is a general reduction in the total amount of GAGs present within the various connective tissues. This tends to lower tissue hydration thereby increasing the concentration of other constituents of the extracellular matrix (in particular, glycoproteins). Under these circumstances the elastic modulus of the tissue is lowered, thus favoring tissue compaction and a consequent further reduction in tissue hydration. Decreases in tissue hydration may decrease tissue permeability. Elastin is highly hydrophobic and collagen has many hydrophobic regions. The surfaces of these fibrous macromolecules are normally lined with hydrophilic GAGs. Age-related loss of GAGs, relative to collagen and elastin, may alter tissue hydrophobicity and enhance the potential for binding of lipophilic compounds. Other investigators have demonstrated the age-related accumulation of lipids in sclera, cornea, tendon and aorta. This lipid accumulation may alter tissue permeability. In this study, we propose to measure the age-related changes in the hydrodynamic permeability of human aorta, sclera and cornea. Variations in extracellular matrix composition will also be determined and related to the permeability measurements. This will allow us to correlate the permeability of a given tissue with its composition and will allow us to determine the relative importance of the various proposed mechanisms by which permeability of connective tissues might change. The results will not only provide important insights into the molecular basis for the aging of connective tissues, but may ultimately suggest methods (dietary or pharmacological) that may ameliorate these age-related changes.
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