CHANGES IN CALCIUM AND VITAMIN D METABOLISM WITH AGE

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Many studies in humans have shown that there is a decline in the capacity of the intestine to absorb calcium (Ca) with increasing age. To study the mechanisms responsible for the decrease in Ca absorption and changes in vitamin D3 metabolism with age, we have developed the rat as an animal model. We have shown that the rat demonstrates age-related changes in Ca absorption and vitamin D3 metabolism that are very similar to those seen in humans. In addition, we have developed a new technique that uses isolated renal cortical slices to study production of 1,25-(OH)2-D3, the biologically active metabolite of vitamin D3, and its regulation in vitro in the mammal. Therefore, we propose to use this renal slice technique to answer the question "What is the mechanism responsible for the decrease in renal 1,25-(OH)2-D3 production with age?" To answer this question, we propose to test three hypotheses: a. The decreased 1,25-(OH)2-D3 production is due to a decreased responsiveness of the adult kidney to parathyroid hormone (PTH). This failure of PTH to modulate renal 1,25-(OH)2-D3 production may be due to age-related changes in one or more of the following renal components: cAMP production and degradation, cAMP-dependent protein kinase activity, and renal protein phosphorylation. b. The decreased 1,25-(OH)2-D3 production during Ca deprivation is due to decreased secretion of biologically active PTH by the adult in response to Ca deprivation. c. The decreased 1,25-(OH)2-D3 production is due to decrease production or action of growth hormone in the adult. By testing the above hypotheses in an animal model, we will determine the mechanisms responsible for the decreased 1,25-(OH)2-D production with age, which is seen in both rat and human. Knowledge of these mechanisms will suggest ways of improving 1,25-(OH)2-D production, Ca absorption, and ultimately Ca balance and bone mineralization in the elderly population.