THE PROJECT: Clinical data from elderly patients and animals studies show that there is a gradual decline in liver function with aging. However, the cellular and molecular basis of functional alterations that take place in aging liver is still a mystery. Among the reasons for this is that most of the genes studied show some but not drastic alterations with aging. Another challenge is to find an in vivo model system where age related changes in gene expression can be manipulated. The aging process seems to have a dominant regulatory effect on at least two liver specific genes: alpha 2u-globulin, and senescence marker protein-2. The alpha 2u-globulin gene is expressed only after puberty only in the livers of prepubertal and senescent rats but not in adult male rats. The expression of both genes are shown to be controlled at the transcriptional level. These two genes are expressed abundantly in rat liver and therefore they are excellent models to study the mechanisms how of aging influences liver gene expression. In this proposal, we first hypothesize that alterations in gene expression by aging, is a reversible phenomenon and directly related to the aging of the whole organism rather than the hepatocytes themselves. We will test this by transplanting hepatocytes from the old rats into the spleens and the livers of the young animals. Based on this hypothesis we expect that the expression of these two genes will be altered by placing them into the young hosts and eliminating the """"""""senile milieu"""""""". Our second hypothesis is that transcriptional decline in alpha 2u- globulin gene expression is regulated by trans-activating factors present in the nuclei of the hepatocytes from the senescent animals. These factor interact with cis acting elements that are present in the 5' flanking region of the a 2u-globulin and inactivate or repress the expression of this gene. Therefore in the second part, we propose experiments to identify and compare the binding sties of these factors in the 5'flanking region of the a 2u-globulin gene.
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