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Genomic analysis of the aging rodent and human liver: impact on xenobiotic metabolism
Citation:
LEE, J., W. O. WARD, H. REN, B. VALLANAT, M. J. DEVITO, AND C. CORTON. Genomic analysis of the aging rodent and human liver: impact on xenobiotic metabolism. Presented at Gordon Research Conference, Biology of Aging, Ventura, CA, February 15 - 20, 2009.
Impact/Purpose:
Abstract discussed the impact of evaluation of the full-genome analysis of the aging liver in mice and humans. The study identified changes in genes that control xenobiotic metabolism and provide evidence that the aged would have different responses to chemicals than young adults.
Description:
Metabolic homeostasis of the organism is maintained by the liver’s ability to detoxify and eliminate xenobiotics. This is accomplished, in part, by xenobiotic metabolizing enzymes (XMEs), which metabolize xenobiotics and determine whether exposure will result in toxicity. Some evidence indicates age may alter the ability of organisms to metabolize and excrete xenobiotics, but the degree to which age affects these processes is not known. Overall, this project was designed to determine the biological significance of the changes in XMEs from early to late life stages in mice, rats and humans and to identify subpopulation – chemical combinations that may lead to adverse effects in humans. Here we focus on the identification of XMEs which exhibit altered expression in aging mice and humans. Gene expression profiles in livers were generated using Affymetrix full-genome chips for 6, 12, 18, 24 month-old mice and in humans between young (21-45 years) and old (69+ years) men and women. In mice we found 69, 94, and 130 XMEs significantly altered in the 12, 18, and 24 months versus 2 months comparison, respectively. Microarray data from this study was compared to other published datasets in dwarf mice (Ames, Little, Snell) and calorically restricted mice. This meta-analysis identified genes altered during “normal” aging, longevity, and caloric restriction. In humans, PCA showed a clear age-dependent separation in expression profiles between young and old hepatic transcripts in males and females. We identified 370 genes that were altered between young and old men and 1163 genes that were altered between young and old women. Protein ubiquitination pathway was affected in both older men and women. We found that age caused minimal numbers of changes in the gene expression of XMEs (8 in males and 33 in females between young and old). Most of these changes were Phase III genes (transporters). The expression of solute carriers increased with age in men, and the majority decreased with age in women. These studies show that the livers from aging humans exhibit a number of changes in XMEs that are different from those observed in mice and that these changes may lead to differences in the metabolism or transport of xenobiotics.