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Determinants of Gene Expression in the Human Liver: Impact of Aging and Sex on Xenobiotic Metabolism
Citation:
Corton, Jon, J. Lee, J. Liu, H. Ren, B. Vallanat, AND M. Devito. Determinants of Gene Expression in the Human Liver: Impact of Aging and Sex on Xenobiotic Metabolism. Experimental Gerontology. Elsevier Science Ltd, New York, NY, 169:111976, (2022). https://doi.org/10.1016/j.exger.2022.111976
Impact/Purpose:
We examined global gene expression differences between young adult (21-45 years) and old (69+ years) human livers with the goal of characterizing differences in expression of genes that are known to be involved in xenobiotic metabolism. We found that aging leads to extensive changes in the human liver transcriptome, most of which are unique to each sex. The genes differentially regulated between old and young groups include many that are involved in xenobiotic metabolism or transport. Our examination of 10 CYP enzyme activities found increased activities of CYP1A2 and CYP2C9 in the old group. While not the main focus of the study, we also identified gene expression differences between males and females that were found to diminish with age. Many XMEs were differentially expressed between sexes. These studies support the hypothesis that aging leads to differences in xenobiotic metabolism that impacts susceptibility to xenobiotic chemicals and supports evaluation of life-stage dependent differences to refine risk assessment approaches.
Description:
There is a need to characterize the potential susceptibility of older adults to toxicity from environmental chemical exposures. Liver xenobiotic metabolizing enzymes (XMEs) play important roles in detoxifying and eliminating xenobiotics. We examined global gene expression in the livers of young (21–45 years) and old (69+ years) men and women. Differentially expressed genes (DEG) were identified using two-way ANOVA (p ≤ 0.05). We identified 1437 and 1670 DEGs between young and old groups in men and women, respectively. Only a minor number of the total number of genes overlapped (146 genes). Aging increased or decreased pathways involved in inflammation and intermediary metabolism, respectively. Aging led to numerous changes in the expression of XME genes or genes known to control their expression (~90 genes). Out of 10 cytochrome P450s activities examined, there were increased activities of CYP1A2 and CYP2C9 enzymes in the old groups. We also identified sex-dependent genes that were more numerous in the young group (1065) than in the old group (202) and included changes in XMEs. These studies indicate that the livers from aging humans when compared to younger adults exhibit changes in XMEs that may lead to differences in the metabolism of xenobiotics.
URLs/Downloads:
DOI: Determinants of Gene Expression in the Human Liver: Impact of Aging and Sex on Xenobiotic Metabolism
https://pubmed.ncbi.nlm.nih.gov/36244585/