Meta-analysis of gene expression in the mouse liver reveals biomarkers associated with inflammation increased early during aging § Janice S. Lee a, *, William O. Ward a , Hongzu Ren a,b , Beena Vallanat a,b , Gretchen J. Darlington c , Eun-Soo Han d , Juan C. Laguna e , James H. DeFord f , John Papaconstantinou f , Colin Selman g , J. Christopher Corton a a NHEERL/ORD, US EPA, Research Triangle Park, NC 27711, United States b NHEERL Toxicogenomics Core, US EPA, Research Triangle Park, NC 27711, United States c Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, Houston, TX 77030, United States d Department of Biological Science, University of Tulsa, Tulsa, OK 74104, United States e Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona, Spain f Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, United States g Integrative and Environmental Physiology, Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK 1. Introduction Developed countries have observed an astonishing increase in human life expectancy over the last two centuries, with roughly 30 years being added to average life expectancy from birth since the start of the 20th century (Christensen et al., 2009). For example, while more than 12% of the population in the United States is currently over the age of 65, this will increase to nearly 20% by 2030 (He et al., 2005). These changing demographics will undoubtedly have significant implications for society as a whole, because aging is inevitably linked to physiological decline, loss of independence, and increases in a range of pathologies with subsequent decreases in the quality of life (Vaupel, 2010). Although advances in medicine and better nutrition have contributed to an increase in longevity, the growing population of older Americans has the potential for greater susceptibility to adverse health effects from environmental pollutants due in part to changes in protective mechanisms that respond to stressors. For example, several studies have found older adults to be especially sensitive to air pollutants (Fischer et al., 2003; Gouveia and Fletcher, 2000). Increased sensitivity may be due to remnant effects from past exposures as well as weakened immune responses (Sandstrom et al., 2003). The aging population may Mechanisms of Ageing and Development 133 (2012) 467–478 A R T I C L E I N F O Article history: Received 1 December 2011 Received in revised form 23 May 2012 Accepted 29 May 2012 Available online 13 June 2012 Keywords: Aging Longevity Liver Meta-analysis Microarrays Xenobiotic metabolism Inflammation A B S T R A C T Aging is associated with a loss of cellular homeostasis, a decline in physiological function and an increase in various pathologies. Employing a meta-analysis, hepatic gene expression profiles from four independent mouse aging studies were interrogated. There was little overlap in the number of genes or canonical pathways perturbed, suggesting that independent study-specific factors may play a significant role in determining age-dependent gene expression. However, 43 genes were consistently altered during aging in three or four of these studies, including those that (1) exhibited progressively increased expression starting from 12 months of age, (2) exhibited similar expression changes in models of progeria at young ages and dampened or no changes in old longevity mouse models, (3) were associated with inflammatory tertiary lymphoid neogenesis (TLN) associated with formation of ectopic lymphoid structures observed in chronically inflamed tissues, and (4) overlapped with genes perturbed by aging in brain, muscle, and lung. Surprisingly, around half of the genes altered by aging in wild-type mice exhibited similar expression changes in adult long-lived mice compared to wild-type controls, including those associated with intermediary metabolism and feminization of the male-dependent gene expression pattern. Genes unique to aging in wild-type mice included those linked to TLN. Published by Elsevier Ireland Ltd. § The information in this document has been funded by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommenda- tion for use. Abbreviations: Ct, cycle threshold; PCR, polymerase chain reaction; XME, xenobiotic metabolizing enzyme. * Corresponding author. Present address: NCEA, US EPA, Research Triangle Park, NC 27711, United States. E-mail addresses: lee.janices@epa.gov (J.S. Lee), ward.william@epa.gov (W.O. Ward), ren.hongzu@epa.gov (H. Ren), vallanat.beena@epa.gov (B. Vallanat), gretchen@bcm.tmc.edu (G.J. Darlington), eun-han@utulsa.edu (E.-S. Han), jclagunae@ub.edu (J.C. Laguna), jhdeford@utmb.edu (J.H. DeFord), jpapacon@utmb.edu (J. Papaconstantinou), c.selman@abdn.ac.uk (C. Selman), corton.chris@epa.gov (J.C. Corton). Contents lists available at SciVerse ScienceDirect Mechanisms of Ageing and Development jo ur n al ho mep ag e: www .elsevier .c om /lo cate/m ec hag ed ev 0047-6374/$ – see front matter . Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.mad.2012.05.006