Hepatic Gene Expression Changes in an Experimental Model of Accelerated Senescence: The SAM-P8 Mouse Laia Vila `, Nu ´ria Roglans, Marta Alegret, Antoni Camins, Merce ` Palla `s, Rosa Marı ´a Sa ´nchez, Manuel Va ´zquez-Carrera, and Juan Carlos Laguna Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona and IBUB (Institute of Biomedicine University of Barcelona), Spain. The senescence-accelerated mouse (SAM) is an experimental model of aging, established through phenotypic selection from a common genetic pool of AKR/J mice. Here we use complementary DNA microarray, Western blot, and electrophoretic mobility shift assay to consider whether changes in liver gene expression observed in 5-month-old SAM-prone 8 (P8) mice, compared to SAM-R1 controls, are similar to those reported in aged rodents. Livers from SAM-P8 mice presented 88 differentially expressed transcripts, 59% of which were upregulated and 41% were downregulated. Of these, 14% were related to inflammatory/immunity processes, 10% were related to the xenobiotic metabolism (XM) and 3% to nervous system pathophysiology (NSP). Depressed expression and activity of genes related to XM, and altered expression of genes related to NSP, are similar to changes observed in aged rodents. Increased expression of heat shock protein 1 and Jun-B, reduced activity of activator protein 1 and absence of nuclear factor-jB activation indicate the lack of a strong liver inflammatory response in 5-month-old SAM-P8 mice. Key Words: SAM mice—Liver—Inflammation—Xenobiotic metabolism. M EDICAL advances during the past century have increased the average life span for humans; as a consequence, the number of elderly people in western societies has been continuously growing, and it is estimated that by the year 2050, nearly 25% of Americans will be at least 65 years old (1). As the number of people reaching advanced age increases, there will be an associated need for increased medical care. Despite this situation, the molecular changes underlying the physiological decline associated with senescence are poorly defined. With aging comes a decline in physiologic function in most organ systems (2). Work from different laboratories including our own has shown that humans and rodents share common phenotypical changes associated with liver senes- cence. These include increased plasma and liver tissue triglyceride content and decreased hepatic fatty acid oxida- tion (3–6). In addition to regulating lipid and carbohydrate metabolism, the liver plays a pivotal role in the breakdown of potentially toxic lipophilic endotoxins and xenotoxins, as well as in the production of many kinds of serum proteins implicated in the control of hormonal, inflammatory, and coagulation processes. Through these and other processes the liver influences entire body physiology in many ways, suggesting that the elucidation of the age-related changes in gene expression in the liver may lead to a better under- standing (and thereby treatment) of physiological dysfunc- tion in the elderly population. The senescence-accelerated mouse (SAM) is an experi- mental model of aging, established through phenotypic selection (based on the degree of senescence, the life span, and the age-associated pathologic phenotypes) from a com- mon genetic pool of AKR/J strain mice. The SAM-resistant (R) series (substrains SAM-R1, 4, and 5) exhibit normal aging characteristics, whereas the SAM-prone (P) series (substrains SAM-P1–3 and 6–11) display accelerated aging, including loss of skin glossiness, increased skin coarseness, hair loss, periophthalmic lesions, and increased lordoky- phosis of the spine (7). SAM-P8 mice are characterized by both accelerated aging and neuronal dysfunctions (8), appearing from age 2 to 8 months, and severe liver pathology with fatty degeneration and inflammatory mono- nuclear cell infiltration at late age (10 months and older age) (9). The life span of SAM-P8 mice ranges from 10 to 17 months, whereas SAM-R1 mice live for 19–21 months and age normally with an increased propensity for nonthymic lymphoma, histiocytic sarcoma, and ovarian cyst. In this study, we used Affymetrix GeneChips arrays to characterize differences between the liver gene expression patterns of 5-month-old SAM-P8 and SAM-R1 mice [before the appearance of severe liver pathology in the SAM-P8 mice strain (9)]. Our results indicate that, besides specific changes in lipid metabolism [as described in our previous article (6)], the livers of SAM-P8 mice show marked changes in the expression of genes related to inflammatory/ immune processes, xenobiotic metabolism, and nervous system pathophysiology. MATERIAL AND METHODS Animals and Experimental Design Five male SAM-P8 mice and SAM-R1 mice were provided by Harlan Interfauna Ibe ´rica (Barcelona, Spain). 1043 Journal of Gerontology: BIOLOGICAL SCIENCES Copyright 2008 by The Gerontological Society of America 2008, Vol. 63A, No. 10, 1043–1052 by guest on November 15, 2015 http://biomedgerontology.oxfordjournals.org/ Downloaded from