Acute liver CCl 4 intoxication causes low HSP70 gene expression and a delayed transition through the cell cycle in aged rats Nicoletta Gagliano a,b , Beatrice Arosio a,b , Fabio Grizzi c , Carlo Vergani a,b , Giorgio Annoni a,d, * a Cattedra di Geron. e Geriatria Dept. of Geriatrics, Ospedale Maggiore IRCCS, Via Pace 9, Milan, Italy b Department of Internal Medicine, Milan University, Milan, Italy c Scienti®c Direction, Istituto Clinico Humanitas, Rozzano, Milan, Italy d Department of Clinical Medicine, Prevention and Medical Biotechnology, Milan-Bicocca University, Milan, Italy Received 28 December 2001; received in revised form 7 March 2002; accepted 7 March 2002 Abstract Since there is still debate about the ability of the aged liver to regenerate, we compared some aspects of this response in young, adult and old rodents. 2, 6, 12 and 19-month-old rats were intraperitoneally injected with CCl 4 3 mg/kg) or left untreated CT) and killed either 2 h group A) or 24 h group B) after intoxication. Liver injury was checked histologically and by assaying transaminases. mRNA levels of albumin Alb), c-fos, c-myc, hepatocyte growth factor HGF), transforming growth factor TGF)-a andTGF-b1werealsoanalyzed.HeatshockproteinHSP)70geneexpressionwasevaluated,andliver GSH content. Transaminases and histology show more damage in aged rats. Alb mRNA was reduced starting at 12 months in group A and at all ages in group B; c-fos and c-myc mRNAs reached the highest levels in 6-month-old rats and the lowest in thoseaged12and19monthsofgroupA.IngroupB,c-foswasdetectableonlyin6-monthanimals,butc-mycatallages.HGF, TGF-a and TGF-b1mRNAswereup-regulatedintreatedrats,buttoalesserextentintheaged.HSP70mRNA,absentinCT, wassigni®cantlyincreasedattheageof6months,undetectableintheoldestratsingroupA;ingroupBitwasonlyvisiblein6- monthanimals.GSHcontentwasreducedwithaging.Inconclusion,duringagingtheliverregenerativemachineryispreserved but its activation is reduced and delayed. q 2002 Elsevier Science Inc. All rights reserved. Keywords: Liver regeneration; Aging; HSP70 gene 1. Introduction Theprocessofagingaffectsorgans,tissuesandcell types in the same organism in different ways and one of the least affected seems to be the liver. Although it is not fully exempt from age-related morphological changes, functional tests remain almost unchanged in the oldest subjects Tietz et al., 1992; Schmucker, 1998). As a consequence, a common belief is that the liver ages fairly well and this is generally ascribed to its regenerative ability. Liver regeneration can be elicited experimentally by surgical removal of a large proportion of the parenchyma or by acute chemical treatment Fausto and Mead, 1989; Jansen et al., 1990; Michalopulos, 1990; LaBrecque, 1994; Columbano and Shinozuka, 1996). In young±adult rodents, reduction of the liver mass induces cell proliferation. During this process hepatocytes pass through two phases: a `priming' Experimental Gerontology 37 2002) 791±801 0531-5565/02/$ - see front matter q 2002 Elsevier Science Inc. All rights reserved. PII:S0531-556502)00022-0 www.elsevier.com/locate/expgero * Corresponding author. Tel./fax: 139-25-503-5357. E-mail address: giorgio.annoni@unimib.it G. Annoni).