Review Pro-inflammatory genetic background and zinc status in old atherosclerotic subjects Robertina Giacconi a, *, Calogero Caruso b , Marco Malavolta a , Domenico Lio b , Carmela R. Balistreri b , Letizia Scola b , Giuseppina Candore b , Elisa Muti a , Eugenio Mocchegiani a a Immunolgy Center, Laboratory of Nutrigenomic and Immunosenenscence, Research Department, INRCA, Via Birarelli 8, 60121 Ancona, Italy b Immunosenescence Study Group, Department of Patho-biology and Biomedical Methodologies, University of Palermo, Palermo, Italy 1. Introduction Inflammation plays an important role in atherosclerosis (AT) development and cardiovascular disease (CVD). It has been postulated that the occurrence of CVD in old age is a late consequence of evolutionary programming for a pro-inflammatory response to fight infections in adulthood (Van Den Biggelaar et al., 2004; De Martinis et al., 2005). The progressive increase in proinflammatory status with advancing age is provoked by a continuous antigenic load and stress; this condition is detrimental to longevity and related to the mortality risk in ageing population (Bruunsgaard et al., 2001; Caruso et al., 2005). Evidence is also accumulating on the crucial role played by the genetic background in susceptibility to AT or CVD. Indeed, single nucleotide polymorphisms (SNPs) located within the promoter regions of pro-inflammatory cytokines, affecting cytokine produc- tion, may predispose to AT progression (Bennermo et al., 2004; Louis et al., 1998; Giacconi et al., 2004). Conversely, SNPs or other genetic variations, determining increased or decreased production of anti- and pro-inflammatory cytokines respectively, seem to be associated with successful ageing (Lio et al., 2003). Zinc exerts an important role in modulating the inflammatory/immune response during ageing, because of its influence on the correct balance between anti- and pro-inflammatory cytokines produced by Th1 and Th2 cells, respectively (Prasad, 2000)(Fig. 1). Indeed, a good availability of this trace element is associated with reduced IL-6 and TNF-a plasma levels, increased NK cell activity and seems to predispose to healthy longevity (Mocchegiani et al., 2002, 2006; Giacconi et al., 2004). Moreover, the presence of pro/anti- inflammatory genotypes or a specific genetic background affecting zinc status is likely associated with the inflammation, influencing, as such, susceptibility to age-related diseases or promoting healthy longevity (Mocchegiani et al., 2006; Cipriano et al., 2006; Giacconi et al., 2004; Vasto et al., 2007). Intracellular zinc availability is regulated by metallothioneins (MT) that are specific cysteine-rich proteins whose task it is to bind and transfer zinc to other apoenzymes or apoproteins during transient stress or inflammatory conditions (Maret and Krezel, 2007). In this way, zinc activates certain zinc dependent antioxidant enzymes or zinc related signalling pathways to fight Ageing Research Reviews 7 (2008) 306–318 ARTICLE INFO Article history: Received 2 February 2008 Received in revised form 23 May 2008 Accepted 10 June 2008 Keywords: Inflammation Polymorphisms Atherosclerosis Zinc status Elderly ABSTRACT Inflammation and genetics are prominent mechanisms in the pathogenesis of atherosclerosis (AT) and its complications. In this review we discuss the possible impact on AT development of several genetic determinants involved in inflammation, oxidative stress and cytoprotection (IL-6, TNF-a, IL-10, CD14, TLR4, MT, HSP70). Genetic polymorphisms of these genes may affect a differential inflammatory response predisposing to AT. However, allelic polymorphisms of genes which increase the risk of AT frequently occur in the general population but, only adequate gene–environment–polymorphism interactions promote the onset of the disease. Zinc deficiency has been suggested as an environmental risk factor for AT. With advancing age, the incidence of zinc deficiency increases for several reasons. Among them, dietary intake, malabsorption and genetic background of inflammatory markers may be involved. A crucial contribution may also be played by increased oxidative stress which may lead to the appearance of dysfunctional proteins, including metallothioneins (MT) that are in turn involved in zinc homeostasis. The detection of candidate genes related to inflammation and promoting AT and their reciprocal influence/interaction with zinc status might allow earlier appropriate dietary interventions in genetically susceptible subjects. ß 2008 Elsevier Ireland Ltd. All rights reserved. * Corresponding author. Tel.: +39 071 8004214; fax: +39 071 206791. E-mail address: rogiacconi@libero.it (R. Giacconi). Contents lists available at ScienceDirect Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr 1568-1637/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.arr.2008.06.001