Members of silent information regulator (Sir) proteins regulate lifespan in multiple models organism. The most studied sirtuin is sir2 in yeast, an NAD+- dependent deacetylase that remove acetyl groups from another protein, thereby regulating the biological function of their targets. In addition Sir2 appears to be a limiting component in yeast ageing. Due to their established role in controlling lifespan in lower organism, there is growing interest in determining the effect of sirtuins in mammal cells. Like their yeast homologs, the mammalian sirtuins (SIRT1-7) were originally described as deacetylase proteins (class III HDAC) requiring NAD+ as a cofactor to deacetylate substrates ranging from histones to transcriptional regulators (Blander et al, 2004). Based in the phylogenetic analysis mammalian sirtuins can be divided into four classes: SIRT1-SIRT3 belongs to class I, SIRT4 to class II, SIRT5 to class III and SIRT6 and SIRT7 to class IV (Frye et al, 2000). Also, it is described that mammalian sirtuins have diverse cellular localization and target multiple substrates, consequently affecting a broad range of cellular functions. Specifically, SIRT6 is in the nucleus where promotes DNA repair and protect against genomic instability (Michishita et al, 2008). Moreover, it’s described that SIRT6 could modulate telomeric chromatin and regulates genomic stability on the cellular level and ageing-associated pathologies at the organismal level (Mostoslavsky et al, 2006). On the other hand, a recent paper has demonstrated that SIRT6 binds to the NF-κB subunit RelA and attenuates Nf-κB signalling by modifying chromatin at NF-κB target genes (Kawahara et al, 2009). NF-κB family is considered an emerging modulator of ageing-related pathways in mammals that controls the activity of genes involved in apoptosis, cell senescence, inflammation, and immunity. Ageing and hypertension represent two major independent risk factors for cardiovascular disease. Many of the cardiovascular complications associated with both ageing and hypertension are attributable, at least in part, to endothelial dysfunction. The pathophysiology of endothelial dysfunction is complex and involves multiple mechanisms. One potential trigger for endothelial dysfunction is inflammation (Clapp et al, 2004) and recently it has been increasingly linked to cellular senescence process (Erusalimsky, 2009). The aim of this study was to investigate whether SIRT6 has an effect in endothelial cells senescence and dysfunction and the model of action. In this presentation we will show that SIRT6 is expressed in endothelial cells, mRNA expression (n=3-6) analysis of SIRT1 and SIRT6 was measured by quantitative polymerase chain reaction using Taqman probes. SIRT6 expression was higher in differentiated endothelial cells compared to hematopoietic progenitor cells and presented similar levels to SIRT1 in mature endothelial cells. Furthermore, comparing early and late passages of endothelial cells showed a decreased of SIRT6 expression due to replicative senescence, in both, mRNA (n=3) and protein levels (n=3) measured by western blot. SIRT6 depletion by RNA interference induced a decrease in endothelial cells proliferation quantified by BrdU immunofluorescence assay (n=4), increased senescence-associated-b-galactosidase positive cells (n=4) and diminished ability of the cells to form tubule networks on Matrigel coating (n=5-6), all features of cell senescence. Consistent with this notion, SIRT6-depleted cells presented higher levels of intercellular-adhesion-molecule-1 (ICAM-1) in both, mRNA (n=9) and protein levels (n=3) analysed by flow cytometry. Also showed an increase of PAI-1 mRNA levels (n=9) and lower levels of eNOS mRNA (n=9) and protein (n=3). On the other hand, we examined the accumulation of γH2AX foci by immunofluorescence in SIRT6 depleted cell (n=3). We detected a significant increase in γH2AX foci and in the co-localization with TRF-1, meaning that SIRT6 attenuates DNA damage and telomere dysfunction. Finally, we studied the downstream mechanism by which senescence is induced in SIRT6 depleted cells, higher levels of p21, a cyclin-dependent kinase, was present in SIRT6-depleted cells compared to controls (n=4). These data demonstrate that SIRT6 is highly expressed in endothelial cells where it confers protection from both genomic DNA damage and telomere dysfunction. Besides, our finding that SIRT6 depletion induces senescent phenotype suggests that increasing the activity of this sirtuin may be a relevant approach to delay vascular ageing.