Excess caloric intake is one of the most important determinants of metabolic syndrome development. Overnutrition and sedentary lifestyle cause accumulation and inflammation of visceral fat, reduced fatty acid trapping and ectopic fatty acid deposition, hepatic insulin resistance, adrenergic overdrive, and activation of the renin-angiotensin system. These pathophysiological alterations account for the five metabolic syndrome components (as described above) and predispose to metabolic syndrome complications that shorten life expectancy (Neels & Olefsky, 2006). Caloric restriction, however, prevents the development of alterations associated with metabolic syndrome and prolongs lifespan in mammals (Cruzen & Colman, 2009). There are several biochemical pathways activated by caloric restriction in mice, many of which cross-interact with metabolism and insulin signaling (Avogaro et al., 2009). At least in Drosophila, the effects of dietary restriction are modulated by, but not strictly dependent on, the insulin/IGF-1 axis through its most important downstream transcription factor FOXO (Giannakou et al., 2008; Min et al., 2008), which is an important checkpoint of metabolic regulation. The potential regulatory role of insulin/IGF-1 pathway in lifespan determination has support also in humans, because common variants in several genes of this pathway, including FOXO3A, are associated with human longevity (Pawlikowska et al., 2009).
The evolutionary conserved SIR-2 is a NAD+-dependent histone deacetylase; it regulates lifespan in response to caloric restriction in many organisms. Mammalian homologs of SIR2 comprise a family of seven proteins termed sirtuins (SIRT1–SIRT7). These are implicated in metabolic processes and stress resistance (Imai et al., 2000; Guarente, 2006). Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. SIRT1 represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and re-localizes to DNA breaks to promote repair. Remarkably, increased SIRT1 expression promoted survival in a mouse model of genomic instability and it suppressed age-dependent transcriptional changes (Oberdoerffer et al., 2008). Indeed, chromatin rearrangement is considered one of the most important mechanisms of action of sirtuins (Vaquero, 2009). This occurs through the process of deacetylation, a common reaction that removes an acetyl functional group (CH3-C = O) from a chemical compound. As part of the gene regulation process, chromatin histones are acetylated and deacetylated on lysine residues in the N-terminal tail. The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation/deacetylation is emerging as a significant posttranslational regulatory mechanism analogous to phosphorylation, which might also interact with methylation, ubiquitination, sumoylation, and other biochemical reactions for dynamic control of cellular signaling. It is still unknown whether deacetylation represents a nonspecific evolutionarily conserved mechanism of lifespan regulation or is simply a way to switch on and off relevant molecular targets in a stimulus- and tissue-specific manner. Caloric restriction extends lifespan in a variety of organisms, and there is some evidence that this may be mediated by induction of SIRT1 (Westphal et al., 2007). In yeast, SIR2 is a major determinant of longevity because (i) increased SIR2 gene dosage extends lifespan; (ii) loss-of-function mutations shorten it (Kaeberlein et al., 1999); and iii) caloric restriction did not extend lifespan when SIR2 is absent (Lin et al., 2002). This issue is controversial, however, because SIR2 mutants accumulate extra-chromosomal DNA alterations that might independently shorten yeast lifespan. Moreover, it was subsequently found that caloric restriction can be independent of SIR2 in a different yeast strain (Kaeberlein et al., 2004), suggesting the existence of multiple, albeit similar, pathways that regulate lifespan (Lamming et al., 2005). In Drosophila as well, SIR2 appears to mediate the effects of food restriction on lifespan, because these effects are completely abolished in SIR2 mutant flies and in SIR2 overexpressing flies (Rogina & Helfand, 2004). In mammals, SIRT1 deacetylates many key transcription factors and co-factors, such as the tumor suppressor p53, FOXO proteins, peroxisome proliferation activating receptor (PPAR)-gamma coactivator-1α, and nuclear factor-kB (Motta et al., 2004; Yeung et al., 2004; Rodgers et al., 2005). In Caenorhabditis elegans, the effects of caloric restriction are mediated by SIR2 independently of FOXO (Wang & Tissenbaum, 2006), while in mammals deacetylation of FOXO4 by SIRT1 may modulate the effects of caloric restriction (Kobayashi et al., 2005). The effects of SIRT1 appear to be beneficial, as they trigger metabolic changes similar to those observed in caloric restriction. Indeed, caloric restriction increases the levels of SIRT1 in the liver and muscle, which are key insulin-sensitive organs (Cohen et al., 2004). Moreover, SIRT1−/− mice are insensitive to the metabolic effects of caloric restriction (Chen et al., 2005). The mechanisms accounting for this phenomenon range from stress resistance through p53 and FOXO modulation (Luo et al., 2001; Brunet et al., 2004), endocrine regulation by IGF-1, insulin, or yet undefined soluble factors (Cohen et al., 2004). The insulin/IGF-1 axis is crucial to lifespan regulation in a variety of organisms and accumulating evidences demonstrate that SIRT1 modulates the downstream effects of this pathway (Lemieux et al., 2005). In light of these observations, SIRT1 has been proposed as a possible target for the treatment of metabolic syndrome (Jiang, 2008). We have recently shown that SIRT1 expression is reduced in peripheral blood mononuclear cells (PBMCs) of nondiabetic subjects with metabolic syndrome compared with nonmetabolic syndrome subjects. In addition, we found that PBMC SIRT1 expression is directly related to insulin sensitivity and negatively related to carotid intima media thickness, a marker of early atherosclerosis (de Kreutzenberg et al., 2010). Mechanistically, reduction of SIRT1 expression and activity could be attributed to the negative effects played by excess glucose and saturated fatty acids, through cellular NAD+ depletion and reduced NAMPT activity, which are essential for SIRT1 functions. This effect, which was in part modulated by the increased oxidative stress induced by exposure to high glucose or fatty acid concentrations, caused downstream c-Jun N-terminal Kinase (JNK) activation and p53 acetylation, events typically linked with cellular activation and inflammation (de Kreutzenberg et al., 2010). Interestingly, many of these negative metabolic effects could be prevented in vitro by incubation with resveratrol, a natural plant-derived polyphenolic phytoalexin which is also a constituent of red wine. In THP-1 cells, resveratrol induced SIRT1 expression and prevented SIRT1 downregulation as well as p53 acetylation induced by high glucose and oxidative stress (de Kreutzenberg et al., 2010). Importantly, it was shown that resveratrol has the potential to increase replicative lifespan in the yeast Saccharomyces cerevisiae (Howitz et al., 2003). Some evidences indicate that this effect may be mediated by SIRT1: resveratrol lowered the Michaelis constant of SIRT1 for both acetylated substrates and NAD+ and increased cell survival by stimulating SIRT1-dependent deacetylation of p53. However, there is no definite demonstration that resveratrol is a direct SIRT1 activator: one recent study found that resveratrol, as well as several other putative SIRT1 activators, exhibits multiple off-target activities on receptors, enzymes, transporters, and ion channels that may indirectly determine an effect on SIRT1 and its substrates (Pacholec et al., 2010). In addition, it is possible that the antioxidant resveratrol acts on SIRT1 substrates by preserving SIRT1 from its oxidative stress-induced downregulation, as we have shown (de Kreutzenberg et al., 2010). Despite this inconsistency on the mechanisms that link resveratrol to SIRT1, the longevity-modulating effect of resveratrol was confirmed in other species, including a worm (C. elegans) and the fruit fly Drosophila melanogaster (Wood et al., 2004) a vertebrate (Nothobranchius furzeri), and a short-lived fish (Valenzano et al., 2006). It is still not clear whether the same effects of resveratrol are retained in mammals, including humans, but the well-known J-shaped curve describing the relationship between alcohol consumption and all-cause mortality indicates that a moderate alcohol use, especially red wine, might extend human lifespan (Gronbaek, 2002). The concentration of resveratrol found in red wine is many fold lower than pharmacologic levels achieved in animal experimental models (Bertelli, 2007), but long-term exposure in humans might amplify its effect, and our experiments provide indirect support to the hypothesis that resveratrol acts through SIRT1.