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Keywords:

  • aging;
  • disease;
  • sirtuin

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References

The sirtuins are highly conserved NAD-dependent deacetylases that were shown to regulate lifespan in lower organisms and affect diseases of aging in mammals, such as diabetes, cancer, and inflammation. Most relevant to the amelioration of disease, the SIR2 ortholog SIRT1 has been shown to deacetylate many important transcription factors to exert an overarching influence on numerous metabolic pathways. Here we discuss several diseases of aging for which SIRT1 has been recently shown to confer protection. These findings suggest that manipulating sirtuin activity pharmacologically may be a fruitful area to improve human health.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References

Aging increases susceptibility to a variety of diseases, such as diabetes, cardiovascular disease, cancer, neurodegenerative diseases, and inflammation. The molecular mechanisms that links aging to age-related diseases, in general, are not understood. Genes that were shown to influence aging in lower organisms may afford an avenue to arrive at a molecular understanding of how aging poses a risk factor for these diseases. In this regard, sirtuins are especially interesting because it has been possible to alter their activities by small molecules that could be developed into drugs. Indeed, manipulation of SIRT1 activity genetically or pharmacologically has been shown to impact numerous diseases in rodent models. In this article, we will review a subset of recent findings that relate sirtuins to several age-related diseases, and discuss possible mechanisms linking these sirtuins to the etiology of diseases.

Sirtuins and metabolic diseases

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References

Calorie restriction (CR) was first described as a reduction in food intake in laboratory rodents of 30–40% of ad libitum levels that would extend their lifespan by up to 50% (Weindruch & Walford, 1988). CR was shown to promote survival in organisms ranging from yeast to rodents, and perhaps primates (Guarente, 2006; Colman et al., 2009). CR was proposed to be mediated by the SIR2 gene family, which were first shown to have antiaging functions in yeast (Kaeberlein et al., 1999), Caenorhabtidis elegans (Tissenbaum & Guarente, 2001) and Drosophila (Rogina & Helfand, 2004; Wood et al., 2004). The discovery that yeast Sir2 and the mammalian SIRT1 are NAD+-dependent deacetylases (Imai et al., 2000) provided a possible mechanistic insight into how sirtuins might sense diet and metabolism, and thus set the rate of aging.

Several lines of evidence point to a fundamental role for sirtuins in mammalian CR. First, several outputs of CR do not occur in SIRT1 KO mice, including longevity (Chen et al., 2005a; Boily et al., 2008; Li et al., 2008). Second, as discussed later, transgenic mice that over-express SIRT1 show physiological properties of CR mice when fed ad libitum (Bordone et al., 2007; Banks et al., 2008; Pfluger et al., 2008). Third, as also discussed later, small molecule activators of SIRT1 also confer phenotypes of CR on fed mice, which extend to the detailed transcriptional patterns of gene expression (Barger et al., 2008; Smith et al., 2009). Fourth, physiological studies of mammalian sirtuins show that they link diet to physiology by targeting over-arching metabolic pathways, e.g. PGC-1α and mitochondrial biogenesis for SIRT1 (Lagouge et al., 2006), and CPS1 and the urea cycle for SIRT5 (Nakagawa et al., 2009).

A recent paper showed that deleting SIRT1 from the brain prevented two important aspects of CR – down-regulation of the somatotropic axis (GH and IGF1) and up-regulation in physical activity (Cohen et al., 2009). Down-regulation of the somatotropic axis in dwarf mice is associated with extended life span. The regulation of the somatotropic axis by SIRT1 likely occurs in the hypothalamus, as SIRT1 was not deleted in the pituitaries of these mice. The fact that ad-libitum fed mice already showed a reduced level of somatotropic signaling in mutant mice indicates that in wild type SIRT1 must be repressed during CR in those hypothalamic neuron that govern GH release by the pituitary. This finding may explain why whole-body activation of SIRT1 by resveratrol or transgenes has not yet been shown to extend life span in mice. How the somatotropic axis may affect human aging is not clear.

Metabolic syndrome is the mirror image of CR; it is triggered by dietary excess and results in poor health and shortened life span. The discovery of the enzymatic activity of SIRT1 allowed screening for small molecules that could activate it. The first such screen identified resveratrol, a polyphenolic compound made by plants that had previously been associated with health benefits (Howitz et al., 2003). This compound was subsequently shown to protect mice from metabolic disability resulting from a high-fat diet (Baur et al., 2006; Lagouge et al., 2006). In more recent studies, resveratrol was given to ad libitum-fed mice (4.9 mg kg−1 day−1) from middle age (14 months) to old age (30 months), and these mice were compared to mice not given resveratrol and fed either a calorie restricted diet or ad libitum (Barger et al., 2008). Genome-wide transcriptional analysis showed a striking transcriptional overlap of resveratrol-fed mice compared to CR mice in heart, skeletal muscle and brain. A total of 745 genes for heart, 1164 for muscle and 1129 genes for brain were significantly altered in the same direction by both CR and resveratrol. Only a handful of genes affected by resveratrol were not affected by CR. Both resveratrol and CR-stimulated insulin mediated glucose uptake in muscle ex vivo. However, the mechanisms for insulin sensitization appeared to differ. CR increased Akt phosphorylation in response to insulin, but resveratrol did not. Likewise CR increased levels of GLUT4, the major glucose transporter in muscle, but resveratrol did not. Additionally, resveratrol and CR both prevented age-related cardiac dysfunction, as assessed by left ventricular and systolic determinations and myocardial performance index.

As resveratrol has been proposed to affect targets in addition to SIRT1 (Dasgupta & Milbrandt, 2007), it is important to consider newer classes of SIRT1 activators that may be more specific. For example, mice were first fed with high-fat diet and then treated with SIRT1 activators, SRT501 (1000 mg kg−1, oral dosing) or SRT1720 (100 mg kg−1, oral dosing) for 3 days. Causal Network Modeling of gene expression data was performed from livers of these mice (Smith et al., 2009). Both SRT501 and SRT1720 data sets were modulated to indicate increased metabolism, mitochondrial biogenesis, and decreased inflammation, which was similar to the CR gene expression profiles. Both SRT1720 and SRT501 increased expression of PPARα, PPARγ and ERRα which are markers of mitochondrial biogenesis and fatty acid oxidation, and decreased expression of the Nrip 1, repressor of mitochondrial biogenesis.

The aforementioned findings were consistent with an earlier study by Feige et al. (2008), which demonstrated that SRT1720 protected mice or rats from diet-induced obesity, in this case by promoting fat consumption in skeletal muscle, liver, and brown adipose tissue. SRT1720 was also shown in mice fed a high-fat diet to increase oxygen consumption and promote energy expenditure in white adipose tissue, and improve average distance run on a treadmill, and locomotor functions.

To genetically test the hypothesis that SIRT1 participates in the regulation of metabolism, Banks et al. (2008) generated BAC transgenic mice moderately overexpressing SIRT1 under its natural promoter (SirBACO). By placing SirBACO mice on a high-fat diet or backcrossing onto db/db mice, the authors showed that SIRT1 overexpression does not improve glucose metabolism in normally fed young mice, but prevents the adverse effects of obesity on glucose metabolism, as determined by glucose tolerance tests. SirBACO mice were also protected against aging-induced diabetes when fed a normal diet. Control transgenic mice expressing catalytically inactive SIRT1 (H355Y) showed no differences in glucose tolerance, demonstrating that SIRT1 catalytic activity is required for its insulin-sensitizing effects. Pfluger et al. (2008) reported that independently derived BAC SIRT1 transgenic mice showed lower lipid-induced inflammation along with better glucose tolerance when fed a high-fat diet and were almost entirely protected from hepatic steatosis. The authors suggested that beneficial effects of SIRT1 were because of at least two mechanisms. First was induction of NRF1, a master regulator of antioxidant proteins and MnSOD itself, which are known to be under control of PGC1-α. Second was repression of NFκB activity, which would lower levels of pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα) and IL-6. Another recent study (Kemper et al., 2009) reported that the nuclear bile acid receptor FXR is a target of SIRT1 in metabolic regulation. Acetylation of FXR inhibited its activity and is dynamically regulated p300 and SIRT1 under normal conditions. Downregulation of hepatic SIRT1 increased FXR acetylation with deleterious metabolic outcomes and FXR acetylation levels were elevated in two mouse models of metabolic disorders, ob/ob mice and mice chronically fed a western-style diet. Treatment with the SIRT1 activator resveratrol or adenoviral-mediated expression of SIRT1 substantially reduced FXR acetylation levels in these disease model mice suggesting small molecules that inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders. All told, these recent studies solidify the notion that SIRT1 will be a significant target for treating metabolic diseases.

Sirtuins and cancer

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References

The possible role of SIRT1 in cancer has posed a dilemma. On the one hand, as a gene promoting cell survival, one might predict that SIRT1 would possess an oncogenic function. For example, SIRT1 deacetylates and down-regulates p53, which may extend the longevity of cell types such as neurons and muscle cells, but engender cancer in tissues with dividing cells. On the other hand, as a gene promoting organismal survival, one might predict a tumor suppressor function for SIRT1. Indeed, CR itself suppresses cancers of many types. Not surprisingly, the literature has been conflicted, and we will review later papers claiming either oncogenic or tumor suppressor functions for SIRT1.

The first suggestion that SIRT1 might be oncogenic was the finding that the HIC1 (hypermethylated in cancer) product binds to the SIRT1 promoter and represses transcription (Chen et al., 2005b) As HIC1 is silenced in certain tumors, the up-regulation of SIRT1 was proposed to play a role in tumorigenesis. More recently, Zhao et al. (2008) and Kim et al. (2008) showed that deleted in breast cancer 1 protein binds to and inhibits the catalytic domain of SIRT1 in human cells. DBC1 may also block the association between SIRT1 and its substrates. The DBC1 gene was initially identified in a large interval of chromosome 8p21 that is deleted in human breast cancer (Sundararajan et al., 2005). DBC1-mediated repression of SIRT1 leads to increased levels of p53 acetylation and up-regulation of p53 activities, including apoptosis. Thus, it seems possible that an up-regulation of SIRT1 activity in human breast cancer may facilitate tumorigenesis. However, it is important to note that the DBC1 gene itself has not been pinpointed as the relevant tumor suppressor locus removed in the deletions in chromosome 8p21. In summary, these studies showed that SIRT1 activity can be down-regulated through the endogenous DBC1 protein, and this interaction may have relevance to human breast cancer.

On the other hand, other studies have shown a pattern that is consistent with SIRT1 having antiproliferation and antiapoptotic effects during cancer development. Kabra et al. (2009) have found that SIRT1 knockdown by short hairpin RNA accelerates tumor xenograft formation by HCT116 cells, whereas SIRT1 overexpression inhibits tumor formation. Furthermore, pharmacological inhibition of SIRT1 by SIRT1-specific inhibitor EX-527 stimulates cell proliferation under conditions of growth factor deprivation. SIRT1 overexpression was observed in ∼25% of stage I/II/III colorectal adenocarcinomas but rarely found in advanced stage IV tumors.

Another study by Wang et al. (2008a) also suggested that the SIRT1 activator resveratrol serves as an excellent therapy for BRCA1-associated breast cancer. Activation of SIRT1 by resveratrol showed a protective effect, particularly in BRCA1 mutant cancer cells. The reason for this is that BRCA1 positively regulates SIRT1 gene expression, and human BRCA1-mutant breast cancers thus have lower levels of SIRT1 than control tissues. Further, mammary tumors from BRCA1 mutant mice have low levels of SIRT1. One of the outcomes of low SIRT1 is activation of SIRT1-repressed genes, such as survivin, which has been shown to inhibit apoptosis (Zaffaroni et al., 2005). These findings suggest a pathway in which BRCA1 activates SIRT1, which represses the tumorigenic gene survivin.

Wang et al., 2008b also showed that SIRT1 serves as a tumor suppressor more broadly in murine tumors and in some types of human cancers. In this study, SIRT1 +/−; p53+/− mice develop tumors in multiple tissues at a much earlier age than SIRT1+/+; p53+/− mice. Further, activation of SIRT1 by resveratrol treatment reduced tumorigenesis in SIRT1+/−; p53+/− mice. Likewise, Oberdoerffer et al., 2008 showed that resveratrol protected irradiated p53+/− mice from cancer. On the other hand, Boily et al. (2009) showed that the presence or absence of SIRT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. Resveratrol topically applied to skin profoundly reduced tumorigenesis and this chemoprotective effect was significantly reduced in SIRT1-null mice, suggesting that only part of the protection afforded by resveratrol requires SIRT1. With regard to humans, eight different cancers (lung, breast, colon, stomach, liver, bladder, skin, and thyroid) exhibited reduced levels of SIRT1 compared to normal controls (Wang et al., 2008b). Other studies also indicate a tumor suppressor role for SIRT1. Firestein et al. (2008) tested a transgenic gut-specific SIRT1 over-expressing strain of mice in a APCmin/+ model of colon cancer. SIRT1 transgenic mice were significantly protected against cancer. In vitro, SIRT1 deacetylated and repressed the pro-growth transcription factor, β-catenin, known to be stabilized in colon cancer cells. In colon cancer cell lines, over-expressed SIRT1 prevented nuclear accumulation of β-catenin, suggesting that this sirtuin may be a nuclear entry for any β-catenin that inappropriately enters that compartment in differentiating intestinal epithelial cells.

The aforementioned studies raise the possibility that SIRT1 functions as a tumor suppressor by repressing non-p53 factors that drive cell growth (e.g. β-catenin). This activity may offset any loss of tumor suppression because of deacetylation of p53 itself. Consistent with this idea, SIRT1 was also shown to deacetylate and destabilize the oncogene myc (Yuan et al., 2009). All of the aforementioned data suggest that SIRT1 activation may be useful in preventing cancer. That said, it is possible that SIRT1 inhibition may be effective in treating certain pre-existing cancers, for example by up-regulating p53-mediated apoptosis.

Sirtuins and inflammatory diseases

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References

Inflammation is an important factor in the pathogenesis of several age-related degenerative diseases. The master regulator of innate immunity is NF-κB, which governs an ancient signaling pathway found in insects and vertebrates (Salminen et al., 2007). NF-κB is a heterodimeric complex of p50 (encoded by NFKB1) and p65 (RELA). In the inactive state, NF-κB complexes are sequestered in the cytoplasm by Iκ-B inhibitory proteins. A variety of signals like oxidative stress and DNA damage stimulate the phosphorylation and subsequent degradation of IκB, which leads to the nuclear translocation of NF-κB. NF-κB controls the activity of genes involved in apoptosis, cell senescence, inflammation, and immunity, and its activity increase with age in many mammalian tissues and stem cells (Salminen et al., 2007). Indeed, genetic hyperactivation of NF-κB results in diseases in murine models including muscle wasting (Cai et al., 2004) and obesity-induced insulin resistance (Arkan et al., 2005).

Two different sirtuins, SIRT1 and SIRT6, inhibit transcription of genes by NF-κB. SIRT1 was shown to physically interact with and deacetylate the RelA/p65 subunit of NF-κB and thereby inhibit its ability to activate transcription (Yeung et al., 2004). By damping the activation of NF-κB, SIRT1 augments apoptosis in response to the pro-inflammatory factor, tumor necrosis factor α. Lee et al. (2009) showed recently that overexpression of SIRT1 also protects pancreatic beta cells against cytokine toxicity by suppressing NF-κB. In this study, SIRT1 chemical activators like resveratrol also prevented cytokine toxicity, NO production and iNOS expression and maintained normal insulin-secreting responses to glucose in isolated rat islets. In addition, Sequeira et al. (2008) showed that SIRT1-null mice suffer from a mild autoimmune condition that is manifest by the deposition of immune complexes in the liver and kidney. Many of the mice were shown to develop high titer antinuclear antibodies.

In addition to SIRT1, SIRT6 was also shown to be involved in regulation of the NF-kB signaling pathway. Kawahara et al. (2009) showed that SIRT6 is physically present at promoters of genes activated by NF-κB. By docking with RelA/p65, SIRT6 deacetylates histone H3 lysine 9 (H3K9) to repress transcription of NF-κB target genes. Underscoring the biological importance of this activity, haploinsuffiency of RelA rescues the early lethality and degenerative syndrome of SIRT6-deficient mice. Thus, both SIRT1 and SIRT6 down-regulate the NF-κB signaling pathway. However, another study by Van Gool et al. (2009) indicated that intracellular NAD levels actually promoted TNFα protein synthesis in SIRT6 dependent manner. This regulation evidently occurred at a post-transcriptional step, but its mechanism or how this might relate to the other, anti-inflammatory activities of sirtuins is not yet clear.

NF-κB has been implicated as a candidate activator of aging-related transcriptional changes in multiple human and mouse tissues (Adler et al., 2007). Genetic blockade of NF-κB in the skin of chronologically aged mice reversed the global gene expression program and tissue characteristics to those of young mice. Further, NF-κB blockade increased the proliferative capacity of the skin and reversed several markers of cellular senescence to levels observed in young animals. Therefore, NF-κB blockade may alleviate aspects of aging that are because of hyper-activity of NF-κB. Activation of SIRT1 and/or SIRT6 might be one approach to creating such a blockade.

In summary, the aforementioned studies suggest that the blockade of NF-κB may protect against pro-inflammatory diseases. However, NF-κB signaling and its interactions with other signaling networks play important roles in the functions of the immune system and other tissues. It will be necessary to modulate NF-κB activity, for example by sirtuin activation, in a way that maintains normal functions, even while protecting against autoimmune diseases, inflammatory diseases, and other degenerative diseases.

Sirtuins and cardiac dysfunction

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References

Heart is among the primary target tissues showing decline of the ability to respond to adverse conditions during aging. Cardiac hypertrophy is a common response of myocytes to different physiological and pathological stimuli. Because myocytes do not have the ability to divide, the only way for them to deal with work overload is to undergo hypertrophy, in which myocytes grow in size and induce a group of genes. Prolonged pathological hypertrophy leads to congestive heart failure and sudden death because of arrhythmias.

Although sirtuins are heavily investigated in aging and aging diseases, little was known about the role of sirtuins in heart until recently. Alcendor et al. (2009) showed that low (2.5-fold) to moderate (7.5-fold) overexpression of SIRT1 in transgenic mouse hearts attenuated age-dependent cardiac hypertrophy, apoptosis, fibrosis, cardiac dysfunction, and expression of senescent markers. In contrast, a high level (12.5-fold) of SIRT1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating cardiomyopathy. Moderate overexpression of SIRT1 protected the heart from oxidative stress induced by paraquat, and increased expression of antioxidants, such as catalase via FOXO-dependent mechanisms, whereas high levels of SIRT1 increased oxidative stress. This study suggested that increasing SIRT1 activity could retard aging and confers stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate increases of SIRT1.

In another study, Vakhrusheva et al. (2009) showed that SIRT7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. SIRT7-deficient mice developed heart hypertrophy and inflammatory cardiomyopathy with extensive fibrosis in the heart. SIRT7 was shown to decaetylate p53 in this study and SIRT7-deficient primary cardiomyocytes displayed an increase in basal apoptosis and diminished resistance to oxidative and genotoxic stress. Sundaresan et al. (2009) have shown by using both SIRT3-deficient and SIRT3-overexpressing mice that SIRT3 blocks cardiac hypertrophy by augmenting Foxo3a-dependent antioxidant mechanisms. SIRT3-deficient mice showed signs of cardiac hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced severe cardiac hypertrophy, whereas SIRT3-expressing Tg mice were protected from similar stimuli. In primary cultures of cardiomyocytes, SIRT3 blocked cardiac hypertrophy by activating FOXO-dependent, antioxidant genes, thereby decreasing cellular levels of ROS.

SIRT1 is also associated with processes that may indirectly benefit cardiac function. For example, SIRT1 promotes NO production in smooth muscle by deacetylating the eNOS enzyme (Mattagajasingh et al., 2007). In addition, SIRT1 deacetylates LXR to drive reverse cholesterol transport in macrophages (Li et al., 2007). On sum, mounting evidence suggests that sirtuin activation will confer significant cardiac protection.

Recent progress in understanding aging and aging-related diseases has led to novel therapeutic targets. Among these, the sirtuins are of interest first because they appear to impact a wide variety of aging-related diseases, and second because they can be modulated by small molecules. As sirtuins appear to counter aging, drugs that have been generated so far are compounds that are activators. These new drugs may mimic at least some of the effects of CR in forestalling or preventing aging-related diseases. In the long run, drugs that can target specific tissues and function as sirtuin activators or, perhaps in some cases even inhibitors, may maximize the potential to manipulate sirtuins for human benefit.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Sirtuins and metabolic diseases
  5. Sirtuins and cancer
  6. Sirtuins and inflammatory diseases
  7. Sirtuins and cardiac dysfunction
  8. References
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