HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Anastasiou, D. Articles by Krek, W. Search for Related Content PubMed PubMed Citation Articles by Anastasiou, D. Articles by Krek, W.

REVIEW

SIRT1: Linking Adaptive Cellular Responses to Aging-Associated Changes in Organismal Physiology

Dimitrios Anastasiou and Wilhelm Krek

Institute of Cell Biology, ETH Zurich, Zurich, Switzerland wilhelm.krek{at}cell.biol.ethz.ch

	Abstract

 
Sirtuins comprise a family of enzymes implicated in the determination of organismal life span in yeast and the nematode. The mammalian sirtuin SIRT1 has been shown to deacetylate several proteins in an NAD⁺-dependent manner. SIRT1 substrates are involved in the regulation of apoptosis/cell survival, endocrine signaling, differentiation, chromatin remodeling, and transcription. Thus SIRT1 provides a molecular link between nutrient availability and adaptive transcriptional responses. This review presents current evidence as to how SIRT1 functions are relevant to changes in tissue physiology that occur with ageing and its implications for future pharmacological intervention to alleviate such degenerative processes.

	Introduction

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
The sirtuin protein family comprises members with protein deacetylase and ADP-ribosyltranferase activity (4, 36, 46). Sirtuin deacetylases are also referred to as class III deacetylases, being distinct from class I and II enzymes in that their activity depends on NAD⁺ (oxidised nicotinamide adenine nucleotide) and is not sensitive to the broad deacetylase inhibitor tricho-statin A (TSA) (22, 36). Thus, given the importance of histone deacetylation in the regulation of gene expression, sirtuins have been proposed to provide a molecular link between cellular metabolic status, as expressed by the NAD⁺/NADH levels, and adaptive transcriptional responses (7).

The founding member of the family S. cerevisiae Sir2p (silence information regulator 2) deacetylates histones and thus mediates transcriptional silencing at telomeric, rDNA (encoding ribosomal RNA), and mating type loci (7). In addition, overexpression of Sir2p extended the life span of yeast cells, supporting the hypothesis that Sir2p is a key mediator of yeast longevity. A similar finding was also reported for Sir2-1, its C. elegans ortholog (71). Furthermore, experimental evidence suggests that Sir2 may partially mediate the beneficial effects of caloric restriction on longevity, most likely as a modulator of the IGF (insulin-like growth factor) signaling pathway, another well-known mediator of organismal life span (7, 30, 66).

Based on such observations, the involvement of mammalian sirtuins in determining organismal life span has been the subject of extensive investigation. Seven sirtuins have been described in humans, named SIRT1–7 (4, 26). SIRT1, the best characterized among them, is a nuclear deacetylase whose substrates include proteins primarily but not exclusively involved in transcriptional regulation, thus influencing diverse aspects of organismal physiology such as differentiation, cell survival, and metabolism (FIGURE 1).

View larger version (43K): [in this window] [in a new window]   FIGURE 1. Interacting partners, substrates, and downstream effectors of SIRT1 Unlike proteins depicted in the inner circle, p19ARF and UCP2 are currently not known to physically interact with SIRT1, but their expression levels are sensitive to the latter.

	SIRT1 and Cancer

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
Cancer is a term coined to describe a vastly heterogeneous set of diseases that are characterized by aberrant proliferation to the expense of physiological body functions. Although malignancies occur in younger individuals too, sporadic cancer incidence shows a striking correlation with age (23). Genetic and epigenetic processes have both been linked to age-induced cancer, and mouse models have provided extensive evidence that genes involved in the maintenance of genomic stability and cancer are also intimately linked to the development of ageing phenotypes (23, 47).

	SIRT1 and Epigenetic Changes Occuring in Cancer

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
Several lines of evidence implicate SIRT1 in epigenetic regulation of gene expression in cancer cells (FIGURE 2). SIRT1 was identified as a component of the polycomb repressive complex 4 (PRC4), which harbors the SET domain histone methyltransferase Ezh2 (44). Four distinct PRC complexes have been identified to date that differ in their subunit composition and substrate specificity. In a mouse model of prostate cancer, the protein levels of all PRC4 components tested, including SIRT1, were upregulated (44). Concomitantly, expression of PRC4 target genes was accordingly modified in these tissues. Although there is no evidence confirming a causal role for PRC4 in cancer initiation, it is possible that PRC4-mediated histone modifications contribute to cancer-specific epigenetic changes.

View larger version (35K): [in this window] [in a new window]   FIGURE 2. Molecular interconnections between SIRT1 and pathways involved in tumor initiation/progression

siRNA-mediated downregulation of SIRT1 leads to H4-K16 hyperacetylation and reduction in H3-Tri-MeK9 and H4-MeK20 in mammalian cells, whereas, in vitro, SIRT1 preferentially deacetylates H4-K16 (36, 74). Interestingly, Fraga et al. reported a consistent loss of H4-K16 acetylation and H4-K20 trimethylation in various tumors and tumor-derived cell lines, suggesting that these modifications constitute epigenetic hallmarks of cancer (25).

SIRT1 localizes specifically to the promoters of tumor suppressor genes whose DNA is hypermethylated and are silenced in many cancers (37, 63). Downregulation of SIRT1 levels and/or activity resulted in increased H4-K16 as well as H3-K9 acetylation in such promoters and sufficed to induce reexpression of the corresponding genes in breast and colon cancer cells (63).

	Nonhistone Targets of SIRT1 in Tumor Development

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
Besides histone modifications (73), posttranslational modification of transcription factors, including acetylation (43), constitutes an additional level of transcriptional control. Such modifications can regulate various aspects of transcription factor function, including DNA binding, stability, subcellular localization or recruitment of co-factors (e.g., Refs. 6, 12). SIRT1 deacetylates several transcription factors involved in the regulation of cell cycle progression and apoptosis consistent with a role in the fundamental processes underlying cancer (FIGURE 2).

SIRT1 deacetylates the tumor suppressor p53 to inhibit its transcriptional activity, resulting in reduced apoptosis in response to various genotoxic stimuli (50, 75). On the other hand, in cultured primary cells, SIRT1 is required for the expression of the tumor suppressor p19^ARF, which promotes p53 stability (16). MEFs (mouse embryonic fibroblasts) lacking SIRT1 have an increased resistance to senescence induced by chronic oxidative stress, a phenomenon associated with decreased levels of the tumor suppressor p19^ARF and thus p53 levels (16). Conversely, in the same cellular system, SIRT1 is not required for oncogene-induced senescence, despite the fact that the latter is also known to involve p19^ARF. Of note, however, Langley et al. reported that SIRT1 localizes to PML bodies to attenutate p53-dependent cellular senescence induced by PML-IV or activated Ras overexpression (45).

SIRT1 associates with the tumor suppressor HIC1, which has been shown to act synergistically with p53 in tumorigenesis (13). Both SIRT1 and HIC1 can bind the SIRT1 promoter to repress gene transcription and thus allow p53 acetylation and activation (13). HIC1^–/–cells exhibit elevated levels of SIRT1, hypoacetylated p53, and enhanced resistance to DNA damage-induced apoptosis, which can be reversed by expression of dominant-negative SIRT1. Interestingly, HIC1 expression is progressively reduced during aging due to promoter methylation, which would lead to higher SIRT1 levels, reduced p53 activity, and prolonged life span. Concomitantly, such a model would also predict a higher propensity to form tumors due to higher SIRT1 activity consistent with the inverse relationship between longevity and tumor suppression (11).

SIRT1 has been shown to regulate the transcription factor NF-B as well as several forkhead family transcription factors, including FOXO1, FOXO3a, and FOXO4 (10, 19, 56, 72, 76, 78). SIRT1 deacetylates and inactivates NF-B, leading to enhanced cell death in response to the inflammatory cytokine TNF- (78). NF-B is required for the transcription of growth factors and cytokines involved in inflammation, which has been linked to diseases such as Type 2 diabetes and cancer (39). Other NF-B target genes include antiapoptotic factors such as cIAP (cellular inhibitor of apoptosis) and selective members of the Bcl2 family and the antioxidant MnSOD (manganese superoxide dismutase), which protect cells from TNF--induced apoptosis (38).

MnSOD is also a target of forkhead transcription factors, and SIRT1 enhances its expression in a FOXO-dependent manner (28). Forkhead factors regulate genes that are involved in cell cycle arrest and survival, and due to their negative regulation by the PKB pathway, which is frequently hyperactivated in cancers (9), they are thought to contribute to tumor suppression. The effects of SIRT1 on FOXO target gene transcription are heterogeneous, including both activation and repression through an NH₂ terminal domain (28, 64, 76). SIRT1 is thought to enhance the expression of FOXO target genes involved in stress responses and cell cycle arrest such as MnSOD, GADD45, and p27 (10, 19, 72), whereas it suppresses transcription of some insulin response element (IRS)-driven genes (IGFBP1 and PEPCK) (56).

Interestingly, FOXO is under the negative control of IKKß (inhibitor of B kinase ß) too, which targets it for ubiquitin-mediated proteolysis (35). IKKß is also required for NF-B activation, implying a cross-talk between the two pathways (38). How SIRT1 coordinates the activities of these two factors in a coherent manner remains to be investigated. This will be particularly informative with respect to cancer development as the effects of SIRT1 through these two transcription factors can be seemingly conflicting, as in the case for MnSOD and cell survival.

The recent discovery that Ku70 interaction with the pro-apoptotic protein Bax is regulated by acetylation can provide an alternative route by which SIRT1 promotes cancer cell survival (17). SIRT1-mediated deacetylation of Ku70 preserves its association with Bax, which is inhibited by CBP-driven Ku70 acetylation, thus preventing the translocation of Bax to mitochondria to initiate apoptosis (17).

Cancer drug resistance is a major hindrance in the effectiveness of cancer therapies. Chu et al. observed a positive correlation between SIRT1 protein levels and the expression of P-glycoprotein, a drug efflux pump implicated in cancer multidrug resistance, further expanding the proposed ways SIRT1 regulates cancer cell biology (15).

The work summarized above represents a strong body of evidence supporting a role for SIRT1 in cancer development, in particular as a promoter of cancer cell survival, bearing the characteristics of a potential oncogene (33). Yet it would be of great importance to determine whether this involvement in oncogenesis reflects a more fundamental, causative role of altered SIRT1 activity for tumor progression by determining the incidence of aberrant SIRT1 expression in tumors.

	SIRT1 Functions in Metabolic Regulation

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
Organismal energy homeostasis is achieved by the coordinate action of central and peripheral signals that control apetite and dictate efficient nutrient distribution among tissues to sustain body functions (24). Disturbances in such circuits lead to abnormal weight control and associated pathological side effects, and recent data suggest that they may also underlie key aspects of tumorigenesis (61, 62).

SIRT1 in homeostatic organ functions: regulating glucose metabolism
Ageing is associated with several pathological conditions resulting in aberrant organismal metabolic functions (49). Prevalent among them is Type 2 diabetes, which shows almost an exponential incidence rate increase after the age of 20–30 years (54). Type 2 diabetes is associated with decreased insulin secretion and the development of insulin resistance, which in turn is a major risk factor for cardiovascular disease as well as a series of other medical conditions collectively known as the metabolic syndrome (20).

In response to elevated glucose levels, e.g., following a meal, insulin is secreted by the ß-cells found in the pancreatic islets of Langerhans to promote glucose uptake and catabolism in peripheral tissues. ß-Cell function deteriorates with ageing (54).

SIRT1 is expressed in the pancreatic ß-cells as well as the glucagon-producing -cells (8, 58). In ß-cells, SIRT1 enhances insulin secretion by suppressing the expression of uncoupling protein 2 (UCP2) (FIGURE 3). UCPs uncouple metabolic fuel oxidation from ATP production, thus leading to a decrease of ATP, which is required for the secretion of insulin (48). Consistent with a physiological role of SIRT1 in insulin secretion, mice overexpressing SIRT1 in pancreatic ß-cells exhibited an enhanced response to glucose challenge attributed to higher blood insulin, whereas, conversely, SIRT1^–/– animals had lower levels of circulating insulin (8, 58).

View larger version (48K): [in this window] [in a new window]   FIGURE 3. Function of SIRT1 in tissues relevant to organismal energy homeostasis Despite evidence for SIRT1 functions in skeletal muscle and the brain, little is known about its role in regulating metabolic functions of these tissues. Similarly, the role of SIRT1 in pancreatic -cells, where it is highly expressed, is unknown. TGs, triglycerides; NEFAs, nonesterified fatty acids, also referred to as free fatty acids (FFAs); NCoR, nuclear co-repressor; AcCoA, acetyl-CoA; AceCS-1, acetyl-CoA synthase-1; Ucp2, uncoupling protein 2; PPAR, peroxisome proliferator-activated receptor-; PGC-1, PPAR coactivator-1.

Another site of SIRT1 function in glucose metabolism is the liver, where SIRT1 interacts with the transcriptional co-activator PGC-1 in a ternary complex with hepatocyte nuclear factor 4 (HNF-4) to induce gluconeogenesis following fasting (67) (FIGURE 3). In promoting glucose production, the hepatic function of SIRT1 appears to be the opposite of that in the pancreas, where it promotes insulin secretion, thus leading to glucose utilization by peripheral tissues. In addition to ß-cells, high SIRT1 expression was also observed in pancreatic -cells (58), which play a central role in organismal responses to fasting by stimulating, among others, hepatic gluconeogenesis. Whether these apparently opposing functions reflect a broader role for SIRT1 in balancing body glucose homeostasis by coordinating multiple organ responses to a common stimulus is a notion worth investigating.

Overall, the above evidence suggests a multiple impact of SIRT1 function on body glucose homeostasis through its role in insulin secretion and contribution to survival in the context of pancreatic ß-cells and gluconeogenesis in the liver. Thus the activity of SIRT1 and possibly other sirtuins (77) may also be a relevant therapeutic target for diabetes, where aberrant glucose homeostasis and ß-cell disfunction are key manifestations of the disease.

SIRT1 function in lipid metabolism
Another tissue of interest in metabolic regulation is the adipose tissue. The adipose tissue is the major site of triglyceride storage, an important energy source when glucose availability is limited. During fasting and starvation, adipose triglyceride (TG) stores are mobilized to give rise to free fatty acids (FFA), which can be utilized by other tissues for energy production (24). Furthermore, the metabolic activities of adipose tissue may have an impact on organismal longevity since adipose-specific ablation of IGF receptor results in an approximately 18% increase in life span in mice (5).

SIRT1 was shown to suppress adipocyte differentiation by inhibiting the adipogenic factor PPAR (peroxisome proliferator-activated receptor-) through the transcriptional co-repressor NCoR (60). Furthermore, it was suggested that SIRT1 is required for TG mobilization since SIRT1^+/– animals exhibited low levels of blood FFAs following fasting or ß-adrenergic stimulation.

Interestingly, the bacterial sirtuin ortholog CobB deacetylates and activates the enzyme acetyl-CoA synthase (ACS), which catalyses the synthesis of acetyl-CoA, a key molecule in mitochondrial oxidation and lipid synthesis (69, 70). Recently, Hallows et al. demonstrated that SIRT1 also activates the mammalian acetyl-CoA synthase 1 (AceCS-1) via deacetylation, raising the possibility that a phylogenetically conserved molecular mechanism mediated by SIRT1 and possibly other sirtuins modulates lipid metabolism by regulating intracellular acetyl-CoA levels (32).

Dyslipidemia is a common feature of the metabolic syndrome-associated disorders, including cardiovascular disease and atherosclerosis (24). Thus it would be of interest to investigate whether modulation of SIRT1 activity can be considered as a possible target for treating these conditions or symptoms thereof.

	Neuroprotective and Cardioprotective Roles of SIRT1

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
Immunohistochemical studies have identifed the heart and central nervous system as sites of high murine SIRT1 expression during embryogenesis and in adult animals (68). Furthermore, mice with genetic ablation of the SIRT1 locus exhibit multiple developmental defects, some of which are consistent with this localization (14). Experimental evidence suggests that SIRT1 has a protective role against neuronal and cardiac damage.

In the Wallerian degeneration slow (wld^s) mice, increased nuclear NAD⁺ underlies the protection exhibited in the neurons of these mice against neurodegenerative agents (2). Importantly, the neuroprotective effects of NAD⁺ require SIRT1 (2). Moreover, sirtinol and resveratrol, two compounds that inhibit and activate SIRT1, respectively, affect this process in a manner consistent with the proposed involvement of SIRT1 (2). Similar effects of sirtinol and resveratrol were also observed in an independent in vitro model of cerebral ischaemia (65).

These observations also extend to the heart. In isolated neonatal rat cardiomyocytes, sirtuin inhibition by either nicotinamide or sirtinol induced cell death in a p53-dependent manner (1). SIRT1 overexpression also caused an increase in cardiomyocyte size and protected cells from apoptosis following serum starvation (1). Importantly, SIRT1 levels were dramatically increased in a dog model of heart failure, possibly a result of a failed attempt to prevent cell death (18).

Risk of neurodegenerative and cardiovascular pathological conditions such as Alzheimer’s and ischaemic heart disease, respectively, increase dramatically with age and together account for the vast majority of death rates (31, 41). A causative role for the devastating outcomes of ischemic conditions is also connected to how promptly they are treated so as to minimize tissue damage. This, in combination with lifestyle factors such as diet, which is proposed to affect sirtuin function, renders sirtuins an important potential target for preventive treatments in the context of these diseases.

	SIRT1 and Muscle Mass Maintenance

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
SIRT1 deacetylates and thus negatively modulates the transcription factor MyoD, which is one of the key executors of the muscle differentiation programme (27). SIRT1 activity in turn is dictated by the progressively decreasing levels of NAD⁺ during muscle differentiation, thus alleviating SIRT1-mediated MyoD suppression and allowing differentiation (27).

SIRT1 was also found acting in conjuction with HDAC4 to regulate the activity of another transcription factor with roles in muscle differentiation, myocyte enhancing factor 2 (MEF2) (79). HDAC4 recruits a small ubiquitin-like modifier (SUMO) E3-ligase, which attaches SUMO to lysine residues on MEF2 that are previously deacetylated by SIRT1. This leads to inhibition of MEF2-mediated transcription (79). It is unclear, however, whether this function of SIRT1 also leads to inhibition of muscle differentiation and whether it is sensitive to intracellular NAD/NADH levels.

Multiple factors contribute to muscle mass reduction during ageing and diseases such as cancer or muscular dystrophy. These include oxidative and inflammatory damage due to neutrophil and macrophage recruitment as well as muscle wasting due to increased protein catabolism (52, 57).

Balanced protein turnover is paramount for the maintenance of proper muscle mass (52). Increased protein catabolism associated with cachexia is attributed to the action of specific E3 ubiquitin ligases that target proteins for proteasome-mediated proteolysis (29). Two such proteins have been identified, MuRF1 (for muscle RING finger 1) and MAFbx/atrogin-1 (for muscle atrophy F-box), which are transcriptionaly controlled by the NF-B and FOXO pathways, respectively (29). NF-B activation in response to the inflammatory cytokine TNF- leads to suppression of MyoD gene expression, whereas MyoD is also proposed to be a substrate of the MAFbx E3 ligase (29). Furthermore, MyoD activity is required for the postproliferative differentiation of precursor muscle cells following injury (57).

Since SIRT1 was found to modulate both NF-B and FOXO transcription factors in heterologous systems (see above), in conjunction with its role in regulation of MyoD and MEF2, a broader role of SIRT1 in the control of muscle mass maintenance during injury and ageing is conceivable.

	Reproduction

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
There is an inverse correlation between age and fecundity in that, as animals age, their ability to produce viable offspring decreases (59). Experimental evidence in model organisms suggests that a hormonal cue from the reproductive system, most likely IGF, regulates life span in both the nematode and the mouse (40).

SIRT1 is highly expressed in the developing spermatocytes, and deletion of the SIRT1 gene leads to severe sperm abnormalities and sterility (51). In this context, SIRT1 would apper to be important to the reproductive capacity of the animal, thus defying its role in longevity based on the above. Interestingly, reduction of IGF signaling starting at the time of hatching in C. elegans extends life span and delays reproduction, whereas IGF signaling reduction in the adult increases life span to the same extend without affecting reproduction (40). Thus it is possible that SIRT1 holds a role in the adult reproductive system that extends beyond embryonic development, possibly by controlling IGF signaling through its documented roles in regulating forkhead factor activity.

	Conclusion

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 
Ageing-related changes in body physiology involve multiple target tissues with varying consequences on organismal fitness, both at the macroscopic as well as the molecular level (41). Since a clear increasing trend in world population age is evident (http://www.who.int/ageing/en/), the possibility to alleviate ageing-related phenotypes with the aim to ameliorate life quality is highly desirable.

Members of the sirtuin protein family have been implicated in the regulation of organismal longevity from yeast to mice (30). In this article, we have reviewed current evidence implicating SIRT1, the best-studied mammalian sirtuin, in molecular processes linked to physiological tissue changes associated with ageing. Recent work supports the involvement of other sirtuins in some of these phenotypes (55, 77). Of note, mice lacking SIRT6 exhibit several charactersitics of premature ageing, which, at the cellular level, can be attributed to defects in base-excision repair (BER), a mechanism employed by cells to prevent chromosomal instability (55).

A focused effort to develop HDAC inhibitors has been long underway following evidence that many cancers, and in particular leukemias, exhibit aberrant chromatin acetylation patterns (53). Similarly, early development of pharmacological agents that modulate sirtuin activity (3) provides a promising outlook for our ability to intervene in the progression of degenerative processes associated with ageing (FIGURE 4). Furthermore, the functional synergism observed between SIRT1 and other sirtuins and HDACs (32, 79) can provide a novel framework of investigation into combinatorial therapies with a broader targeting of protein deacetylases.

View larger version (18K): [in this window] [in a new window]   FIGURE 4. Potential impact of pharmacological modulation of SIRT1 to age-related phenotypes

	References

Top Introduction SIRT1 and Cancer SIRT1 and Epigenetic Changes... Nonhistone Targets of SIRT1... SIRT1 Functions in Metabolic... Neuroprotective and... SIRT1 and Muscle Mass... Reproduction Conclusion References

 

1. Alcendor RR, Kirshenbaum LA, Imai S, Vatner SF, and Sadoshima J. Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytes. Circ Res 95: 971–980, 2004.[Abstract/Free Full Text]
2. Araki T, Sasaki Y, and Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 305: 1010–1013, 2004.[Abstract/Free Full Text]
3. Baur JA and Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5: 493–506, 2006.[CrossRef][ISI][Medline]
4. Blander G and Guarente L. The Sir2 family of protein deacetylases. Annu Rev Biochem 73: 417–435, 2004.[CrossRef][ISI][Medline]
5. Bluher M, Kahn BB, and Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299: 572–574, 2003.[Abstract/Free Full Text]
6. Bode AM and Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 4: 793–805, 2004.[CrossRef][ISI][Medline]
7. Bordone L and Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6: 298–305, 2005.[CrossRef][ISI][Medline]
8. Bordone L, Motta MC, Picard F, Robinson A, Jhala US, Apfeld J, McDonagh T, Lemieux M, McBurney M, Szilvasi A, Easlon EJ, Lin SJ, and Guarente L. Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4: e31, 2005.[Medline]
9. Brazil DP, Yang ZZ, and Hemmings BA. Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem Sci 29: 233–242, 2004.[CrossRef][ISI][Medline]
10. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, and Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011–2015, 2004.[Abstract/Free Full Text]
11. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120: 513–522, 2005.[CrossRef][ISI][Medline]
12. Chen LF and Greene WC. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 5: 392–401, 2004.[CrossRef][ISI][Medline]
13. Chen WY, Wang DH, Yen RC, Luo J, Gu W, and Baylin SB. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 123: 437–448, 2005.[CrossRef][ISI][Medline]
14. Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, Bronson R, Appella E, Alt FW, and Chua KF. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA 100: 10794–10799, 2003.[Abstract/Free Full Text]
15. Chu F, Chou PM, Zheng X, Mirkin BL, and Rebbaa A. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res 65: 10183–10187, 2005.[Abstract/Free Full Text]
16. Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S, Kaushal D, Cheng HL, Fischer MR, Stokes N, Murphy MM, Appella E, and Alt FW. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2: 67–76, 2005.[CrossRef][ISI][Medline]
17. Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, Frye R, Ploegh H, Kessler BM, and Sinclair DA. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell 13: 627–638, 2004.[CrossRef][ISI][Medline]
18. Crow MT. Sir-viving cardiac stress: cardioprotection mediated by a longevity gene. Circ Res 95: 953–956, 2004.[Free Full Text]
19. Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, and Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 101: 10042–10047, 2004.[Abstract/Free Full Text]
20. de Luca C and Olefsky JM. Stressed out about obesity and insulin resistance. Nat Med 12: 41–42; discussion 42, 2006.
21. Denu JM. Linking chromatin function with metabolic networks: Sir2 family of NAD(+)-dependent deacetylases. Trends Biochem Sci 28: 41–48, 2003.[CrossRef][ISI][Medline]
22. Denu JM. The Sir 2 family of protein deacetylases. Curr Opin Chem Biol 9: 431–440, 2005.[CrossRef][ISI][Medline]
23. DePinho RA. The age of cancer. Nature 408: 248–254, 2000.[CrossRef][Medline]
24. Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116: 337–350, 2004.[CrossRef][ISI][Medline]
25. Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Perez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, and Esteller M. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37: 391–400, 2005.[CrossRef][ISI][Medline]
26. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273: 793–798, 2000.[CrossRef][ISI][Medline]
27. Fulco M, Schiltz RL, Iezzi S, King MT, Zhao P, Kashiwaya Y, Hoffman E, Veech RL, and Sartorelli V. Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state. Mol Cell 12: 51–62, 2003.[CrossRef][ISI][Medline]
28. Giannakou ME and Partridge L. The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol 14: 408–412, 2004.[CrossRef][ISI][Medline]
29. Glass DJ. A signaling role for dystrophin: inhibiting skeletal muscle atrophy pathways. Cancer Cell 8: 351–352, 2005.[CrossRef][ISI][Medline]
30. Guarente L and Picard F. Calorie restriction: the SIR2 connection. Cell 120: 473–482, 2005.[CrossRef][ISI][Medline]
31. Hadley EC, Lakatta EG, Morrison-Bogorad M, Warner HR, and Hodes RJ. The future of aging therapies. Cell 120: 557–567, 2005.[CrossRef][ISI][Medline]
32. Hallows WC, Lee S, and Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci USA 103: 10230–10235, 2006.[Abstract/Free Full Text]
33. Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 100: 57–70, 2000.[CrossRef][ISI][Medline]
34. Harvey AC and Downs JA. What functions do linker histones provide? Mol Microbiol 53: 771–775, 2004.[CrossRef][ISI][Medline]
35. Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, and Hung MC. IkappaB kinase promotes tumorigenesis through inhibition of fork-head FOXO3a. Cell 117: 225–237, 2004.[CrossRef][ISI][Medline]
36. Imai S, Armstrong CM, Kaeberlein M, and Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403: 795–800, 2000.[CrossRef][Medline]
37. Jones PA and Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 3: 415–428, 2002.[ISI][Medline]
38. Karin M. NF-kappaB and cancer: mechanisms and targets. Mol Carcinog 45: 355–361, 2006.[CrossRef][ISI][Medline]
39. Karin M, Lawrence T, and Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124: 823–835, 2006.[CrossRef][ISI][Medline]
40. Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell 120: 449–460, 2005.[CrossRef][ISI][Medline]
41. Kirkwood TB. Human senescence. Bioessays 18: 1009–1016, 1996.[CrossRef][ISI][Medline]
42. Kitamura YI, Kitamura T, Kruse JP, Raum JC, Stein R, Gu W, and Accili D. FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2: 153–163, 2005.[CrossRef][ISI][Medline]
43. Kouzarides T. Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19: 1176–1179, 2000.[CrossRef][ISI][Medline]
44. Kuzmichev A, Margueron R, Vaquero A, Preissner TS, Scher M, Kirmizis A, Ouyang X, Brockdorff N, Abate-Shen C, Farnham P, and Reinberg D. Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation. Proc Natl Acad Sci USA 102: 1859–1864, 2005.[Abstract/Free Full Text]
45. Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, and Kouzarides T. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21: 2383–2396, 2002.[CrossRef][ISI][Medline]
46. Liszt G, Ford E, Kurtev M, and Guarente L. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 280: 21313–21320, 2005.[Abstract/Free Full Text]
47. Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, and Alt FW. DNA repair, genome stability, and aging. Cell 120: 497–512, 2005.[CrossRef][ISI][Medline]
48. Lowell BB and Spiegelman BM. Towards a molecular understanding of adaptive thermogenesis. Nature 404: 652–660, 2000.[Medline]
49. Luchsinger JA. A work in progress: the metabolic syndrome. Sci Aging Knowledge Environ 2006: pe19, 2006.[Abstract/Free Full Text]
50. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, and Gu W. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107: 137–148, 2001.[CrossRef][ISI][Medline]
51. McBurney MW, Yang X, Jardine K, Hixon M, Boekelheide K, Webb JR, Lansdorp PM, and Lemieux M. The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Mol Cell Biol 23: 38–54, 2003.[Abstract/Free Full Text]
52. McKinnell IW and Rudnicki MA. Molecular mechanisms of muscle atrophy. Cell 119: 907–910, 2004.[CrossRef][ISI][Medline]
53. Minucci S and Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6: 38–51, 2006.[CrossRef][ISI][Medline]
54. Moller N, Gormsen L, Fuglsang J, and Gjedsted J. Effects of ageing on insulin secretion and action. Horm Res 60: 102–104, 2003.[ISI][Medline]
55. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, and Alt FW. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124: 315–329, 2006.[CrossRef][ISI][Medline]
56. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, and Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell 116: 551–563, 2004.[CrossRef][ISI][Medline]
57. Mourkioti F and Rosenthal N. IGF-1, inflammation and stem cells: interactions during muscle regeneration. Trends Immunol 26: 535–542, 2005.[CrossRef][ISI][Medline]
58. Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Meneur C, Permutt MA, and Imai S. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2: 105–117, 2005.[CrossRef][ISI][Medline]
59. Partridge L and Gems D. Mechanisms of ageing: public or private? Nat Rev Genet 3: 165–175, 2002.[CrossRef][ISI][Medline]
60. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, and Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429: 771–776, 2004.[CrossRef][Medline]
61. Plas DR and Thompson CB. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24: 7435–7442, 2005.[CrossRef][ISI][Medline]
62. Pollak MN, Schernhammer ES, and Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 4: 505–518, 2004.[CrossRef][ISI][Medline]
63. Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, Herman JG, and Baylin SB. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet 2: e40, 2006.[CrossRef][Medline]
64. Ramaswamy S, Nakamura N, Sansal I, Bergeron L, and Sellers WR. A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2: 81–91, 2002.[CrossRef][ISI][Medline]
65. Raval AP, Dave KR, and Perez-Pinzon MA. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab 26: 1141–1147, 2006.[ISI][Medline]
66. Rine J. Cell biology. Twists in the tale of the aging yeast. Science 310: 1124–1125, 2005.[Abstract/Free Full Text]
67. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, and Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118, 2005.[CrossRef][Medline]
68. Sakamoto J, Miura T, Shimamoto K, and Horio Y. Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain. FEBS Lett 556: 281–286, 2004.[CrossRef][ISI][Medline]
69. Starai VJ, Celic I, Cole RN, Boeke JD, and Escalante-Semerena JC. Sir2-dependent activation of acetyl-CoA synthetase by deacetylation of active lysine. Science 298: 2390–2392, 2002.[Abstract/Free Full Text]
70. Starai VJ and Escalante-Semerena JC. Identification of the protein acetyltransferase (Pat) enzyme that acetylates acetyl-CoA synthetase in Salmonella enterica. J Mol Biol 340: 1005–1012, 2004.[CrossRef][ISI][Medline]
71. Tissenbaum HA and Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410: 227–230, 2001.[CrossRef][Medline]
72. van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, and Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem 279: 28873–28879, 2004.[Abstract/Free Full Text]
73. Vaquero A, Loyola A, and Reinberg D. The constantly changing face of chromatin. Sci Aging Knowledge Environ 2003: RE4, 2003.
74. Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, and Reinberg D. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16: 93–105, 2004.[CrossRef][ISI][Medline]
75. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, and Weinberg RA. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107: 149–159, 2001.[CrossRef][ISI][Medline]
76. Yang Y, Hou H, Haller EM, Nicosia SV, and Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J 24: 1021–1032, 2005.[CrossRef][ISI][Medline]
77. Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, and Kahn CR. Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci USA 101: 16525–16530, 2004.[Abstract/Free Full Text]
78. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, and Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J 23: 2369–2380, 2004.[CrossRef][ISI][Medline]
79. Zhao X, Sternsdorf T, Bolger TA, Evans RM, and Yao TP. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol 25: 8456–8464, 2005.[Abstract/Free Full Text]

This article has been cited by other articles:

				K. A. Rasbach and R. G. Schnellmann Isoflavones Promote Mitochondrial Biogenesis J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 536 - 543. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Anastasiou, D. Articles by Krek, W. Search for Related Content PubMed PubMed Citation Articles by Anastasiou, D. Articles by Krek, W.