Received 5 January 2007; accepted 4 February 2007

* Corresponding author. Tel.: +65 6516 1040; fax: +65 6779 1453.E-mail address: bchtbl@nus.edu.sg (B.L. Tang).

Available online at www.sciencedirect.com

Molecular Aspects of Medicine 29 (2008) 187200

www.elsevier.com/locate/mam0098-2997/$ - see front matter 2007 Elsevier Ltd. All rights reserved.Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1882. An overview of SIRT1 and its physiological roles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

2.1. Sir2/SIRT1 and longevity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1882.2. SIRT1 and oncogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1902.3. SIRT1 and metabolic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

3. SIRT1 and neurodegenerative diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923.1. SIRT1 in the brain and neuronal survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923.2. SIRT1 and neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1923.3. A connection between CR, SIRT1 and Rho-ROCK signaling in neurodegeneration?. . . . . . . . . . . . 193Abstract

SIRT1 is the mammalian homologue of yeast silent information regulator (Sir)-2, a member of the sirtuin family ofprotein deacetylases which have gained much attention as mediators of lifespan extension in several model organisms.Induction of SIRT1 expression also attenuates neuronal degeneration and death in animal models of Alzheimers diseaseand Huntingtons disease. SIRT1 induction, either by sirtuin activators such as resveratrol, or metabolic conditioning asso-ciated with caloric restriction (CR), could be neuroprotective in several ways. It could promote the non-amyloidogeniccleavage of the amyloid precursor protein, enhance clearance of amyloid b-peptides, and reduced neuronal damagethrough potential inhibition of neuroinammatory signaling pathways. In addition, increased SIRT1 activity could alterneuronal transcription proles to enhance anti-stress and anti-apoptotic gene activities, and has been proposed to underliethe inhibition of axonal degeneration in the Wallerian degeneration slow (Wlds) phenotype. As neuronal degeneration is amajor pathophysiological aspect of human aging, understanding the mechanism of SIRT1 neuroprotection promises novelstrategies in clinical intervention of neurodegenerative diseases. 2007 Elsevier Ltd. All rights reserved.

Keywords: Alzheimers disease; Huntingtons disease; Neurodegeneration; Neuron; SIRT1; SirtuindDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive,

Singapore 117597, Singaporeoi:10.Bor Luen Tang *, Christelle En Lin ChuaReview

SIRT1 and neuronal diseases1016/j.mam.2007.02.001

SIR2 deletion leads to histone hyperacetylation in yeast. The enzyme has received much attention as it turns

at the nucleolus (Kennedy et al., 1997), and inhibits rDNA recombination as well as the formation of extra-chromosomal rDNA circles (ERCs). The latter is a primary cause of yeast replicative aging (Sinclair and Gua-rente, 1997). Over-expression of Sir2 promotes replicative lifespan of yeast, as well as longevity in invertebratemodels of the worm Caenorhabditis elegans (Tissenbaum and Guarente, 2001) and the y Drosophila (Rogina

188 B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200and Helfand, 2004). In the higher organisms, the involvement of ERC suppression, has however not beendemonstrated.

Of particular clinical interest to Sir2/SIRT1s link to longevity is the associated condition or regime of calo-ric restriction (CR), whereby a reduction in food/energy uptake has been shown to enhance the lifespan ofmodels ranging from yeast to rodents. Lin et al. (2000) rst showed that increased longevity induced byout to be a key mediator of yeast Saccharomyces cerevisiaes replicative lifespan (Kaeberlein et al., 1999; Linet al., 2000; Howitz et al., 2003).

The mammalian Sir2 gene family (or sirtuins) has seven homologues (SIRT1-7), with the nuclear SIRT1being the closest to Sir2, and the best understood in terms of cellular activity and functions. Amongst thenon-histone cellular substrates of SIRT1 are the tumor suppressor p53, the transcription factor NF-jB andthe FOXO family of transcription factors. All the above are involved in transcriptional control of key genesin cell proliferation and cell survival. SIRT1 also deacetylates nuclear receptor peroxisome-proliferator acti-vated receptor-c (PPARc) and its transcriptional co-activator PPARc coactivator-a (PGC-a), which regulatesa wide range of metabolic activities in muscle, adipose tissues and liver. SIRT1 substrates therefore haveapparent functions that could link nutrient availability and energy metabolism to adaptive changes in tran-scriptional proles that aects cell survival in multiple systems.

The sirtuins have intrigued workers in various elds of aging medicine, ranging from oncologist to geron-tologist, because of early links and subsequent ndings of Sir2/SIRT1 as a longevity factor in multiple modelorganisms. The interest in SIRT1 has also intensied over the past two years with further discoveries of its rolein cancer, metabolic diseases and neurodegenerative disorders. The main focus of this review shall be SIRT1srole in neuronal aging and neurodegenerative diseases. In the paragraphs directly below, however, a briefoverview of SIRT1 cellular physiology is rst presented.

2. An overview of SIRT1 and its physiological roles

2.1. Sir2/SIRT1 and longevity

Observations of a link between the Sir complex and yeast replicative lifespan (number of budded genera-tions) was made more than ten years ago through the work of Guarente and colleagues. An early insight intoone mechanism whereby Sir2 could increase yeast replicative lifespan comes from the discovery that Sir2 acts4. SIRT1-mediated neuronal survival and the Wlds mutant protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1945. Concluding remarks future directions and possible translational applications . . . . . . . . . . . . . . . . . . . . . 194

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

1. Introduction

The yeast silent information regulator (Sir) gene products function in a complex as transcriptional repres-sors or silencers, acting largely through histone deacetylation, at the telomeres, mating-type loci and therDNA gene loci (Blander and Guarente, 2004). The SIR2 gene, required for silencing of rDNA loci, is evo-lutionarily conserved from prokaryotes to human. Sir2 is a nicotinamide adenine dinucleotide (NAD)-depen-dent class III protein deacetylase (Imai et al., 2000; Denu, 2005), with ADP-ribosyltransferase activity in vitro.CR in yeast (cultured in reduced glucose) requires the activation of Sir2 by NAD, and lifespan extension

B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200 189by CR is not observed in yeast lacking the SIR2 gene. Subsequent nding by the authors indicated that anincrease in respiration plays a key role in CRs eect on lifespan, an observation that is in line with Sir2s activ-ity being controlled by the cellular NAD/NADH ratio (Lin et al., 2002). This notion is supported by the nd-ing by Sinclairs group that CR and Sir2 activity is regulated by nicotinamide and pyrazinamidase/nicotinamidase 1 (PNC1) (Anderson et al., 2003). Furthermore, sirtuin activators such as resveratrol (which,together with several other polyphenolic compounds, could increase SIRT1s anity for certain target pro-teins, most probably through an allosteric mechanism), could mimic calorie restriction, resulting in increasedDNA stability and lifespan extension (Howitz et al., 2003).

In spite of the above, the importance of Sir2 to CR response in yeast has remained a subject of intensivedebate (Haigis and Guarente, 2006; Sinclair et al., 2006; Longo and Kennedy, 2006). Kennedy and colleagueshad asserted that CRs lifespan extension eect is independent of Sir2, provided that ERCs are kept at lowlevels (Kaeberlein et al., 2004), and that nicotinamide inhibits life span extension by CR through a Sir2-inde-pendent mechanism (Kaeberlein et al., 2005a). They champion instead a view that the CR eect is dependenton nutrient-dependent kinases such as target of rapamycin (TOR), protein kinase A (PKA) and Sch9 (theyeast homologue of Akt kinase) (Kaeberlein et al., 2005c; Longo and Kennedy, 2006). The debate is likelyto continue in spite of the Sinclair groups recent nding that the Sir-2 independent eect of CR could be med-iated by Hst2, another Sir2 homologue in yeast (Lamming et al., 2005). It should also be noted that the eectsof Sir2 on chronological lifespan (length of viability in the nonreplicative, stationary gowth phase) are oppo-site to that on replicative lifespan, with the former being enhanced by SIR2 deletion (Fabrizio et al., 2005).

Sir2 homologue associated lifespan extension in multicellular organisms, where CR eects could be man-ifested at multiple levels of intercellular organizations and metabolic connections, is denitely more compli-cated in mechanistic terms. Genetic analysis in worm had led to the isolation of a set of genes that regulatedauer-formation (the DAF mutants), and implicated the insulin/insulin-like growth factor (IGF) signalingpathway in connection with longevity (Gems and Partridge, 2001). Lifespan extension of C. elegans byover-expression of the worm sir-2.1 appeared to act through the FOXO family transcription factor DAF-16, which is downstream of the insulin receptor signaling pathway (Tissenbaum and Guarente, 2001). Sin-clairs group (Wood et al., 2004) have shown that resveratrol and other sirtuin activators mimic CR andextended the lifespan (without reducing fecundity) of both worm and y in a manner that is dependent ona functional Sir2 homologue. Recent ndings in worms have identied members of the multi-functional 14-3-3 family as Sir-2.1 binding partners. 14-3-3 binding occurs in times of stress, and are required for the Sir-2.1-induced transcriptional activation of DAF-16, stress resistance and life-span extension (Berdichevskyet al., 2006; Wang et al., 2006). However, low insulin-like signaling does not promote Sir-2.1/DAF-16 inter-action, and neither gene products are required for lifespan regulation by the insulin-like signaling pathway.The stress-induced pathway involving Sir-2.1 and 14-3-3 interaction may therefore act in parallel with theinsulin-like pathway, rather than intersecting it, to activate DAF-16 and extend life span. Interestingly, ithas been shown earlier that food restriction, or CR, lengthens life span by a mechanism that is distinct fromthat of DAF mutants (Lakowski and Hekimi, 1998). Guarente and colleagues have also shown that resvera-trol extends worm lifespan largely through Sir-2.1-mediated repression of ER stress genes, such as abu-11(Viswanathan et al., 2005).

Decrease in insulin/IGF signaling has, paradoxically, been strongly linked to lifespan increases in severalmodel organisms (Warner, 2005; Katic and Kahn, 2005). This aspect of lifespan regulation in metazoansmay be of particular relevance to our discussions on SIRT1 and neuronal diseases below. Mutations of C. ele-gans daf-2 (Kimura et al., 1997) and Drosophila InR (Tatar et al., 2001), both homologues of the mammalianinsulin receptor, resulted in an extended lifespan. Intriguingly, at least for the worm, the insulin/IGF signalingcascades action in neurons appears to be able to regulate the senescence of the entire organism. Restoring daf-2 pathway signaling to neurons alone by cell type specic targeting of transgene resulted in a reduction of life-span to the level of wild type worms (Wolkow et al., 2000; Braeckman et al., 2001). In the worm therefore,there seem to be a link between downregulation of neuronal insulin/IGF signaling and longevity.

Although CR could exert a wide range of eects in mammals, it is likely that at least part of these eectsmay be mediated through Sir2/SIRT1. Whether SIRT1 participates directly in lifespan determination in mam-mals has not yet been shown. However, it was shown that CR resulted in an increase in physical activity of

mice, and this eect appears to require SIRT1 because it is lost in SIRT1 knockout mice (Chen et al., 2005).

190 B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200There is also evidence that SIRT1 mediates CR eect in connection with insulin/IGF signaling in mammals.Mice heterozygous for IGF-1 receptor deletion are known to live signicantly longer than wild type mice (Hol-zenberger et al., 2003). Sinclair and colleagues (Cohen et al., 2004b) have shown that SIRT1 expression isinduced in CR rats, and interestingly, in human cells that are cultured in serum from the caloric-restricted ani-mals. Insulin and insulin-like growth factor 1 (IGF-1) appears to attenuate this CR-induced SIRT1 expres-sion, and may enhance susceptibility of cells to apoptotic stimuli. These data could potentially explain whya reduction or defect in IGF-1 signaling turned out to be benecial to long term cell survival and lifespanextension, and that insulin/IGF-1 signaling could potentially counter the cell survival eect of CR and SIRT1(Tang, 2006). Conversely, SIRT1 could also directly inuence insulin/IGF signaling in mice, as illustrated bythe fact that SIRT1-decient mice have increased expression of IGF binding protein-1 (IGFBP1) and someanatomical characteristics of Sirt1-decient mice phenocopy those of transgenic mice over-expressing IGFBP1(Lemieux et al., 2005). This link between insulin/IGF signaling, CR-induced longevity and Sir2/SIRT1 actionis interesting and should be a line of intensive research in the near future.

2.2. SIRT1 and oncogenesis

Genomic instability is a known cause of cellular and organism aging, and also a cause for cancer. Yeast Sir2has been implicated in DNA damage and genome stability. A reduction of spontaneous DNA mutations inSIR2 mutants is a possible reason for the observed chronological lifespan extension (Fabrizio et al., 2005).On the other hand, Sir2 may protect against DNA damage by directing DNA double-strand breaks to homol-ogous and non-homologous repair paths (Lee et al., 1999).

Mammalian SIRT1 interacts with a host of factors with known involvement in cancer, and might act insome cases to promote cancer cell survival. SIRT1 binds and deacetylates the tumor supressor p53 (Luoet al., 2001; Vaziri et al., 2001), thereby inhibiting p53-mediated transactivation and p53-dependent apoptosisin response to DNA damage and oxidative stress. SIRT1 could be recruited to the promyelocytic leukemiaprotein (PML) nuclear bodies, where it co-localizes with p53. There, SIRT1 could antagonize PML-inducedacetylation of p53 and rescue PML-mediated cellular senescence (Langley et al., 2002). SIRT1-decient cellsfrom SIRT1 knockout mice exhibited p53 hyperacetylation after DNA damage (Cheng et al., 2003). SIRT1could also attenuate apoptosis by deacetylating the DNA repair factor Ku70, which was recently found tohave a role in sequestering the pro-apoptotic factor Bax away from the mitochondria (Sawada et al., 2003;Cohen et al., 2004a). The ability of SIRT1 to attenuate apoptosis would conceivably enhance the survivalof transformed cells. Furthermore, it was recently shown that a loss of the tumor suppressor hypermethylatedin cancer 1 (HIC1) promotes tumorigenesis via activating SIRT1, with a consequential attenuation of p53function (Chen et al., 2005). HIC1 forms a transcriptional repression complex with SIRT1, which actuallyrepresses SIRT1s own transcription. Inactivation of HIC1 therefore upregulates SIRT1 expression and inac-tivates p53. As aging increases promoter hypermethylation and epigenetic silencing of HIC1, the resultantupregulation of SIRT1 could promote survival of aging cells and increases cancer risk. Another recent devel-opment indicated that the cell-cycle and apoptosis regulator E2F1 also induces SIRT1 expression (Wang et al.,2006). SIRT1 could, in turn, bind E2F1 and inhibit E2F1s activities, providing a kind of negative feedbackloop. DNA damage by genotoxic cancer drugs like etoposide causes E2F1-dependent induction of SIRT1expression, and silencing of SIRT1 increases sensitivity to etoposide. This attests to a general pro-survivaleect of SIRT1, which may inuence the outcome of cancer chemotherapy.

A classical class of substrate for SIRT1 is the FOXO family of transcription factors (Brunet et al., 2004;Motta et al., 2004; Van der Horst et al., 2004; Nemoto et al., 2004), which are important regulators of genesthat are involved in stress response, cell cycle arrest and cell survival (Lam et al., 2006). The consequence ofSIRT1 deacetylation of FOXO family members is rather complex, and is apparently promoter specic. On thewhole, SIRT1 appears to enhance the expression of FOXO target genes that are involved in cell cycle arrestand resistance to oxidative stress, but inhibits FOXO target genes associated with cell death induction, thusappearing to tip the balance towards cell survival (Giannakou and Partridge, 2004).

SIRT1 directly interacts with the RelA/p65 subunit of NF-jB, and the latters deacetylation is correlatedwith a loss of NF-jB regulated gene expression and sensitized cells to TNF-a induced apoptosis (Yeung et al.,

2004). This may appeared to be a departure from the apoptosis suppression activity of SIRT1 described above.

B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200 191It should however be noted that NF-jB activition may also be anti-apoptotic under certain circumstances,particularly for neuronal cells (Wooten, 1999; Aleyasin et al., 2004). The FOXO and NF-jB regulated path-ways have obvious points of crosstalk, as both are regulated by the inhibitor of jB kinase b (IjKb). The eectof SIRT1 acting through these two sets of transcriptional factors may not always appear coherent and con-sistent in terms of enhancement of cell survival or otherwise. On the whole, however, the feeling is that SIRT1could potentially be oncogenic in promoting cancer cell survival. Another recent nding of relevance is thending of elevated SIRT1 expression in drug-resistant cancer cell lines, which appeared to elevate the expres-sion of the P-glycoprotein multidrug resistance eux pump (Chu et al., 2005). A pro-oncogenic role for SIRT1under the right circumstances therefore appears likely. Interestingly, it has been recently shown that anothermammalian nuclear sirtuin, SIRT6, functions in resistance to DNA damage, promoting DNA repair and sup-pressing genomic instability in mouse cells. SIRT6-decient mice die young and had multiple metabolic abnor-malities and conditions that overlap with aging-associated degenerative processes (Mostoslavsky et al., 2006).Both SIRT1 and SIRT6 may inuence oncogenesis in mammals in ways that await further investigation.

2.3. SIRT1 and metabolic regulation

In view of Sir2/SIRT1s possible connections with CR and longevity, much eort has been directed towardsan understanding of how SIRT1 may aect lifespan by modulating aspects of nutrient availability and energymetabolism in animals (Bordone and Guarente, 2005; Longo and Kennedy, 2006; Anastasiou and Krek,2006). In mammalian cells, acute nutrient withdrawal elevates SIRT1 expression and concomitantly activatesFOXO3a, while the silencing of FOXO3a actually inhibited starvation-induced increase in SIRT1 expression.Stimulation of SIRT1 transcription by FOXO3a is apparently mediated through two p53 binding sites in theSIRT1 promoter region, and SIRT1 expression was not induced in starved p53-decient mice (Nemoto et al.,2004). The interaction and reciprocal regulation of expression between SIRT1 and its target transcriptionalfactors could therefore play key roles in regulating nutrient response and metabolism in mammals.

One important aspect with regard to SIRT1s role in energy metabolism of mammals is how the enzymemay inuence pancreatic insulin secretion and glucose metabolism. In a study examining transgenic mice withb-cell-specic SIRT1 over-expression, increased SIRT1 levels improved glucose tolerance and enhanced insu-lin secretion in response to glucose (Moynihan et al., 2005). In another report, it was shown that SIRT1 mayregulate insulin secretion via repression of the uncoupling protein 2 (UCP2) by binding directly to the UCP2gene promoter (Bordone et al., 2006). Sirt1 knockout mice display constitutively high UCP2 expression.Silencing of SIRT1 via siRNA in b-cell lines elevates UCP2 levels and attenuated insulin secretion. Silencingof UCP2, however, restored the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 isresponsible for the defect in glucose-stimulated insulin secretion.

In the liver, SIRT1 controls the gluconeogenic/glycolytic pathways through the transcriptional coactivatorPGC-1a (Nemoto et al., 2005). In response to fasting signals, SIRT1 induces gluconeogenic genes and hepaticglucose output, but represses glycolytic genes through deacetylation of PGC-1a (Rodgers et al., 2005). It wasrecently shown that resveratrol treatment signicantly increased the aerobic capacity of mice, which is asso-ciated with an induction of genes for oxidative phosphorylation/mitochondrial biogenesis. This could beexplained by SIRT1-mediated PGC-1a acetylation and an increase in PGC-1a activity (Lagouge et al., 2006).

In adipose tissue, Sirt1 represses adipocyte dierentiation and genes controlled by the adepogenic regulatorPPARc (Picard et al., 2004). Mice with reduced SIRT1 have compromised fatty acids mobilization from whiteadipocytes upon fasting. Over-expression of SIRT1 in 3T3-L1 adipocytes attenuates adipogenesis, while siR-NA-mediated silencing of SIRT1 enhances it. SIRT1 over-expression in dierentiated fat cells triggers lipolysisand loss of fat content. SIRT1 may also modulate aspects energy sensing and gene expression in skeletal mus-cle (Freyssenet, 2007). Its ability to mobilize fat and prevent lipid accumulation could, directly or indirectly,impact on aging and obesity-related disorders such as atherosclerosis and type II diabetes. This notion appearsto be supported by the recent ndings of Sinclair and colleagues (Baur et al., 2006; Baur and Sinclair, 2006).The authors showed that resveratrol treatment attenuated the adverse physiological states associated withmiddle-aged mice on a high-calorie diet, and signicantly increased their survival. Resveratrol induced a myr-iad of changes, including increased insulin sensitivity, reduced IGF-I levels, increased AMP-activated protein

kinase (AMPK) and PGC-1a activity, increased mitochondrial number, and improved motor function.

192 B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200Proling analysis revealed that resveratrol attenuated most of the signicant alterations or perturbations inmetabolic pathways caused by the high-calorie diet. Resveratrol, acting at least partially through SIRT1 acti-vation, may therefore counter obesity-related disorders and diseases of aging to a clinically signicant extent.

3. SIRT1 and neurodegenerative diseases

3.1. SIRT1 in the brain and neuronal survival

In mouse embryos, Sirt1 was expressed at high levels in the heart, brain, spinal cord, and dorsal root gan-glia (Sakamoto et al., 2004). High SIRT1 levels in the embryonic brain suggest that it might have a role inneuronal and/or brain development. This notion is in agreement with some of the phenotypes associated withSIRT1 knockout mice, in which postnatal survival is infrequent and which have developmental defects such asexencephaly and retinal anomaly (Cheng et al., 2003; McBurney et al., 2003).

If SIRT1 promotes survival and stress tolerance in mammalian cells, it is also likely to do so for centralnervous system (CNS) neurons. Data in this regard is, however, scarce, as earlier studies have not used neu-ronal cells. In the adult rat brain, SIRT1 can be found in the hippocampus, cerebellum and the cerebral cortex.The antioxidant vitamin E has been shown to reduce oxidative damage and reduction of SIRT1 caused by ahigh fat and sugar diet, with the restoration of Sirt1 levels (Wu et al., 2006). This study suggests that SIRT1levels in the brain are aected by oxidative stress and energy homeostasis. A role for SIRT1 in the protectionof cardiac myocytes against ischemia induced apoptosis has been well documented (Alcendor et al., 2004; Pil-lai et al., 2005). A recent interesting study employing organotypic hippocampal slice culture as an in vitromodel of cerebral ischemia showed that resveratrol pretreatment mimics ischemic preconditioning via SIRT1(Raval et al., 2006). When SIRT1 was inactivated by sirtinol after ischemic preconditioning or resveratrol pre-treatment, neuroprotection is abolished. This study demonstrated a neuroprotective role of SIRT1 in ischemicinjury, which could be elicited by a small molecule such as resveratrol, and is therefore of substantial clinicalinterest. Contrastingly, another earlier report had shown that sirtuin inhibitor nicotinamide enhances neuro-nal cell survival in acute anoxic injury (Chong et al., 2005), although a clear involvement of SIRT1 in this casewas not clearly demonstrated.

3.2. SIRT1 and neurodegenerative diseases

Several ndings have converged on the notion that SIRT1s neuroprotective eect could be extended todegenerating neurons. Parker et al. (2005) showed that resveratrol, acting through Sir-2.1 and SIRT1 activa-tion respectively, protected C. elegans and mouse neurons against the cytotoxicity of the mutant polygluta-mine protein huntingtin. Huntingtin is the product of the gene mutated in the hereditary neurodegenerativedisorder Huntingtons disease, whose expansion of a polyglutamine stretch resulted in a mutant polypeptidethat could form cytotoxic aggregates in neurons (Borrell-Pages et al., 2006). Although C. elegans has no hun-tingtin orthologue, over-expression of a huntingtin fragment in touch receptor neurons resulted in a gain-of-function mechanosensory defect that could model the disease. Both resveratrol and an increased sir-2.1 genedosage alleviated the worm neuronal dysfunction in a DAF16-dependent manner. Furthermore, resveratroldecreased cell death associated with neurons cultured from a mutant huntingtin (109Q) knockin mice, in amanner that is reversible by two SIRT1 inhibitors, sirtinol and nicotinamide.

A link between SIRT1 and Alzheimers disease (AD) is also increasingly evident (Anekonda and Reddy,2006; Anekonda, 2006). The amyloid hypothesis (Hardy and Selkoe, 2002) depicts that extracellular plaquesconsist of aggregated beta-amyloid (Ab) peptide generated from proteolytic cleavages of the amyloid precur-sor protein (APP) as the etiological agent of AD pathology. Both intracellular and extracellular soluble olig-omeric forms of Ab could in fact initiate synaptic malfunctions and the onset of AD symptoms (Wirths et al.,2004; Cuello, 2005). NF-jB signaling in microglia is known to be critically involved in neuronal death inducedby Ab peptides (Valerio et al., 2006). Chen et al. (2005) showed that stimulation of microglia with Abincreased acetylation of RelA/p65 subunit of NF-jB at lysine 310. Over-expression of SIRT1 and resveratroltreatment markedly reduced NF-jB signaling stimulated by Ab and had strong neuroprotective eects. This

result connects the known role of SIRT1 in modulating NF-jB activity (Yeung et al., 2004) with AD. It should

B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200 193be kept in mind that for AD, as with other neurodegenerative diseases, the benecial eect of resveratrol ismultifaceted. Its immediate eect is more likely associated with its activity as an antioxidant (Pervaiz, 2003;Frank and Gupta, 2005), but at a more extended time frame, its activation of SIRT1 and modulation ofNF-jB signaling may result in other benecial eects, such as anti-inammation.

Another possible link between SIRT1 and AD came from the potential benets of CR on AD symptomsand progression. It is well known in the epidemiology of neurodegenerative diseases that the incidence of spo-radic Parkinsons disease (PD) and AD are both correlated with multiple genetic factors, diet and socialbehavior (Mattson et al., 2002). High calorie diets are associated with the risk of AD, and CR has been pro-posed to protect against both PD and AD (Mattson, 2003). Firmer evidence for this idea was obtained whenPatel et al. (2005) showed that short-term CR substantially decreased the accumulation of Ab plaques in twoAD-prone APP/presenilin transgenic mice lines, and also decreased gliosis marked by astrocytic activation. Inanother study, Passinetti and colleagues (Wang J et al., 2005) also showed that a CR dietary regimen preventsAb peptide generation and neuritic plaque deposition in the brain of another mouse model of AD (Tg2576mice). In this latter study, the authors suggested that CR resulted in the promotion of APP processing viathe non-amyloidogenic a-secretase-mediated pathway. They observed a larger than two fold increase in theconcentration of brain sAPPa (a product of a-secretase cleavage) and a statistically signicant 30% increasein ADAM10 (a putative a-secretase) levels in CR animals compared to control. There also appeared to be amoderate increase in the levels of the insulin degrading enzyme (IDE), which has been associated with brainamyloid clearance (Farris et al., 2004). In another recent report, the same group showed that CR resulted inreduced contents of Ab in the temporal cortex of squirrel monkeys, in a manner that was inversely correlatedwith SIRT1 protein concentrations in the same brain region (Qin et al., 2006a). It is not particularly clear inthe above reports whether CRs eects in attenuating amyloid production were mediated through SIRT1 acti-vation. As discussed below, recent evidence suggests that this may indeed be the case, and may actually involvea novel signaling crosstalk.

3.3. A connection between CR, SIRT1 and Rho-ROCK signaling in neurodegeneration?

Two classes of drugs, non-steroidal anti-inammatory drugs (NSAIDs) and statins, have recently beennoted to have a potential benecial eect on AD via a mechanism involving Rho-ROCK (Rho kinase) signal-ing (Tang, 2005). NSAIDs could stimulate the secretion of sAPPa into the conditioned media of cultured cells(Avramovich et al., 2002), and may function through a rather indirect way of perturbing the isoprenoid path-way, particularly geranylgeranylation (Zhou et al., 2003). NSAIDs blocked an increase in Ab42 production bygeranylgeranyl pyrophosphate (GGpp) treatment of SH-SY5Y cells expressing mutant APP. The downstreamtargets of the drugs appeared to be Rho and ROCK. The dominant-negative form of Rho, but not Cdc42 orRac1, caused a decrease in Ab42. Inactivation of Rho by C3-transferase, and treatment of both APP-express-ing cells and mice with the ROCK inhibitor Y-27632, also reduced Ab42 both in vitro and in vivo. Statinsappear to synergize with the farnesyl transferase inhibitor-1 (FTI-1) to promote sAPPa shedding (Pedriniet al., 2005). ROCK activation by arachidonic acid and a constitutively active ROCK mutant diminishedsAPPa shedding, whereas a kinase-dead ROCK mutant enhanced sAPPa shedding. Both NSAIDs and statinsmight therefore enhance the nonamyloidogenic, a-secretase processing of APP through a pathway involvingRho and ROCK. These drugs may also be benecial to AD by modulating brain inammation through thesame pathway, as Cordal and Landreth (2005) showed that statin inhibited Ab-stimulated expression of thepro-inammatory cytokine interleukin-1b and nitric oxide production in microglia and monocytes in a man-ner that is attenuated by mevalonate and GGpp attenuated this inhibition. Both a geranylgeranyl transferaseinhibitor and C3 transferase could also block Ab-induced inammation.

Since both CR and the drugs appear to enhance non-amyloidogenic processing of APP and decrease amy-loid production, is there a possible link between their mechanisms of action? A recent study by Pasinetti andcolleagues provided tantalizing clues to the existence of such a link (Qin et al., 2006). The authors showed thatCR increases SIRT1 and NAD levels in Tg2576 mouse brain. Viral-mediated SIRT1 over-expression in pri-mary neuron cultures from Tg2576 mouse and CHO cells expressing mutant APP elevated sAPPa, butreduced Ab secretion and, interestingly, ROCK1 expression as well. Furthermore, expression of a constitu-

tively active ROCK1 prevented SIRT1-mediated elevation of sAPPa. In a SIRT1 transgenic line, an elevation

194 B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200of SIRT1 levels in the brain correlated with a reduction in ROCK1 protein content. These ndings suggestthat SIRT1 may enhance asecretase-mediated non-amyloidogenic APP processing in a manner that couldbe negatively inuenced by ROCK1 signaling. On the other hand, ROCK1 expression itself appears to be neg-atively regulated by SIRT1. Although further exploration would be necessary to clarify the relationshipbetween SIRT1 and the Rho-ROCK pathway, it is likely that we are looking at a feedback loop with somepathological, if not physiological, relevance.

4. SIRT1-mediated neuronal survival and the Wlds mutant protein

A separate link between SIRT1 and neuroprotection comes from recent studies on possible mechanism offunction of the Wlds protein, the product of the gene mutated in Wallerian degeneration slow (wlds) mice(Perry et al., 1990). These mice exhibit a very signicant delay in axonal degeneration induced by physicalor chemical injury (Coleman and Perry, 2002; Coleman, 2005). The mechanistic basis for the delayed regen-eration is apparently associated with the mutant Wlds chimeric protein itself. Wlds consists of the N-terminal70 amino acids of the ubiquitin fusion degradation protein 2a (Uf2a) fused with the complete sequence of nic-otinamide mononucleotide adenylyltransferase 1 (Nmnat1). The latter is an essential key enzyme in the NADbiosynthesis pathway. Opinion is divided as to whether the delay in axonal degeneration is caused by a dom-inant negative eect of the truncated Uf2a fragment, or the increase in Nmnat1 activity, which would lead toincrease NAD. The former notion is supported by the fact that proteasome inhibitors could inhibit axonaldegeneration (Zhai et al., 2003).

Milbrandt and colleagues have, however, provided some evidence that the increase in Nmnat1 activity is atleast partially responsible for axonal protection by Wlds. Furthermore, Nmnat1 appeared to exert its eectsthrough SIRT1 activation, as neuroprotection is blocked by sirtinol and siRNA-mediated silencing of SIRT1(but not other mammalian Sir2 homologues) (Araki et al., 2004). Interestingly, the authors found that overalltissue NAD levels are unaltered in mutant mice compared to control, a phenomenon reminiscent to thatobserved in yeast over-expressing the Nmnat homologue nicotinate phosphoribosyltransferase-1 (NPT-1)(Anderson et al., 2002). NPT-1 increases Sir2-dependent silencing and extends yeast replicative life span byup to 60%. The group followed up this line of investigation by over-expressing enzymes from multipleNAD biosythesis pathways, together with exogenous administration of their respective substrates, in dorsalroot ganglion (DRG) cultures to assess their capacity to protect axons after axotomy (Sasaki et al., 2006).The authors observed that axonal protection could be provided by these other enzymes and their substratesto varying degrees, indicating that stimulation of NAD biosynthesis in various ways may be useful in prevent-ing or delaying axonal degeneration.

Other ndings have however suggested that the increased Nmnat1 activity could not fully account for theneuroprotective phenotype. Wang J et al. (2005) showed that NAD delays axonal regeneration by a local pro-tective mechanism that is SIRT1-independent. The degeneration of axonal segments that have been separatedfrom their soma (and therefore unlikely to involve the nuclear SIRT1) could apparently be delayed by theexogenous application of NAD or its precursor nicotinamide. Transgenic over-expression of Nmnat1 itselfhave far inferior axonal degeneration delaying eect compared to the Wlds mutant protein (Conforti et al.,2007). Viral-mediated over-expression of Nmnat1 was signicantly less potent than Wlds in delaying degener-ation of DRG explants, while an enzyme-dead version of Wlds still displayed residual neurite protection.Although the studies above have systemic dierences and neuronal degeneration had been assessed at dierenttime points, it does appear that enhanced Nmnat1 activity cannot fully explain the phenotype conferred byWlds. It was therefore suggested that the linker region between the two fused proteins may play a yet unde-ned role in the potency of Wlds (Fainzilber and Twiss, 2006), particularly in view of its ability to inuence thecellular localization of the fusion protein (Laser et al., 2006).

5. Concluding remarks future directions and possible translational applications

The role of Sir2/SIRT1 in cellular and organism aging has prompted intensive research in the past few yearson how this protein deacetylase may work at the interphase between energy metabolism, cell survival and life-

span extension. The emerging picture is one that suggests that SIRT1 activation, at least when supercially

B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200 195viewed, brings about a healthier state of metabolic physiology in mammals and promotes cell survival in gen-eral. Perhaps a downside is that SIRT1 might be tumor promoting under certain circumstances. Neurons arehowever terminally dierentiated cells and oncogenesis from neurons is notoriously dicult. An excitingaspect of SIRT1 mediated neuroprotective and anti-degenerative eect is that these could potentially beachieved by small compound activators that are natural products (such as resveratrol) and non-invasiveregimes such as caloric restriction. Even as hopes are raised in exploiting small compound activators of SIRT1in countering neuronal diseases, neuronal injury and neurodegeneration, much basic neurobiology remains tobe learned. What we think we know about the functions of SIRT1 in neurons during development and in thepostnatal brain had been largely extrapolations from studies in other cell types. Knowledge of any specicSIRT1 functions in the CNS is scarce, and there are pressing problems of immediate interest.

A particularly intriguing problem would be the possible interaction between SIRT1 activity and the insulin/IGF signaling axis, and how this interaction inuence neuronal cell survival on one hand, and organism life-span on the other. It is intriguing and paradoxical that while insulin/IGF signaling is anti-apoptotic and pro-motes neuronal survival, downregulation of the pathway actually promotes lifespan extension. The work ofCohen et al. (2004) suggests that IGF-1 inuences SIRT1 activity, but at the moment it is dicult to judgeto what extent this occurs for neurons in vivo. It is yet unclear which step or aspect of IGF-1 signaling atten-uates SIRT1 expression, and whether SIRT1 activity has a reciprocal eect on the expression of componentsof the IGF signaling system. While IGF-1 anti-apoptotic signaling could provide acute protection to apoptoticinsults, high SIRT1 activity may oer longer lasting protection due to changes in cellular transcript proles, intime frames which are more in line with the lifespan of an organism. The FOXO family members are all neg-atively regulated by signaling through the IGF-1-Phosphatidylinositol 3-kinase-Akt kinase signaling pathway(Brunet et al., 1999). Phosphorylation of FOXOs by Akt kinase and consequent sequestration by 14-3-3 mayattenuate apoptotic stimuli, but may also at the same time reduce the expression of antioxidative stress andother stress-resistance genes. The above seemingly entangled web serves to illustrate the complex regulatoryrelationship between IGF-1, SIRT1 and the FOXO transcription factors, which would take some eort inworking out.

An equally intriguing problem is the how CR and SIRT1 activation may aect the amyloidogenic process-ing of APP, and the possible relationship between SIRT1 activity and Rho-ROCK signaling (as discussed inSection 3.3). In this regard, SIRT1 activation could result in increased expression of a-secretases (for whichthere is some evidence) or a decrease in b and c-secretases levels. Modulation of the cytoskeletal networkvia upstream regulators of Rho and its downstream eectors are known to participate in a myriad of processesduring neuronal development (Govek et al., 2005), growth (Guan and Rao, 2003; Fukata et al., 2003) andregeneration (Tang, 2003; McKerracher and Higuchi, 2006). Understanding how the Rho-ROCK pathwaymay interact with SIRT1-mediated activities is therefore of obvious importance. The roles of other mamma-lian sirtuins in the brain are also unclear at the moment. Anekonda and Reddy (2006) had put forward somespeculations arguments on how SIRT2 and SIRT3 may be involved in neurodegeneration. SIRT2 is a predom-inantly cytoplasmic protein that colocalizes with microtubules and could deacetylate lysine-40 of a-tubulinboth in vitro and in vivo. SIRT2 silencing via siRNA results in tubulin hyperacetylation. SIRT2 activitymay therefore inuence cytoskeletal network stability and impact on the role of the microtubule binding pro-tein tau in AD pathogenesis (Avila, 2006).

Finally, could modulation of SIRT1 activity be realistically explored to treat neuronal diseases and neuro-degeneration? While CR and resveratrol seem easy enough to administer, it is still debatable if either of thesecould confer neuroprotection through SIRT1 activation. A general reduction in fat, and particularly choles-terol intake, would have benecial eects on AD (Panza et al., 2006; Mielke and Lyketsos, 2006). CR may notbe generally applicable to all neurodegenerative diseases. Although it appeared to be also benecial in primatemodels of Parkinsonism (Maswood et al., 2004), its transient improvement of motor performance in a mousemodel of amyotrophic lateral sclerosis (ALS) is oset by its hastening of clinical onset of disease (Hamadehet al., 2005).

It has also been pointed out that resveratrols activation of Sir2/SIRT1 appears to be substrate specic, andthere is some doubts on its activity with regards to substrates in vivo (Kaeberlein et al., 2005b; Borra et al.,2005). While resveratrols multiple benecial eect on metabolic health is clear (Sinclair, 2005; Baur et al.,

2006), its mechanism of action is, as mentioned, multifaceted and complex. Pertaining to neurodegenerative

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Braeckman, B.P., Houthoofd, K., Vaneteren, J.R., 2001. Insulin-like signaling, metabolism, stress resistance and aging in Caenorhabditis

196 B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200elegans. Mech. Ageing Dev. 122, 673693.

Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J., Greenberg, M.E., 1999. Akt

promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857868.

Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., Hu, L.S.,

Cheng, H.L., Jedrychowski, M.P., Gygi, S.P., Sinclair, D.A., Alt, F.W., Greenberg, M.E., 2004. Stress-dependent regulation of FOXO

transcription factors by the SIRT1 deacetylase. Science 303, 20112015.

Chen, D., Steele, A.D., Lindquist, S., Guarente, L., 2005. Increase in activity during calorie restriction requires Sirt1. Science 310, 1641.

Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.F., Kwon, H., Yi, S., Mucke, L., Gan, L., 2005. SIRT1 protects against microglia-

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Chen, W.Y., Wang, D.H., Yen, R.C., Luo, J., Gu, W., Baylin, S.B., 2005. Tumor suppressor HIC1 directly regulates SIRT1 to modulate

p53-dependent DNA-damage responses. Cell 123, 437448.diseases and AD, resveratrol has extensively documented antioxidative (Frank and Gupta, 2005) and amyloidtoxicity protective (Han et al., 2004) eects. Marambaud et al. (2005) have recently showed that the resveratrolreduces Ab production in vitro by enhancing intracellular Ab degradation by the proteasome in a rather spe-cic manner. The bioavailability resveratrol in its aglycone form upon gastrointestinal uptake is apparentlylow due to its quick conversion to glucuronic acid and sulphate conjugates. A better understanding of howresveratrol administration aects brain SIRT1 activity is certainly useful. On the other hand, the neurologicaleects of activating neuronal SIRT1 must be extensively assessed, for example through behavioral studies per-formed on SIRT1 transgenics. Such an understanding will also aid in the screening for more specic actingneuronal SIRT1 activators.

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200 B.L. Tang, C.E.L. Chua / Molecular Aspects of Medicine 29 (2008) 187200

SIRT1 and neuronal diseasesIntroductionAn overview of SIRT1 and its physiological rolesSir2/SIRT1 and longevitySIRT1 and oncogenesisSIRT1 and metabolic regulation

SIRT1 and neurodegenerative diseasesSIRT1 in the brain and neuronal survivalSIRT1 and neurodegenerative diseasesA connection between CR, SIRT1 and Rho-ROCK signaling in neurodegeneration?

SIRT1-mediated neuronal survival and the Wlds mutant proteinConcluding remarks - future directions and possible translational applicationsReferences