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Molecular Endocrinology, doi:10.1210/me.2007-0079
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Molecular Endocrinology 21 (8): 1745-1755
Copyright © 2007 by The Endocrine Society

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Sirtuin Functions in Health and Disease

Hiroyasu Yamamoto, Kristina Schoonjans and Johan Auwerx

Institut de Génétique et de Biologie Moléculaire et Cellulaire (H.Y., K.S., J.A.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur, 67404 Illkirch, France; and Institut Clinique de la Souris (J.A.), 67404 Illkirch, France

Address all correspondence and requests for reprints to: Johan Auwerx, M.D., Ph.D., Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, Boîte Postale 10142, 67404 Illkirch, France. E-mail: auwerx{at}igbmc.u-strasbg.fr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SIRTUINS ARE NICOTINAMIDE...
 SIRTUINS AND THE CONTROL...
 SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
 REFERENCES
 
Sirtuins or Sir2 (silent information regulator 2)-related enzymes have originally been defined as a family of nicotinamide adenine dinucleotide-dependent enzymes that deacetylate lysine residue on various proteins. Certain sirtuins have in addition an ADP-ribosyltransferase activity. The sirtuins are remarkably conserved throughout evolution from archaebacteria to eukaryotes. The mammalian sirtuins SIRT1–SIRT7 are implicated in a variety of cellular functions ranging from gene silencing, over the control of the cell cycle and apoptosis, to energy homeostasis. On a whole-body level, the wide range of cellular activities of the sirtuins suggests that they could constitute therapeutic targets to combat metabolic, neurodegenerative, and proliferative diseases. Here, we review some of the recent data related to the sirtuins and discuss their mode of action, their biological role in cellular and organismal models, and their possible association to age-related human diseases.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SIRTUINS ARE NICOTINAMIDE...
 SIRTUINS AND THE CONTROL...
 SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
 REFERENCES
 
THE RISING INCIDENCE of obesity-related diseases, such as diabetes, dyslipidemia, and cardiovascular and cerebrovascular diseases in industrialized countries has become a public health problem of major importance. Many therapeutic and preventive strategies to prevent or combat obesity have seen the light of day, but few have survived the test of time. One phenomenon that caught the interest in this context is the so-called "French paradox." First noted by Irish physician Samuel Black in 1819, the French paradox makes an allusion to the fact that the French are perceived as having a relatively low incidence of cardiovascular and metabolic disease, although their diet is rich in saturated fat. The high consumption of red wine, which is rich in the polyphenol resveratrol, is thought to be one of the primary factors contributing to this selective advantage.

Meanwhile, since the 1930s, it has been also well known that caloric restriction (CR) can retard the aging process and delay the onset of numerous aging-related diseases, such as cancer, cardiovascular diseases, and metabolic diseases. CR significantly expands lifespan in organisms ranging from yeast and nematodes to rodents and monkeys (1, 2). Interestingly, the beneficial health outcomes of CR resemble those that are induced by resveratrol in a number of animal models, suggesting that the molecular pathways by which resveratrol acts are similar to those activated by CR. Recently, it was suggested that the sirtuins could be the common mediators that explain both the effects of resveratrol and CR pathways. In this review, we will discuss the molecular mechanism that underlies the biological activity of these sirtuins, their functional roles in whole-body physiology, and their possible associations to human diseases.


   SIRTUINS ARE NICOTINAMIDE ADENINE DINUCLEOTIDE-DEPENDENT HISTONE DEACETYLASES OR ADP-RIBOSYL TRANSFERASES
TOP
 ABSTRACT
 INTRODUCTION
 SIRTUINS ARE NICOTINAMIDE...
SIRTUINS AND THE CONTROL...
 SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
 REFERENCES
 
The founding member of the sirtuin protein family was the silent information regulator 2 protein (Sir2p) of Saccharomyces cervisiae, a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase (HDAC) that regulates chromatin silencing (3, 4, 5, 6, 7). Yeast strains with abnormal levels of Sir2p show defects in many cellular functions, including transcriptional and recombinational silencing, senescence, and DNA repair. In S. cervisiae, there are four sirtuins (NAD+-dependent histone deacetylases Hst1–Hst4) in addition to Sir2p, whereas in mammals seven homologs, i.e. SIRT1–SIRT7, have been identified (8, 9) (Table 1Go). The remarkable conservation of members of the sirtuin gene family from yeast to humans indicates that these proteins play vital physiological roles (9).


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  		Table 1. Main Characteristic of Mammalian Sirtuins

 
Among the large HDAC protein family, sirtuins were originally categorized as class III HDACs. Whereas classes I and II HDACs use zinc as a cofactor and are inhibited by trichostatin A (10), sirtuins are not inhibited by trichostatin A and convert acetylated protein substrates in a reaction that uses NAD+ into a deacetylated protein, nicotinamide, and the acetyl ester metabolites 2'-O- and 3'-O-acetyl-ADP ribose (AADPR), which are formed by the transfer of the acetyl group to the ADP-ribose portion of NAD+ (6, 7, 11, 12, 13, 14) (Fig. 1Go). The deacetylase activity of the sirtuins is controlled by the cellular [NAD+]/[NADH] ratio, i.e. NAD+ works as an activator, whereas nicotinamide and reduced nicotinamide adenine dinucleotide (NADH) inhibit their activity (15, 16, 17, 18, 19).


Figure 1
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  		Fig. 1. Two Reactions Catalyzed by Sirtuins, i.e. Deacetylation and ADP-Ribosylation

Sirtuins (SIRT1–SIRT3, SIRT5) catalyze a deacetylation reaction in which an acetyl group is transferred to the ADP-ribose (ADPR) moiety of NAD+ and 2'-O-acetyl-ADPR is produced. 3'-O-acetyl-ADPR is formed nonenzymatically from 2'-O-acetyl-ADPR. In contrast, SIRT4 and SIRT6 catalyze ADP-ribosylation of proteins rather than deacetylation.

 
Because sirtuins are class III HDACs, it was logical that their function initially became associated with transcriptional repression. Acetylated histones H1, H3, and H4 are known to be physiological substrates for the sirtuins, and lysine 16 in histone H4 appears to be the most critical residue for sirtuin-mediated transcriptional silencing (20, 21). Afterwards, it has been recognized that a growing number of nonhistone proteins are also deacetylated by the sirtuins, largely expanding their biological roles. These nonhistone sirtuin substrates include several transcriptional regulators, such as the nuclear factor-{kappa}B (NF{kappa}B), forkhead box type O transcription factors (FOXO), and the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator 1{alpha} (PGC-1{alpha}), but also enzymes, such as acetyl coenzyme A (CoA) synthetase 2 (AceCS2), and structural proteins, such as {alpha}-tubulin (Table 1Go).

Interestingly, AADPR, a product generated in the deacetylation reaction catalyzed by the sirtuins, also has a role as a second messenger because it is involved in establishing a transcriptionally silent and functionally heterochromatic state (20, 22). AADPR achieves this effect by two independent mechanisms that involve on the one hand a conformational change in SIRT1, which in a feedforward loop potentiates the gene-silencing effects of the Sir complex (20), and on the other hand, by binding to the histone variant macro H2A1.1, which is present in inactive heterochromatic regions (22). Because cellular [NAD+]/[NADH] ratio, nicotinamide, and AADPR levels are governed by cellular energetics, SIRT1 may be an extremely versatile energy sensor that enables transcription to sense the metabolic state of the cell.

Two sirtuins, SIRT4 and SIRT6, are lacking important deacetylase activity but instead have a robust NAD+-dependent ADP-ribosyl transferase activity (Fig. 1Go). The ADP-ribosyl transferase activities of these two SIRTs are not a complete surprise in view of the initial report on the enzymatic activity of yeast Sir2p, which described a mono-ADP-ribosyl transferase activity (23). Posttranslational modification of protein substrates by mono-ADP-ribosylation involves the creation of an N- or S-glycosidic linkage between a specific amino acid (such as arginine or cysteine) on the acceptor protein and the ADP-ribose residue of NAD+.

The seven mammalian sirtuins show significant sequence homology and contain conserved catalytic and NAD+ binding domains (Fig. 2Go and Table 1Go). Although based on sequence similarities, eukaryotic sirtuins have been divided into four broad phylogenetic groups, with SIRT1, SIRT2, and SIRT3 composing class I, SIRT4 constituting class II, SIRT5 forming class III, and SIRT6 and SIRT7 forming class IV (9), there is no obvious correlation between this classification and the specific biological functions of the sirtuins. Another more relevant way to functionally classify the sirtuins is based on their intracellular localizations (24) (Table 1Go). Four sirtuins, SIRT1, SIRT3, SIRT6, and SIRT7, are nuclear proteins, but their subnuclear localizations are distinct. SIRT1 is detected in the nuclei but is excluded from the nucleoli, whereas SIRT6 and SIRT7, are associated with heterochromatic regions and nucleoli, respectively (24, 25). SIRT2 is generally localized in the cytoplasm, but, during the G2/M phase, it binds chromatin in the nucleus (26). SIRT3, SIRT4, and SIRT5 are present in the mitochondria. Although initially described as a mitochondrial protein, recent studies suggest that SIRT3 can also be a nuclear protein that transfers to the mitochondria during cellular stress (119). The exact localization of the SIRT3–SIRT5 in the mitochondria has, however, not yet been defined experimentally.


Figure 2
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  		Fig. 2. Schematic of the Structural Domains of the Mammalian Sirtuins

 
All seven sirtuins are ubiquitously expressed in human tissues, although higher levels of mRNA expression are detected in the brain and testis for most sirtuins (8, 24). Except for SIRT2 and SIRT5, the expression for the sirtuins is higher in fetal relative to adult brain, which might indicate the possibility that they play important roles in the development of the neuronal system.


   SIRTUINS AND THE CONTROL OF CELL PROLIFERATION, STRESS RESISTANCE, AND CANCER
TOP
 ABSTRACT
 INTRODUCTION
 SIRTUINS ARE NICOTINAMIDE...
 SIRTUINS AND THE CONTROL...
SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
 REFERENCES
 
Many factors that control cell proliferation and apoptosis are identified as sirtuin substrates, such as p53 (27, 28, 29). SIRT1 is reported to be associated with the tumor suppressor protein p53. p53 has several acetylation sites, and its hyperacetylation stabilizes and activates it to trigger apoptosis and cell-cycle arrest (30, 31, 32). Conversely, the deacetylation of p53 by SIRT1 is predicted to induce its destruction by the MDM2 (mouse double minute 2)-dependent ubiquitin-mediated pathway. In fact, overexpression of SIRT1 inhibits p53 transcriptional activity and p53-dependent apoptosis in response to DNA damage and oxidative stress, whereas overexpression of dominant-negative SIRT1 protein can potentiate these cellular stress responses (28, 29). In thymocytes from SIRT1-deficient mice, the levels of p53 acetylation were significantly up-regulated after exposure to ionizing radiation (33), indicating that SIRT1 has a role in increasing the stress resistance of cells. Increased p53 acetylation has also been associated with senescence (34). Interestingly, SIRT1 was shown recently to promote replicative senescence, through a process that implicates p19ARF, which positively regulates p53 through inhibiting MDM2 (35). This effect is in marked contrast to Sir2p function in yeast, which extends replicative lifespan (12, 36, 37).

Sirtuins also affect the activity of the FOXO family of transcription factors (38, 39). Genetic epistasis in Caenorhabditis elegans and metabolic studies in mice indicate that FOXO genes regulate cell differentiation, transformation, and metabolism (40). In C. elegans, mutation of the FOXO ortholog Daf16 (abnormal dauer formation) rescues the dauer state, caused by mutations of the insulin/IGF receptor ortholog Daf2 (41, 42, 43). In mammalian cells, growth factor-induced activation of phosphatidylinositol 3-kinase leads to an increase in the activity of the serine/threonine kinase AKT/protein kinase B (44, 45), which in turn leads to phosphorylation and inactivation of the FOXO proteins by their retention in the cytoplasm (46, 47, 48, 49). The translocation of FOXO3a from the cytoplasm to the nucleus is induced by its deacetylation by SIRT1 in response to oxidative stress (50). In the nucleus, SIRT1 and deacetylated FOXO3a form a complex that induces cell-cycle arrest and resistance to oxidative stress but inhibits the ability of FOXO3a to induce apoptosis. SIRT1-mediated deacetylation also affects FOXO1 nucleocytoplasmic shuttling, leading to the expression of FOXO1 target genes, hence inducing gluconeogenesis and glucose release from hepatocytes (51).

SIRT1 is also reported to play an important role during myocyte differentiation. The levels of SIRT1 and the [NAD+]/[NADH] ratio decrease during muscle differentiation. Overexpression of SIRT1 retards muscle differentiation via formation of a complex with the acetyltransferase PCAF (p300/CBP-associated factor) and MyoD, whereas in cells with reduced SIRT1 expression, muscle gene expression and differentiation are enhanced (52). In addition, the muscle cell transcription factor, myocyte enhancer factor MEF2 is inactivated through deacetylation by SIRT1 (53). SIRT1 also was reported to bind and deacetylate the androgen receptor (AR) at a conserved lysine motif, thereby repressing the ligand-induced AR transcriptional activity by the inhibition of coactivator-induced interactions between the AR amino and carboxyl termini (54).

Hst2, the yeast ortholog of SIRT2 can induce Sir2p-independent lifespan extension and rDNA silencing in yeast (10), highlighting the redundancies of the SIRTs in the control of lifespan in yeast. As to the mammalian SIRT2, it deacetylates a number of substrates, including {alpha}-tubulin and histone H4K16Ac (55, 56). In mammalian cell culture systems, SIRT2 was shown to play an important role in the control of the cell cycle (26, 57). The global levels of H4K16 acetylation peak at the S and G2 phase, dropping before cells enter mitosis, coinciding with the increased expression of SIRT2, its nuclear translocation, and association with chromatin (26). In SIRT2-deficient mouse embryonic fibroblasts (MEFs), H4K16 acetylation remains high during mitosis, delaying S-phase entry. This suggests that the SIRT2-mediated conversion of H4K16Ac to its deacetylated form may be pivotal to the formation of condensed chromatin. SIRT2 has also been suggested to act as a tumor suppressor gene in human gliomas (58). Down-regulation of SIRT2 gene expression and/or deletion of the chromosomal region harboring the SIRT2 gene is frequently observed in gliomas. SIRT2 expression might hence serve as a potential diagnostic molecular marker for gliomas, and modulation of its activity might be of interest for the management of gliomas.

The nuclear protein SIRT6 is a weak deacetylase but is endowed with a robust ADP-ribosyltransferase activity. SIRT6–/– MEFs have an increased frequency of various chromosomal aberrations, which indicates that SIRT6 is involved in maintaining genome integrity (25). SIRT6 deficiency also impairs the proliferation of these MEFs and enhances their sensitivity to DNA-damaging agents. This regulation of genomic stability by SIRT6 is related to its function in base excision repair (BER) of single-stranded DNA breaks. Interestingly, overexpression of the DNA polymerase involved in BER, Polß, rescues these defects (25, 59, 60). SIRT6–/– mice die prematurely subsequent to several rather acute degenerative processes, including loss of sc fat, reduction of bone mineral density, colitis, and lymphopenia associated with increased lymphocyte apoptosis (25). SIRT6 may also control metabolism, because SIRT6–/– mice exhibits low levels of serum IGF-I and a gradual decrease of serum glucose. It remains, however, unclear how SIRT6 influences BER and whether the altered serum IGF and insulin levels of SIRT6–/– mice directly contribute to aging-like phenotypes or, alternatively, reflect compensatory changes.

SIRT7 is a nucleolar protein that is associated with active rRNA genes in which it interacts with RNA polymerase I (61). SIRT7 overexpression increases rRNA transcription, whereas its down-regulation decreases rRNA transcription. Interestingly, SIRT7 expression is enriched in tissues with a high proliferation potential, such as liver, spleen, and testis. This is in contrast to tissues with a low cellular turnover rate, such as skeletal and heart muscle and brain that express low levels of SIRT7. SIRT7 seems hence to drive ribosome biogenesis in dividing cells, and it has been associated with thyroid and breast cancer (62, 63). SIRT7 gene expression is up-regulated in these cancers, and, moreover, its levels are closely related to tumor development and disease progression of breast cancer. Additional study will, however, be required to identify the mechanism underlying enhanced SIRT7 gene expression in these cancers.

All of these studies combined suggest important roles of the sirtuins in the control of cell proliferation: SIRT1 inhibits p53 and modulates FOXO activity, SIRT2 controls chromosome condensation during the cell cycle, SIRT6 acts in BER, whereas SIRT7 activates rRNA transcription.


   SIRTUINS CONTROL METABOLIC ACTIVITY
TOP
 ABSTRACT
 INTRODUCTION
 SIRTUINS ARE NICOTINAMIDE...
 SIRTUINS AND THE CONTROL...
 SIRTUINS CONTROL METABOLIC...
SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
 REFERENCES
 
The fact that several of the protein substrates, such as AceCS2 and PGC-1{alpha}, which are deacetylated by the sirtuins, are involved in metabolism indicated a metabolic role for this protein family (64, 65, 66, 67). This hypothesis was substantiated through studies that used both cell-based approaches as well as a combination of whole animal genetic and pharmacological approaches.

Two groups reported the phenotypes of germ-line SIRT1–/– mice, which showed some similarities but also revealed differences, potentially the result from the methods used to generate the mice (33, 68). In general, SIRT1–/– mice were smaller at birth and showed an elevated postnatal lethality attributable to developmental problems that are not observed in yeast, C. elegans, or Drosophila. In an outbred background, some of the SIRT1–/– mice survived to adulthood, but they have fertility problems and display a variety of other problems, including skeletal, eye, and cardiac defects. The study of some of these genetically engineered SIRT1 mouse models revealed a role of SIRT1 in pancreatic homeostasis. In the pancreas, SIRT1 was preferentially localized in the islets of Langerhans. In the SIRT1–/– mice, insulin secretion in response to glucose was lower compared with wild-type littermates, indicating that SIRT1 positively regulates insulin secretion in pancreatic ß-cells (69). Conversely, ß-cell-specific SIRT1-overexpressing transgenic mice exhibit an improved glucose tolerance and an enhanced glucose-stimulated insulin secretion (70). From the microarray analysis comparing gene expression patterns in SIRT1-overexpressing- and knockdown pancreatic ß-cell lines, uncoupling protein 2 (UCP2), a protein that negatively regulates insulin secretion in pancreatic ß-cells, was identified as a target that was repressed by SIRT1. SIRT1 decreases UCP2 gene expression by directly binding to the UCP2 promoter, leading to a better coupling of mitochondrial respiration and ATP synthesis, which will induce insulin secretion (69, 70).

PPAR{gamma} is a key regulator in adipogenesis and fat storage through the control of the expression of many adipocyte-specific genes (71). SIRT1 represses PPAR{gamma} actively via docking with two of its corepressors, NcoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). Hence, SIRT1 was suggested to act as a corepressor of PPAR{gamma}-mediated transcription. From a functional point of view, the repression of PPAR{gamma} by SIRT1 attenuates adipogenesis, and up-regulation of SIRT1 triggers lipolysis and loss of fat in differentiated fat cells (72). Conversely, the reduction in SIRT1 expression in SIRT1+/– mice hence compromises the mobilization of fatty acids from adipose tissue during fasting.

Perhaps the most relevant target of SIRT1 in the metabolic arena is the cofactor PGC-1{alpha}, the master regulator of mitochondrial biogenesis. PGC-1{alpha} is activated by SIRT1-mediated deacetylation (65, 66). In the liver, the activation of PGC-1{alpha} will facilitate the gluconeogenic activity of hepatocyte nuclear factor 4{alpha} and stimulate hepatic glucose output (66). In the muscle and brown adipose tissue (BAT), the SIRT1-mediated deacetylation of PGC-1{alpha} is translated into enhanced mitochondrial activity, which translated in increased exercise tolerance and thermogenesis, leading to protection against the onset of obesity and associated metabolic dysfunction (73). For its deacetylase activity, SIRT1 is strictly dependent on cellular NAD+ levels, which reflect cellular energy status. The changes in cellular NAD+ levels that affect SIRT1 deacetylase activity hence seem to inform PGC-1{alpha} about the cellular energy status. PGC-1{alpha} can then adapt cellular energy production through its commanding role on mitochondrial biogenesis and function. These studies place SIRT1, which acts as cellular energy sensor, upstream of PGC-1{alpha} as an important regulator of mitochondrial activity.

It is clear that many of these studies, which focused on a given tissue type, indicated potential links between metabolic homeostasis and SIRT1 action. As discussed, SIRT1 enhances insulin secretion in response to glucose in the pancreas through the repression of UCP2 (69, 70); in the liver, SIRT1 induces gluconeogenesis and represses glycolysis (66); in adipose tissue, SIRT1 inhibits fat storage and increases lipolysis via repression of PPAR{gamma} (72). These pleiotropic, often opposing, metabolic effects of SIRT1 in different tissues complicated the elucidation of the impact of SIRT1 on whole-body metabolic homeostasis. Two recent studies using the SIRT1 activator resveratrol shed more light on this complex role of SIRT1 in metabolism (73, 74). In one study, it was shown that resveratrol mimics several aspects of CR in mice on a high-calorie diet, by prolonging lifespan, improving insulin sensitivity, and enhancing motor function (74). This study hence extends previous work that SIRT1 activation by resveratrol mimics CR and delays aging in a wide range of organisms going from S. cerevisiae (75) over C. elegans to Drosophila (76). In a second independent study, treatment of mice with a higher dose of resveratrol was also shown to protect them against diet-induced obesity and the associated insulin resistance (73). This study demonstrated that the amelioration of insulin sensitivity was linked to an enhanced mitochondrial function subsequent to activation of PGC-1{alpha} by SIRT1-mediated PGC-1{alpha} deacetylation (73). The enhanced mitochondrial activity furthermore led to an increase in oxidative type-muscle fibers and enhanced resistance to muscle fatigue. Moreover, a significant association between three single-nucleotide polymorphisms in the SIRT1 gene and energy homeostasis in humans indicated that SIRT1 constitutes an attractive and validated target to regulate energy and metabolic homeostasis in man (73).

SIRT3 was originally thought to be a mitochondrial protein, but recently it was demonstrated that mitochondrial transfer from its normal nuclear location was induced during cellular stress (77, 78, 119). The expression of SIRT3 is finely regulated. In mice, caloric restriction (CR) up-regulates SIRT3 expression levels in white adipose tissue and BAT. Furthermore, cold exposure also induces SIRT3 in BAT (79). Interestingly, the constitutive expression of SIRT3 promotes the expression of PGC-1{alpha}, UCP1, and other genes involved in mitochondrial functions, indicating that SIRT3 modulates adaptive thermogenesis in BAT, a process that most likely involves both nuclear and mitochondrial activities. One mitochondrial activity of SIRT3 is the deacetylation and activation of the mitochondrial form of AceCS2, an enzyme that catalyzes the formation of acetyl CoA from acetate (64, 67). Deacetylation of AceCS2 hence increases the conversion of acetate into acetyl CoA, an intermediate of the tricarboxylic acid cycle. AceCS2 is abundantly expressed in heart and skeletal muscle but absent from liver, and its expression is induced when energy becomes limiting, as during CR and ketogenesis (80). Because SIRT3 facilitates the metabolic use of acetate, it may hence be especially important to ensure energy production under conditions when ATP is scarce (64, 67, 80). In analogy to this function of SIRT3, SIRT1 deacetylates and activates the cytoplasmic AceCS1 to provide acetyl CoA, which acts as a building block for fatty acid and cholesterol synthesis (64). For only one of the human sirtuins, i.e. SIRT3, a direct genetic link with longevity has been established. In fact, mutations in the SIRT3 gene enhancer, which up-regulate its expression, were enriched in long-lived individuals (81).

Another mitochondrial SIRT protein, SIRT4, was shown recently to interact with glutamate dehydrogenase (GDH) (82). Glutamate formed from glutamine is converted to the tricarboxylic acid cycle intermediate {alpha}-ketoglutarate by GDH in the mitochondria (82, 83). This promotes mitochondrial activation and increases the ATP/ADP ratio, which subsequently activates insulin secretion in pancreatic ß-cells. SIRT4 uses NAD+ to ADP-ribosylate and decrease the activity of GDH, consequently reducing the production of {alpha}-ketoglutarate and the generation of ATP (82). In SIRT4-deficient pancreatic ß-cells, GDH activity increases, leading to a stimulation of insulin secretion in response to glutamine. SIRT4 therefore has an inhibitory effect on amino acid-stimulated insulin secretion (AASIS). It seems reasonable to speculate that AASIS is activated during chronic CR, because protein turnover is increased and amino acids are used as carbon and energy sources to drive gluconeogenesis in this condition. Consistent with this, SIRT4 repression of GDH is alleviated during long-term CR, resulting in activation of AASIS in ß-cells and potentially gluconeogenesis in liver. CR hence decreases SIRT4 activity, which is opposed to the induction of SIRT1 activity during CR. Furthermore, SIRT4 and SIRT1 exert, respectively, a negative and positive control on insulin secretion, which is striking given that their activities are both controlled by a single metabolite, i.e. NAD+.


   SIRTUINS IN NEURAL PROTECTION AND NEURODEGENERATIVE DISEASES
TOP
 ABSTRACT
 INTRODUCTION
 SIRTUINS ARE NICOTINAMIDE...
 SIRTUINS AND THE CONTROL...
 SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
PERSPECTIVES
 REFERENCES
 
Axonal degeneration is a major morphological characteristic observed in both peripheral neuropathies and neurodegenerative diseases, such as Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (84, 85). Axonal degeneration usually occurs in the early stage in degenerative processes and often precedes or correlates closely with clinical symptoms such as cognitive decline. There are several reports that support an axonal protective role for SIRT1 in the neuronal system. A self-destructive degeneration process is observed at the distal portion of a transected axon, which is called Wallerian degeneration (86). Wallerian degeneration slow (wlds) is a mouse line with delayed axonal degeneration in response to axonal injury (87, 88, 89). This phenomenon is thought to be derived from overexpression of a chimeric nuclear molecule (Wlds protein) that corresponds to the full-length nicotinamide mononucleotide adenyltransferase 1 (Nmnat 1), an enzyme required for both the de novo and salvage pathways of NAD+ biosynthesis (90, 91, 92) (Fig. 3Go), and a short region of a ubiquitin fusion degradation protein 2a. In a recent study, overexpression of Nmnat 1 alone could prevent axonal degeneration, indicating that the protective effect of Nmnat 1 could be mediated by an increase of neuronal NAD+ reserve and/or SIRT1 activity (93).


Figure 3
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  		Fig. 3. Superpathway of NAD+ Biosynthesis in Mammals

NAD+ is synthesized via two major pathways, the de novo and salvage pathways, and these two pathways converge at nicotinic acid mononucleotide. In the de novo pathway, the nicotinic acid moiety of NAD+ is synthesized from tryptophan via the kynurenine pathway. In the NAD+ salvage pathway, NAD+ is generated through the recycling of its degradation product such as nicotinamide. ART, ADP-ribosyl transferase; NA, nicotinic acid; NAAD, nicotinic acid adenine dinucleotide; NAM, nicotinamide; NaMN, nicotinic acid mononucleotide; Nampt, nicotinamide phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NPT, nicotinic acid phosphoribosyltransferase; NR, nicotinamide riboside; Nrk, nicotinamide riboside kinase; PARP, poly-ADP-polymerases; PBEF, pre-B cell colony-enhancing factor.

 
It is well known that CR protects neurons from degeneration in mouse models of AD and Parkinson’s disease, and SIRT1 might facilitate neuronal survival (94, 95, 96, 97). Although it is reported that caloric intake and insulin sensitivity are linked to AD, the mechanism underlying these connections are not fully clarified as of yet (98, 99). The pathology of AD is characterized by the presence of amyloid plaques, intracellular neurofibrillary tangles, and pronounced cell death (100). The amyloid plaque is composed of amyloid-ß (Aß) peptide, which is cleaved from the amyloid precursor protein sequentially by ß-secretase and {gamma}-secretase (101, 102, 103). This abnormal Aß peptide deposition within the brain is the hallmark of AD neuropathology, and accumulation of aggregated Aß is hypothesized to initiate a pathological cascade resulting in the onset and progression of AD (104). Aß peptides can induce NF{kappa}B activity in microglia via TNF-receptor type 1 or receptor of advanced glycation end product (105, 106). SIRT1 activation or the administration of the SIRT1 activator resveratrol markedly reduces this NF{kappa}B signaling (107). This strongly suggests that SIRT1 can attenuate Aß-stimulated neurotoxicity and AD-related inflammatory responses via inhibition of microglial NF{kappa}B signaling. SIRT1 is furthermore supposed to prevent Aß peptide generation through promotion of the nonamyloidogenic processing of amyloid precursor protein by the inhibition of Rho kinase 1 expression (108).

In addition to this inflammatory cascade leading to neuronal cell death, another intrinsic cell death pathway, i.e. mitochondria-based cell death pathway, is attracting attention in the context of AD. In fact, Aß peptides, which can directly enter the mitochondrial inner membrane, are able to bind to a mitochondrial-matrix protein termed Aß-binding alcohol dehydrogenase and localize to the mitochondria (109). This reduces ATP production and increases the generation of oxygen radicals (110), which subsequently may induce mitochondria-dependent cell death because damaged mitochondria are unable to maintain the energy demands of the cells. Consistent with these observations, in AD mouse models, a strong association between Aß and the inner mitochondrial membrane together with increased free-radical generation and decreased cytochrome c oxidase activity has been reported (111, 112). SIRT1 could, through its stimulating activity on mitochondria (73), contribute to this process in AD.

Also in Huntington’s disease (HD), another neurodegenerative disease, mitochondrial insufficiency is observed. HD patients are characterized by marked reductions in glucose metabolism and increased levels of lactate in the basal ganglia, by a reduced activity of several key components of the oxidative phosphorylation pathways in the mitochondria of the striatal neurons (113) and by pronounced morphological abnormalities, including derangement of the mitochondrial matrix and cristae (114). These mitochondrial dysfunctions are supposed to be associated with dysregulation of PGC-1{alpha} transcription and/or activity by the mutant huntingtin protein (115, 116, 117). Because recent reports show that PGC-1{alpha} activity is regulated by SIRT1 (66, 73) and because some aspects of mitochondrial metabolism are controlled by some of the sirtuins, the modulation of sirtuin activity could be an interesting approach for the therapy of these neurodegenerative diseases. In fact, the potential of such a strategy was validated in nematode HD models and in mouse neuronal cell lines (118). In these models, the expanded polyglutamine (PolyQ) track in HD-associated protein huntingtin (htt) were shown to induce PolyQ-dependent neuronal dysfunction. This abnormality caused by the mutant PolyQ could be rescued by overexpression of SIRT1 or by resveratrol treatment (118). This favorable effect was suppressed by sirtuin inhibitors, such as nicotinamide or sirtinol, directly proving that SIRT1 activation could be useful in HD.


   PERSPECTIVES
TOP
 ABSTRACT
 INTRODUCTION
 SIRTUINS ARE NICOTINAMIDE...
 SIRTUINS AND THE CONTROL...
 SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
REFERENCES
 
The founding member of the sirtuin family, Sir2p in yeast or SIRT1 in mammals, has now been well established as a key molecule that affects longevity within the context of CR in several model organisms ranging from yeast to mouse, although the mechanisms involved may be distinct in the different species. The vital role that the sirtuins play in cellular metabolic control indicated that they could be important determinants of whole-body metabolism and protect against many chronic diseases associated with metabolic dysfunction. Likewise, potential applications of the sirtuins in neuronal cell survival and response to stress and cell-cycle control hint to eventual importance of this gene family in the pathogenesis of neurodegenerative diseases and cancer. Additional insight into the biological actions of the sirtuins will require the definition of the exact roles of each of the gene family members in vivo with appropriate genetic, pharmacological, and physiological tools. Once this is achieved, it is expected that a select member of the sirtuins could become potential interesting targets for future therapies against age-related diseases.


   FOOTNOTES
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online April 24, 2007

Abbreviations: Aß, Amyloid-ß; AADPR, acetyl-ADP ribose; AASIS, amino acid-stimulated insulin secretion; AceCS2, acetyl coenzyme A synthetase 2; AD, Alzheimer’s disease; AR, androgen receptor; BAT, brown adipose tissue; BER, base excision repair; CoA, coenzyme A; CR, caloric restriction; FOXO, forkhead box type O transcription factor; GDH, glutamate dehydrogenase; HD, Huntington’s disease; HDAC, histone deacetylase; MEF, mouse embryonic fibroblast; NAD, nicotinamide adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; NF{kappa}B, nuclear factor {kappa}B; Nmnat 1, nicotinamide mononucleotide adenyltransferase 1; PGC-1{alpha}, peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha}; PolyQ, polyglutamine; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; Sir2p, silent information regulator 2 protein; UCP, uncoupling protein.

Received for publication February 12, 2007. Accepted for publication April 18, 2007.


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 SIRTUINS CONTROL METABOLIC...
 SIRTUINS IN NEURAL PROTECTION...
 PERSPECTIVES
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NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ  |  HNF4α  |  AR
Coregulators:   PGC-1  |  Sirt1



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