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Molecular Endocrinology 21(8):17451755

Copyright 2007 by The Endocrine Society
doi: 10.1210/me.2007-0079

MINIREVIEW

Sirtuin Functions in Health and Disease

Hiroyasu Yamamoto, Kristina Schoonjans, and Johan Auwerx
Institut de Genetique et de Biologie Moleculaire et Cellulaire (H.Y., K.S., J.A.), Centre National de la
Recherche Scientifique/Institut National de la Sante et de la Recherche Medicale/Universite Louis
Pasteur, 67404 Illkirch, France; and Institut Clinique de la Souris (J.A.), 67404 Illkirch, France
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 SIRT1SIRT7 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 wholebody 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. (Molecular Endocrinology 21: 17451755,
2007)

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.

HE 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

First Published Online April 24, 2007

Abbreviations: A, Amyloid-; AADPR, acetyl-ADP ribose;
AASIS, amino acid-stimulated insulin secretion; AceCS2,
acetyl coenzyme A synthetase 2; AD, Alzheimers 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, Huntingtons disease; HDAC,
histone deacetylase; MEF, mouse embryonic fibroblast;
NAD, nicotinamide adenine dinucleotide; NADH, reduced
nicotinamide adenine dinucleotide; NFB, nuclear factor B;
Nmnat 1, nicotinamide mononucleotide adenyltransferase 1;
PGC-1, peroxisome proliferator-activated receptor coactivator 1; PolyQ, polyglutamine; PPAR, peroxisome proliferator-activated receptor ; Sir2p, silent information regulator
2 protein; UCP, uncoupling protein.
Molecular Endocrinology is published monthly by The
Endocrine Society (http://www.endo-society.org), the
foremost professional society serving the endocrine
community.

SIRTUINS ARE NICOTINAMIDE ADENINE

DINUCLEOTIDE-DEPENDENT HISTONE
DEACETYLASES OR ADP-RIBOSYL
TRANSFERASES
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 (37). Yeast
strains with abnormal levels of Sir2p show defects in
1745

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1746 Mol Endocrinol, August 2007, 21(8):17451755

many cellular functions, including transcriptional and

recombinational silencing, senescence, and DNA repair. In S. cervisiae, there are four sirtuins (NADdependent histone deacetylases Hst1Hst4) in addition to Sir2p, whereas in mammals seven homologs,
i.e. SIRT1SIRT7, have been identified (8, 9) (Table 1).
The remarkable conservation of members of the sirtuin
gene family from yeast to humans indicates that these
proteins play vital physiological roles (9).
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, 1114) (Fig. 1).
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 (1519).
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-B (NFB), forkhead box type O
transcription factors (FOXO), and the peroxisome proliferator-activated receptor (PPAR) coactivator 1
(PGC-1), but also enzymes, such as acetyl coenzyme
A (CoA) synthetase 2 (AceCS2), and structural proteins, such as -tubulin (Table 1).
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

Yamamoto et al. Minireview

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

Sirtuins (SIRT1SIRT3, SIRT5) catalyze a deacetylation reaction in which an acetyl group is transferred to the ADPribose (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.

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

Table 1. Main Characteristic of Mammalian Sirtuins

Targets

Biological Function

SIRT1

Nucleus (nuclei)

Intracellular Localization

Deacetylase

PGC-1, FOXOs, NFB

SIRT2
SIRT3
SIRT4
SIRT5
SIRT6

Cytoplasm
Nucleus and mitochondria
Mitochondria (matrix)
Mitochondria
Nucleus (heterochromatic
region)
Nucleus (nucleoli)

Deacetylase
Deacetylase
ADP-ribosyl transferase
Deacetylase
ADP-ribosyl transferase

H4, -tubulin
AceCS2
GDH
Unknown
DNA polymerase

Metabolism/inflammation/
neurodegeneration
Cell cycle/tumorigenesis
Metabolism
Insulin secretion
Unknown
DNA repair

Unknown

RNA polymerase I

rDNA transcription

SIRT7

Activity

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Yamamoto et al. Minireview

NAD-dependent ADP-ribosyl transferase activity

(Fig. 1). 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. 2 and Table 1). 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 1).
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 SIRT3SIRT5 in the
mitochondria has, however, not yet been defined
experimentally.
All seven sirtuins are ubiquitously expressed in human tissues, although higher levels of mRNA expres-

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

Mol Endocrinol, August 2007, 21(8):17451755 1747

sion 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
Many factors that control cell proliferation and apoptosis are identified as sirtuin substrates, such as p53
(2729). 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
(3032). Conversely, the deacetylation of p53 by
SIRT1 is predicted to induce its destruction by the
MDM2 (mouse double minute 2)-dependent ubiquitinmediated 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 dominantnegative SIRT1 protein can potentiate these cellular
stress responses (28, 29). In thymocytes from SIRT1deficient 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 (4143).
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 (4649). 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 nu-

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1748 Mol Endocrinol, August 2007, 21(8):17451755

cleocytoplasmic 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 Sir2pindependent 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 -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 DNAdamaging 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, Pol, 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

Yamamoto et al. Minireview

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

The fact that several of the protein substrates, such as
AceCS2 and PGC-1, which are deacetylated by the
sirtuins, are involved in metabolism indicated a metabolic role for this protein family (6467). 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,

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Yamamoto et al. Minireview

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 -cells (69). Conversely,
-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 -cell lines, uncoupling protein 2
(UCP2), a protein that negatively regulates insulin secretion in pancreatic -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 is a key regulator in adipogenesis and fat
storage through the control of the expression of many
adipocyte-specific genes (71). SIRT1 represses
PPAR 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-mediated transcription. From a
functional point of view, the repression of PPAR 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, the master
regulator of mitochondrial biogenesis. PGC-1 is activated by SIRT1-mediated deacetylation (65, 66). In
the liver, the activation of PGC-1 will facilitate the
gluconeogenic activity of hepatocyte nuclear factor 4
and stimulate hepatic glucose output (66). In the muscle and brown adipose tissue (BAT), the SIRT1-mediated deacetylation of PGC-1 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 about the cellular energy status. PGC-1 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 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 re-

Mol Endocrinol, August 2007, 21(8):17451755 1749

sponse 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 (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 by SIRT1-mediated PGC-1 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, 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

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1750 Mol Endocrinol, August 2007, 21(8):17451755

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
-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 -cells. SIRT4 uses NAD
to ADP-ribosylate and decrease the activity of GDH,
consequently reducing the production of -ketoglutarate and the generation of ATP (82). In SIRT4-deficient
pancreatic -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 -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.

Yamamoto et al. Minireview

zyme required for both the de novo and salvage pathways of NAD biosynthesis (9092) (Fig. 3), 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).
It is well known that CR protects neurons from degeneration in mouse models of AD and Parkinsons
disease, and SIRT1 might facilitate neuronal survival
(9497). 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- (A) peptide, which is cleaved from the amyloid precursor protein sequentially by -secretase and -secretase (101
103). This abnormal A peptide deposition within the
brain is the hallmark of AD neuropathology, and ac-

SIRTUINS IN NEURAL PROTECTION AND

NEURODEGENERATIVE DISEASES
Axonal degeneration is a major morphological characteristic observed in both peripheral neuropathies and
neurodegenerative diseases, such as Alzheimers 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 (8789). 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 en-

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.

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Yamamoto et al. Minireview

cumulation of aggregated A is hypothesized to initiate a pathological cascade resulting in the onset and
progression of AD (104). A peptides can induce NFB
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 NFB signaling (107). This strongly suggests that SIRT1 can
attenuate A-stimulated neurotoxicity and AD-related
inflammatory responses via inhibition of microglial
NFB signaling. SIRT1 is furthermore supposed to
prevent A 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, A
peptides, which can directly enter the mitochondrial
inner membrane, are able to bind to a mitochondrialmatrix protein termed A-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 A 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 Huntingtons 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 transcription and/or activity by
the mutant huntingtin protein (115117). Because recent reports show that PGC-1 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

Mol Endocrinol, August 2007, 21(8):17451755 1751

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
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.
Acknowledgments
Received February 12, 2007. Accepted April 18, 2007.
Address all correspondence and requests for reprints to:
Johan Auwerx, M.D., Ph.D., Institut de Genetique et de Biologie Moleculaire et Cellulaire, 1 Rue Laurent Fries, Bote
Postale 10142, 67404 Illkirch, France. E-mail: auwerx@
igbmc.u-strasbg.fr.
Disclosure Statement: The authors have nothing to
disclose.

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