Annals of Medicine

ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: www.tandfonline.com/journals/iann20

Sirtuins: The ‘magnificent seven’, function,

metabolism and longevity

Nassim Dali‐Youcef, Marie Lagouge, Sébastien Froelich, Christian Koehl,

Kristina Schoonjans & Johan Auwerx

To cite this article: Nassim Dali‐Youcef, Marie Lagouge, Sébastien Froelich, Christian
Koehl, Kristina Schoonjans & Johan Auwerx (2007) Sirtuins: The ‘magnificent seven’,
function, metabolism and longevity, Annals of Medicine, 39:5, 335-345, DOI:
10.1080/07853890701408194

To link to this article: https://doi.org/10.1080/07853890701408194

Published online: 08 Jul 2009.

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Annals of Medicine. 2007; 39: 335–345

REVIEW ARTICLE

Sirtuins: The ‘magnificent seven’, function, metabolism and longevity

NASSIM DALI-YOUCEF1,3, MARIE LAGOUGE1, SÉBASTIEN FROELICH1,4,

CHRISTIAN KOEHL3, KRISTINA SCHOONJANS1 & JOHAN AUWERX1,2,3
1
Institut de Génétique et de Biologie Moléculaire et Cellulaire de Strasbourg (IGBMC), INSERM/CNRS/ULP, Illkirch,
France, 2Institut Clinique de la Souris, Genopole, Illkirch, France, 3Laboratoire de Biochimie Générale et Spécialisée,
Hôpitaux Universitaires de Strasbourg, Strasbourg, France, and 4Service de Neurochirurgie, Hôpital de Hautepierre, C.H.U.
de Strasbourg, Strasbourg, France

Abstract
The sirtuin family of histone deacetylases (HDACs) was named after their homology to the Saccharomyces cerevisiae gene
silent information regulator 2 (Sir2). In the yeast, Sir2 has been shown to mediate the effects of calorie restriction on the
extension of life span and high levels of Sir2 activity promote longevity. Like their yeast homologs, the mammalian sirtuins
(SIRT1-7) are class III HDACs and require NAD+ as a cofactor to deacetylate substrates ranging from histones to
transcriptional regulators. Through this activity, sirtuins are shown to regulate important biological processes ranging from
apoptosis, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. We review here the current
knowledge regarding the role of sirtuins in metabolism, longevity, and discuss the possible therapeutic applications that
could result from the understanding of their function in different organs and pathologies.

Key words: Calorie restriction, longevity, metabolism, SIRT

Introduction yeast from gene silencing, DNA repair, progression

Histone acetylation is the main type of covalent
histone modification and is achieved by a class of
enzymes termed histone acetyltransferases (HATs)
(1). HATs acetylate histones on lysines, whereas
histone deacetylation involves another family of
enzymes, the histone deacetylases (HDACs) ((2), a
review). These HDACs are classified in three groups
on the basis of their homology with the yeast
Saccharomyces cerevisiae HDACs: RPD3 (group I),
HDA1 (group II), and Sir2 (group III). Class I and
II enzymes are inhibited by trichostatin (TSA),
whereas class III HDACs are not inhibited by TSA
and are NAD+-dependent (3,4), suggesting a reg-
ulation of Sir2 molecules by the metabolic state of
the cells (reviewed in (5)). Since the Sir2 family of
proteins are also able to exert their enzymatic activity
not only on histones but also on numerous other
proteins, such as the transcriptional regulators, they
are involved in many cellular processes, ranging in
of the cell cycle, to the control of ageing.
The Sir2 protein first deacetylates histones and
then localizes with the yeast protein Sir4, to form a
tight silencing complex binding to the telomeres (6).
The localization of Sir2 complex to the histone tails,
initially identified to induce transcriptional repres-
sion of the silent mating type loci HML and HMR
(homothallic mating-type loci left and right, respec-
tively) (7,8), produces chromatin silencing, and a
recent study reported that the Sir2 complex reduces
the promoter occupancy by the transcription factors
IIB and IIE (TFIIB, TFIIE) and the RNA poly-
merase II (Pol II) preventing hence the proper
assembly of the preinitiation complex of the tran-
scriptional machinery (9). Most interesting was the
fact that overexpression of the gene encoding the
Sir2 protein leads to a decrease in histone acetylation
(10) and an increase in life span in yeast (11), in the
nematode Caenorhabditis elegans (12) and in metazo-
ans (13). Likewise, Sir2-activating compounds

Correspondence: Johan Auwerx, Institut de Génétique et de Biologie Moléculaire et Cellulaire de Strasbourg (IGBMC), INSERM/CNRS/ULP, 1 rue
Laurent Fries, BP 10142, 67404 Illkirch, France. E-mail: auwerx@igbmc.u-strasbg.fr
ISSN 0785-3890 print/ISSN 1365-2060 online # 2007 Taylor & Francis
DOI: 10.1080/07853890701408194
336 N. Dali-Youcef et al.

CR could affect metabolism and longevity in

Abbreviations humans. To better understand the mechanisms by
SIR2 silent information regulator 2 which CR extends life span, it is instructive to take a
HAT histone acetyltransferase close look at studies carried out in various species.
HDAC histone deacetylase
CR calorie restriction
PKB/AKT protein kinase B Studies based on non-mammalian models
GDP guanosine diphosphate Studies in Saccharomyces cerevisiae
GTP guanosine triphosphate
NAD+ nicotinamide adenine In yeast, reduction in glucose levels in the media,
dinucleotide mimicking CR, results in a substantial extension in
NADH reduced form of NAD+ life span, which is Sir2p- and NAD+-dependent,
Pol II RNA polymerase II since mutants for Sir2p and nicotinate phosphor-
TFIIB transcription factor IIB ibosyl transferase (NPT1), an enzyme required for
TFIIE transcription factor IIE NAD+ formation, failed to reproduce this effect
Daf-16 ‘dauer’ larvae transcription (19). In the same study, mutants for components of
factor-16 the glucose-signaling pathway, such as the GTP-
FOXO forkhead box subgroup ‘O’ GDP (guanosine triphosphate-guanosine dipho-
transcription factor sphate) exchange factor CDC25, the glucose sensing
HML homothallic mating-type loci left receptors gpr1 and gpa2, and hexokinase, the first
HMR homothallic mating-type loci enzyme in the glycolytic pathway, mimicked the CR-
right mediated increase in longevity. This life span
NFkB nuclear factor kappa B extension due to CR was attributed to an increase
transcription factor in respiration (20). Indeed a mutation in the gene
PGC-1a peroxisome proliferator-activated encoding the cytochrome c1 CYT1 is no longer able
receptor gamma (PPARc) to promote CR-mediated longevity, suggesting that
coactivator-1a blocking the mitochondrial electron transport chain
and respiration prevents life span extension.
Moreover, overexpression of Hap4 in yeast, a gene
known to cause a switch from fermentation to
(STACs), such as resveratrol, present in the skin of respiration, yielded a 35% extension in life span
red grapes, promote longevity in yeast (14) and other under normal glucose conditions. It is well estab-
organisms ranging from the worm and drosophila lished that respiration increases the NAD+/NADH
(15) to the mouse (16). On the other hand, both ratio through oxidation of NADH by the NADH
mutations of the Sir2 gene and pharmacological dehydrogenase (21).
inhibition of Sir2 protein by nicotinamide induces an The Sir2p-mediated conversion of NAD+ leads to
acceleration of ageing in yeast (17). Although the the formation of nicotinamide (NAM), a powerful
functions of Sir2 have been relatively well estab- Sir2/SIRT1 inhibitor (17) and O-acetyl-ADP-ribose
lished in yeast and C. elegans, their function in (O-AA-ribose) (22) (Figure 2A). Recent evidence
mammals remains rather elusive. This review will demonstrated an active role of O-AA-ribose in the
give an overview of the role of the sirtuin family of regulation of gene silencing by the Sir2/3/4 assembly
proteins in different species and their potential complex (23). In yeast, an alternative route to
contribution to disease. synthesize NAD+, other than its de novo production
from the amino acid tryptophan, and which starts
from nicotinic acid (NA), is present under the form
SIRT1/Sir2, caloric restriction, metabolism, of the NAD+ salvage pathway. In the NAD+ salvage
neurodegeneration, and longevity
pathway, NAM obtained from NAD+ cleavage is
In the last few years, an increasing number of studies deaminated to NA by the nicotinamidase PNC1.
from S. cerevisiae, C. elegans, Drosophila melanogaster, NA formed through the actions of PNC1 then
and mouse models have linked caloric restriction undergoes a series of reactions giving successively
(CR) and metabolism with longevity. The matter rise to nicotinate mononucleotide (NAMN), nicoti-
has been extensively reviewed by Bordone and nate adenine dinucleotide (NAAD), and NAD+, that
Guarente (18); in this section we give an overview are catalyzed by the enzymes nicotinate phosphor-
of how SIRT1, the mammalian Sir2 homolog, which ibosyl transferase (NPT1), nicotinate mononucleo-
is the best characterized sirtuin family member, and tide adenyltransferases (NMAT1/2), and NAD+
 Sirtuins and metabolism 337

Figure 1. Sir2/SIRT1 and signaling pathways in different species. In yeast Sir2p activity is increased through increased expression of the
NAD+ salvage pathway enzyme, nicotinamidase PNC1, but also by increasing the NAD+/NADH ratio (or lowering NADH levels) in
response to calorie restriction (CR). Mutation of the glucose sensing receptors Gpr1 and Gpa2 mimics the CR effects on Sir2p, which
inhibit the formation of the deleterious extrachromosomal circular DNA repeats (ERCs) and contribute to life span extension in yeast. The
glucose and nutrients fermentation pathway activates the AKT-related kinase Sch9 which induces oxidative stress and participates in yeast
ageing. Inactivation of this pathway promotes longevity in yeast. The longevity pathway is conserved amongst worms, flies and mammals.
Activation of the insulin growth factor receptor IGFR (Daf-2/dIGFR) activates the insulin receptor substrate IRS (p65/CHICO), which
stimulates phosphoinositol-3 kinase PI3K (AGE-1/dPI3K), which in turn phosphorylates the PKB/AKT kinase. AKT phosphorylates and
inactivates FOXO (Daf-16/dFOXO). Inactivation of the insulin receptor pathway promotes longevity in worms, drosophila, and mammals
through increased activity of FOXO. Sir2/SIRT1 activation induces life span extension through interaction with Daf-16/FOXO factors.
Gpr-15G-protein coupled receptor-1; Gpa-25G-alpha protein-2; FGM5Fermentable growth medium; PNC15pyrazinamidase/
Nicotinamidase 1; Sir2p5yeast silent information regulator 2; NADH5reduced form of nicotinamide adenine dinucleotide;
Sch95Saccharomyces cerevisiae protein kinase 9; ERCs5extrachromosomal circular DNA repeats; Daf-165‘dauer’ larvae transcription
factor-16; AGE-15worm homolog of the phosphoinositol-3 kinase; AKT5protein kinase B; Rpd35reduced potassium dependence 3 (class
II histone deacetylase); IGF-15insulin growth factor-1; FOXO5forkhead box subgroup ‘O’ transcription factor; IRS5insulin receptor
substrate; CHICO5 drosophila homolog of IRS; SIRT15sirtuin 1.

synthetase (QNS1), respectively (24). The newly
recycled NAD+ then serves again as a cofactor for
Sir2p-mediated deacetylation (Figure 2A).
Multiple protagonists of the NAD+ salvage path-
way participate in life span extension in yeast.
Furthermore, an intense debate about whether
Sir2p-dependent CR life span extension could be
due to a depletion in the noncompetitive Sir2p
inhibitor NAM, rather than a modification in the
NAD+/NADH ratio, is still ongoing. Interestingly,
CR increased the expression of PNC1 and hence
PNC1 activity, which is required and sufficient to
extend life span in yeast through Sir2p activation.
Conversely, mutations in the yeast PNC1 gene
accelerate cellular ageing (25). These observations
hence suggested that NAM depletion, through the
activation of PNC1, is sufficient to activate Sir2 and
increase longevity in yeast. Moreover, mutation of
PNC1 and overexpression of Nnt1, a NAM methyl-
transferase which reduced the excess NAM levels,
338 N. Dali-Youcef et al.

Figure 2. A: yeast and mammalian NAD+ salvage pathways. Yeast (red) Sir2p utilizes the cofactor NAD+ to deacetylate proteins and in this
reaction produces nicotinamide (NAM) and O-acetyl-ADP-ribose (O-AA-ribose). NAM is deaminated by the nicotinamidase PNC1 to
form nicotinic acid (NA). NA will give rise successively to nicotinate mononucleotide (NAMN), nicotinate adenine dinucleotide (NAAD)
and nicotinamide adenine dinucleotide (NAD+) by the enzymes nicotinate phosphoribosyl-transferase (NPT1), nicotinate mononucleotide
adenyltransferase (NMAT), and nicotinamide adenine dinucleotide (NAD) synthetase (QNS), respectively (red arrows). In mammals
(blue) NAM is recycled to NAD+ in two steps through the formation of nicotinamide mononucleotide (NMN) by means of the NAM
phosphoribosyltransferase NamPT (PBEF/visfatin) and nicotinamide mononucleotide adenyltransferase (NMNAT) (blue arrows). B:
SIRT1 protective functions in metabolism and diseases. SIRT1 can be regulated positively by CR and SIRT-activating compounds and
negatively by SIRT inhibitors. SIRT1 activation induces survival of cardiomyocytes, protects neurons from cell death, and favors insulin
secretion by repressing the uncoupling protein 2 (UCP2). SIRT1 decreases white adipocyte tissue formation through repression of PPARc
and promotes gluconeogenesis in response to fasting through PGC-1a, and stimulates mitochondrial biogenesis in the brown adipose tissue
(BAT) and the muscle through activation of PGC-1a. NA5nicotinic acid; NAD+5nicotinamide adenine dinucleotide; NAM5
nicotinamide; NMN5nicotinamide mononucleotide; PNC15 pyrazinamidase/Nicotinamidase 1; NamPT15nicotinamide phosphoribosyl
transferase 1; PBEF5pre-B cell enhancing factor; NPT15nicotinate phosphoribosyl transferase 1; NMAT1/25nicotinate mononucleotide
adenyltransferase 1/2; QNS5NAD synthetase; NMNAT15nicotinamide mononucleotide adenyltransferase; O-AA-ribose5O-acetyl-
ADP-ribose; UCP-25uncoupling protein 2; NFkB5nuclear factor kappa B; PPARc5peroxisome proliferator-activated receptor gamma;
PGC-1a5peroxisome proliferator-activated receptor gamma coactivator-1 alpha; BAT5brown adipose tissue; SIRT15sirtuin 1.

restored the CR-induced life span extension in
PNC1 mutants, suggesting that other factors (such
as NADH lowering) might play a role in CR-
mediated life span extension (26). Other compo-
nents of the NAD+ salvage pathway, like NPT1, the
rate-limiting enzyme in the NAD+ biosynthesis, have
also been shown to regulate life span in yeast.
Increased dosage of NPT1, but not of NMAT,
enhanced the total cellular NAD+ levels and
enhanced the transcriptional activity of the catalytic
domain of Sir2p thereby extending yeast life span
(27), whereas NPT1 mutations yielded a defect in
silencing at silent mating-type loci, telomeres, and
rDNA (28). Overexpression of two related mito-
chondrial NADH dehydrogenases, Nde1 and Nde2,
decreased NADH levels without changing NAD+
levels, but still increased yeast life span both under
normal glucose culture conditions (2%) and CR
conditions (0.5%), suggesting that reducing the
quantity of the competitive Sir2p inhibitor NADH
might also contribute to the CR-induced increase in
yeast longevity (26). Interestingly, Hst2, a Sir2
homolog that contributes to rDNA stability, is
another mediator of CR-induced life span extension
in yeast, indicating that other Sir2 homologs could
regulate longevity under CR conditions (29). Taken
together, these data suggest that Sir2 requires NAD+
to deacetylate proteins, and manipulations of the
salvage pathway that converge on enhanced NAD+
availability induce Sir2-dependent life span

extension in the budding yeast (24). Under CR other
pathways, such as a decrease in the competitive Sir2
inhibitor NADH (by increasing Nde activity) or the
noncompetitive Sir2 inhibitor NAM (by increasing
PNC1 activity), could contribute to control Sir2
activity. Furthermore, a Sir2-independent CR-
mediated life span extension mechanism exists that
is mediated via Hst2.
Three important factors are thought to participate
in Sir2-mediated longevity. First, one of the con-
sequences of increased Sir2 activity is the significant
reduction in the number of extrachromosomal
circular DNA repeats (ERCs) (11), whose accumu-
lation is deleterious to yeast and accelerates ageing
(30), probably through sequestration of transcrip-
tion factors essential for their replication. The
second mechanism that contributes to the yeast life
span acts via the fermentable growth medium-
induced (FGM) pathway. Under fermentation con-
ditions, glucose and other nutrients activate a yet
unknown pathway that activates Sch9, a kinase
related to the mammalian protein kinase B (PKB)/
AKT, a negative regulator of the stress resistance
genes. This results in the subsequent accumulation
of reactive oxygen species (ROS), thereby accelerat-
ing ageing (31). Interestingly, mutation of Sch9
yields a substantial increase in yeast life span
probably through increasing stress resistance
(32,33) (Figure 1). It is at present not known
whether this pathway is similar to Daf-16/FOXO
signaling, which participates in the control of ageing
in other organisms, and whether Sch9 mutations
affect ERCs formation. Finally, yeast evolving in a
high osmolarity live much longer than those in a
balanced osmolarity medium. A high osmolarity
shock activates a subset of osmotic responsive genes
that change the metabolism to favor glycerol
biosynthesis thereby generating more NAD+, the
Sir2 cofactor necessary to mediate longevity (34).
Studies in Caenorhabditis elegans and Drosophila
melanogaster
In C. elegans, the yeast Sir2p ortholog, Sir2.1,
extends life span through the forkhead transcription
factor Daf-16 (homolog of mammalian FOXO)
signaling pathway. Loss of function studies of
components of the Daf-2 (homolog of the mamma-
lian insulin receptor) signaling pathway, such as in
Daf-2 or the homolog of the mammalian phospha-
tidyl-inositol-3 kinase (PI3K), AGE-1, extend the
worm’s life span (Figure 1) (35,36). This pathway
controls the entry of worms in ‘dauer’, a larval
developmental state of growth arrest that is induced
upon food limitation, and which is a feature of young
Sirtuins and metabolism 339
larvae before reproductive maturation (reviewed in
(37)). Activation of Daf-2/AGE-1 signaling results in
the phosphorylation of AKT kinase that sequesters
Daf-16 in the cytoplasm resulting in its inactivation
(38,39). The long-lived mutants require the entry of
Daf-16 into the nucleus to activate target genes
necessary for dauer formation. Duplication of
chromosomal regions containing Sir2.1 in the
nematode extends life span by up to 50%.
Interestingly, the Sir2.1-duplicated strains carrying
a mutated Daf-16 displayed the same decreased life
span as observed in Daf-16 mutants, proving that
Sir2.1 acts upstream of Daf-16. In addition, Sir2.1-
duplicated strains do not further extend life span of
Daf-2 mutants indicating that extra copies of Sir2.1
promote longevity through the Daf-2/Daf-16 signal-
ing pathway (12). A direct interaction between
Sir2.1 and Daf-16, facilitated by the nematode 14-
3-3 protein, furthermore suggests that these three
proteins physically interact (40,41).
Also dSir2, the drosophila Sir2 ortholog, controls
life span extension under CR conditions, and
mutants that remove or decrease dSir2 levels are
no longer able to promote the CR-mediated long-
evity. The dSir2-mediated life extension seems to
work in the same pathway as the Rpd3 histone
deacetylase, since Rpd3 is thought to negatively
regulate dSir2, and CR induces a decrease in Rpd3
expression (13). Moreover, long-lived Rpd3 mutant
flies display high dSir2 expression levels (42).
Interestingly, flies deficient in the homolog of the
mammalian insulin receptor substrate (IRS) protein,
CHICO, show a significant increase in life span
(43). Recent studies showed that activation of
dFOXO in the fly brain and/or fat body extends life
span and inhibits the endogenous insulin-dependent
signaling in the fat body (44,45). Although both CR
and downregulation of the insulin pathway partici-
pate in life span extension, it is still not proven that
the two pathways work in concert and converge on
dFOXO to promote longevity in drosophila.
Studies in mammals
The mammalian NAD+ salvage pathway is different
from the yeast pathway. NAM is directly trans-
formed to nicotinamide mononucleotide (NMN) by
the enzyme nicotinamide phosphoribosyltransferase
(NamPT) (46), which then yields NAD+ through
the action of nicotinamide mononucleotide adenyl
transferase (NMNAT) (Figure 2A). NamPT was
found to be the equivalent of the pre-B-cell-enhancing
factor (PBEF), a protein that stimulated B-cell colony
formation (47), and visfatin, an adipokine expressed in
visceral fat with glucose-lowering properties (48).
340 N. Dali-Youcef et al.
Although some evidence exists that NamPT activates
SIRT1 transcriptional activity (27), NamPT over-
expression in mice would be necessary to determine
whether NamPT is the functional homolog of yeast
PNC1 in life span extension.
The role of the insulin-signaling pathway in the
determination of mammalian life span has been
studied in insulin-like growth factor receptor (IGF-
R)-deficient mice. Although IGF-R2/2 mice die
shortly after birth, IGF-R+/2 animals are viable,
display reduced IGF-R levels, and live longer than
IGF-R+/+ littermates. IGF-R+/2 animals exhibit low
AKT kinase activity suggesting an increase in FOXO
activity, reproducing features of the Daf-16-
mediated longevity pathway in C. elegans. In addi-
tion, IGF-R+/2 mice are more resistant to oxidative
stress. This phenotype was, however, gender-depen-
dent since only IGF-R+/2 female mice displayed a
significant increase in life span, whereas IGF-R+/2
males showed a modest, non-significant increase in
longevity (49). Mice in which the insulin receptor was
specifically inactivated in the adipose tissue also live
longer and are protected against age-related obesity
and its subsequent metabolic abnormalities (50).
In mammals, SIRT1 has been linked with meta-
bolic control. The importance of SIRT1 in the
nutrient control of glucose homeostasis was demon-
strated to involve the modulation of the acetylation
status and hence the stimulation of the activity of the
metabolic coregulator peroxisome proliferator-acti-
vated receptor gamma (PPARc) coactivator-1a
(PGC-1a). In the liver, SIRT1 in a complex
including the hepatocyte nuclear factor-4 (HNF-4)
deacetylates and activates PGC-1a, promoting glu-
coneogenesis following fasting (51). SIRT1 also
functions together with PGC-1a, beyond the liver.
Indeed, activated PGC-1a promotes mitochondrial
function in the skeletal muscle and the brown
adipose tissue, leading to enhanced energy expendi-
ture, increased exercise performance, and protection
from diet-induced insulin resistance and hepatostea-
tosis (16,52). Although these studies suggest that
PGC-1a is a privileged partner for SIRT1, other
signaling pathways are also solicited (Figure 2B).
For instance, in white adipose tissue, where the
activation of SIRT1 by resveratrol decreased fat
accumulation and its inhibition resulted in triglycer-
ide accumulation, it was suggested that SIRT1
activation repressed the nuclear receptor PPARc
(53), an effect that, in addition to SIRT1, also
involved the nuclear receptor corepressor (NcoR)
and silencing mediator SMRT (54). A recent study
also emphasized the role of the endothelial nitric
oxide synthase (eNOS) signaling in CR-mediated
increases in mitochondrial biogenesis and life span in
mice. CR animals showed an increase in mitochon-
drial biogenesis that correlated with an increase in
the expression of SIRT1, PGC-1a and eNOS in
various tissues. Interestingly, these effects were
completely inhibited in eNOS2/2 animals in which
life span was significantly reduced (55).
SIRT1 has also been demonstrated to augment
insulin secretion in response to glucose in pancreatic
b-cells of b-cell-specific SIRT1-overexpressing
(BESTO) transgenic mice (56). This response was
accompanied by a decrease in the expression of the
uncoupling protein-2 (UCP-2) that could increase
ATP production in the b-cells of BESTO transgenic
mice. UCPs uncouple oxygen consumption from
ATP generation by allowing leakage of protons (H+),
thereby participating in the reduction of ROS
generation. The SIRT1-mediated decrease in
UCP-2 expression impedes H+ ‘leakage’ and allows
a more efficient coupling of electron transport with
the ATP production. Likewise, UCP-22/2 mice also
exhibit a similar phenotype with improved glucose
tolerance and enhanced insulin secretion (57).
SIRT1 achieves this effect on UCP-2 expression by
directly binding to and repressing UCP-2 gene
transcription in pancreatic b-cells (58). SIRT1 can
also form a complex with FOXO1 and the promye-
locytic leukemia protein PML to activate two insulin
transcription factors, NeuroD and MafA, which may
protect the pancreatic b-cell pathway from oxidative
damage (59). An approach to increase SIRT1
dosage in pancreatic b-cells could hence be of
potential interest to maintain a healthy b-cell
function in diabetic patients.
SIRT1 and SIRT3 deacetylate acetyl coenzyme A
synthetase (AceCS). AceCS catalyzes the formation
of acetyl-CoA from acetate, coenzyme A, and ATP.
Whereas SIRT1 has been shown to deacetylate the
cytoplasmic AceCS1, whose activity controls acetyl-
CoA levels in the cytoplasm for fatty acid synthesis,
SIRT3 deacetylates the mitochondrial AceCS2
which regulates acetyl-CoA-requiring pathways in
the mitochondria such as the tricarboxylic acid cycle
(60). Since acetate metabolism is impaired in
diabetes and ageing, it is legitimate to speculate on
the potential role of SIRT1 and SIRT3 in the
pathophysiology of these diseases through the
regulation of AceCS1 and AceCS2. Further valida-
tion of these observations in in vivo models is still
required.
A central role for SIRT1 in disease of the central
nervous system has also been highlighted in animal
models. In the Wallerian degeneration slow (Wlds)
mouse model, SIRT1 activation protects axons
against neuronal injury. This Wlds mouse bears
in fact a dominant mutation producing an

overexpressed chimeric Wlds protein composed of
the ubiquitin assembly protein Ufd2a and the NAD+
salvage pathway enzyme NMNAT1. Decreasing
SIRT1 activity reduces the axonal protection origin-
ally observed, whereas SIRT1 activation by resver-
atrol decreases the axonal degeneration after
neuronal injury. This suggests that the neuroprotec-
tion in the Wlds mouse model is achieved by
increasing the neuronal NAD+ reserve and/or
SIRT1 activity (61). Furthermore it has been
reported that the SIRT1 agonist resveratrol protects
C. elegans neurons expressing a fragment of the
Huntington disease-associated protein huntingtin
and mammalian neurons from mutant polygluta-
mine cytotoxicity in a HdhQ111 knock-in mouse
model of Huntington disease (62). In addition,
SIRT1 activation significantly decreases neuronal
cell death induced by amyloid-beta (Ab) peptides
through inhibition of NFkB signaling (63). Specific
brain hSIRT1 overexpression in transgenic animals
induces a significant increase in the a-secretase
activity, an enzyme that cleaves the amyloid pre-
cursor peptide (APP) within the Ab peptide,
favoring thereby the nonamyloidogenic pathway of
the APP processing (64). In addition, a recent study
demonstrated the protective effect of CR against
Alzheimer’s disease-type brain amyloidosis in mon-
keys. Monkeys maintained on CR diet had signifi-
cantly reduced contents of Ab peptides in the
temporal cortex that correlated with enhanced
SIRT1 concentrations as compared to monkeys
under normal diet (65). From these studies, it
became clear that pharmacological strategies aiming
at activating SIRT1 would impede Ab peptide
deposition in the brain and prevent the development
of Alzheimer’s disease.
From the animal studies discussed above, it was
suggested that SIRT1 could contribute to the
pathogenesis of some complex diseases. SIRT1
could hence be considered as a serious candidate
target for therapeutic interventions in metabolic and
neurodegenerative disorders. In line with this
hypothesis, genetic variants (SNPs) in the human
SIRT1 gene have been shown to be tightly asso-
ciated with energy expenditure (52). We predict that
future human studies will link SIRT1 even more
tightly with metabolic and neurodegenerative dis-
eases, stimulating the development of therapeutics
for their treatment.
Emerging functions for the other sirtuins
SIRT2
The tubulin-deacetylase protein SIRT2 (66) has
been demonstrated to be downregulated in human
Sirtuins and metabolism 341
gliomas, which are amongst the most frequent
malignant brain tumors (67). The SIRT2 gene maps
at chromosome 19q13.2, a region frequently deleted
in human gliomas. Furthermore, ectopic expression
of SIRT2 in a glioma cell line decreased colony
formation suggesting a potential tumor suppressor
role of SIRT2. This could be explained by the fact
that SIRT2 plays an important role in the control of
mitotic exit in the cell cycle where increased SIRT2
activity severely delays cell cycle progression through
mitosis (68), but also by the fact that SIRT2 acts as a
mitotic checkpoint protein that prevents chromoso-
mal instability and the formation of hyperploid cells
in the early metaphase (69). Further studies such as
SIRT2 brain-specific inactivation in genetically
engineered mice should bring an insight into the
mechanism and the role of SIRT2 in the pathophy-
siology of this aggressive type of brain cancer. Very
recently, SIRT2 was described as an oligodendro-
glial cytoplasmic protein, localized to the outer and
juxtanodal loops in the myelin sheath, that decreases
cell differentiation through a-tubulin deacetylation
suggesting a potential implication in myelinogenesis
(70).
SIRT3
The mitochondrial SIRT3 deacetylase (71,72) has
been linked with adaptative thermogenesis. SIRT3
expression is induced in mice in both white and
brown adipose tissue (BAT) by CR and in BAT
upon cold exposure. SIRT3 furthermore activates
known mitochondrial genes such as PGC-1a and
UCP-1 suggesting an important role of SIRT3 in
thermogenesis (73). In addition, the SIRT3 gene has
been linked to longevity. In fact, the genotype
defined by the G477T polymorphism in exon 3,
was associated with survivorship (74). Furthermore,
a VNTR (a 72-bp repeat core) polymorphism in
intron 5 of the SIRT3 gene, that acts as an allele-
specific enhancer activity on a reporter gene, was
associated with longevity in male subjects (75). This
VNTR might represent the functional variant that
accounts for the association between the silent
marker G477T and longevity in old male subjects.
SIRT4
Although the mitochondrial expressed protein
SIRT4 has a conserved sirtuin domain, it seems
not to possess in vitro deacetylase activity (76).
However, SIRT4 ADP-ribosylates and inhibits the
mitochondrial glutamate dehydrogenase (GDH).
GDH controls amino acid-stimulated insulin secre-
tion by regulating glutamine and glutamate oxidative
342 N. Dali-Youcef et al.

Table I. Expression pattern, cellular distribution, and function of sirtuin deacetylases. Sirtuins are differentially expressed in different
organs based on their transcripts.

Expression levels
Cellular Putative Potential link
Gene High Low compartmentation target genes with diseases

SIRT1 Br, Te, Sk, Li, Sp, He Lu, Nuclear p53,Ku70, NFkB, ageing, obesity, Insulin
Ki (+++), Ov, BM PGC-1a, MEF2D, resistance, inflammation,
Th, Ut (++) MyoD, PPARc, diabetes, heart failure, axonal
FOXO, p300, degeneration, AIDS
AceCS1, tat
SIRT2 Br, Sk (+++), Li, Th, Lu, BM, Ut, Cytoplasmic a-tubulin downregulated in human gliomas
Te, Ki, He (++) Ov, Sp
SIRT3 Ov (+++), most Mitochondrial PGC-1a, AceCS2 adaptive thermogenesis,
other organs (++) overexpressed in node-positive
breast cancer
SIRT4 Br, Te, He, BM, Sp Mitochondrial Glutamate inhibits amino acid-stimulated
Lu (+++), Li, dehydrogenase insulin secretion
Sk, Ki, Th, Ut,
Ov (++)
SIRT5 Br, Te, Sk, Ki, He Sp Mitochondrial unknown unknown
(+++) Li, Ov, Lu,
Th, Ut, BM (++)
SIRT6 Fetal Br (+++), Br, Sp, Th, Ut, BM, Lu Nuclear DNA polb age-related diseases
Li, Te, Sk, Ki, He,
Ov (++)
SIRT7 Br, Te, Ki Lower in other organs Nuclear RNA polymerase highly expressed in thyroid
Sp, Te, Li, Ki, Br, Sk, He (proteins) Pol I cancers, overexpressed in node-
Pa (proteins) positive breast cancer

Abbreviations: Br5Brain; He5heart; Ki5kidney; Sk5skeletal muscle; Li5liver; Te5testis; Lu5lung; Sp5spleen; Ov5ovary; Ut5uterus;
BM5bone marrow; Th5thyroid.

metabolism. Inhibition of GDH activity by SIRT4
decreases insulin secretion in mouse pancreatic b-
cells in response to amino acids (76). Interestingly,
the two different sirtuins SIRT1 and SIRT4 seem to
work in opposite directions to control insulin
secretion. Furthermore SIRT4 expression is down-
regulated in response to CR in b-cells, which is
opposite to the regulation of SIRT1 during CR.
More studies are still needed to see whether SIRT4
(and SIRT1) can be integrated in the pathophysiol-
ogy of type 1 and 2 diabetes that both are
characterized by alterations in insulin secretion.
SIRT6
Whereas little is known about the activity of SIRT5,
SIRT6 is suggested to control genomic DNA
stability and DNA repair. SIRT62/2 mice die
prematurely and display severe defects including
important lymphopenia, loss of subcutaneous fat,
decreased bone mineral density, metabolic defects
with a profound imbalance in glucose homeostasis
and decreased IGF-1 levels. The phenotype of the
SIRT62/2 mice mimics multiple pathologies found
in elderly humans (77). Although SIRT6 was
originally described as an exclusive ADP-ribosyl-
transferase (78), it was recently demonstrated that
SIRT6 deacetylates histones and the DNA repair
enzyme, DNA polymerase b (polb) in vitro (77). An
effect on DNA repair was hence proposed to explain
the phenotype in SIRT62/2 mice, and it was
suggested that SIRT6 could play an essential role
in maintaining organ integrity as animals age.
SIRT7
SIRT7 is the only sirtuin to be localized in the
nucleolus and is a component of the RNA poly-
merase I (Pol I) transcriptional machinery. SIRT7
interacts with RNA Pol I and histones, and positively
regulates the transcription of rDNA during tran-
scriptional elongation, which accounts for about
60% of total transcription in metabolically active
cells in mammals (79). SIRT7 overexpression
increases Pol I-mediated transcription in a NAD+-
dependent manner, whereas SIRT7 inhibition
induces a decrease in the transcription of Pol I and
its association with rDNA (80). Depletion of
SIRT7 stopped cell proliferation and triggered
apoptosis. It was suggested that SIRT7 may regu-
late rDNA transcription by sensing cellular NAD+
levels and that diet-induced changes in NAD+/
NADH ratio might modulate SIRT7 to link the
cellular energy status with rRNA synthesis and

ribosome production. It is worth noting that SIRT1
negatively regulates RNA Pol I through deacetyla-
tion of TAFI68 (81), which goes opposite of SIRT7
action.
Concluding remarks
In the last decade, sirtuin biology has come a long
way from their original description as yeast NAD+-
dependent class III HDACs, that control yeast life
span. In mammals, seven orthologs of Sir2 have
been identified, SIRT1 to 7, and the exact biological
function of most of these sirtuins still remains only
partially characterized. Of particular interest is the
fact that SIRT1 not only deacetylates histones to
mediate gene silencing, but is able to interact with
and deacetylate some well known transcriptional
regulators thereby modulating specifically various
biological processes. Hence modulating the expres-
sion of SIRT1 or its activity, by using sirtuin-
activating compounds such as resveratrol, will have
pleiotropic effects. SIRT1 activation reduces fat
accumulation and adipocyte differentiation through
repression of the activity of the adipogenic nuclear
receptor PPARc. SIRT1 also promotes mitochon-
drial function and energy expenditure and conse-
quently protects mice from diet-induced obesity,
through deacetylation and subsequent activation of
PGC-1a in the skeletal muscle and in the brown
adipose tissue. The SIRT1/PGC-1a interaction is
also important in the liver, where SIRT1 activation
upon fasting induces gluconeogenesis and prevents
against hepatosteatosis. In addition, SIRT1 signifi-
cantly enhances insulin secretion in the pancreatic b-
cells. In combination, these studies illustrate that
SIRT1 is a major modulator of metabolism. SIRT1
activation also seems to be endowed with neuropro-
tective activities as suggested from the study of
models of Huntington or Alzheimer’s disease.
Furthermore, other sirtuins might play important
roles in some diseases, as illustrated by SIRT2,
which is downregulated in human gliomas.
Obviously, more studies, in animal models and
humans, are still needed to define the exact role of
sirtuins in the pathophysiology of human diseases. It
can, however, be predicted that therapeutic inter-
ventions aiming at activating or blocking sirtuins,
depending on the context, will one day become
helpful in the treatment of human diseases.
Acknowledgements
We thank greatly members of the Auwerx laboratory
for critical reading of the manuscript and helpful
discussions. This work was supported by grants of
Sirtuins and metabolism 343
the Centre National de la Recherche Scientifique
(CNRS); Institut National pour la Science et la
Recherche Médicale (INSERM); National Institutes
of Health (NIH); the European Union (EU) and the
Hôpitaux Universitaires de Strasbourg.
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