Recent progress in the biology and
physiology of sirtuins
Toren Finkel1, Chu-Xia Deng2& Raul Mostoslavsky3
Thesirtuins areahighly conservedfamily ofNAD1-dependentenzymesthatregulatelifespaninlowerorganisms.Recently,
the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress
resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology,
the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of
enzymes somehow regulates how long we live.
sion. Often, science has its own version of the Russian playwright’s
famousmaxim. Inour case,the dramabeginsintheautumn of1914,
with the seemingly irrelevant observations of a young professor
describing the beneficial effects of rats placed on a calorie-restricted
diet. Some suspect that these remarkable observations were largely
ignored and forgotten because of concerns about the scientist him-
earlier shocked the scientific community by postulating that in some
roundly ridiculed and derided by his older colleagues. For whatever
reason, Rous’s curious observations remained dormant for nearly
twodecades.Over time,however,other scientists gradually extended
these ideas and demonstrated the benefits of caloric restriction in
species ranging from humans to yeast. Indeed, it was in the latter
implicated a family of NAD1-dependent enzymes, now collectively
termed the sirtuins. In the following sections, we review the recent
progress in our understanding of sirtuin biology with particular
emphasis on their role in mammalian species. Although much
remains unanswered and controversies remain unresolved, as with
Chekhov’s gun it is only with the passage of time that the true sig-
nificance of Rous’s observations can finally be understood.
or observation that is introduced early on in a drama
(such as the gun in Act I of Uncle Vanya) but whose
true significance is only revealed atthe play’s conclu-
A new family of deacetylases
The founding member of the sirtuin family, yeast Sir2 (silent
information regulator 2), was originally isolated in a screen for silen-
lished asimportant regulators ofsilencing atthemating typelocus as
well as telomeric DNA. The Sir family was rescued from relative
obscurity when Guarente and colleagues, using Saccharomyces cere-
visiae as a model system, independently identified these proteins as
key regulators of lifespan2,3. Subsequent analysis revealed that Sir2
functioned biochemically as a histone deacetylase, in a unique reac-
tion requiring the energetic intermediate NAD1as a co-factor4.
Remarkably, analysis in other model organisms (including
Caenorhabditis elegans and Drosophila) also implicated Sir2 homo-
increased following caloric-restriction treatment. Perhaps more
by caloric restriction is abolished5,6. Subsequent studies have quali-
fied some of these observations and have demonstrated that in yeast,
strain-, species- and context-dependent7,8.
Todate, sevenmammalianhomologues havebeenidentified, with
mammalian SIRT1 closest evolutionarily to yeast Sir2. Specific
mouse models in which one or more sirtuin genes has been knocked
out have been recently created (Fig. 1). Cell biological studies have
further demonstrated different subcellular compartments for each
family member, with SIRT6 and SIRT7 being nuclear proteins,
SIRT3, SIRT4 and SIRT5 mitochondrial proteins, and SIRT1 and
SIRT2 being found both in the nucleus and the cytoplasm, in a cell-
and tissue-dependent context9. The observation that these proteins
death at four weeks
increased mitochondrial GDH activity
Defect in the
change in AceCS2 activity, ATP levels
and mitochondrial protein acetylation
Most mice die perinatally,
retinal, bone and
cardiac defects observed
Figure 1 | Mouse knockout models as tools for exploring sirtuin function.
Gene targeting of SIRT1, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7 has been
reported. The phenotypes include a reduction in median lifespan, ranging
from a usual survival of days (SIRT1) to weeks (SIRT6) or months (SIRT7).
In contrast, although biochemical phenotypes have been reported, Sirt32/2
and Sirt42/2mice appear outwardly normal. Initial reports suggest that
Sirt52/2mice also exhibit no obvious phenotype49.
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Macmillan Publishers Limited. All rights reserved
require NAD1as part of their enzymatic action immediately sug-
gested a mechanistic link between sirtuin activity and intracellular
definitive evidence that these proteins play any direct role in mam-
malian lifespan regulation, as neither pharmacological sirtuin acti-
lifespan inmice. Nonetheless, the explosion of interest in the sirtuins
centres on the nagging notion that in some fashion, these proteins
provide the connection between what we eat and how long we live.
Sirtuins in DNA repair
Arole for sirtuins inmaintaining genomic integrity was suggestedby
inhibit recombination of ribosomal DNA as well as to relocalize to
sites of DNA breaks5,10. Furthermore, yeast sirtuin family members
are capable of deacetylating histone proteins and the absence of this
activity results in silencing defects, increased genomic instability and
to the mammalian sirtuins. The first example came with analysis of
SIRT6-deficient cells that demonstrated increased sensitivity to gen-
otoxic damage and accumulation of chromosomal abnormalities11.
Recent studies have shown that SIRT6 also acts as a histone deace-
tylase that can influence the telomeres of human cells12.
SIRT1 can deacetylate various factors linked to the repair of DNA
damage, including the Werner helicase and NBS1 (ref. 13). A role for
SIRT1 in genomic integrity was further substantiated by the recent
demonstration of increased chromosomal aberrations and impaired
DNA repair in Sirt12/2embryos14. In addition, following oxidative
Although such recruitment appears to be important in protecting
against genomic instability, this response is accompanied by the de-
repression of previously silenced genes15. These observations suggest
that like yeast Sir2, SIRT1 appears to regulate epigenetic silencing and
the histone methyltransferase SUV39H1 (refs 16, 17).
Sirtuins and cell fate
Mammalian sirtuins also appear to have an important role in regu-
lating cellular stress resistance and modulating the threshold for cell
death. In part, this increased stress resistance comes from the inter-
factors. These mammalian transcription factors regulate both energy
status and stress resistance, two properties intimately connected to
lifespan extension. SIRT1 can bind and deacetylate FOXO3a, leading
to a selective augmentation of FOXO-regulated stress resistance
genes18,19. Subsequent experiments have extended these observations
bers can interact. In addition, a recent report suggested that SIRT1
can also protect cells against stress by regulating the heat shock
response20. The interaction of SIRT1 and p53 can also modulate
the threshold for cell death in the setting of exogenous stress21,22.
Indeed, FOXO proteins and p53 proteins can directly interact under
various means that include p53-dependent microRNAs23–25. Besides
p53, SIRT1 can regulate other targets linked to cell death, including
Ku70, E2F1 and TGF-b signalling26. In addition, the coordinated
action of SIRT3 and SIRT4 appear to inhibit cell death by maintain-
ing mitochondrial NAD1levels following stress27. Although in most
examples sirtuin activity appears to antagonize stress-induced cell
death pathways, SIRT1 can also deacetylate components of the NF-
kB complex, leading to increased apoptosis28.
to envisage a role for these proteins in mediating processes such as
cellular senescence and stem cell function. Consistent with such a
in mouse embryonic fibroblasts following forced oncogene express-
of SIRT6 appears to augment senescence in primary keratinocytes30.
ity can forestall senescence, it is important to note that an analysis of
studies of Sirt12/2mouse embryonic fibroblasts has come to the
opposite conclusion31. With regards to differentiation, sirtuins have
been shown to inhibit adipogenesis by modulating PPAR-c (peroxi-
some proliferative activated receptor c) and to effect muscle and
neuronal differentiation32,33. Recent studies in mouse embryonic
oxygen species homeostasis and differentiation34. The observation
that SIRT1 can also interact with members of the polycomb family
of repressors, a family of proteins intricately connected to stem cell
self-renewal, suggests that additional links between sirtuins, differ-
entiation and stem cell function are likely to emerge35.
Sirtuins and metabolic regulation
In mammals, blood glucose concentration is maintained within a
narrow range under a variety of physiological conditions. During
starvation, maintenance of serum glucose is achieved in part by
implementing a program of hepatic gluconeogenesis. Increasing
evidence suggests an important role for sirtuins in this physiological
adaptation. The peroxisome proliferator-activated receptor gamma-
cetylation36,37, and this coactivator also plays a fundamental part in
regulating gluconeogenesis and fatty acid oxidation pathways within
the liver. The ability of PGC-1a to modulate these latter two path-
ways appears to require SIRT1 (refs 37, 38). Recently, distinct roles
for protein acetylation and SIRT1-dependent deacetylation have
been shown to regulate the hepatic response to both short term
(,6h) and long term (.18h) fasting39. In this case, the opposing
actions of SIRT1 and the p300/CBP acetyltransferase choreograph
hepatic glucose production in the setting of nutrient stress. Finally,
the observation that SIRT6-deficient mice demonstrate severe hypo-
glycaemia suggests a potential role for other sirtuins in glucose pro-
duction and homeostasis11.
late serum glucose levels by regulating pancreatic insulin secretion. A
transgenic mouse with b cell-specific SIRT1-overexpression was noted
to have increased glucose-stimulated insulin secretion and improved
in regulating pancreatic insulin secretion.
regulation of glucose homeostasis (Fig. 2). As was previously dis-
has a significant regulatory role in fat mobilization and fatty acid
oxidation32,44. The regulation of PGC-1a activity also suggests a role
for sirtuins in the generation of new mitochondria, as PGC-1a is a
key regulator of mitochondrial biogenesis. These observations,
coupled with recent links between SIRT1 and autophagy45, suggest
that sirtuins might regulate the flux of mitochondria within cells by
balancing PGC-1a mediated generation with autophagy-dependent
clearance. In addition to the connection between SIRT1 and the
mitochondria, SIRT3-dependent deacetylation regulates the activity
of the mitochondrial enzyme acetyl coenzyme A synthetase 2
(AceCS2)46,47as well as Complex I of the electron transport chain48.
acetylation is markedly increased, suggesting that other important
targets undoubtedly exist48,49. Finally, a very recent study has impli-
cated SIRT5, another mitochondrial sirtuin, as an important regu-
lator of the urea cycle50.
Although the role of sirtuins in regulating metabolism has centred
on key metabolic organs, such as liver and pancreas, early studies in
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levels of SIRT1 rise in tissues as diverse as skeletal muscle and cir-
culating mononuclear cells51,52. The role of sirtuins in the metabolic
adaptation of these cell types is largely unexplored. The intriguing
of the wide spectrum of metabolic effects sirtuins may eventually
be shown to regulate53,54. The observation that SIRT1 can directly
deacetylate core components of the circadian clock machinery is
particularly fascinating, as the ultimate goal of such rhythms is to
coordinate the sleep-wake cycle of an organism with environmental
cues, including coordinating and matching intracellular metabolism
to external food availability.
Sirtuins and age-related diseases
Given the wealth of data connecting sirtuins to glucose homeostasis
and insulin secretion, it seemed reasonable to suspect that these
proteins might also regulate the susceptibility to developing insulin
resistance and diabetes. Two recent studies using moderate trans-
genic overexpression of SIRT1 demonstrate that such engineered
animals do indeed exhibit improved glucose tolerance when chal-
two different conclusions regarding the effects of moderately
increased SIRT1expression onbasalenergyhomeostasis. Inaddition
to these gain of function studies, inhibition of SIRT1 by genetic or
pharmacological means can induce insulin resistance57. These data
support the notion that manipulating sirtuin activity might result in
protection from a host of metabolic derangements. Such notions
have also been aided by the association of SIRT1 genetic variants
with human energy expenditure and obesity58,59. In animal models,
treatment with the sirtuin activator resveratrol appears to protect
against diet-induced obesity and glucose intolerance60,61. Some con-
cerns have been raised regarding whether resveratrol in mammalian
of sirtuin activity. For instance, resveratrol also activates the AMPK
pathway, although recent evidence suggests that AMPK activity is
intimately connected to sirtuin function62. Some of the concerns
raised regarding the specificity of resveratrol have also been
addressed by the use of newer and seemingly more specific sirtuin
activators, which again appear to provide some protection in animal
models of diet-induced obesity and insulin resistance63,64.
Although the link between sirtuins and metabolic disease has been
intensely studied, there is a growing body of evidence that similar
relationships may hold for a wide swath of age-related maladies. For
instance, the ability of SIRT1 to regulate p53 activity potentially
implicates the sirtuins in tumorigenesis. Indeed, depending on the
context, argumentshavebeenmadethatSIRT1mighteither increase
or decrease cancer risks65. Recently, the notion that SIRT1 might act
as a non-traditional tumour suppressor was highlighted by observa-
tions that in the context of a p531/2mouse, haploinsufficiency of
SIRT1resulted inincreased tumourformation14whileoverexpressed
SIRT1 reduced tumours15. In addition, a direct connection between
established66. Finally, overexpression of SIRT1 can inhibit tumori-
genesis in a mouse model of colon cancer triggered by constitutive
Wnt signalling67. With observations that SIRT6 regulates DNA
repair, and that SIRT2 activity is necessary for proper cytokinesis, a
strong possibility exists that other sirtuin family members will also
affect cancer predisposition.
The sirtuins also appear to have a prominent role in vascular
biology, and may regulate aspects of age-dependent atherosclerosis.
Part of these effects may come through regulation of lipid and cho-
lesterol metabolism, including the ability of SIRT1 to modulate the
activity of the nuclear receptor LXR, a critical factor in reverse cho-
lesterol transport68. In addition, a conditional deletion of SIRT1 in
endothelial cells has been demonstrated to impair the angiogenic
response following an ischaemic insult69. SIRT1 can also deacetylate
and regulate endothelial nitric oxide synthase (eNOS) activity, a key
regulatorofvascular tone70.These resultsareparticularlyinteresting,
because in mouse models, caloric restriction has been shown to
inducemitochondrial biogenesisthrough aneNOS-dependent path-
way71. Other sirtuins can also affect cardiovascular physiology, as
ant vasoconstrictor angiotensin II regulates SIRT3 expression73.
yet to emerge. Initial reports had implicated SIRT1 in a specific
model of axonal degeneration74, although subsequent studies have
raised the possibility that the neuronal pathology observed in this
model may occur through a sirtuin-independent pathway75.
Similarly, although (as discussed above) SIRT1 is in general thought
Fat mobilization Lipid metabolism
↑ Insulin secretion
↓ β-catenin activity
↓ Tumour formation
↑ Resistance to
Figure 2 | The diverse physiological roles of the
sirtuins. Shown are examples of the organ-
specific physiology of SIRT1, along with some of
the direct or indirect targets of sirtuin regulation
(see text for details). In addition, examples of
some of the SIRT1-regulated intracellular
parameters are presented, ranging from
modulation of progenitor differentiation to
altering the threshold for apoptosis. At the
beginning of a compound name or process (for
example, ‘Tumour formation’ at bottom right),
down-arrow indicates ‘decreasing’, up-arrow
indicates ‘increasing’ and ‘D’ indicates ‘change
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and in vivo that this may not hold true in the brain76. Despite these
observations, in amouse model ofAlzheimer’s disease, brain specific
overexpression of SIRT1 appears to reduce neurodegeneration77,78.
disease79. These results suggest that increased SIRT1 or decreased
flags for the development of broadly acting sirtuin-based pharma-
ceuticals for these types of conditions.
From their humble origins as silencing factors in yeast, members of
the sirtuin family have emerged as broad regulators of cellular fate
and mammalian physiology. As impressive as the recent progress has
been, much of our understanding has come from studies involving
only SIRT1, whereas the other six mammalian sirtuins—presumably
equally important—have received significantly less attention. Even
for SIRT1, many questions remained unanswered, including a full
understanding of how the activity of the enzyme is regulated under
both normal and stress conditions, as well as during ageing (Fig. 3).
The recent discovery of interacting proteins that can both positively
and negatively regulate SIRT1 deacetylase activity80–82suggests that
similar interacting proteins may exist for the other sirtuin family
members. Pharmacological manipulation of sirtuin activity that
began with the use of resveratrol has now extended to a variety of
newer agents that appear to have greater specificity. Some of these
agents have already begun human clinical trials83. Whereas the
primary benefit of these drugs may lie in preventing diet-induced
metabolic disorders, direct effects on vascular health, tumorigenesis
and even overall lifespan are at least within the realm of possibility,
given the wide spectrum of sirtuin biology.
From an evolutionary standpoint, it remains unclear why the sir-
tuin family has emerged as a key regulator of so many seemingly
varied processes. Perhaps some of this prominence can be attributed
to the enzyme’s dependence on NAD1, forever linking sirtuin
activity to the underlying metabolic state of the cell. In the 1940s
and 50s, it became clear that ingested sugar, fat and protein was
eventually reduced to a single, simple and versatile intermediate.
Fifty years later, it was realized that this same intermediate, acetyl-
CoA, could also be used to modify histones and hence regulate gene
have emerged as perhaps the most immediate and versatile connec-
tion between intracellular energetics and intracellular fate. Indeed,
theevolvingandintricateconnection betweenacetylation, energetics
and gene expression is now just beginning to be revealed84. In this
regard, although numerous individual studies have linked sirtuins
to changes in gene expression, regulation of genomic stability or
alterations in intracellular metabolism, the real excitement lies in
the understanding that these disparate functions are perhaps all
interconnected—that sirtuins serve as the bridge between what we
eat and what we are. More twists and turns await us in this drama, as
weareindeedfarfrom thefinal curtain.Butfornow atleast, manyof
the curious observations of the past are beginning to make sense.
After waiting for nearly a century, the significance of Chekhov’s
gun may have finally been realized.
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The promoter of SIRT1 is positively and
negatively regulated by the binding of various
transcription factors and repressors, including
H1C1, CtBP, p53, FOXO3A and E2F1. The
acetylation and hence activity of many of these
factors are in turn controlled by SIRT1. The
SIRT1 message is also regulated by the RNA
binding protein HuR and the p53-regulated
microRNA miR-34A. Finally, SIRT protein
activity is regulated positively and negatively by
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well as by the overall metabolic state, as reflected
in the NAD/NADH ratio.
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Acknowledgements We apologize to our colleagues for being unable to cite all
appropriate references owing to space limitations. Highlighted references are a
subjective appraisal of some of the most interesting manuscripts published in the
by NIH Intramural funds (T.F, C.-X.D.), The Ellison Medical Foundation (T.F.), The
Sidney Kimmel Cancer Research Foundation (R.M.) and the V Foundation (R.M.).
Author Contributions All authors contributed to the writing of this Review.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. Correspondence should be addressed to C.-X.D.
NATUREjVol 460j30 July 2009
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