Aging Cell (2010) 9, pp285290

Doi: 10.1111/j.1474-9726.2010.00548.x

REVIEW

Aging and disease: connections to sirtuins

Gizem Donmez and Leonard Guarente
Paul F. Glenn Laboratory and Department of Biology, Massachusetts
Institute of Technology, Cambridge, MA 02139, USA

Summary
The sirtuins are highly conserved NAD-dependent deacetylases that were shown to regulate lifespan in lower
organisms and affect diseases of aging in mammals, such
as diabetes, cancer, and inflammation. Most relevant to
the amelioration of disease, the SIR2 ortholog SIRT1 has
been shown to deacetylate many important transcription
factors to exert an overarching influence on numerous
metabolic pathways. Here we discuss several diseases of
aging for which SIRT1 has been recently shown to confer
protection. These findings suggest that manipulating sirtuin activity pharmacologically may be a fruitful area to
improve human health.
Key words: aging; disease; sirtuin.

Introduction
Aging increases susceptibility to a variety of diseases, such as
diabetes, cardiovascular disease, cancer, neurodegenerative
diseases, and inflammation. The molecular mechanisms that
links aging to age-related diseases, in general, are not understood. Genes that were shown to influence aging in lower
organisms may afford an avenue to arrive at a molecular
understanding of how aging poses a risk factor for these diseases. In this regard, sirtuins are especially interesting
because it has been possible to alter their activities by small
molecules that could be developed into drugs. Indeed,
manipulation of SIRT1 activity genetically or pharmacologically has been shown to impact numerous diseases in rodent
models. In this article, we will review a subset of recent findings that relate sirtuins to several age-related diseases, and
discuss possible mechanisms linking these sirtuins to the
etiology of diseases.

Aging Cell

Sirtuins and metabolic diseases

Calorie restriction (CR) was first described as a reduction in food
intake in laboratory rodents of 3040% of ad libitum levels
that would extend their lifespan by up to 50% (Weindruch &

Correspondence
Leonard Guarente, Paul F. Glenn Laboratory and Department of Biology,
Massacusetts Institute of Technology, Cambridge, Massachusetts 02139,
USA. Tel.: +617 253 6965; fax: +617 452 4130; e-mail: leng@mit.edu

Walford, 1988). CR was shown to promote survival in organisms

ranging from yeast to rodents, and perhaps primates (Guarente,
2006; Colman et al., 2009). CR was proposed to be mediated
by the SIR2 gene family, which were first shown to have antiaging functions in yeast (Kaeberlein et al., 1999), Caenorhabtidis
elegans (Tissenbaum & Guarente, 2001) and Drosophila (Rogina
& Helfand, 2004; Wood et al., 2004). The discovery that yeast
Sir2 and the mammalian SIRT1 are NAD+-dependent deacetylases (Imai et al., 2000) provided a possible mechanistic insight into
how sirtuins might sense diet and metabolism, and thus set the
rate of aging.
Several lines of evidence point to a fundamental role for sirtuins in mammalian CR. First, several outputs of CR do not occur
in SIRT1 KO mice, including longevity (Chen et al., 2005a; Boily
et al., 2008; Li et al., 2008). Second, as discussed later, transgenic mice that over-express SIRT1 show physiological properties of CR mice when fed ad libitum (Bordone et al., 2007;
Banks et al., 2008; Pfluger et al., 2008). Third, as also discussed
later, small molecule activators of SIRT1 also confer phenotypes
of CR on fed mice, which extend to the detailed transcriptional
patterns of gene expression (Barger et al., 2008; Smith et al.,
2009). Fourth, physiological studies of mammalian sirtuins show
that they link diet to physiology by targeting over-arching metabolic pathways, e.g. PGC-1a and mitochondrial biogenesis for
SIRT1 (Lagouge et al., 2006), and CPS1 and the urea cycle for
SIRT5 (Nakagawa et al., 2009).
A recent paper showed that deleting SIRT1 from the brain prevented two important aspects of CR down-regulation of the
somatotropic axis (GH and IGF1) and up-regulation in physical
activity (Cohen et al., 2009). Down-regulation of the somatotropic axis in dwarf mice is associated with extended life span. The
regulation of the somatotropic axis by SIRT1 likely occurs in the
hypothalamus, as SIRT1 was not deleted in the pituitaries of
these mice. The fact that ad-libitum fed mice already showed a
reduced level of somatotropic signaling in mutant mice indicates
that in wild type SIRT1 must be repressed during CR in those
hypothalamic neuron that govern GH release by the pituitary.
This finding may explain why whole-body activation of SIRT1 by
resveratrol or transgenes has not yet been shown to extend life
span in mice. How the somatotropic axis may affect human
aging is not clear.
Metabolic syndrome is the mirror image of CR; it is triggered
by dietary excess and results in poor health and shortened life
span. The discovery of the enzymatic activity of SIRT1 allowed
screening for small molecules that could activate it. The first
such screen identified resveratrol, a polyphenolic compound
made by plants that had previously been associated with health
benefits (Howitz et al., 2003). This compound was subsequently

Accepted for publication 1 January 2010

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shown to protect mice from metabolic disability resulting from a

high-fat diet (Baur et al., 2006; Lagouge et al., 2006). In more
recent studies, resveratrol was given to ad libitum-fed mice
(4.9 mg kg)1 day)1) from middle age (14 months) to old age
(30 months), and these mice were compared to mice not given
resveratrol and fed either a calorie restricted diet or ad libitum
(Barger et al., 2008). Genome-wide transcriptional analysis
showed a striking transcriptional overlap of resveratrol-fed mice
compared to CR mice in heart, skeletal muscle and brain. A total
of 745 genes for heart, 1164 for muscle and 1129 genes for
brain were significantly altered in the same direction by both CR
and resveratrol. Only a handful of genes affected by resveratrol
were not affected by CR. Both resveratrol and CR-stimulated
insulin mediated glucose uptake in muscle ex vivo. However, the
mechanisms for insulin sensitization appeared to differ. CR
increased Akt phosphorylation in response to insulin, but resveratrol did not. Likewise CR increased levels of GLUT4, the major
glucose transporter in muscle, but resveratrol did not. Additionally, resveratrol and CR both prevented age-related cardiac dysfunction, as assessed by left ventricular and systolic
determinations and myocardial performance index.
As resveratrol has been proposed to affect targets in addition
to SIRT1 (Dasgupta & Milbrandt, 2007), it is important to consider newer classes of SIRT1 activators that may be more specific. For example, mice were first fed with high-fat diet and
then treated with SIRT1 activators, SRT501 (1000 mg kg)1, oral
dosing) or SRT1720 (100 mg kg)1, oral dosing) for 3 days. Causal Network Modeling of gene expression data was performed
from livers of these mice (Smith et al., 2009). Both SRT501 and
SRT1720 data sets were modulated to indicate increased metabolism, mitochondrial biogenesis, and decreased inflammation,
which was similar to the CR gene expression profiles. Both
SRT1720 and SRT501 increased expression of PPARa, PPARc
and ERRa which are markers of mitochondrial biogenesis and
fatty acid oxidation, and decreased expression of the Nrip 1,
repressor of mitochondrial biogenesis.
The aforementioned findings were consistent with an earlier
study by Feige et al. (2008), which demonstrated that SRT1720
protected mice or rats from diet-induced obesity, in this case by
promoting fat consumption in skeletal muscle, liver, and brown
adipose tissue. SRT1720 was also shown in mice fed a high-fat
diet to increase oxygen consumption and promote energy
expenditure in white adipose tissue, and improve average distance run on a treadmill, and locomotor functions.
To genetically test the hypothesis that SIRT1 participates in the
regulation of metabolism, Banks et al. (2008) generated BAC
transgenic mice moderately overexpressing SIRT1 under its natural promoter (SirBACO). By placing SirBACO mice on a high-fat
diet or backcrossing onto db db mice, the authors showed that
SIRT1 overexpression does not improve glucose metabolism in
normally fed young mice, but prevents the adverse effects of
obesity on glucose metabolism, as determined by glucose tolerance tests. SirBACO mice were also protected against aginginduced diabetes when fed a normal diet. Control transgenic
mice expressing catalytically inactive SIRT1 (H355Y) showed no

differences in glucose tolerance, demonstrating that SIRT1 catalytic activity is required for its insulin-sensitizing effects. Pfluger
et al. (2008) reported that independently derived BAC SIRT1
transgenic mice showed lower lipid-induced inflammation along
with better glucose tolerance when fed a high-fat diet and were
almost entirely protected from hepatic steatosis. The authors
suggested that beneficial effects of SIRT1 were because of at
least two mechanisms. First was induction of NRF1, a master
regulator of antioxidant proteins and MnSOD itself, which are
known to be under control of PGC1-a. Second was repression
of NFjB activity, which would lower levels of pro-inflammatory
cytokines, such as tumor necrosis factor a (TNFa) and IL-6.
Another recent study (Kemper et al., 2009) reported that the
nuclear bile acid receptor FXR is a target of SIRT1 in metabolic
regulation. Acetylation of FXR inhibited its activity and is dynamically regulated p300 and SIRT1 under normal conditions. Downregulation of hepatic SIRT1 increased FXR acetylation with
deleterious metabolic outcomes and FXR acetylation levels were
elevated in two mouse models of metabolic disorders, ob ob
mice and mice chronically fed a western-style diet. Treatment
with the SIRT1 activator resveratrol or adenoviral-mediated
expression of SIRT1 substantially reduced FXR acetylation levels
in these disease model mice suggesting small molecules that
inhibit FXR acetylation by targeting SIRT1 or p300 may be promising therapeutic agents for metabolic disorders. All told, these
recent studies solidify the notion that SIRT1 will be a significant
target for treating metabolic diseases.

Sirtuins and cancer

The possible role of SIRT1 in cancer has posed a dilemma. On
the one hand, as a gene promoting cell survival, one might predict that SIRT1 would possess an oncogenic function. For example, SIRT1 deacetylates and down-regulates p53, which may
extend the longevity of cell types such as neurons and muscle
cells, but engender cancer in tissues with dividing cells. On the
other hand, as a gene promoting organismal survival, one might
predict a tumor suppressor function for SIRT1. Indeed, CR itself
suppresses cancers of many types. Not surprisingly, the literature
has been conflicted, and we will review later papers claiming
either oncogenic or tumor suppressor functions for SIRT1.
The first suggestion that SIRT1 might be oncogenic was the
finding that the HIC1 (hypermethylated in cancer) product binds
to the SIRT1 promoter and represses transcription (Chen et al.,
2005b) As HIC1 is silenced in certain tumors, the up-regulation
of SIRT1 was proposed to play a role in tumorigenesis. More
recently, Zhao et al. (2008) and Kim et al. (2008) showed that
deleted in breast cancer 1 protein binds to and inhibits the catalytic domain of SIRT1 in human cells. DBC1 may also block the
association between SIRT1 and its substrates. The DBC1 gene
was initially identified in a large interval of chromosome 8p21
that is deleted in human breast cancer (Sundararajan et al.,
2005). DBC1-mediated repression of SIRT1 leads to increased
levels of p53 acetylation and up-regulation of p53 activities,
including apoptosis. Thus, it seems possible that an up-regulation

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Aging and disease: connections to sirtuins, G. Donmez and L. Guarente 287

of SIRT1 activity in human breast cancer may facilitate tumorigenesis. However, it is important to note that the DBC1 gene
itself has not been pinpointed as the relevant tumor suppressor
locus removed in the deletions in chromosome 8p21. In
summary, these studies showed that SIRT1 activity can be downregulated through the endogenous DBC1 protein, and this
interaction may have relevance to human breast cancer.
On the other hand, other studies have shown a pattern that is
consistent with SIRT1 having antiproliferation and antiapoptotic
effects during cancer development. Kabra et al. (2009) have
found that SIRT1 knockdown by short hairpin RNA accelerates
tumor xenograft formation by HCT116 cells, whereas SIRT1
overexpression inhibits tumor formation. Furthermore, pharmacological inhibition of SIRT1 by SIRT1-specific inhibitor EX-527
stimulates cell proliferation under conditions of growth factor
deprivation. SIRT1 overexpression was observed in 25% of
stage I II III colorectal adenocarcinomas but rarely found in
advanced stage IV tumors.
Another study by Wang et al. (2008a) also suggested that the
SIRT1 activator resveratrol serves as an excellent therapy for
BRCA1-associated breast cancer. Activation of SIRT1 by resveratrol showed a protective effect, particularly in BRCA1 mutant
cancer cells. The reason for this is that BRCA1 positively regulates SIRT1 gene expression, and human BRCA1-mutant breast
cancers thus have lower levels of SIRT1 than control tissues. Further, mammary tumors from BRCA1 mutant mice have low
levels of SIRT1. One of the outcomes of low SIRT1 is activation
of SIRT1-repressed genes, such as survivin, which has been
shown to inhibit apoptosis (Zaffaroni et al., 2005). These findings suggest a pathway in which BRCA1 activates SIRT1, which
represses the tumorigenic gene survivin.
Wang et al., 2008b also showed that SIRT1 serves as a tumor
suppressor more broadly in murine tumors and in some types of
human cancers. In this study, SIRT1 + ); p53+ ) mice develop
tumors in multiple tissues at a much earlier age than SIRT1+ +;
p53+ ) mice. Further, activation of SIRT1 by resveratrol treatment reduced tumorigenesis in SIRT1+ ); p53+ ) mice. Likewise, Oberdoerffer et al., 2008 showed that resveratrol
protected irradiated p53+ ) mice from cancer. On the other
hand, Boily et al. (2009) showed that the presence or absence
of SIRT1 had no effect on incidence and tumor load of skin papillomas induced by the classical two-stage carcinogenesis protocol. Resveratrol topically applied to skin profoundly reduced
tumorigenesis and this chemoprotective effect was significantly
reduced in SIRT1-null mice, suggesting that only part of the protection afforded by resveratrol requires SIRT1. With regard to
humans, eight different cancers (lung, breast, colon, stomach,
liver, bladder, skin, and thyroid) exhibited reduced levels of
SIRT1 compared to normal controls (Wang et al., 2008b). Other
studies also indicate a tumor suppressor role for SIRT1. Firestein
et al. (2008) tested a transgenic gut-specific SIRT1 over-expressing strain of mice in a APCmin + model of colon cancer. SIRT1
transgenic mice were significantly protected against cancer.
In vitro, SIRT1 deacetylated and repressed the pro-growth
transcription factor, b-catenin, known to be stabilized in colon

cancer cells. In colon cancer cell lines, over-expressed SIRT1 prevented nuclear accumulation of b-catenin, suggesting that this
sirtuin may be a nuclear entry for any b-catenin that
inappropriately enters that compartment in differentiating intestinal epithelial cells.
The aforementioned studies raise the possibility that SIRT1
functions as a tumor suppressor by repressing non-p53 factors
that drive cell growth (e.g. b-catenin). This activity may offset
any loss of tumor suppression because of deacetylation of p53
itself. Consistent with this idea, SIRT1 was also shown to deacetylate and destabilize the oncogene myc (Yuan et al., 2009). All
of the aforementioned data suggest that SIRT1 activation may
be useful in preventing cancer. That said, it is possible that SIRT1
inhibition may be effective in treating certain pre-existing cancers, for example by up-regulating p53-mediated apoptosis.

Sirtuins and inflammatory diseases

Inflammation is an important factor in the pathogenesis of
several age-related degenerative diseases. The master regulator of innate immunity is NF-jB, which governs an ancient
signaling pathway found in insects and vertebrates (Salminen et al., 2007). NF-jB is a heterodimeric complex of p50
(encoded by NFKB1) and p65 (RELA). In the inactive state,
NF-jB complexes are sequestered in the cytoplasm by Ij-B
inhibitory proteins. A variety of signals like oxidative stress
and DNA damage stimulate the phosphorylation and subsequent degradation of IjB, which leads to the nuclear translocation of NF-jB. NF-jB controls the activity of genes
involved in apoptosis, cell senescence, inflammation, and
immunity, and its activity increase with age in many mammalian tissues and stem cells (Salminen et al., 2007).
Indeed, genetic hyperactivation of NF-jB results in diseases
in murine models including muscle wasting (Cai et al.,
2004) and obesity-induced insulin resistance (Arkan et al.,
2005).
Two different sirtuins, SIRT1 and SIRT6, inhibit transcription of
genes by NF-jB. SIRT1 was shown to physically interact with and
deacetylate the RelA p65 subunit of NF-jB and thereby inhibit
its ability to activate transcription (Yeung et al., 2004). By damping the activation of NF-jB, SIRT1 augments apoptosis in
response to the pro-inflammatory factor, tumor necrosis factor
a. Lee et al. (2009) showed recently that overexpression of
SIRT1 also protects pancreatic beta cells against cytokine toxicity
by suppressing NF-jB. In this study, SIRT1 chemical activators
like resveratrol also prevented cytokine toxicity, NO production
and iNOS expression and maintained normal insulin-secreting
responses to glucose in isolated rat islets. In addition, Sequeira
et al. (2008) showed that SIRT1-null mice suffer from a mild
autoimmune condition that is manifest by the deposition of
immune complexes in the liver and kidney. Many of the mice
were shown to develop high titer antinuclear antibodies.
In addition to SIRT1, SIRT6 was also shown to be involved in
regulation of the NF-kB signaling pathway. Kawahara et al.
(2009) showed that SIRT6 is physically present at promoters of

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288 Aging and disease: connections to sirtuins, G. Donmez and L. Guarente

genes activated by NF-jB. By docking with RelA p65, SIRT6

deacetylates histone H3 lysine 9 (H3K9) to repress transcription
of NF-jB target genes. Underscoring the biological importance
of this activity, haploinsuffiency of RelA rescues the early lethality and degenerative syndrome of SIRT6-deficient mice. Thus,
both SIRT1 and SIRT6 down-regulate the NF-jB signaling pathway. However, another study by Van Gool et al. (2009) indicated that intracellular NAD levels actually promoted TNFa
protein synthesis in SIRT6 dependent manner. This regulation
evidently occurred at a post-transcriptional step, but its mechanism or how this might relate to the other, anti-inflammatory
activities of sirtuins is not yet clear.
NF-jB has been implicated as a candidate activator of agingrelated transcriptional changes in multiple human and mouse
tissues (Adler et al., 2007). Genetic blockade of NF-jB in the
skin of chronologically aged mice reversed the global gene
expression program and tissue characteristics to those of young
mice. Further, NF-jB blockade increased the proliferative capacity of the skin and reversed several markers of cellular senescence to levels observed in young animals. Therefore, NF-jB
blockade may alleviate aspects of aging that are because of
hyper-activity of NF-jB. Activation of SIRT1 and or SIRT6 might
be one approach to creating such a blockade.
In summary, the aforementioned studies suggest that the
blockade of NF-jB may protect against pro-inflammatory diseases. However, NF-jB signaling and its interactions with other
signaling networks play important roles in the functions of the
immune system and other tissues. It will be necessary to modulate NF-jB activity, for example by sirtuin activation, in a way
that maintains normal functions, even while protecting against
autoimmune diseases, inflammatory diseases, and other degenerative diseases.

Sirtuins and cardiac dysfunction

Heart is among the primary target tissues showing decline of the
ability to respond to adverse conditions during aging. Cardiac
hypertrophy is a common response of myocytes to different
physiological and pathological stimuli. Because myocytes do not
have the ability to divide, the only way for them to deal with
work overload is to undergo hypertrophy, in which myocytes
grow in size and induce a group of genes. Prolonged pathological hypertrophy leads to congestive heart failure and sudden
death because of arrhythmias.
Although sirtuins are heavily investigated in aging and aging
diseases, little was known about the role of sirtuins in heart until
recently. Alcendor et al. (2009) showed that low (2.5-fold) to
moderate (7.5-fold) overexpression of SIRT1 in transgenic mouse
hearts attenuated age-dependent cardiac hypertrophy, apoptosis, fibrosis, cardiac dysfunction, and expression of senescent
markers. In contrast, a high level (12.5-fold) of SIRT1 increased
apoptosis and hypertrophy and decreased cardiac function,
thereby stimulating cardiomyopathy. Moderate overexpression
of SIRT1 protected the heart from oxidative stress induced by
paraquat, and increased expression of antioxidants, such as cat-

alase via FOXO-dependent mechanisms, whereas high levels of

SIRT1 increased oxidative stress. This study suggested that
increasing SIRT1 activity could retard aging and confers stress
resistance to the heart in vivo, but these beneficial effects can be
observed only at low to moderate increases of SIRT1.
In another study, Vakhrusheva et al. (2009) showed that
SIRT7 increases stress resistance of cardiomyocytes and prevents
apoptosis and inflammatory cardiomyopathy in mice. SIRT7deficient mice developed heart hypertrophy and inflammatory
cardiomyopathy with extensive fibrosis in the heart. SIRT7 was
shown to decaetylate p53 in this study and SIRT7-deficient primary cardiomyocytes displayed an increase in basal apoptosis
and diminished resistance to oxidative and genotoxic stress.
Sundaresan et al. (2009) have shown by using both SIRT3-deficient and SIRT3-overexpressing mice that SIRT3 blocks cardiac
hypertrophy by augmenting Foxo3a-dependent antioxidant
mechanisms. SIRT3-deficient mice showed signs of cardiac
hypertrophy and interstitial fibrosis at 8 weeks of age. Application of hypertrophic stimuli to these mice produced severe
cardiac hypertrophy, whereas SIRT3-expressing Tg mice were
protected from similar stimuli. In primary cultures of cardiomyocytes, SIRT3 blocked cardiac hypertrophy by activating FOXOdependent, antioxidant genes, thereby decreasing cellular levels
of ROS.
SIRT1 is also associated with processes that may indirectly
benefit cardiac function. For example, SIRT1 promotes NO production in smooth muscle by deacetylating the eNOS enzyme
(Mattagajasingh et al., 2007). In addition, SIRT1 deacetylates
LXR to drive reverse cholesterol transport in macrophages (Li
et al., 2007). On sum, mounting evidence suggests that sirtuin
activation will confer significant cardiac protection.
Recent progress in understanding aging and aging-related diseases has led to novel therapeutic targets. Among these, the sirtuins are of interest first because they appear to impact a wide
variety of aging-related diseases, and second because they can
be modulated by small molecules. As sirtuins appear to counter
aging, drugs that have been generated so far are compounds
that are activators. These new drugs may mimic at least some of
the effects of CR in forestalling or preventing aging-related diseases. In the long run, drugs that can target specific tissues and
function as sirtuin activators or, perhaps in some cases even
inhibitors, may maximize the potential to manipulate sirtuins for
human benefit.

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