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Arch Biochem Biophys. 2010 September 1; 501(1): 79–90. doi:10.1016/j.abb.2010.05.003.
Regulation of SIRT1 in cellular functions: role of polyphenols
Sangwoon Chung, Hongwei Yao, Samuel Caito, Jae-woong Hwang, Gnanapragasam
Arunachalam, and Irfan Rahman
Department of Environmental Medicine, Lung Biology and Disease Program, University of
Rochester Medical Center, Rochester, NY, USA
Abstract
Sirtuin 1 (SIRT1) is known to deacetylate histones and non-histone proteins including transcription
factors thereby regulating metabolism, stress resistance, cellular survival, cellular senescence/aging,
inflammation-immune function, and endothelial functions, and circadian rhythms. Naturally
occurring dietary polyphenols, such as resveratrol, curcumin, quercetin, and catechins, have
antioxidant and anti-inflammatory properties via modulating different pathways, such as NF-κB- and
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mitogen activated protein kinase-dependent signaling pathways. In addition, these polyphenols have
also been shown to activate SIRT1 directly or indirectly in a variety of models. Therefore, activation
of SIRT1 by polyphenols is beneficial for regulation of calorie restriction, oxidative stress,
inflammation, cellular senescence, autophagy/apoptosis, autoimmunity, metabolism, adipogenesis,
circadian rhythm, skeletal muscle function, mitochondria biogenesis and endothelial dysfunction. In
this review, we describe the regulation of SIRT1 by dietary polyphenols in various cellular functions
in response to environmental and pro-inflammatory stimuli.
Keywords
Polyphenols; SIRT1; oxidants; resveratrol; inflammation
INTRODUCTION
Sirtuins, the class III histone deacetylases (HDACs), are widely distributed and have been
shown to regulate a variety of physiopathological processes, such as inflammation, cellular
senescence/aging, cellular apoptosis/proliferation, metabolism, and cell cycle regulation.
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There are seven mammalian enzymes belonging to class III HDACs: SIRT1 to SIRT7. The
details of localization, main functions, and substrate of SIRT1 to SIRT7 are given in Table 1.
The best characterized and well-studied among the human sirtuins is sirtuin1 (SIRT1), a nuclear
protein reported to regulate critical metabolic and physiological processes [1–5] (Figure 1).
SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), plays an important
role in regulation of pathogenesis of chronic diseases including diabetes, chronic inflammatory
pulmonary diseases, neurodegenerative diseases, cardiovascular diseases, and chronic renal
diseases. Sir2 is the first to be reported to extend lifespan up to 70% in yeast, fly and the
© 2010 Elsevier Inc. All rights reserved.
Address for Correspondence: Irfan Rahman, PhD, Department of Environmental Medicine, Lung Biology and Disease Program,
University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY 14642, USA, Phone: 1-585-275-6911, Fax:
1-585-276-0239, irfan_rahman@urmc.rochester.edu.
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Chung et al. Page 2
nematode via maintaining silent chromatin by deacetylating core histones [6–10]. The
mechanism in regulation of SIRT1 or Sir2 on these processes is due to its ability to deacetylate
histones and non-histone proteins, such as nuclear factor (NF)-κB, forkhead box class O
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(FOXO) 3, p53, peroxisome proliferator activated receptor (PPAR)-γ, PPAR-γ coactivator 1α
(PGC-1α), and endothelial nitric oxide synthase (eNOS) [2–4].
Polyphenols, such as resveratrol, quercetin and catechins, have been shown to activate SIRT1
either directly or indirectly in vitro and in vivo [11–16]. Hence, the activation of SIRT1 by
polyphenols would be beneficial in therapeutic intervention of a variety of chronic diseases.
This review focuses on cellular and biological functions of SIRT1 and its regulation by
polyphenols. Understanding the role and mechanisms of polyphenols in SIRT1 regulation and
cellular functions will help in identification of pharmacological agents for their possible use
as nutraceuticals in management of chronic diseases.
SIRT1 REGULATION
SIRT1 regulation by nicotinamide adenine dinucleotide (NAD+)
Unlike class I and II HDACs, SIRT1 activity requires NAD+ as cofactor and is not inhibited
by trichostatin A [17]. SIRT1 removes acetyl groups from proteins by transferring the acetyl
group to NAD+, generating two metabolites; 2′-O-acetyl-ADPribose and nicotinamide (NAM).
Thus, the deacetylating activity of SIRT1 can be inhibited by the reaction product, NAM [8,
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9,18,19]. There are two different routes of NAD+ biosynthesis in yeast and mammalian cells
i.e. de novo production and salvage pathway [20]. In mammals, NAM can be converted into
NAD+ through the salvage pathway; first converted to nicotinamide mononucleotide (NMN)
by a rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) and then to
NAD+ by nicotinamide mononucleotide adenylyltransferase (NMNAT). Mammalian SIRT1
or Sir2 activation by NAD+ salvage pathway is shown to confer protection against high glucose
environment in endothelial cells as well as myocardial infarction and ischemia/reperfusion
injury in the heart [21–23]. It has also been shown that activation of NAD+ salvage pathway
extends replicative lifespan in vascular smooth muscle cells by activating SIRT1 [24].
Therefore, activation of the enzymes (e.g. NAMPT or NMNAT) involved in NAD+ salvage
pathway plays an important role in regulating SIRT1 activity [25,26]. Resveratrol and quercetin
are indirect activators of SIRT1 and have been to shown to activate the expression/activity of
NAMPT and AMP-activated kinase (AMPK) [27–30]. AMPK is also shown to activate
NAMPT thereby increasing intracellular level of NAD+ [24,31]. Furthermore, activation of
AMPK by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) increased the
SIRT1 protein in skeletal muscle and attenuated LPS-induced lung inflammation [32,33].
Interestingly, SIRT1 and AMPK are reported to mutually affect the functions of each other
[24,29,30]. Therefore, further studies are required to investigate whether resveratrol’s real
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target is SIRT1, NAMPT, or AMPK since recent studies showing that SIRT1 is not a direct
target of resveratrol [34,35].
Interplay of SIRT1 with poly(ADP-ribose) polymerase 1 (PARP-1): NAD+ as a common
substrate
In addition to SIRT1, PARP-1 also requires NAD+ as a substrate particularly during the DNA
strand breaks to form ADP-ribose polymers, which non-covalently modifies targeting proteins.
PARP-1 is a nuclear protein that is involved in DNA repair and chromatin remodeling. PARP-1
has been shown to possess a dual role in cell survival and necrosis via inducing autophagy and
ATP depletion, respectively [36]. PARP-1 and SIRT1 were first shown to crosstalk in
apoptosis-inducing factor (AIF)-mediated apoptosis [37]. Although the inhibition of SIRT1 by
PARP-1 activation and subsequent NAD+ depletion has been determined in response to
H2O2-induced cell senescence [38], the effect of oxidative/genotoxic stimuli on PARP-1
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activation and SIRT1 activity still remains to be shown. Exposure of environmental and
oxidative/genotoxic stresses leads to NAD+ depletion by concomitant decrease in SIRT1
activity and PARP-1 activation [38–41]. Furthermore, treatment with benzo[a]pyrene, a
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component of cigarette smoke (CS), causes intracellular NAD+ depletion by PARP-1 activation
leading to cellular necrosis [42]. Over-activation of PARP-1 results in NAD+ depletion along
with cellular senescence or death [43]. Recently, it has been shown that a methylxanthine
derivative (a component of tea polyphenols) theophylline, an anti-inflammatory agent, protects
against NAD+ depletion via PARP-1 inhibition and associated sparing of SIRT1 activity in
macrophages and lung cells of patients with chronic obstructive pulmonary disease (COPD)
[44–46]. Hence, a functional link may exist between PARP-1 and SIRT1 through NAD+
cofactor availability, and any changes in levels of intracellular NAD+ and/or PARP-1 activity,
particularly in response to oxidants and environmental stimuli/inhaled pollutants, may
influence SIRT1 activity. Surprisingly, inhibition of PARP-1 did not restore CS-induced
decrease in SIRT1 activity in lung epithelial cells even in the present of resveratrol. This may
be due to SIRT1 post-translational modifications, such as carbonylation/alkylation, thereby
impairing the restoration of SIRT1 activity even the levels of NAD+ is elevated after PARP-1
inhibition [47]. Recent studies in double mutating PARP-1 and SIRT1 showed genome
instability and chromatin modifications and increased lethality in mice [48], suggesting the
key roles of PARP-1 and SIRT1 in cellular functions. It is interesting to note that PARP-1 can
be subjected to acetylation and subsequent activation in the stress conditions (UV irradiation
and genotoxic stresses), which is regulated by SIRT1 [49]. Therefore, it seems that a negative
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feedback loop exists between SIRT1 and PARP-1 in regulating cellular function.
SIRT1 regulation by oxidative stress and redox modification
SIRT1 has been shown to reduce cellular oxidative stress burden indirectly through
deacetylation of FOXO3a (deacetylation of FOXO3a leads to up-regulation of catalase and
MnSOD) [50]. SIRT1 also regulates aging and oxidative stress in the cardiomyocytes and
endothelial cells, and oxidative stress leads to a redistribution of SIRT1 on chromatin [51–
53]. Thus, SIRT1 either directly or indirectly can influence the redox property of the cell. In
addition to reduce cellular oxidative stress burden, SIRT1 is also regulated by oxidative stress.
We have recently shown that the levels of SIRT1 are decreased in vitro in lung epithelial cells,
endothelial cells, and macrophages in response to cigarette smoke extract (CSE), as well as in
lungs of patients with COPD [47,54–56]. SIRT1 also undergoes oxidative/nitrosative post-
translational modifications as shown by increased nitration of tyrosine residue and
carbonylation (acrolein/4-hydroxy-2-nonenal-adducts formation) on cysteine residue in lungs
of smokers and patients with COPD compared with nonsmokers as well as in human monocyte/
macrophage cells and endothelial cells treated with aldehyde and CSE [39,47,54]. Furthermore,
SIRT1 is shown to be a redox-sensitive molecule since intracellular thiols regulate its level and
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activity. Treatment with buthionine sulfoximine, an inhibitor for glutathione biosynthesis,
further decreases SIRT1 levels in response to oxidative/carbonyl stress, whereas elevation of
intracellular thiols pool by N-acetyl-L-cysteine rescues oxidant/carbonyl-mediated depletion
of SIRT1 levels in epithelial cells. Furthermore, aldehydes cause carbonyl adducts formation
on SIRT1 on cysteine residues, which is decreased by increasing intracellular thiols [39].
SIRT1 is also subjected to phosphorylation, which affects its activity and protein levels through
proteasome-dependent or independent degradation [39,54,57,58]. Various serine
phosphorylation sites on SIRT1 (S27, S47, S659, and S661) were identified which is regulated
by protein kinase CK2 and JNK under basal physiological conditions [57–61]. We have
recently showed that oxidants/aldehydes derived from tobacco smoke caused SIRT1
phosphorylation in macrophages, epithelial cells as well as in mouse lungs [39]. Proteasome
inhibitors inhibited phosphorylation of SIRT1 suggesting that phosphorylation in addition to
covalent oxidative/nitrosative modifications of SIRT1 cause irreversible modifications of
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SIRT1 and subsequent proteasomal degradation [39,47]. Taken together, it may be surmised
here that SIRT1 is a novel redox-sensitive protein, which can be regulated by post-translational
modifications, such as carbonylation and phosphorylation [39,47,54]. Oxidants/electrophiles
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covalently modify SIRT1 post-translationally, decreasing enzymatic activity and marking the
protein for proteasomal degradation [39]. We and others have shown that SIRT1 is also subject
to S-glutathionylation and its enzymatic activity is modulated by intracellular redox GSH status
[39,62]. Oxidant/carbonyl stress-induced reduction of SIRT1 may have implications in chronic
inflammatory conditions. Recent study indicated that resveratrol and other dietary polyphenols
attenuate mitochondrial oxidative stress in endothelial cells via activation of SIRT1 [63]. We
and others have shown that resveratrol and SRT1720 can activate SIRT1 in a variety of human
cell lines [47,64], but it remains to be seen whether the similar activation of SIRT1 can occur
in vivo by polyphenols in response to oxidative and pro-inflammatory stimuli.
POLYPHENOLS AND SIRT1 ACTIVATORS
Polyphenols are secondary metabolites of plants and represent a vast group of compounds
having aromatic ring(s), characterized by presence of one or more hydroxyl groups with
varying structural complexities. The most widely distributed group of plant phenolics are
flavonoids. The flavonoids subclasses comprise of flavonols, flavones, isoflavones,
antocyanidins, and others. The commonly studied dietary polyphenols, such as resveratrol,
quercetin, and catechins, have been reported to possess antioxidant and anti-inflammatory
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properties. Resveratrol (3,5,4’-trihydroxystilbene) is a phytoalexin found in red wine and
grapes, which has two phenolic rings connected by a double bond and has two isoforms; trans-
resveratrol and cis-resveratrol, the former being more stable in its biological activity. Quercetin
(3,3’,4’,5,7-pentahydroxylflavone) is a plant-derived flavonol found in apples, tea, capers, and
onion, used as a nutritional supplement. Catechins are monomeric flavanols comprising of
chemically similar compounds, such as epicatechin, epigallocatechin, epicatechin gallate
(EGC), and epigallocatechin gallate (EGCG). EGCG predominates among the various tea
polyphenols and is considered to be the major bioactive and well-studied catechin. Several
reports highlighted that dietary supplementation of polyphenols may protect against
neurodegenerative, cardiovascular, inflammatory, metabolic diseases, and cancer by
enhancing SIRT1 deacetylase activity. However, the therapeutic and pharmacological potential
of these natural compounds remains to be translated in humans in clinical conditions. This is
in part due to the lack of knowledge of their mode of action as well as their multiple signaling
targets, non-specificity, complex pharmacokinetic properties (e.g. absorption,
biotransformation, and bioavailability). Furthermore, these polyphenols may act as pre-
emptying or prophylactic agents in terms of dietary intake/interventions in susceptible
conditions rather than as therapeutic agents.
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Resveratrol is the first polyphenolic compound which has been shown to activate SIRT1
[13–16]. However, the mechanism of SIRT1 activation by resveratrol has been debated, and
recent studies show that resveratrol is not specific activator of SIRT1 [34,35]. In addition, there
are some scanty reports available that quercetin and catechins also activate mammalian SIRT1
or yeast Sir2 albeit to a lesser extent as compared to resveratrol [6,11,12]. However, the separate
studies show that polyphenols, such as EGCG and quercetin did not exhibit any ability to
activate SIRT1 in cellular system [12,65,66]. On the contrary, these polyphenols inhibit SIRT1
activity [12]. This is due to their instability to form oxidized form and produce reactive oxygen
species in the medium (i.e. EGCG) or the formation of SIRT1-inhibitory metabolites (i.e.
quercetin and its metabolites) [12].
A number of other compounds (mainly analogs of resveratrol) have been reported to activate
SIRT1 activity in mammals [67–69]. A newly identified and more potent SIRT1 activator,
SRT1720, has been reported to be 800–1000-fold more effective than resveratrol [69]. Milne
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and their colleagues identified SRT1460 and SRT2183 which can increase SIRT1 enzyme
activity by about 3–5 fold [69]. SRT2172 has been shown to be more effective in inhibiting
matrix metalloproteinase-9 (MMP-9) production in monocytes as compared to resveratrol
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[64]. Interestingly, recent studies also showed that SRT1720, SRT2183, and SRT1460 are
nonspecific for SIRT1 activation [34]. Therefore, development of specifically pharmacological
SIRT1 activator is crucial in understanding the role of SIRT1 in cellular function and
potentially clinical application of SIRT1 activators.
CELLULAR AND BIOLOGICAL FUNCTIONS OF SIRT1: ROLE OF
POLYPHENOLS
In calorie restriction (CR)
Sir2 has been identified as one of the key proteins in not only establishing the transcriptional
silencing via deacetylating histone H4 at lys16 (K16), but also extending the lifespan in yeast,
C. elegans, and drosophila [9,70]. CR is the major mechanism known to extend the lifespan
of organisms. Activation and regulation of SIRT1 has been extensively studied in
understanding the underlying mechanism of CR-mediated lifespan extension. Activation of
Sir2 or mammalian SIRT1 has been shown to contribute to the beneficial effects of CR in yeast
and more complex organisms [16,50,71–75]. A recent study has shown enhanced renal cell
adaption to hypoxia in condition of CR, which is mediated by activating SIRT1-FOXO3
pathway [75]. CR not only increases SIRT1 levels and activity, but also skews the NAD+/
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NADH ratio towards higher NAD+ levels as well as decreased NAM [31]. Under ad-libitum
condition, glucose is converted to pyruvate by glycolysis whereas glycolysis is decreased and
there is a shift towards respiration under CR condition [72,76]. This shift increases the
NAD+/NADH ratio leading to SIRT1 activation. SIRT1 is also shown to increase
gluconeogenesis in the liver leading to hepatic glucose output, which is a characteristic under
CR [77]. Indeed, SIRT1 transgenic mice have the phenotypes resembling CR [78]. It is
interesting to note that Sir2-independent pathway also exists in CR-mediated the lifespan
extension [79–81]. The effect of resveratrol on lifespan extension has been tested in C.
elegans, yeast, fruitfly, mice, and human cells [9,13,82–84]. These synthetic compounds or
analogs of resveratrol may provide a potential therapeutic benefit in mimicking CR by
activating SIRT1 [85–87].
Polyphenols have been shown to activate SIRT1 which in turn mimic the CR, and hence halt
the aging process. The role of SIRT1 is also highlighted in chronic lung diseases, such as asthma
and COPD, where lung levels of SIRT1 are altered [55,64,88]. This is in particular important
as COPD is now considered a disease of accelerated aging where SIRT1 levels are dramatically
reduced as the disease progresses. Hence, using SIRT1 activators either by novel synthetic
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resveratrol derivatives or other polyphenolic compounds may halt the progression of
accelerated aging and/or reverse abnormal cellular immune-inflammatory functions including
steroid resistance to inhibit inflammatory response in chronic lung disorders. It is interesting
to note that a dietary supplementation of 0.1% quercetin significantly reduced the lifespan of
mice [89]. This may be due to the SIRT1 inhibition by quercetin metabolite quercetin-3-O-
glucuronide in vivo [12]. Similar possibilities may exist with other polyphenols and their
interactions with quinones and aldehydes or other biochemical molecules which needs to be
determined particularly in vivo.
In metabolism
SIRT1 activity requires NAD+ as a cofactor whereas it can be inhibited by NADH which reflect
the energy status of a cell [72,90]. Both NAD+ and NADH play an important role in cellular
metabolism and survival [91]. It is therefore proposed that SIRT1 acts as a molecular link
between cellular metabolism via the redox equivalents, NAD+/NADH levels, mitochondria
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biogenesis, and cellular functions. Decreased SIRT1 activity by altered NAD+ level has effects
on its substrate, PGC-1α. As an important mitochondrial activity regulator, PGC-1α modulates
energy production by regulating mitochondrial biogenesis and function [87]. Recent in vivo
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studies have revealed that resveratrol supplementation leads to increased mitochondrial activity
and PGC-1α activity with a concomitant decrease in their acetylation status [87,92]. SIRT1-
mediated deacetylation of PGC-1α by resveratrol acts as regulator of mitochondrial energy
balance and biogenesis. Increasing lines of evidence suggests that the activation of SIRT1
might be effective in intervention and prevention of type 2 diabetes [93,94]. SIRT1 modulates
glucose-ATP signaling and insulin secretion from pancreatic β-cells mainly via regulating
uncoupling protein 2 (UCP2), FOXO2 and NAD+-dependent pathway [95]. Overexpression
of SIRT1 in pancreatic β-cells improves glucose tolerance and enhances insulin secretion in
response to glucose, while SIRT1 knockdown exhibits impaired glucose-stimulated insulin
secretion [95,96]. Furthermore, SIRT1 overexpression attenuates the high fat-induced hepatic
steatosis by induction of manganese superoxide dismutase (MnSOD) and NF-E2-related
factor-1 (Nrf1) as well as by lowering the activity of TNF-α and IL-6 via downregulation of
NF-κB activity [97]. Deficiency of SIRT1 enhances liver steatosis with increased liver lipid
contents and inflammation as compared to wild-type mice in response to moderate and high
fat diets [98]. These observations suggest that polyphenol-dependent activation of SIRT1 may
be a potentially therapeutic approach for management of metabolic diseases.
In energetics
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The dependence on NAD+ as a cofactor links SIRT1 activity to the energetic state of the cell.
AMPK has been shown to regulate energy expenditure by modulating NAD+ metabolism and
SIRT1 activity suggesting a direct involvement of AMPK in regulating SIRT1 and energy
metabolism [24]. Indeed, mice deficient with SIRT1 are hypermetabolic but lethargic, and they
can not utilize ingested food inefficiently. Further investigation shows that SIRT1 knockout
mice are defective in energy generation system, which is reflected by interrupted generation
of ATP in liver mitochondria during food deprivation [90]. These results indicate both AMPK
and SIRT1 might act as energy sensors that regulate energy metabolism [99]. It has been shown
that oxidative stress and CS reduce SIRT1 level/activity, and implicate in altered cellular
energetics. This is confirmed by the study that CSE lowers ATP levels by blocking the
mitochondrial respiratory chain leading to cellular necrosis [100]. However, it is unknown
whether this decreased ATP level is associated with reduced SIRT1 in response to CS/oxidative
stress.
In addition to antioxidant and anti-inflammatory effect, polyphenols have been shown to
regulate energy metabolism. Polyphenol EGCG is shown to reduce energy absorption and
increase fat oxidation in diet-induced obesity of mice [101]. This is associated with SIRT1 and
PGC-1α activation thereby improving mitochondria function and protecting subsequent
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metabolic diseases [87].
In inflammation
SIRT1 protein is associated directly with RelA/p65 subunit of NF-κB, and deacetylates lys310
residue of RelA/p65, a site that is critical for NF-κB transcriptional activity [102]. Recent
studies have shown that SIRT1 also deacetylates and suppresses the transcription activity of
activator protein-1 (AP-1) leading to down-regulation of cyclooxygenase-2 (COX-2) gene
expression [103–105]. SIRT1 knockout or knockdown leads to increased NF-κB activation
and proinflammatory cytokine release whereas activation by SIRT1 activators (e.g. SRT1720
and resveratrol) inhibits NF-κB-mediated inflammatory mediators release in vitro and in
vivo suggesting the role of SIRT1 in regulation of inflammation, and activation of SIRT1 by
activators or polyphenols would be an approach for the intervention of various chronic
inflammatory diseases [55,69,84,106–109]. Furthermore, SIRT1 level is reduced in rat lung
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and human macrophage cells exposed to CS as well as in lungs of smokers and patients with
COPD [55,56], implicating a pivotal role of SIRT1 in the pathogenesis of COPD. Recently, it
has been shown that SIRT1 activators also inhibit NF-κB-mediated inflammatory mediators
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release and possibly overcome steroid-resistance in response to oxidative stress [55,56,64,
110]. However, the role of endogenous SIRT1 in the development of emphysema/COPD and
resistance to steroid therapy and whether or polyphenols (resveratrol, quercetin, cucumin, and
catechins) can reverse steroid-resistance is not known. Similarly, SIRT1 activation by
resveratrol leads to down-regulation of NF-κB which was associated with abrogation of colitis
[108]. Overall, it can be surmised that activation of SIRT1 might act as a novel
immunomodulatory approach in intervention of chronic inflammatory diseases, such as COPD,
diabetes, and colitis via modulating NF-κB-dependent pathway.
Polyphenols (e.g. catechins and curcumin) have been shown to induce hypoacetylation of
RelA/p65 by directly inhibiting the activity of histone acetyltransferase (HAT) enzymes
leading to the down-regulation of NF-κB function and associated inflammatory response
[65]. It is possible that dietary polyphenols could induce protein deacetylase activity, such as
HDAC2/SIRT1, which in turn may inhibit the transcription of pro-inflammatory genes (Figure
2). This is supported by the report that resveratrol inhibits inflammatory cytokine expression
in response to lipopolysaccharide challenge in rat lungs [109]. Furthermore, the expression of
various genes encoding other pro-inflammatory factors, such as COX-2, MMPs, adhesion
molecules, and inducible nitric oxide synthase (iNOS) can be significantly inhibited by
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resveratrol, quercetin, curcumin and catechins via down-regulating NF-κB and AP-1
transcription factors [111–114]. Green tea catechin EGCG has been shown to inhibit CSE-
induced pro-inflammatory cytokine release in lung epithelial cells, which is associated with
inhibition of NF-κB and AP-1 [115–117]. Similar to curcumin, quercetin and catechins also
modulate a myriad of inflammatory signaling pathways [11,118,119]. However, the role of
quercetin and catechins in modulation of SIRT1 and hence controlling the inflammatory
response is currently interesting areas of research. In light of the above observations, it appears
that polyphenols (e.g. resveratrol, quercetin, and catechins) can modulate a variety of
proinflammatory pathways via activating SIRT1 thereby inhibits NF-κB and/or AP-1 pathways
[63,120,121].
In immune function
SIRT1 has been shown to be associated with the regulation of immune function since SIRT1
is expressed at high levels in the thymus including CD4+ and CD8+ thymocytes, and knockout
of SIRT1 enhances thymocytes apoptosis after ionizing radiation in mice [122]. This is
supported by a recent finding that SIRT1 inhibits T cell activation and the loss of SIRT1
function results in abnormally increased T cell activation and a breakdown of CD4+ T cell
tolerance [105]. In addition, SIRT1-deficient mice are unable to maintain T cell tolerance and
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are susceptible to autoimmune diseases [105,122]. Furthermore, SIRT1 deacetylates forkhead
box class P3 (FOXP3) thereby increasing the number and function of regulatory T cell [123].
Sera from adult SIRT1-null mice contained antibodies that reacted with nuclear antigens
leading to formation of immune complexes, which were deposited in the livers and kidneys of
these animals. Some of the SIRT1-null animals developed a disease resembling diabetes
insipidus when they approached 2 years of age [124]. These observations are consistent with
a role for SIRT1 in sustaining normal immune function and thus delaying the onset of
autoimmune diseases, and highlights the role of novel SIRT1 activators in amelioration or
prevention of these diseases [105]. Resveratrol is shown to have anti-asthmatic effects in mouse
model [125]. On the contrary, administration of sirtinol, a SIRT1 inhibitor, significantly
attenuated antigen-induced airway inflammation and hyperresponsiveness that are
characteristics of asthma [88]. Therefore, further studies are required to study whether immune
function is altered in these sirtinol- or resveratrol-treated mice as compared to control although
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immune dysfunction plays an important role in pathogenesis of asthma. Accumulating
evidence has shown that polyphenols, such as resveratrol, catechins, and quercetins, have a
regulatory role in immune function in vitro and in vivo [126–131]. Therefore, polyphenols may
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have beneficial effects to in prevention of the progression of chronic diseases where immune
dysfunction occurs. Nevertheless, the role of polyphenols in SIRT1-mediated regulation in
immune function remains to be studied.
In cellular apoptosis and tumorigenesis
SIRT1 regulates a variety of processes that alter cell response to genotoxicity, including the
detoxification of reactive oxygen species (ROS) by up-regulation of MnSOD, DNA repair
mechanisms (cyclin D, GADD45, p27/Kip1) and sensitivity of cells to apoptosis [53,84,132–
135] (Figure 3). This is due to the deacetylation and activation of a transcription factor FOXO3a
[133,136]. Pharmacological inhibition of SIRT1 decreases cellular resistance to stress and
hence promote cellular apoptosis due to reduced constraint on FOXO3/4 otherwise inhibited
by SIRT1 [133]. FOXO3a activity is regulated by phosphorylation and acetylation [137]. These
modifications lead to the loss of its transactivation properties; whereas transcriptional activity
of FOXO3a is restored by deacetylation carried out by SIRT1 [136,138]. Thus, SIRT1 regulates
the ability of FOXO3a to induce cell cycle arrest; and high SIRT1 activity promotes cell
survival suggesting SIRT1 tips FOXO-dependent response away from cell death and towards
stress resistance [133]. FOXO1 is also involved in protection of SIRT1 against apoptosis in
cardiomyocytes [139]. Furthermore, SIRT1-mediated COX-2 expression reduces oxidative
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stress-induced renal medullary interstitial cell apoptosis [140]. SIRT1 is also shown to regulate
the expression of genes involved in apoptosis, such as Fas ligand, pro-apoptotic BH3-only
proteins, Bcl-2 interacting mediators of cell death (BIM) and TNF-related apoptosis-inducing
ligand [133,136]. A separate study showed that specific overexpression of NAMPT in heart
reduced the size of myocardial infarction and apoptosis via increasing the contents of NAD+
in response to prolonged ischemia and reperfusion [22]. It is not known if SIRT1-mediated
regulation of FOXO3a or other factors plays a role in oxidant/carbonyl stress-induced apoptosis
and whether polyphenols, such as resveratrol, regulate apoptosis via activating SIRT1 or
NAMPT.
SIRT1 also interacts with p53 and deacetylates its C-terminal regulatory domain thereby
decreasing its ability to induce cellular apoptosis [141–143]. SIRT1 inhibitors have ability to
induce cancer cell damage by sensitizing the cells to p53-dependent apoptosis [6]. Therefore,
oxidative stress/CS-mediated SIRT1 reduction may acetylate p53 leading to sustained lung
cell apoptosis. Although it has been shown that nuclear SIRT1 levels are decreased in vivo and
in vitro in response to CS/oxidants exposure [56], it is however, not known if SIRT1-mediated
regulation of p53 (acetylation) plays a role in CS/oxidants-mediated apoptosis and senescence
and whether polyphenols can reverse this via SIRT1. Several other SIRT1 protein substrates
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involved in cell stress response signaling have also been identified, including Ku70, a pro-
apoptotic factor that is down-regulated and deacetylated by SIRT1 [77,144]. However, the role
of polyphenols in SIRT1-mediated these proteins deacetylation and cellular apoptosis is
unclear and needs further investigation.
A role of SIRT1 in tumorigenesis is still controversial because SIRT1 has been shown to act
as both tumor promoter and/or tumor suppressor. The levels of SIRT1 are increased in cancer
and SIRT1 transgenic mice develop tumors suggesting a tumor-promoting role of SIRT1
[145–147]. This is attributed to the deacetylation of tumor-suppressor protein p53 on lysine
382 by SIRT1 leading to its inhibition and subsequent tumorigenesis [19,142]. Thus, the
inhibition of SIRT1 by its inhibitors would induce cell death of cancer cells by activating and
acetylating p53. Interestingly, SIRT1 also acts as a tumor suppressor in vitro and in vivo. SIRT1
is known to sensitize tumor cells to TNF-α-induced cell death via inhibiting transactivation of
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Chung et al. Page 9
NF-κB [84]. It is proposed that the ability of SIRT1 to induce either apoptosis or cell survival
depends on the apoptotic stimuli and on whether this deacetylase is inhibiting NF-κB or p53.
In mouse colon cancer model, SIRT1 suppresses intestinal tumor formation in vivo through
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deacetylation of β-catenin [148]. Breast cancer associated gene 1 (BRCA1) is the most
frequently mutated tumor suppressor gene found in familial breast cancers. Wang et al.
revealed that SIRT1 expression is much lower in the BRCA1-associated breast cancer than
BRCA1-wildtype breast cancer in human [149]. They further showed that activation of SIRT1
by resveratrol induced apoptosis in BRCA-1 deficient cancer cells and strongly inhibited tumor
formation. A separate study demonstrated that knockout or overexpression of SRIT1 did not
exhibit any effect on incidence and tumor load of skin papillomas in mice [145]. Therefore,
the effect of SIRT1 on tumorigenesis is complicated, and its effect may be cancer-specific and
is related with the status of cancer cells (e.g. deactivation and/or activation of tumor suppressor
genes).
Polyphenols are well known chemopreventive agents which are known to induce apoptosis
and cell cycle arrest in cancer cells. Resveratrol has been shown to have anti-carcinogenic
effect in vitro and in vivo [145,149–152]. Similarly, quercetin inhibits cell proliferation in
different cancer cells [153]. The underlying mechanism of these polyphenols’ anti-
carcinogenic effect is associated with the regulation of SIRT1 [145,149]. Other mechanisms
such as antioxidant and anti-inflammatory properties involved in anti-carcinogenic effect of
polyphenols can not be excluded because of the complicated effect of SIRT1 on tumorigenesis
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[154].
In cellular proliferation/senescence
SIRT1 has been shown to control cell cycle, proliferation and senescence due to its regulation
on FOXO and p53 proteins. Senescent mouse embryonic fibroblasts and human endothelial
cells have decreased levels of SIRT1 [155,156]. SIRT1 can interact, deacetylate and activate
FOXO3, a transcription factor promoting a variety of cellular responses, such as cell cycle
arrest, cellular senescence, proliferation, and resistance to oxidative stress and apoptosis
(Figure 3) [133]. The mechanism of SIRT1/FOXO3 or SIRT1/p53 pathway in cellular
proliferation and senescence is associated with altered transcription of downstream cell cycle
inhibitors (e.g. p16, p21, and p27) [38,157]. These cyclin-dependent kinase inhibitors are the
biological markers for cell cycle arrest and cellular senescence. We have shown that FOXO3
and p53 are acetylated when SIRT1 is reduced in response to oxidants/CS exposure in mouse
lung [158]. Oxidative stress/CS exposure has been shown to induce senescence in lung
epithelial cells and fibroblasts, and cellular senescence occurs in mouse lung exposed to CS
and lungs of patients with COPD [159]. Therefore, studies on SIRT1-FOXO3 pathway will
provide more insight into imbalance of cellular proliferation/senescence in response to
oxidative stress, and whether polyphenols have effect on this pathway although polyphenols
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(e.g. resveratrol) regulate cellular senescence [160,161]. Accumulating evidence shows that
SIRT1 interacts eNOS-nitric oxide system thereby regulating vascular senescence and
dysfunction as well as atherosclerosis [162]. Moreover, it is possible that SIRT1 regulates the
function of p21 by posttranslational modification since p21 itself can be subject to acetylation/
deacetylation [163]. However, it remains to be seen whether SIRT1 is also involved in p21-
mediated regulation of cell proliferation/senescence and whether polyphenols can inhibit
acetylation of p21 via activating SIRT1.
In autophagy
Autophagy is a dynamic process which is responsible for the turnover of cellular organelles
and proteins thereby maintaining cell homeostasis and conferring adaption to adverse
environmental stimuli. Excessive autophagy will lead to cell death. Inhibition of gene required
for autophagy prevents CR-induced lifespan extension [164]. This is associated with the
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Chung et al. Page 10
negative regulation of SIRT1 on the mammalian target of rapamycin (mTOR) [165], an
evolutionarily-conserved protein kinase for modulating autophagy. Resveratrol reduces the
activity of mTOR in a SIRT1 dependent manner [165]. SIRT1 can interact and deacetylate
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pro-autophagic Atg5, Atg7, and Atg8 [166]. Furthermore, SIRT1-deficient mice have
accumulation of damaged organelles and disruption of homeostasis which resembles to Atg5
knockout mice [166]. NAMPT is also shown to regulate cell survival through autophagy in
cardiomyocytes, which is associated with the alteration of NAD+ [167]. These results suggest
that SIRT1 plays an important role in regulating autophagy. Interestingly, inhibition of AMPK
by adenine 9-beta-d-arabinofuranoside or dominant negative AMPK significantly reduced
autophagy in cardiac myocytes [168,169]. Both SIRT1 and AMPK regulate each other [170],
therefore, the differential roles of these molecules in autophagy is an interesting area of research
particularly in response to oxidative stress. SIRT1 is shown to deacetylate the major AMPK
kinase LKB1, thereby increasing its activity and ability to activate AMPK [171]. Thus, the
SIRT1-LKB1-AMPK pathway may be involved in regulating autophagy. In addition to activate
SIRT1, resveratrol is also shown to inhibit p70 S6 kinase thereby suppressing autophagy
[172]. Other polyphenols, such as quercetin can also inhibit LPS-induced type-II microtubule-
associated protein 1A/1B-light chain 3 production and aggregation [173]. It seems that multiple
target molecules are involved in the regulation of polyphenols effects on autophagy.
Investigations of these molecular pathways would identify the molecular target(s) in regulation
of autophagy in chronic inflammatory diseases, such as COPD and diabetes, where autophagy
is dysregulated [174–177].
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In skeletal muscle function
Skeletal muscle dysfunction including function and structural alteration is an important feature
in a variety of chronic inflammatory diseases, such as diabetes and COPD [178–180].
PGC-1α has been shown to regulate the expression of genes involved in fatty acid oxidation
to increase lipid utilization thereby allowing skeletal muscle cells to survive under conditions
of nutrient restriction [181]. It is interesting to note that PGC-1α mRNA is reduced while
PGC-1α is acetylated in skeletal muscles from mice lacking SIRT1 [181,182], suggesting that
SIRT1 regulates PGC-1α by transcriptional and post-translational mechanisms. Treatment with
nicotinamide, an inhibitor of SIRT1, decreased the expression of PGC-1α-target genes for
mitochondrial and fatty acid utilization in primary skeletal muscle cells [181]. Therefore,
regulation of SIRT1/PGC-1α pathway using SIRT1 activators would modulate or induce
mitochondrial antioxidant genes thereby restoring skeletal muscle function. It is likely that
SIRT1 activators including resveratrol increase AMPK thereby induce PGC1-α and restore
mitochondrial function or increase mitochondrial biogenesis in skeletal muscle [183,184].
Dietary polyphenols, such as resveratrol, quercetin, and catechin, in green tea are beneficial in
improving exercise endurance by regulating lipid metabolism [185]. A variety of polyphenols
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including resveratrol activate SIRT1 and PGC-1α leading to reprogramming of muscle gene
expression and improvement of mitochondrial function thereby protecting against metabolic
stresses [87]. Further study suggests that activation and deacetylation of PGC-1α by resveratrol
is mediated via enhanced SIRT1 activity [87]. Recently, a role of quercetin in exercise
performance and skeletal muscle function via SIRT1 has also been reported [186]. Skeletal
muscle atrophy is one of the key characteristics in cancer cachexia, which has a negative impact
on prognosis, leading to asthenia, immobility and early death. Treatment with polyphenols (i.e.
resveratrol, quercetin and curcumin) significantly attenuated total protein degradation in mouse
myotubes in vitro, and administration of resveratrol attenuated weight loss and protein
degradation in skeletal muscle of mice bearing the MAC16 tumor [187]. Hence, the
development of specific SIRT1 activators with low toxicity and high bioavailability will pave
an avenue to intervene the progression of chronic inflammatory and metabolic diseases by
ameliorating skeletal muscle dysfunction.
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Chung et al. Page 11
In adipogenesis
Adipocytes are highly specialized cells that play a major role in adipogenesis. Excess adipocyte
number is a hallmark of obesity and major risk factor for development of type 2 diabetes,
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cardiovascular diseases, and hypertension. SIRT1 is identified as a regulator of biological
process including adipogenesis and adipolysis [188,189]. SIRT1 represses PPAR-γ, an adipose
specific nuclear hormone receptor by interacting with its cofactors, nuclear receptor co-
repressor and silencing mediator of retinoid and thyroid hormone receptors (SMRT), thereby
reducing adipogenesis and promoting lipolysis [190]. It is interesting to note that SIRT1
activates FOXO1 and CCAAT/enhancer-binding protein α interaction leading to increased
adiponectin gene transcription, which is an essential factor for regulation of adipogenesis
[189]. Moreover, treatment with resveratrol significantly up-regulates the mRNA and protein
levels of adiponectin, which is associated with increased levels of FOXO1 in adipose tissue
[191]. Other polyphenols, such as quercetin and catechins, also have anti-adipogenesis activity,
which is related with increased phosphorylation of AMPK [192–194]. Resveratrol treatment
also increased the SIRT1 expression, thus in turn, resulted in decreased lipid accumulation by
repressing PPAR-γ [190]. Furthermore, SIRT1 positively regulates liver X receptor via
deacetylation at lysine K432 and thus may play an important role in lipid homeostasis [195].
Thus, due to its biological and cellular regulatory mechanisms, SIRT1 merits particular
attention for pharmacological intervention for obesity and age-related disease. Recently,
activation of SIRT1 by resveratrol was shown to regulate sterol regulatory element binding
protein 1 (SREBP1), which is involved in modulation of lipogenic genes, such as fatty acid
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synthase, suggesting that SIRT1 plays an important role in attenuation of fat deposition by
inhibiting SREBP1 expression [196].
In endothelial function and cardioprotection
Impairment of endothelial function critically contributes to the pathogenesis of several diseases
including diabetes, arteriosclerosis, cardiovascular and pulmonary diseases. SIRT1 is highly
expressed in vasculature, which plays a critical role in regulating endothelial cell-mediated
vascular homeostasis and remodeling (Figure 4) [197]. However, the level/activity of SIRT1
is significantly decreased associated with increased acetylation of eNOS in endothelial cells
in response to oxidant/aldehyde treatments [54]. Endothelial specific over-expression of SIRT1
significantly blunted high fat-induced atherogenesis in apoE−/− mice via improving endothelial
cell survival and function [198]. This may be due to deacetylation of the calmodulin-binding
domain of eNOS (on lysine residues at K496 and K506) leading to enhanced nitric oxide
production [199]. On the other hand, inhibition of SIRT1 down-regulates eNOS level leading
to premature senescence-like phenotype in endothelial cells [157,200]. Moreover, SIRT1
activation attenuates oxidative stress-induced apoptosis and NF-κB gene expression and
thereby improves endothelial dysfunction [201,202].
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Moderate overexpression (∼2.5 folds) of SIRT1 protects the heart from oxidative stress through
FOXO-dependent mechanism [1]. PARP activation, which can lead to cardiomyocyte cell
death through a p53-dependent mechanism, is also modulated by SIRT1 activity [203,204].
Resveratrol showed considerable protection against cardiac dysfunction [205–207], which
confirms the beneficial role of polyphenols in cardioprotection. It is likely that polyphenols
may mimic the effect of preconditioning of heart by activation of SIRT1 to protect against
ischemia-reperfusion in heart.
Activation of SIRT1 by resveratrol regulates endothelial vasoprotective phenotype via up-
regulation of Krüppel-like factor 2 in human vascular endothelial cells [208]. Recent studies
also showed that resveratrol therapy ameliorates endothelial dysfunction by regulating vascular
endothelial growth factor, eNOS, caveolin-1, and heme oxygenase (HO)-1 leading to
neovascularization of the hypercholesterolemic myocardium and confers protection against
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Chung et al. Page 12
myocardial injury caused by ischemia-reperfusion [206,209]. It is also known that resveratrol
protects ischemia-reperfusion injury in mice via activation of SIRT1 in myocytes and
endothelium. In addition to resveratrol, quercetin and catechins also have shown to protect
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against endothelial dysfunction in vitro and in vivo [210–213]. Therefore, SIRT1 activation
through nutraceutical polyphenols may be beneficial in intervention treatment of diabetes,
arteriosclerosis, cardiovascular and pulmonary diseases where endothelial dysfunction occurs.
In circadian rhythm
The circadian clock controls intrinsic daily rhythms of physiology and behavior through
negative feedback of transcriptional-translational loops [214]. The genes encoding these
proteins are regulated by the heterodimers of transcription activator core CLOCK and BMAL1
via the binding to E-box elements in their promoters. This regulatory pathway is modulated
by posttranslational modifications, such as acetylation and phosphorylation, that affect the
activity and stability of circadian core proteins [215,216]. CLOCK has intrinsic HAT activity
[217], and it can acetylate histone H3, H4, BMAL1, and Per2, leading to transcriptional
inhibition and specific gene expression [214]. SIRT1 has been reported to counteract the HAT
activity of CLOCK [218,219]. In light of tight coupling between circadian rhythms and
metabolic regulation [220], the NAD+ substrate dependency of SIRT1 suggests that it might
constitute a functional link between metabolic activity and circadian proteins [216]. Recent
reports have shown that NAD+-dependent SIRT1 deacetylates histone H3, H4, BMAL1, Per,
and Cry and thereby regulates the transcription of circadian proteins and hence circadian cycle
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[215,219,221,222]. It is also known that inflammation and circadian rhythm disorder are
intimately associated with fatigue and diminished locomotor activity [223]. The role of
polyphenols in regulating these circadian proteins is still not clear. However, the possibility of
regulation of circadian rhythm by polyphenols via increasing SIRT1 activity is fascinatingly
therapeutic modes against various metabolic and chronic inflammatory diseases.
CONCLUSIONS AND FUTURE DIRECTIONS
The yeast Sir2 or mammalian ortholog SIRT1 has been identified as key regulator of lifespan
in several model organisms. Activation of SIRT1 by polyphenols have beneficial effects on
regulation of CR, oxidative stress, inflammation, adipogenesis, cellular senescence, autophagy,
apoptosis, circadian rhythm, autoimmunity, skeletal muscle function, metabolism,
mitochondria biogenesis and endothelial dysfunction. However, the molecular mechanism of
these SIRT1-mediated processes is not well understood. Remarkably, the expression level and
activity of SIRT1 are reduced in several chronic diseases, including diabetes, chronic
inflammatory lung diseases, neurodegenerative diseases and cardiovascular diseases.
Activation of SIRT1 results in the multiple beneficial health outcomes, such as improvement
in insulin sensitivity, decreased adiposity, increased mitochondrial functions, decreased
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glucose levels, and enhanced physiological functions. Many of these improvements are a direct
consequence of enhanced SIRT1 deacetylase activity suggesting that SIRT1 would be a
pharmacologically therapeutic target in various metabolic, proliferative, and inflammatory
diseases. Dietary polyphenols (e.g. resveratrol, quercetin, and catechins) have been shown to
increase SIRT1 level/activity in several systems along with their other well-known properties,
such as activation of Nrf2 (antioxidant response) and inhibition of NF-κB (anti-inflammatory
response). However, most polyphenols are poorly absorbed, rapidly metabolized and oxidized
and undergo sulfation and glucuronidation and also lead to formation of their own oxidation
products. The biochemical mode of action of dietary polyphenols on activation of SIRT1 is an
important area for further research. Future studies are required to understand on the
mechanisms of the in vivo effects of polyphenols are required to understand the SIRT1-
mediated improvement of various abnormal cellular and biological functions. Additional
aspects about bioactivity, absorption, and stability of dietary polyphenols with respect to
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Chung et al. Page 13
modulation of SIRT1 activity are also important areas of further research. Overall, regulation
of SIRT1 activity by dietary polyphenols is a promising therapeutic strategy against many
chronic inflammatory diseases including the diseases which are associated with inflammaging.
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Acknowledgments
This study was supported by the NIH 1R01HL085613, 1R01HL097751, 1R01HL092842 and NIEHS Environmental
Health Science Center grant P30-ES01247.
ABBREVIATIONS
AIF apoptosis-inducing factor
AMPK AMP-activated kinase
AP activator protein
BIM Bcl-2 interacting mediators of cell death
BRCA1 breast cancer associated gene 1
COPD chronic obstructive pulmonary disease
COX-2 cyclooxygenase-2
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CR calorie restriction
CS cigarette smoke
CSE cigarette smoke extract
EGC epicatechin gallate
EGCG epigallocatechin gallate
eNOS endothelial nitric oxide synthase
FOXO forkhead box class O
FOXP forkhead box class P
HAT histone acetyltransferase
HDAC histone deacetylase
iNOS inducible nitric oxide synthase
mTOR mammalian target of rapamycin
MMPs metalloproteinases
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MnSOD manganese superoxide dismutase
NAD nicotinamide adenine dinucleotide
NAM nicotinamide
NAMPT nicotinamide phosphoribosyltransferase
NF-κB nuclear factor kappa B
NMN nicotinamide mononucleotide
NMNAT nicotinamide mononucleotide adenylyltransferase
Nrf1 NF-E2-related factor-1
PARP poly(ADP-ribose) polymerase
PGC peroxisome proliferator-activated receptor γ coactivator
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Chung et al. Page 14
PPAR peroxisome proliferator activated receptor
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ROS reactive oxygen species
SIRT1 Sirtuin1
SMRT silencing mediator of retinoid and thyroid hormone receptors
SREBP1 sterol regulatory element binding protein 1
UCP2 uncoupling protein 2
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Figure 1. A schematic diagram for the role of SIRT1 in cell functions
SIRT1 regulates a variety of cellular processes via deacetylating transcription factors and
proteins thereby controlling the progression of chronic inflammatory and metabolic diseases
as well as cancer.
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Figure 2. Role of SIRT1 in inflammation
SIRT1 suppresses NF-κB transcription factor by deacetylation of RelA/p65 subunit.
Acetylation of NF-κB increases the transcription of proinflammatory mediators. Polyphenols,
such as resveratrol and quercetin, can increase the activity of SIRT1 leading to repression of
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inflammation.
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Figure 3. Role of FOXO and SIRT1 in cell functions
FOXO transcription factor is shown to regulate cellular signaling involved in DNA repair, cell
cycle, oxidative stress, and apoptosis. Acetylation of FOXO is associated with inflammatory
cell activation and cellular apoptosis. Under resting conditions, inflammation-related genes are
controlled by SIRT1 deacetylase. However, when NF-κB and FOXO are acetylated by CBP/
p300, transcription of proinflammatory and apoptotic genes are initiated.
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Figure 4. Oxidative stress-induced alteration in cellular survival and angiogenic signaling pathways
Oxidative stress down-regulates SIRT1 thereby modulating the endothelial cell survival and
angiogenic signaling by acetylating eNOS, p53, and PARP-1. SIRT1 and PARP utilize
NAD+ as a common substrate. Oxidants activate PARP-1 and deplete intracellular NAD+ pool
associated with activation of various cellular pathways leading to apoptosis and stress response.
Polyphenols, such as resveratrol and quercetin, attenuate oxidative stress-mediated
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modification of SIRT1 either by increasing the activity of SIRT1 or reversing the
posttranslational modifications of SIRT1. Activation of SIRT1 leads to angiogenesis and the
inhibition of inflammatory/apoptotic signaling.
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Table 1
Mammalian SIRTs family: cellular functions and polyphenol effects
Sirtuin Intracellular Substrate Function Polyphenol Ref.
Location effect
Chung et al.
SIRT1 Nucleus and NF-κB, p53, Cell survival, Increase by [12–14,
cytoplasm FOXO differentiation, resveratrol and 16,39,
inflammation, and quercetin 224]
metabolism
SIRT2 Cytoplasm α-tublin, Cell cycle Activation by [225]
Histone H4 resveratrol
SIRT3 Nucleus and Acetyl-CoA Metabolism Increase by [226]
mitochondria synthetase kaempferol
SIRT4 Mitochondria ADP ribosyl Metabolism Not known [227]
transferase
SIRT5 Mitochondria Mitochondrial Mitochondrial Not known [228]
protein function
SIRT6 Nucleus ADP-ribosyl DNA repair Not known [229]
transferase
and Histone
H3
SIRT7 Nucleus RNA rRNA transcription Increase by [230]
polymerase I resveratrol
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