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BBAPAP-38329; No. of pages: 9; 4C: 3

Biochimica et Biophysica Acta xxx (2009) xxx–xxx

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a p a p

1 Review

2 Biochemical effects of SIRT1 activators

3 Joseph A. Baur ⁎
4 Institute for Diabetes, Obesity, and Metabolism, and Department of Physiology, University of Pennsylvania School of Medicine, 415 Curie Blvd, CRB 728, Philadelphia, PA 19104, USA
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a r t i c l e i n f o a b s t r a c t

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7 Article history: SIRT1 is the closest mammalian homologue of enzymes that extend life in lower organisms. Its role in 23
8 Received 23 July 2009 mammals is incompletely understood, but includes modulation of at least 34 distinct targets through its 24
9 Received in revised form 6 October 2009 nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase activity. Recent experiments using small 25
10 Accepted 28 October 2009
molecule activators and genetically engineered mice have provided new insight into the role of this enzyme 26
11 Available online xxxx
in mammalian biology and helped to highlight some of the potentially relevant targets. The most widely 27
13
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14

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15 Keywords:
employed activator is resveratrol, a small polyphenol that improves insulin sensitivity and vascular function, 28
16 SIRT1 boosts endurance, inhibits tumor formation, and ameliorates the early mortality associated with obesity in 29
17 Resveratrol mice. Many of these effects are consistent with modulation of SIRT1 targets, such as PGC1α and NFκB, 30
18 SRT1720 however, resveratrol can also activate AMPK, inhibit cyclooxygenases, and influence a variety of other 31
19 Longevity enzymes. A novel activator, SRT1720, as well as various methods to manipulate NAD+ metabolism, are 32
20 Sirtuin emerging as alternative methods to increase SIRT1 activity, and in many cases recapitulate effects of 33
21 Polyphenol resveratrol. At present, further studies are needed to more directly test the role of SIRT1 in mediating 34
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beneficial effects of resveratrol, to evaluate other strategies for SIRT1 activation, and to confirm the specific 35
targets of SIRT1 that are relevant in vivo. These efforts are especially important in light of the fact that SIRT1 36
activators are entering clinical trials in humans, and “nutraceutical” formulations containing resveratrol are 37
already widely available. 38
© 2009 Published by Elsevier B.V. 39
43
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41
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44 1. Sirtuins linked to longevity. Extra copies of these genes extend lifespan in 65

worms [5] and flies [6], and the relevance of the mammalian 66
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45 SIRT1 came to the attention of the pharmaceutical industry via homologue, SIRT1, to human health has been a subject of much 67
46 an unlikely route. A screen for particularly stress-resistant strains of discussion in recent years. 68
47 budding yeast turned up a mutation in a gene called SIR4 (Silent The first enzymatic activity described for Sir2 was a weak ability to 69
48 Information Regulator 4) [1] that, as the name implies, had transfer the ADP-ribose moiety of nicotinamide adenine dinucleotide 70
49 previously been shown to mediate transcriptional silencing at (NAD+) to other proteins and itself [7]. However the major 71
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50 specific loci [2]. Further experimentation revealed that in addition physiologically relevant activity of this enzyme, and its mammalian 72
51 to being stress-resistant, yeast carrying the mutant sir4-42 allele are counterpart, SIRT1, is the NAD+-dependent deacetylation of acety- 73
52 able to produce more buds before entering a terminal senescent lated lysine residues on histone and non-histone substrates [8,9], 74
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53 state—the yeast equivalent of an extension of lifespan. The authors which proceeds through a novel mechanism involving an ADP- 75
54 then went on to show that two additional SIR genes, SIR2 and SIR3, ribosylated intermediate [10]. In fact, the description of ADP- 76
55 are required to mediate the effect, and subsequently, that increasing ribosyltransferase activity was prescient, since other sirtuins, such 77
56 the gene dosage of wild type SIR2 in the absence of other as SIRT4 in mammals, appear to function exclusively as ADP- 78
57 modifications is sufficient to extend yeast lifespan [3]. Intriguingly, ribosyltransferases [11]. The use of NAD+ as a cofactor for deacetyla- 79
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58 SIR2 is conserved all the way up to the level of mammals, where tion is unique to sirtuins and may provide a way to couple their 80
59 seven homologues have been identified (SIRT1-7), with SIRT1 being activity to its metabolic state of the cell and/or allow their activity to 81
60 the closest based on sequence homology [4]. In fact, closer be sensed by other enzymes. Whereas class I and II histone 82
61 inspection has revealed that almost all organisms, including yeast, deacetylases simply release acetate, sirtuins (also called class III 83
62 contain multiple SIR2 homologues (termed “sirtuins”), but it is SIR2 deacetylases) release nicotinamide and a novel metabolite, O-acetyl- 84
63 itself, and the closest corresponding gene in each organism that ADP-ribose (AAR), that has been speculated to act as a second 85
64 have thus far received the most attention, and been most firmly messenger (Fig. 1). Although its lack of commercial availability and 86
inherent instability have been a barrier to probing its function, 87
⁎ Tel.: +1 215 746 4585; fax: +1 215 898 5408. experiments in yeast have shown that AAR can contribute to changes 88
E-mail address: baur@mail.med.upenn.edu. in the stoichiometry and structure of the Sir2/3/4 complex, and may 89

1570-9639/$ – see front matter © 2009 Published by Elsevier B.V.

doi:10.1016/j.bbapap.2009.10.025

Please cite this article as: J.A. Baur, Biochemical effects of SIRT1 activators, Biochim. Biophys. Acta (2009), doi:10.1016/j.bbapap.2009.10.025
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90 influence heterochromatin spreading [12]. AAR is readily hydrolyzed non-histone substrates have thus far been linked to most of its 136
91 to generate ADP-ribose in mammalian cells [13], and both bind to an reported effects. 137
92 inactive Nudix hydrolase domain in transient receptor melastatin- The first non-histone substrate identified for SIRT1 was p53 138
93 related ion channel 2 (TRPM2), potentiating its ability to induce cell [26,27]. Deacetylation of human p53 at lysine 382 suppresses its 139
94 death in response to oxidative and other insults [14,15]. The normal transcriptional activity and renders cells resistant to DNA damage and 140
95 function of TRMP2 is poorly understood, however cell death is oxidative stress-induced apoptosis. Surprisingly, p53-dependent gene 141
96 accompanied by an influx of Na+ and Ca2+ ions, and it has been transcription and apoptosis were found to be roughly equivalent in 142
97 speculated that milder stimulation may play a role in Ca2+ signaling mice lacking SIRT1 [28]. Although evidence continues to accumulate 143
98 [14]. The quantitative contribution of SIRT1 to the cellular AAR pool that the interplay between SIRT1 and p53 is important in cancer 144
99 has not been assessed, although there is evidence that disruption of development, the mouse results clearly suggest that other targets of 145
100 other sirtuins is sufficient to decrease the concentration in yeast [16] SIRT1 mediate many of its effects in vivo. Consistent with this, and 146
101 and mammalian cells [14]. Moreover, some effects of AAR, such as its with the view that sirtuins might use their deacetylase activity to fine- 147
102 contribution to heterochromatin spreading in yeast [12], may be tune cellular metabolism based on NAD+ availability, a wide range of 148
103 dependent on local production. Recently, evidence has been pre- SIRT1 targets have since been identified (at least 34 distinct proteins), 149
104 sented that both AAR and ADP-ribose can reduce free radical with roles in processes ranging from differentiation to circadian 150
105 production in yeast and divert glucose into the pentose phosphate rhythms (Fig. 2). Some of the best-characterized effects of SIRT1 151
106 pathway, thereby increasing cellular NADPH levels [17]. The former include increasing stress-resistance and influencing metabolism 152

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107 occurs via inhibition of electron transport at complex I, and the latter through class O Forkhead box (FOXO) transcription factors [29], 153
108 through inhibition of glycolysis at the glyceraldehyde-3-phosphate suppressing Nuclear factor kappa B (NFκB)-dependent inflammatory 154
109 dehydrogenase step. These observations highlight the potential responses [30], and promotion of gluconeogenesis, fatty acid 155
110 importance of AAR as a product of SIRT1 activity, even though to oxidation, and mitochondrial biogenesis through peroxisome prolif- 156
111 date much more progress has been made on the characterization of its erator activated receptor gamma coactivator 1α (PGC1α) [31,32]. 157

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112 deacetylation substrates. However, nearly every target that has been identified is a potential 158
113 Histones are a major class of substrates for sirtuins. In yeast, Sir2 mediator of crucial effects in vivo, and there is no doubt that more 159
114 deacetylates histone H4 at lysine 16 to maintain heterochromatin at remain to be discovered. Resolving the relative importance, or net 160
115 the mating type loci, telomeres, and the rDNA [8]. The inherent effect, of SIRT1's deacetylation targets will be an enormous task, but 161
116 instability of tandem repeats at the rDNA leads to formation of may prove well worth the effort. 162
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extrachromosomal rDNA circles (ERCs) that are thought to limit yeast
lifespan [18]. Loss of Sir2 dramatically accelerates ERC formation and
shortens lifespan, while increasing Sir2 activity reduces ERCs and
extends yeast lifespan [3]. Interestingly, Sir2 appears to also promote
DP 2. Resveratrol

A major advance in the effort to understand the role of SIRT1 in

163

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121 longevity in an ERC-independent manner through its effects on vivo was the discovery that resveratrol (3,5,4′-trihydroxystilbene), a 165
122 telomeric heterochromatin [19]. In human cells, SIRT1 can deacetylate small polyphenol found at low doses in wine (Fig. 3), can activate the 166
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123 histones H4 at lysine 16, H3 at lysine 9, and H1 at lysine 26 [20], and enzyme in an in vitro assay and extend yeast lifespan [33]. Resveratrol 167
124 appears to act at discrete sites, to which it is directed by binding has since been reported to extend lifespan in worms and flies, and in 168
125 partners such as Peroxisome proliferator activated receptor gamma all three organisms, the effect is dependent on their respective SIRT1 169
126 (PPARγ) [21] and Clock [22]. Through these interactions, SIRT1 is able homologues [34]. These invertebrate results have become somewhat 170
127 to transcriptionally repress genes involved in adipogenesis, and to controversial, since they have been alternately disputed [35,36] and 171
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128 contribute to circadian oscillations, respectively. There is no evidence reproduced [37–41] in all three organisms (fly results were 172
129 for ERC formation in mammalian cells, although the rDNA appears to reproduced by the original lab using a different assay). More recently, 173
130 be one of the regions in which SIRT1 mediates transcriptional resveratrol has been shown to extend lifespan in a short-lived species 174
131 silencing [23]. At telomeres, a conserved role in chromatin mainte- of fish, although it has not been possible to test the involvement of 175
132 nance may have been picked up by another Sir2 homologue, SIRT6, sirtuins in that organism. Beneficial effects of resveratrol have also 176
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133 which deacetylates histone H3 lysine 9 in that region [24]. Even in the been reported in mammalian cells, and, as discussed in more detail 177
134 absence of ERCs, there is some evidence for a conserved role of SIRT1 below, in mice. A subset of these effects have been shown to depend 178
135 in maintaining global genomic stability in mammals [25], however, on SIRT1 [42–44] including the prevention of skin cancer in vivo [45]. 179
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Fig. 1. Substrates and products of the reaction catalyzed by SIRT1. Note that only the side chain is shown for lysine, since SIRT1 does not have a conventional consensus sequence
[139], although preference for specific peptides can be demonstrated [140].

Please cite this article as: J.A. Baur, Biochemical effects of SIRT1 activators, Biochim. Biophys. Acta (2009), doi:10.1016/j.bbapap.2009.10.025
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Fig. 2. Substrates, transcriptional targets, and binding partners of SIRT1. At least 34 direct deacetylation targets are known, with activities that impact almost every aspect of cellular
physiology. For simplicity, only a few of the major themes are indicated. Several transcriptional targets of SIRT1 have been indicated because they are likely to be physiologically
important and are not obvious results of the deacetylation targets and binding partners listed (although silencing of IGFBP1 is probably related to deacetylation of FOXOs). Note that

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the interaction of SIRT1 with binding partners can have varying results. SIRT1 overexpression silences PPARγ targets [21], but enhances expression of PPARα targets [64]. DBC1
directly inhibits SIRT1 activity [141,142], while HIC1 directs it to its own promoter, silencing SIRT1 expression [143]. TLE1 mediates deacetylation of NFκB [144], and Clock directs
SIRT1 to the promoters of genes involved in circadian rhythms [22,145].

180 However, resveratrol influences many mammalian enzymes, and mice lacking SIRT1 exhibit a markedly reduced protective effect when 202
181 possesses intrinsic antioxidant capacity, greatly complicating the given resveratrol as a preventive agent for skin cancer [45]. Moreover, 203
182 interpretation of its effects. Moreover, it has come to light that the in SIRT1-dependent inhibition of NFκB could contribute to a decrease in 204
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183 vitro activation of SIRT1 by resveratrol is substrate-dependent. cyclooxygenase activity through transcriptional silencing of the Cox2 205
184 Specifically, resveratrol activates the enzyme against an acetylated isoform, and a decrease in Cox2 message has been reported following 206
185 peptide containing a covalently attached fluorophore, but fails to resveratrol treatment [53]. In vitro mechanistic studies have impli- 207
186 affect deacetylation of the same peptide when the fluorophore is cated a large number of downstream pathways in resveratrol's 208
187 removed [36,46]. This result raises questions about the validity of the antiproliferative, pro-apoptotic, and other tumor-suppressive effects, 209
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188 original screen, and suggests that it will be important to test the effect and a complete discussion is beyond the scope of this review. For a 210
189 of resveratrol using full-length endogenous substrates of SIRT1. more comprehensive analysis, the reader is directed to recent reviews 211
190 Despite this controversy, many of resveratrol's effects in mice are dedicated exclusively to this topic [54,55]. 212
191 consistent with activation of SIRT1 and modulation of its targets. The
192 following section highlights some of the salient effects of resveratrol 4. Cardiovascular disease 213
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193 treatment in rodents, along with SIRT1-dependent and independent

194 pathways that may contribute to the observations. Resveratrol has at least three distinct properties that confer 214
protection against cardiovascular disease. It induces a “precondition- 215
195 3. Cancer ing” effect that limits the damage during acute ischemia/reperfusion 216
injuries [56], it improves vascular function [57], and it blocks platelet 217
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196 Resveratrol potently inhibits carcinogenesis at multiple stages in aggregation [58]. 218
197 rodent models [44,47]. Direct inhibition of cyclooxygenases [47], as The protective effect of resveratrol against ischemic injuries is 219
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198 well as the aryl hydrocarbon receptor [48,49] and cytochrome P450 incompletely understood, but can be blocked by antagonists of nitric 220
199 enzymes [50,51], likely account for much of this protection. However, oxide synthase or adenosine in isolated hearts [59], and is absent in 221
200 SIRT1-dependent mechanisms may also play a role, since SIRT1 hearts from inducible nitric oxide synthase (iNOS)-null mice [60]. The 222
201 overexpression is sufficient to blunt intestinal tumorigenesis [52], and protective effect of resveratrol against ischemic injury in brain is lost 223
in PPARα-null mice [61], and again appears to require nitric oxide, 224
although an endothelial nitric oxide synthase (eNOS)-specific 225
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inhibitor is sufficient to completely block the effect in this tissue 226

[62]. At the time when most of these observations were made, no 227
relationship was known between SIRT1 and PPARα or adenosine, and 228
nitric oxide had been shown to function upstream of SIRT1, by 229
increasing expression [63]. However, SIRT1 has since been shown to 230
positively regulate PPARα [64], and to create a potential positive 231
feedback loop by deacetylating and activating eNOS [65], raising the 232
possibility that direct activation of SIRT1 could have a role in 233
preconditioning. Moreover, inhibition of sirtuins by sirtinol or 234
nicotinamide blocks the protective effect of resveratrol against 235
Fig. 3. Structures of SIRT1 activators. Resveratrol is a naturally occurring polyphenol, ischemia in brain [66], and in cultured cardiomyocytes [67], 236
and SRT1720 was synthesized by Sirtris Pharmaceuticals. respectively. 237

Please cite this article as: J.A. Baur, Biochemical effects of SIRT1 activators, Biochim. Biophys. Acta (2009), doi:10.1016/j.bbapap.2009.10.025
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238 Resveratrol induces vasorelaxation in vitro [68] and lowers blood SIRT1 to improve insulin sensitivity. Furthermore, overexpression of 302
239 pressure in obese Zucker rats [69], as well as several experimentally- SIRT1 is sufficient to eliminate ectopic fat deposits in liver and to 303
240 induced models of hypertension [44]. In aortas from obese or aged improve insulin sensitivity in obese mice [85]. Although the 304
241 animals, resveratrol restores acetylcholine-dependent relaxation [70], mechanism is far from completely elucidated, these results provide 305
242 which is dependent on nitric oxide signaling. Resveratrol's protective significant support for the idea that resveratrol might protect against 306
243 effect appears to be mediated by suppression of age- and obesity- the metabolic syndrome and type II diabetes by activating SIRT1. 307
244 induced increases in NADPH oxidase expression. This enzyme is a
245 major contributor to the production of superoxide radicals, which 6. Energy expenditure 308
246 cause local oxidative stress and impair nitric oxide signaling by
247 reacting to form peroxynitrate. Resveratrol also modestly induces Resveratrol has a biphasic effect on energy expenditure. Without 309
248 eNOS expression in vascular tissue, which may help overcome the any significant effect on food intake, resveratrol causes a modest, but 310
249 inactivation of nitric oxide by oxidative stress. The mechanism by significant increase in the body weight of mice at low doses [70], and a 311
250 which resveratrol suppresses NADPH oxidase in vasculature has not loss of body weight and reduction of adiposity at high doses [32]. 312
251 been firmly established, however SIRT1 can inhibit production of an Notably, the elimination of ectopic fat deposits described above occurs 313
252 upstream signal, tumor necrosis factor α (tnfα), by macrophages, even at doses too low to decrease total body weight. Although the 314
253 most likely through inhibition of NFκB [71]. In addition, over- decrease in body weight at high doses of resveratrol is accompanied 315
254 expression the SIRT1 target PGC-1α in vascular endothelial cells is by an increase in oxygen consumption, cold tolerance, and endurance, 316

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255 sufficient to suppress NADPH oxidase expression [72], providing a resting body temperature is unchanged and spontaneous locomotion 317
256 second potentially SIRT1-dependent mechanism. Resveratrol may is decreased, raising interesting questions about where the excess 318
257 further stimulate PGC-1α through activation of AMP-activated energy actually goes [32]. Overexpression of SIRT1 from the β-actin 319
258 protein kinase (AMPK). AMPK is a particularly attractive hypothesis locus, which results in high expression in adipose and brain, decreases 320
259 to explain resveratrol's effects, since there is evidence that the PPARγ body weight and adiposity, similar to the effect of a high dose of 321

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260 ligand rosiglitazone reduces oxidative stress through an AMPK- resveratrol [86]. However overexpression under the endogenous 322
261 dependent mechanism involving suppression of NADPH oxidase promoter from a bacterial artificial chromosome leads to a different 323
262 [73]. AMPK activation by resveratrol can be independent of SIRT1 expression profile, and can actually decrease energy expenditure in 324
263 [74], but can also be mediated by SIRT1-dependent deacetylation of some cases, and possibly increase body weight on a leptin-deficient 325
264 the upstream kinase LKB1 [75]. Whether any or all of these background [85,87]. Therefore it is conceivable that the disparate 326
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268
mechanisms are relevant to the suppression of NADPH oxidase by
resveratrol in vivo remains to be seen.
Resveratrol is able to inhibit platelet aggregation in vitro [76] and
in vivo in hypercholesterolemic rabbits [58] and normal mice [77]. Its
DP effects of resveratrol at high and low doses reflect effects on SIRT1 in
different tissues. Indeed, there is evidence that SIRT1 is differentially
regulated across tissues by diet, suggesting that whole-body activa-
tion may be too simplistic an approach [88]. Of course, many other
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269 activity may be partially related to disruption of Mitogen-activated targets of resveratrol could contribute to its effects on body weight. 331
270 protein kinase (MAPK) signaling [78] and phosphoinositide metab- One such target is the cannabinoid receptor CB1 [89], which can 332
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271 olism [79], as well as enhanced nitric oxide signaling to guanylate regulate body weight through food intake and appetite-independent 333
272 cyclase [77]. It is also tempting to speculate that a major contribution mechanisms. 334
273 to the in vivo effects might be mediated by direct and irreversible
274 inhibition of cyclooxygenase I activity [80], resulting in decreased 7. Learning and memory 335
275 production of thromboxane A2, a potent inducer of clotting and
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276 vasoconstriction. One attractive aspect of this model, given the short Resveratrol improves cognitive function in models of neurode- 336
277 half-life of resveratrol in vivo, is that it does not require a sustained generative diseases, and following neuronal injury, but has not been 337
278 dose. Inhibition of cyclooxygenase I is the same mechanism proposed clearly demonstrated to improve cognition in normal, healthy rodents 338
279 to account for the cardioprotective effects of low-dose aspirin [81], [90,91]. Normal age-related cognitive impairment is ameliorated by 339
280 and intriguingly, resveratrol remains effective even in platelets from resveratrol in a short-lived species of fish, in parallel with an increase 340
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281 aspirin-resistant individuals [82]. in lifespan [92], but similar data have not been reported for any 341
mammalian species. In mice, resveratrol improves rotarod perfor- 342
282 5. Insulin sensitivity mance [32,83], which can have a cognitive component, but may also 343
be explained by changes in endurance. Further research in this area is 344
283 Resveratrol has consistently been found to ameliorate insulin needed to clarify the involvement of SIRT1 in neuroprotective effects 345
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284 resistance in obese animals [32,83]. This effect does not appear to be of resveratrol, and whether activation of SIRT1 could be detrimental, 346
285 directly related to overall body weight, but is accompanied by a rather than protective, in neurons under certain conditions [93,94]. 347
286 dramatic reduction of ectopic fat deposits in non-adipose tissues, Intriguingly, a SIRT1 allele has been linked to cognition in a human 348
287 particularly the liver [83]. In human studies, such ectopic fat deposits association study, although is not yet possible to know what 349
288 have been shown to precede clinical disease in subjects at risk for type consequence the allele has on SIRT1 function [95]. 350
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289 II diabetes, and to associate with reduced respiratory capacity and

290 tissue mitochondrial content [84]. In rodents, the protective effects of 8. Survival 351
291 resveratrol are accompanied by an increase in mitochondrial
292 biogenesis and respiratory capacity that offset effects of obesity Placing mice on a high fat diet (60% by energy content) at 1 year of 352
293 [32,83], and could thereby explain the restoration of insulin age results in an approximately 25% decrease in remaining lifespan, 353
294 sensitivity. PGC-1α, the “master regulator” of mitochondrial biogen- and this effect is completely blocked by resveratrol administration, 354
295 esis is activated upon deacetylation by SIRT1 [31], and this has been independent of any effect on body weight [83]. This effect appears to 355
296 shown to occur in tissues of resveratrol-treated animals, ostensibly represent amelioration of the detrimental effects of obesity, rather 356
297 accounting for the increase in mitochondrial content [32,83]. In than slowing the rate of aging, since no significant change in longevity 357
298 addition, a SIRT1-dependent decrease in the expression of protein has been detected in mice fed a standard diet plus resveratrol at 358
299 tyrosine phosphatase 1B (PTP1B) has been described in resveratrol- similar or higher doses [70]. These results are in accordance with the 359
300 treated animals [42]. Since PTP1B inactivates the insulin receptor, this well-known correlation between insulin sensitivity and longevity, 360
301 provides a second mechanism by which resveratrol might act through since resveratrol dramatically improves glucose tolerance only in the 361

Please cite this article as: J.A. Baur, Biochemical effects of SIRT1 activators, Biochim. Biophys. Acta (2009), doi:10.1016/j.bbapap.2009.10.025
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362 context of obesity. Similarly, whole-body overexpression of SIRT1 resveratrol was selected through an in vitro assay, however it is 426
363 improves glucose tolerance only in obese mice [85,87], although almost impossible to distinguish experimentally from direct activa- 427
364 overexpression in a more limited subset of tissues from the β-actin tion unless the upstream pathway is known. Ultimately, reconciling 428
365 promoter is effective even in lean animals [86]. To date, lifespans have the pharmacokinetics of resveratrol with its biological consequences 429
366 not been published for SIRT1 overexpressing or heterozygous animals. will require a better understanding of its distribution and accumu- 430
367 SIRT1 null animals are short-lived, and do not respond favorably when lation within specific tissues or compartments, and a thorough 431
368 placed on a calorie-restricted diet [94], however these mice manifest a consideration of many potentially relevant targets. These complica- 432
369 number of developmental defects and altered metabolism [96,97], tions highlight the need to verify effects that have been attributed to 433
370 that make it difficult to interpret their phenotypes with respect to SIRT1 using knockout animals and more specific methods of SIRT1 434
371 aging. Two critical questions remaining to be answered are whether activation in vivo. 435
372 SIRT1 overexpression can recapitulate the effect of resveratrol on
373 survival in obese mice, and whether it will influence longevity in lean 10. SRT1720 436
374 animals.
Besides resveratrol, a number of other naturally occurring 437
375 9. “Off-Target” effects of resveratrol polyphenols, such as quercetin, fisetin, and butein activate SIRT1 438
and extend lifespan in lower organisms [33,34]. However, all are 439
376 Perhaps the biggest liability of resveratrol as a tool to probe the structurally related and share the same caveats. Recently, a more 440

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377 function of SIRT1 is its lack of specificity. Resveratrol has other direct potent synthetic SIRT1 activator that is structurally unrelated to 441
378 targets in mammalian cells, some of which were identified prior to resveratrol was described and designated SRT1720 (Fig. 3) [110]. 442

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379 SIRT1, and many of which have their own complex and potentially Although its full spectrum of effects remains to be determined, 443
380 beneficial consequences. For example, some of the cardioprotective SRT1720 would ostensibly not share “off-target” effects of resveratrol, 444
381 and anti-inflammatory effects or resveratrol may be due to direct and is therefore a useful tool for verifying putative SIRT1-dependent 445
382 inhibition of cyclooxygenases [47], and an alternate explanation for effects in vivo. Importantly, SRT1720 does not acutely activate AMPK 446
383 many of the effects attributed to direct SIRT1 activation, such as [111]. Similar to both resveratrol treatment and SIRT1 overexpression, 447
384 increases in mitochondrial biogenesis and fatty acid oxidation, could SRT1720 improves insulin sensitivity and glucose tolerance in obese 448

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385 be provided by indirect activation of AMPK [83,98]. In fact, the mice. Moreover, a longer treatment course lowers body weight, 449
386 relationship between SIRT1 and AMPK is more complex, since each induces mitochondrial biogenesis, eliminates ectopic fat deposits, and 450
387 has been reported to influence the other [75,99], however, activation increases endurance [111]. These phenotypes are associated with 451
388 of AMPK by resveratrol is at least partially independent of SIRT1 deacetylation of the SIRT1 target PGC-1α, suggesting a direct 452
389 [74,100]. Additional direct effects of resveratrol that could have mechanism, and providing further correlation with the effects of 453
390 important consequences in vivo include inhibition of kinases resveratrol. Deacetylation of the SIRT1 substrates FOXO1 and p53 454
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391 [101,102], modulation of the estrogen receptor [103], the aryl were also observed following SRT1720 treatment, and modulation of 455
392 hydrocarbon receptor [49], and a cannabinoid receptor [89], and their activities might contribute the observed phenotypes as well. One 456
393 inhibition of quinone reductase 2 [104], to name a few. important caveat to the long-term studies with SRT1720 is that 457
394 Another important caveat is that the bioavailability of resveratrol activation of AMPK eventually occurs. However, this is most likely a 458
395 in mammals is low enough that the doses required to activate SIRT1 in downstream consequence of the metabolic changes induced by SIRT1 459
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396 vitro and in cells are only briefly or never achieved in serum in vivo activation, since unlike resveratrol, SRT1720 does not stimulate AMPK 460
397 [105]. This has even led to the suggestion that metabolites of in cells. Furthermore, a microarray based study has shown a striking 461
398 resveratrol might be the active forms, rendering most published degree of overlap in the transcriptional effects of resveratrol and 462
399 work on the molecule irrelevant [106]. Notably, concentrations SRT1720 following a relatively short treatment, suggesting that 463
400 insufficient to activate SIRT1 would also be insufficient to affect activation of SIRT1 is responsible for many of the observed changes 464
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401 most of the other targets, or stimulate AMPK, however a minority of [112]. Experiments are currently underway to test whether SRT1720 465
402 higher affinity targets might still be affected. These include the aryl recapitulates other salient effects of resveratrol, such as precondition- 466
403 hydrocarbon receptor (AhR), quinone reductase 2 (NQO2, QR2), and ing, reduction of vascular oxidative stress, prevention of platelet 467
404 the cannabinoid receptor CB1, each of which is affected by nanomolar aggregation, neuroprotection, cancer prevention, and delaying mor- 468
405 concentrations of resveratrol. The CB1 receptor in particular is tality in obese mice. 469
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406 intriguing, since it is already considered a promising drug target for

407 the treatment of obesity and related comorbidities. In fact, the 11. Isonicotinamide 470
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408 antiobesity drug rimonabant, like resveratrol, is an antagonist of this

409 receptor [107]. Although rimonabant was taken off the market due to Nicotinamide, which is produced by sirtuin enzymes, is a potent 471
410 a high incidence of psychiatric disorders, it has been shown to inhibitor of their activity. It has been estimated that physiological 472
411 increase energy expenditure, improve insulin sensitivity, suppress concentrations of nicotinamide are sufficient to reduce basal Sir2 473
412 inflammation, and prevent cancer, similar to resveratrol. One activity in yeast by 2.5-6 fold, and SIRT1 activity in mouse cells by up 474
413 discrepancy is that rimonabant also suppresses food intake, which to 20-fold [113]. The mechanism of inhibition involves re-entry of 475
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414 does not occur with resveratrol treatment, at least in mice. nicotinamide into the catalytic site of the enzyme after its release, 476
415 Suppression of AhR-dependent gene transcription by resveratrol where it can combine with a relatively stable reaction intermediate, 477
416 could account for some of its anti-carcinogenic and anti-inflammatory resulting in regeneration of the original acetylated lysine and NAD+. 478
417 effects, and it has been suggested that this mechanism could account Based on this observation, Sauve et al. [113] were able to show that 479
418 for cardioprotective effects [108]. The function of NQO2, and isonicotinamide can relieve inhibition of Sir2 activity by competing 480
419 consequences of its inhibition are less clear, but it has been suggested with nicotinamide for binding in the same pocket within the enzyme. 481
420 that blocking its activity could lead to induction of phase II antioxidant Since isonicotinamide cannot participate in the reverse reaction, the 482
421 enzymes [104], which has been observed following resveratrol intermediate is stabilized and more likely to complete the deacetyla- 483
422 treatment [109]. The abundance of cellular targets and questions tion step. Isonicotinamide is therefore expected to be an activator of 484
423 about bioavailability raise the possibility that SIRT1 activation might sirtuins under normal physiological conditions (i.e. when their 485
424 occur through an indirect mechanism, downstream of one of the activity is partly held in check by nicotinamide). Consistent with 486
425 higher affinity targets. This requires an enormous fluke, since this, effects of isonicotinamide have been correlated with those of 487

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488 resveratrol in cell culture models, although in most cases the SIRT1- be more effective than niacin [129]. However, it is resveratrol that has 550
489 dependence was not thoroughly tested [114,115]. Recently, it was thus far received the most attention as a potential strategy to activate 551
490 shown that isonicotinamide represses expression of cytosolic phos- SIRT1 therapeutically. Humans have historically been exposed to low 552
491 phoenolpyruvate carboxykinase (PEPCK) and that the effect depends doses of resveratrol primarily through consumption of red wine, and 553
492 on the presence of both SIRT1 and its substrate, hepatocyte nuclear traditional Chinese and Japanese medicines, and it is attractive to 554
493 factor 4α (HNF4α) [116]. Activation of SIRT1 with resveratrol or other speculate that the health benefits associated with these substances 555
494 polyphenols, or overexpression of the enzyme also repressed PEPCK might be at least partially attributed to their resveratrol content. 556
495 transcription, suggesting that a reduction in gluconeogenesis might Intriguingly, a recent study showed that light wine consumption is 557
496 contribute to the long-term improvements in insulin sensitivity in associated with a ∼5-year increase in life expectancy [130], however 558
497 mice treated with resveratrol or overexpressing SIRT1. The high alcohol alone has a significant protective effect (∼ 2 years in the 559
498 concentrations of isonicotinamide required for efficacy likely limit any aforementioned study), and many other wine components are 560
499 in vivo applications, although it appears to be well tolerated in mice, thought to improve health. Moreover, the resveratrol doses employed 561
500 even at 1% in the drinking water over the entire lifespan [117]. in animal studies significantly exceed those that could be obtained 562
from wine. With the more recent availability of higher doses 563
501 12. NAD+ metabolism resveratrol in “nutraceutical” formulations, claims of benefits based 564
on anecdotal evidence have become widespread. In many cases, 565
502 Another strategy for increasing sirtuin activity is by increasing the studies are poorly controlled or uncontrolled, and in almost all cases, 566

OF
503 availability of the cofactor NAD+. There is an unresolved debate in the the formulations administered contain multiple compounds or 567
504 field about whether NAD+:NADH ratio or some combination of complex extracts, making it even more difficult to assess the effect 568
505 absolute NAD+ and nicotinamide concentrations best predicts the of resveratrol per se [131]. Based on peer-reviewed literature, it seems 569
506 activity of sirtuins in vivo [118,119]. However, it is widely agreed that that resveratrol is well tolerated in humans over short periods of time, 570
507 increasing flux through the NAD+ salvage pathway, which generates but further trials are needed to establish its ultimate effects on health 571

RO
508 NAD+ from nicotinamide, is sufficient to cause activation. In yeast, and disease. The first measurements of resveratrol and its metabolites 572
509 Pnc1 catalyzes the rate-limiting step in this pathway, and its in human plasma and urine following an oral dose were reported in 573
510 overexpression is sufficient to extend lifespan in a Sir2-dependent 2001 [132], and since then, and at least 9 additional human trials have 574
511 manner [120]. In mammals, Nicotinamide phosphoribosyltransferase been conducted to assess pharmacokinetic parameters [133,134]. 575
512 (Nampt) plays an analogous role and its overexpression is sufficient to Safety and potential side effects have been investigated in two phase I 576
513
514
515
516
increase the catalytic activity of SIRT1 [121], as well as promote cell
survival in a SIRT3 and SIRT4-dependent manner [122]. In vivo, the
product of its reaction, nicotinamide mononucleotide, appears to be
limiting for SIRT1 activity in pancreatic beta cells [123], and circadian
DP clinical trials. The first employed a single dose of up to five grams, with
a 14-day follow-up [135]. The second employed doses of up to 150 mg
every 4 h for 2 days, followed by an additional 24 h of observation
[136]. Notably, the doses from both studies greatly exceed the ∼5–
577
578
579
580
517 oscillations in Nampt expression cause SIRT1 activity to fluctuate in 22 mg/kg that increased survival in obese mice when the preferred 581
518 liver and white adipose tissue [22,124]. Overexpression of Nampt in method of allometric scaling is employed [137], and the five gram 582
TE
519 the heart is sufficient to promote survival of cardiac myocytes under a dose remains well in excess even by direct extrapolation from body 583
520 number of stresses, although the involvement of sirtuins in this weight. In both studies, the effects reported were minor, and not 584
521 process is not known [125]. These results underscore the fact that clearly linked to the treatment, including symptoms such as headache, 585
522 much additional work will be required to fully elucidate the dizziness, and anomalous biochemical or hematological measure- 586
523 consequences of increasing cellular NAD+, which serves as a cofactor ments that were not consistent across treatment groups. It has also 587
EC

524 in many crucial processes. Another potential route to increased NAD+ been reported in company press releases that SRT501, a proprietary 588
525 synthesis is through the administration of nicotinamide riboside, a formulation of resveratrol developed by Sirtris Pharmaceuticals, has 589
526 precursor that is enriched in milk and may be involved in normal NAD undergone phase I trials employing up to five grams daily for 28 days 590
+
527 metabolism [126]. Much like Pnc1 overexpression, supplementing (www.sirtrispharma.com/news-press.html). This was reported to 591
528 yeast media with nicotinamide riboside is sufficient to confer Sir2- result in improved glucose tolerance, although neither these data, 592
RR

529 dependent lifespan extension, although the latter would presumably nor any other beneficial effect of a SIRT1 activator in humans, has yet 593
530 increase NAD+ without lowering nicotinamide levels. been published in a peer-reviewed journal. This may soon change, 594
531 It is important to keep in mind that resveratrol and SRT1720 are since a number of more advanced clinical trials have been announced 595
532 generally considered to target SIRT1 (albeit that resveratrol may also to test resveratrol against cancer, type II diabetes, Alzheimer's disease, 596
533 affect SIRT7 [127], and data on the specificity of SRT1720 are not and viral infections. In addition, at least one controlled study of 597
CO

534 widely available), while isonicotinamide and NAD+ availability are resveratrol has been initiated in monkeys [138], and Sirtris has 598
535 likely to affect all seven mammalian sirtuins. As has been discussed, announced its intention to proceed with phase I clinical trials of 599
536 each of these strategies to increase SIRT1 activity also comes with a another proprietary SIRT1 activator, designated SRT2104. The entry of 600
537 large number of caveats and probable off-target effects. However, by SIRT1 activators into human trials is exciting, but also highlights the 601
538 combining mechanistically distinct approaches, and incorporating need to better define the pathways that mediate their effects in vivo. 602
UN

539 data from overexpression and loss of function studies, it will be

540 possible to move forward and improve our understanding of the role 14. Summary 603
541 of SIRT1 in vivo. Based on rodent studies, there is good reason to be
542 optimistic that this could lead to the development of therapies that As the homologue of enzymes that promote longevity in lower 604
543 will benefit human health. organisms, SIRT1 provides a tantalizing drug target. The ever-growing 605
list of proteins whose activities are influenced by SIRT1-dependent 606
544 13. Human trials deacetylation supports its potential importance in mammalian 607
biology, but also add to the difficulty in understanding its function. 608
545 Nicotinamide and nicotinic acid are forms of vitamin B3 (niacin), Overexpression studies and treatment of rodents with small molecule 609
546 and their biological functions, including the ability to act as NAD+ activators have led to significant improvements in physiology, many 610
547 precursors, have been adequately reviewed elsewhere [128]. There is of which are consistent with effects on specific SIRT1 targets. 611
548 also significant interest in the potential use of nicotinamide riboside However, many caveats and uncertainties remain. Much of the 612
549 to drive NAD+ synthesis, particularly in nervous tissue, where it may strongest evidence for beneficial effects has been obtained with 613

Please cite this article as: J.A. Baur, Biochemical effects of SIRT1 activators, Biochim. Biophys. Acta (2009), doi:10.1016/j.bbapap.2009.10.025
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