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• Renaud, S., De Lorgeril, M., 1992. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339, 1523-1526.
  In most countries, high intake of saturated fat is positively related to high mortality from coronary heart disease (CHD). However, the situation in France is paradoxical in that there is high intake of saturated fat but low mortality from CHD. This paradox may be attributable in part to high wine consumption. Epidemiological studies indicate that consumption of alcohol at the level of intake in France (20-30 g per day) can reduce risk of CHD by at least 40%. Alcohol is believed to protect from CHD by preventing atherosclerosis through the action of high-density-lipoprotein cholesterol, but serum concentrations of this factor are no higher in France than in other countries. Re-examination of previous results suggests that, in the main, moderate alcohol intake does not prevent CHD through an effect on atherosclerosis, but rather through a haemostatic mechanism. Data from Caerphilly, Wales, show that platelet aggregation, which is related to CHD, is inhibited significantly by alcohol at levels of intake associated with reduced risk of CHD. Inhibition of platelet reactivity by wine (alcohol) may be one explanation for protection from CHD in France, since pilot studies have shown that platelet reactivity is lower in France than in Scotland.
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• Renaud, S., Gueguen, R., 1998. The French paradox and wine drinking. Novartis Foundation Symposium 216, 208-217.
  Despite a high level of risk factors such as cholesterol, diabetes, hypertension and a high intake of saturated fat, French males display the lowest mortality rate from ischaemic heart disease and cardiovascular diseases in Western industrialized nations (36% lower than the USA and 39% lower than the UK). By contrast, mortality from all causes is only 8% lower than in the USA and 6% than in the UK, owing to a high level of cancer and violent deaths. In a recent study of 34,000 middle-aged men from Eastern France with a follow-up of 12 years we have observed that for 48 g of alcohol (mostly wine) per day as the mean intake, mortality from cardiovascular diseases was lower by 30%, all-cause mortality was reduced by 20%, but mortality by cancer and violent death was increased compared with abstainers. Thus the so-called 'French Paradox' (a low mortality rate specifically from cardiovascular diseases) may be due mainly to the regular consumption of wine.
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• Renaud, S., Gueguen, R., Schenker, J., d'Houtaud, A., 1998. Alcohol and mortality in middle-aged men from eastern France. Epidemiology 9, 184-188.
  To evaluate prospectively the effect on mortality of wine drinking in Eastern France, we conducted an analysis on 34,014 consecutive middle-aged men coming for a comprehensive health appraisal between 1978 and 1983. We evaluated education, physical activity, smoking, and drinking habits by a questionnaire. Electrocardiogram, blood pressure, serum total cholesterol, and gamma-glutamyltransferase level were routinely measured. Seventy-seven per cent of the subjects drank wine; there was little difference between social classes in this proportion. We evaluated mortality over 10-15 years of follow-up. We estimated the relative risk (RR) of death by Cox proportional hazard models using nondrinkers as the reference and adjusting for six covariables. For an intake of 22-32 and 33-54 gm of alcohol per day, the RR of all-cause death was 0.70 [95% confidence interval (CI) = 0.59-0.82] and 0.76 (95% CI = 0.66-0.87), respectively. The lower mortality resulted from fewer deaths from cardiovascular disease and cancer. Above 128 gm per day of alcohol consumption, the RR was 1.37 (95% CI = 1.16-1.61). A moderate intake of wine (2-5 glasses per day) was associated with a 24-31% reduction in all-cause mortality, a proportion that was similar for smokers, ex-smokers, and nonsmokers.
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• Kopp, P., 1998. Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? Eur. J. Endocrinol. 138, 619-620.
        Certain populations, e.g. the French and the Greek, suffer little heart disease despite a diet which is relatively high in fat. It has been proposed that regular consumption of red wine in moderate amounts may explain this phenomenon, which has been dubbed the `French paradox'. Resveratrol, a compound found in grapes and wine in significant amounts, was implicated to play a role in this beneficial action of red wine because of its ability to act as an antioxidant and an inhibitor of platelet-aggregation. In addition, resveratrol has been reported to have anticarcinogenic effects in mouse mammary cultures.
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• Constant, J., 1997. Alcohol, ischemic heart disease, and the French paradox. Coronary Artery Disease 8, 645-649.
        Studies comparing alcohol intake and ischemic heart disease have shown either an inverse relation or a U-shaped curve in which the equivalent of two drinks per day of any kind of alcohol is associated with a decreased incidence of coronary disease compared with no drinks, while higher doses result in an increased risk of infarction and stroke. The cardioprotective effects of most alcoholic beverages are probably due to an elevation of high-density lipoprotein and the ability of alcohol to prevent platelet aggregation and increase fibrinolysis; however, there is an increased favorable effect from red wine. The unique cardioprotective properties of red wine reside in the action of flavonoids which are minimal in white wine (with the exception of champagne). The best researched flavonoids are resveratrol and quercetin, which confer antioxidant properties more potent than alpha-tocopherol. Grape juice has about half the amount of flavonoids by volume as red wine.
  Zurück zu Resveratrol Übersicht oder zu Sirtuin Aktivatoren

• Soleas, G. J., Diamandis, E. P., Goldberg, D. M., 1997. Resveratrol: a molecule whose time has come? And gone? Clinical Biochemistry 30, 91-113.
        Resveratrol (3,5,4'-trihydroxystilbene) is the parent compound of a family of molecules, including glucosides and polymers, existing in cis and trans configurations in a narrow range of spermatophytes of which vines, peanuts and pines are the prime representatives. Its synthesis from p-coumaroyl CoA and malonyl CoA is induced by stress, injury, infection or UV- irradiation, and it is classified as a phytoalexin anti-fungicide conferring disease resistance in the plant kingdom.
        In vitro, ex vivo and animal experiments have shown that it possesses many biological attributes that favour protection against atherosclerosis, including antioxidant activity, modulation of hepatic apolipoprotein and lipid synthesis, inhibition of platelet aggregation as well as the production of pro-atherogenic eicosanoids by human platelets and neutrophils. Red wine represents its main source in the human diet, and it has been proposed as a major constituent of the polyphenol fraction to which the health benefits of red wine consumption have been attributed.
        The past several years have witnessed intense research devoted to its measurement in wine and the factors likely to promote its enrichment in this beverage. Up to the present, conclusive evidence for its absorption by human subjects in biologically significant amounts is lacking, and it is questionable (but not yet excluded) that its powerful and beneficial in vitro activities are reproduced as a consequence of sustained moderate red wine consumption.
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• Soleas, G.J., Diamandis, E.P. and Goldberg, D.M., 1997. Wine as a biological fluid: history, production, and role in disease prevention. J. Clin. Lab. Analysis 11, 287-313.
        Wine has been part of human culture for 6,000 years, serving dietary and socio-religious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high-density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl-CoA derivatives. Polymeric aggregation gives rise, in turn to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low-density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo-oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signalling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans.  
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• Rimm, E.B., Klatsky, A., Grobbee, D. and Stampfer, M.J., 1996. Review of moderate alcohol consumption and reduced risk of coronary heart disease - is the effect due to beer, wine, or spirits. British Medical Journal 312, 731-736.
        Objectives: To review the effect of specific types of alcoholic drink on coronary risk. Design-Systematic review of ecological, case-control, and cohort studies in which specific associations were available for consumption of beer, wine, and spirits and risk of coronary heart disease. Subjects-12 ecological, three case-control, and 10 separate prospective cohort studies. Main outcome measures-Alcohol consumption and relative risk of morbidity and mortality from coronary heart disease.
        Results: Most ecological studies suggested that wine was more effective in reducing risk of mortality from heart disease than beer or spirits. Taken together, the three case-control studies did not suggest that one type of drink was more cardioprotective than the others. Of the 10 prospective cohort studies, four found a significant inverse association between risk of heart disease and moderate wine drinking, four found such an association for beer, and four for spirits.
        Conclusions: Results from observational studies, where alcohol consumption can be linked directly to an individual's risk of coronary heart disease, provide strong evidence that all alcoholic drinks are linked with lower risk. Thus, a substantial portion of the benefit is from alcohol rather than other components of each type of drink.  
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• Vu, C. B., Bemis, J. E., Disch, J. S., Ng, P. Y., Nunes, J. J., Milne, J. C., Carney, D. P., Lynch, A. V., Smith, J. J., Lavu, S., Lambert, P. D., Gagne, D. J., Jirousek, M. R., Schenk, S., Olefsky, J. M., Perni, R. B. , 2009. Discovery of imidazo[1,2-b]thiazole derivatives as novel SIRT1 activators. Journal of Medicinal Chemistry 52, 1275-1283
  A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.
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• Bemis, J. E., Vu, C. B., Xie, R., Nunes, J. J., Ng, P. Y., Disch, J. S., Milne, J. C., Carney, D. P., Lynch, A. V., Jin, L., Smith, J. J., Lavu, S., Iffland, A., Jirousek, M. R., Perni, R. B., 2009. Discovery of oxazolo[4,5-b]pyridines and related heterocyclic analogs as novel SIRT1 activators. Bioorganic and Medicinal Chemistry Letters 19, 2350-2353.
  SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.
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• Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., Pistell, P. J., Poosala, S., Becker, K. G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K. W., Spencer, R. G., Lakatta, E. G., Le Couteur, D., Shaw, R. J., Navas, P., Puigserver, P., Ingram, D. K., De Cabo, R., Sinclair, D. A., 2006. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-342.
  Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-coactivator 1 alpha (PGC-1 alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
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Anmerkungen

• David Sinclair hat, laut "Nature", "finanzielle Interessen" an den Ergebnissen dieser Resveratrol-Studie. Er hat gemeinsam mit Kollegen die Firma Sirtris Pharmaceuticals gegründet, die solche wissenschaftlichen Erkenntnisse vermarkten soll.
  - Note: The link above is no longer active, you better use this one: http://www.sirtrispharma.com/about.html. Sirtris was bought in June 2008 for 720 Million Dollars by GlaxoSmithKline. Leonard Guarente, Thomas Salzmann, and David Sinclair are co-chairing the Sirtris Scientific Advisory Board.

• Angewandte Dosis: Der Text stellt fest: 'we added resveratrol at two concentrations that provided an average of 5.26 +/- 0.1  and 22.46 +/- 0.4 mg per kg per day, which are feasible daily doses for humans'.  Nur die Daten mit der höheren Menge werden in dieser Publikation besprochen. Wenn sich dieses "per kg" tatsächlich auf Körpergewicht bezieht, würde dies bei einem 100 kg schweren Menschen bedeuten: 2246 mg (2.246 Gramm) reines Resveratrol pro Tag. 
  Und werfen Sie einen Blick in die Datei in 'Supplements': ' For the PGC-1a experiments, mice at a similar age were fed the HC diet or HC plus resveratrol at a concentration that delivered ~ 186 mg/kg/day for six weeks.'  Das wären 18.6  Gramm pro Tag für eine Person von 100 kg: Hat etwa irgend jemand Bedenken?

• Aber Vorsicht: Es ist nicht richtig, 1 kg Maus mit 1 kg Mensch gleichzusetzen, wie ich durch die Email eines interessierten Lesers lernte (vielen Dank!).  Offensichtlich wird bereits seit dem 19. Jahrhundert kritisch diskutiert, wie man Ergebnisse mit Versuchstieren mit einiger Zuversicht auf den Menschen übertragen kann. Die 'U.S. Food and Drug Administration' hat im Internet einen Entwurf für die Regelungen:
  'Guidance for Industry and Reviewers: Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers'  (http://www.fda.gov/cber/gdlns/dose.htm) -> schade, dieser Link existiert  nicht mehr (März 2010), und ich konnte keinen Ersatz finden.
  (Richtlinien für Industrie und Gutachter: 'Abschätzung einer sicheren Anfangsdosis in klinischen Versuchen mit erwachsenen, gesunden Freiwilligen'):
  Aus dem Entwurf kann man ersehen, dass dies nicht einfach ist. Für den Laien scheint es aber einige prinzipiell interessante Punkte zu geben:
  a) Für die Hochrechnung von Maus (oder anderen Versuchstieren) auf Mensch wird aus empirisch und  theoretisch gut belegten Gründen nicht das Körpergewicht genommen, sondern die Oberfläche.  Für die Übertragung von Tier auf Mensch gibt es Umrechnungsfaktoren für jedes Versuchstier. Bei der Maus ist es z.B. so, dass der Standardfaktor 0.08 verwendet wird (s. Tabelle in dem oben angegebenen Entwurf), das heisst, 22.46 mg/kg Maus x 0.08 = 1.8 mg/kg Mensch. Bei einem 100 kg schweren Menschen (und das gibt es heute viele) würde dies heissen: 180 mg/Tag. Das sieht schon weniger schlimm aus. Aber:
  b) Diese Überlegungen betreffen die Abschätzung einer sicheren Anfangsdosis. Sie sagen nichts über die Wirkung aus, also darüber, ob diese Dosis ausreichend ist, die gewünschten Wirkungen zu erreichen. Und schliesslich gibt es ja den schönen Spruch: 'Mice tell lies', d.h. man sollte vorsichtig sein bei der Übertragung von Mäuse-Ergebnissen auf den Menschen.

• Zwei die Sinclair-Publikation kommentierende, ganz interessante Artikel in Nature
  (nur merkwürdig, dass auf die Mengen kaum eingegangen wird, aber vielleicht weiss das jeder?)
  -  Check,E., 2006. A votre santé: now in pill form? Nature 444, 11
  -  Kaeberlein,M.; Rabinovitch,P.S., 2006. Medicine: Grapes versus gluttony. Nature 444, 280-281

Zum Seitenanfang

• Mai, A., Massa, S., Lavu, S., Pezzi, R., Simeoni, S., Ragno, R., Mariotti, F. R., Chiani, F., Camilloni, G., Sinclair, D. A., 2005. Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. Journal of Medicinal Chemistry 48, 7789-7795.
  In a search for potent inhibitors of class III histone/protein deacetylases (sirtuins), a series of sirtinol analogues have been synthesized and the degree of inhibition was assessed in vitro using recombinant yeast Sir2, human SIRT1, and human SIRT2 and in vivo with a yeast phenotypic assay. Two analogues, namely, 3- and 4-[(2-hydroxy-1-naphthalenylmethylene)amino]-N-(1-phenylethyl)benzamide (i.e., m- and p-sirtinol), were 2- to 10-fold more potent than sirtinol against human SIRT1 and SIRT2 enzymes. In yeast in vivo assay, these two small molecules were as potent as sirtinol. Compounds lacking the 2-hydroxy group at the naphthalene moiety or bearing several modifications at the benzene 2'-position of the aniline portion (carbethoxy, carboxy, and cyano) were 1.3-13 times less potent than sirtinol, whereas the 2'-carboxamido analogue was totally inactive. Both (R)- and (S)-sirtinol had similar inhibitory effects on the yeast and human enzymes, demonstrating no enantioselective inhibitory effect.
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• Ota, H., Tokunaga, E., Chang, K., Hikasa, M., Iijima, K., Eto, M., Kozaki, K., Akishita, M., Ouchi, Y., Kaneki, M., 2005. Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene 25, 176-185.
  The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD⁺-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.
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• Jung-Hynes, B., Nihal, M., Zhong, W., Ahmad, N., 2009. Role of sirtuin histone deacetylase SIRT1 in prostate cancer: a target for prostate cancer management via its inhibition? Journal of Biological Chemistry 284, 3823-3832.
  Prostate cancer (PCa) is a major age-related malignancy, and according to estimates from the American Cancer Society, a man's chance of developing this cancer significantly increases with increasing age, from 1 in 10,149 by age 39 to 1 in 38 by age 59 to 1 in 7 by age 70. Therefore, it is important to identify the causal connection between mechanisms of aging and PCa. Employing and approaches, in this study, we tested the hypothesis that SIRT1, which belongs to the Sir2 (silent information regulator 2) family of sirtuin class III histone deacetylases, is overexpressed in PCa, and its inhibition will have antiproliferative effects in human PCa cells. Our data demonstrated that SIRT1 was significantly overexpressed in human PCa cells (DU145, LNCaP, 22R+¢1, and PC3) compared with normal prostate epithelial cells (PrEC) at protein, mRNA, and enzymatic activity levels. SIRT1 was also found to be overexpressed in human PCa tissues compared with adjacent normal prostate tissue. Interestingly, our data demonstrated that SIRT1 inhibition via nicotinamide and sirtinol (at the activity level) as well as via short hairpin RNA-mediated RNA interference (at the genetic level) resulted in a significant inhibition in the growth and viability of human PCa cells while having no effect on normal prostate epithelial cells. Further, we found that inhibition of SIRT1 caused an increase in FOXO1 acetylation and transcriptional activation in PCa cells. Our data suggested that SIRT1, via inhibiting FOXO1 activation, could contribute to the development of PCa. We suggest that SIRT1 could serve as a target toward developing novel strategies for PCa management.
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• Kawahara, T. L., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C., Boxer, L. D., Chang, H. Y., Chua, K. F., 2009. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62-74.
  Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.
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• Smith, B. C., Denu, J. M., 2006. Sir2 protein deacetylases: evidence for chemical intermediates and functions of a conserved histidine. Biochemistry 45, 272-282.
  Sir2 NAD⁺-dependent protein deacetylases are implicated in a variety of cellular processes such as apoptosis, gene silencing, life-span regulation, and fatty acid metabolism. Despite this, there have been relatively few investigations into the detailed chemical mechanism. Sir2 proteins (sirtuins) catalyze the chemical conversion of NAD⁺ and acetylated lysine to nicotinamide, deacetylated lysine, and 2'-O-acetyl-ADP-ribose (OAADPr). In this study, Sir2-catalyzed reactions are shown to transfer an ¹⁸O label from the peptide acetyl group to the ribose 1'-position of OAADPr, providing direct evidence for the formation of a covalent alpha-1'-O-alkylamidate, whose existence is further supported by the observed methanolysis of the alpha-1'-O-alkylamidate intermediate to yield beta-1'-O-methyl-ADP-ribose in a Sir2 histidine-to-alanine mutant. This conserved histidine (His-135 in HST2) activates the ribose 2'-hydroxyl for attack on the alpha-1'-O-alkylamidate. The histidine mutant is stalled at the intermediate, allowing water and other alcohols to compete kinetically with the attacking 2'-hydroxyl. Measurement of the pH dependence of kcat and k_cat/K_m values for both wild-type and histidine-to-alanine mutant enzymes confirms roles of this residue in NAD⁺ binding and in general-base activation of the 2'-hydroxyl. Also, transfer of an ¹⁸O label from water to the carbonyl oxygen of the acetyl group in OAADPr is consistent with water addition to the proposed 1',2'-cyclic intermediate formed after 2'-hydroxyl attack on the alpha-1'-O-alkylamidate. The effect of pH and of solvent viscosity on the k_cat values suggests that final product release is rate-limiting in the wild-type enzyme. Implications of this new evidence on the mechanisms of deacetylation and possible ADP-ribosylation catalyzed by Sir2 deacetylases are discussed.
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• Tanny, J. C., Dowd, G. J., Huang, J., Hilz, H., Moazed, D., 1999. An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 99, 735-745.
  Despite its conservation in organisms from bacteria to human and its general requirement for transcriptional silencing in yeast, the function of the Sir2 protein is unknown. Here we show that Sir2 can transfer labeled phosphate from nicotinamide adenine dinucleotide to itself and histones in vitro. A modified form of Sir2, which results from its automodification activity, is specifically recognized by anti-mono-ADP-ribose antibodies, suggesting that Sir2 is an ADP-ribosyltransferase. Mutation of a phylogenetically invariant histidine residue in Sir2 abolishes both its enzymatic activity in vitro and its silencing functions in vivo. However, the mutant protein is associated with chromatin and other silencing factors in a manner similar to wild-type Sir2. These findings suggest that Sir2 contains an ADP-ribosyltransferase activity that is essential for its silencing function.
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• Ahuja, N., Schwer, B., Carobbio, S., Waltregny, D., North, B. J., Castronovo, V., Maechler, P., Verdin, E., 2007. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. Journal of Biological Chemistry 282, 33583-33592.
  Sirtuins are homologues of the yeast transcriptional repressor Sir2p and are conserved from bacteria to humans. We report that human SIRT4 is localized to the mitochondria. SIRT4 is a matrix protein and becomes cleaved at amino acid 28 after import into mitochondria. Mass spectrometry analysis of proteins that coimmunoprecipitate with SIRT4 identified insulin degrading enzyme and the ADP/ATP carrier proteins, ANT2 and ANT3. SIRT4 exhibits no histone deacetylase activity but functions as an efficient ADP-ribosyltransferase on histones and bovine serum albumin. SIRT4 is expressed in islets of Langerhans and colocalizes with insulin-expressing beta cells. Depletion of SIRT4 from insulin-producing INS-1E cells results in increased insulin secretion in response to glucose. These observations define a new role for mitochondrial SIRT4 in the regulation of insulin secretion.
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• Du, J., Jiang, H., Lin, H., 2009. Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and ³²P-NAD. Biochemistry 48, 2878-2890.
  Protein ADP-ribosyltransferases catalyze the transfer of adenosine diphosphate ribose (ADP-ribose) from nicotinamide adenine dinucleotide (NAD) onto specific target proteins. Sirtuins, a class of enzymes with NAD-dependent deacetylase activity, have been reported to possess ADP-ribosyltransferase activity, too. Here we used NAD analogues and ³²P-NAD to study the ADP-ribosyltransferase activity of several different sirtuins, including yeast Sir2, human SirT1, mouse SirT4, and mouse SirT6. The results showed that an alkyne-tagged NAD is the substrate for deacetylation reactions but cannot detect the ADP-ribosylation activity. Furthermore, comparing with a bacterial ADP-ribosyltransferase diphtheria toxin, the observed rate constant of sirtuin-dependent ADP-ribosylation is >5000-fold lower. Compared with the k_cat/K_m values of the deacetylation activity of sirtuins, the observed rate constant of sirtuin-dependent ADP-ribosylation is 500 times weaker. The weak ADP-ribosylation events can be explained by both enzymatic and nonenzymatic reaction mechanisms. Combined with recent reports on several other sirtuins, we propose that the reported ADP-ribosyltransferase activity of sirtuins is likely some inefficient side reactions of the deacetylase activity and may not be physiologically relevant.
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• Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Karow, M., Blander, G., Wolberger, C., Prolla, T. A., Weindruch, R., Alt, F. W., Guarente, L., 2006. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126, 941-954.
  Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1 - 7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic beta cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
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• Kowieski, T. M., Lee, S., Denu, J. M., 2008. Acetylation-dependent ADP-ribosylation by Trypanosoma brucei Sir2. Journal of Biological Chemistry 283, 5317-5326.
  Sirtuins are a highly conserved family of proteins implicated in diverse cellular processes such as gene silencing, aging, and metabolic regulation. Although many sirtuins catalyze a well characterized protein/histone deacetylation reaction, there are a number of reports that suggest protein ADP-ribosyltransferase activity. Here we explored the mechanisms of ADP-ribosylation using the Trypanosoma brucei Sir2 homologue TbSIR2rp1 as a model for sirtuins that reportedly display both activities. Steady-state kinetic analysis revealed a highly active histone deacetylase (k cat = 0.1 s(-1), with Km values of 42 microm and for NAD⁺ and 65 microm for acetylated substrate). A series of biochemical assays revealed that TbSIR2rp1 ADP-ribosylation of protein/histone requires an acetylated substrate. The data are consistent with two distinct ADP-ribosylation pathways that involve an acetylated substrate, NAD+ and TbSIR2rp1 as follows: 1) a noncatalytic reaction between the deacetylation product O-acetyl-ADP-ribose (or its hydrolysis product ADP-ribose) and histones, and 2) a more efficient mechanism involving interception of an ADP-ribose-acetylpeptide-enzyme intermediate by a side-chain nucleophile from bound histone. However, the sum of both ADP-ribosylation reactions was approximately 5 orders of magnitude slower than histone deacetylation under identical conditions. The biological implications of these results are discussed.
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• Liszt, G., Ford, E., Kurtev, M., Guarente, L., 2005. Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. Journal of Biological Chemistry 280, 21313-21320.
  Members of the Sir2 family of NAD-dependent protein deacetylases regulate diverse cellular processes including aging, gene silencing, and cellular differentiation. Here, we report that the distant mammalian Sir2 homolog SIRT6 is a broadly expressed, predominantly nuclear protein. Northern analysis of embryonic samples and multiple adult tissues reveals mSIRT6 mRNA peaks at day E11, persisting into adulthood in all eight tissues examined. At the protein level, mSIRT6 is readily detectable in the same eight tissue types, with the highest levels in muscle, brain and heart. Subcellular localization studies using both C- and N-terminal GFP fusion proteins show mSIRT6-GFP to be a predominantly nuclear protein. Indirect immunofluorescence using antibodies to two different mSIRT6 epitopes confirms that endogenous mSIRT6 is also largely nuclear. Consistent with previous findings, we do not observe any NAD+ dependent protein deacetylase activity in preparations of mSIRT6. However, purified recombinant mSIRT6 does catalyze the robust transfer of radiolabel from 32P-alpha- NAD to mSIRT6. Two highly conserved residues within the catalytic core of the protein are required for this reaction. This reaction is most likely mono-ADP ribosylation, as only the modified form of the protein is recognized by an antibody specific mono-ADP-ribose. Surprisingly, we observe that the catalytic mechanism of this reaction is intra-molecular, with individual molecules of mSIRT6 directing their own modification. These results provide the first characterization of a Sir2 protein from phylogenetic class IV.
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• Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L., Barrett, J. C., Chang, H. Y., Bohr, V. A., Ried, T., Gozani, O., Chua, K. F., 2008. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492-496.
  The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD⁺-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.
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• Smith, B. C., Hallows, W. C., Denu, J. M., 2008. Mechanisms and molecular probes of sirtuins. Chemistry and Biology 15, 1002-1013.
  Sirtuins are critical regulators of many cellular processes, including insulin secretion, the cell cycle, and apoptosis. Sirtuins are associated with a variety of age-associated diseases such as type II diabetes, obesity, and Alzheimer's disease. A thorough understanding of sirtuin chemical mechanisms will aid toward developing novel therapeutics that regulate metabolic disorders and combat associated diseases. In this review, we discuss the unique deacetylase mechanism of sirtuins and how this information might be employed to develop inhibitors and other molecular probes for therapeutic and basic research applications. We also cover physiological regulation of sirtuin activity and how these modes of regulation may be exploited to manipulate sirtuin activity in live cells. Development of molecular probes and drugs that specifically target sirtuins will further understanding of sirtuin biology and potentially afford new treatments of several human diseases.
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• Longo, V. D., 2009. Linking sirtuins, IGF-I signaling, and starvation. Experimental Gerontology 44, 70-74.
  Our studies in yeast have shown that the down-regulation of major signal transduction mediators increases stress resistance and causes an up to 10 fold chronological life span extension. Whereas other laboratories have proposed that sirtuins (Sir2 and its homologs), a family of conserved proteins which are NAD(+)-dependent histone deacetylases, can extend longevity in various model organisms, we propose that one sirtuin, i.e., Sir2, can also accelerate cellular aging and death. In Saccharomyces cerevisiae (yeast), the deletion of Sir2 increases DNA damage but in combination with longevity mutations in principal intracellular signal transduction mediators, or in combination with calorie restriction it causes a further increase in the chronological lifespan as well as an increase in the stress resistance and a major reduction in age-dependent genomic instability. Our recent results also provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the activation of a highly conserved neuronal pathway and in the sensitization of neurons to oxidative damage. However, the mean lifespan of the SirT1(+/-) mice is not different from that of wild type animals, and the survival of SirT1(-/-) mice was reduced under both normal and calorie restricted conditions. Here, I review the studies linking SirT1, IGF-I signaling and starvation in various model organisms with a focus on the post-mitotic cells, which indicate that sirtuins can play both protective and pro-aging roles.
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• Kaeberlein, M., 2008. The ongoing saga of sirtuins and aging. Cell Metabolism 8, 4-5.
  Sirtuins are known to slow aging in simple eukaryotes; however, viewing mammalian sirtuins as antiaging proteins may be overly simplistic.
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• Pfister, J. A., Ma, C., Morrison, B. E., D'Mello, S. R., 2008. Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS ONE 3, e4090-
  BACKGROUND: Growing evidence suggests that sirtuins, a family of seven distinct NAD-dependent enzymes, are involved in the regulation of neuronal survival. Indeed, SIRT1 has been reported to protect against neuronal death, while SIRT2 promotes neurodegeneration. The effect of SIRTs 3-7 on the regulation of neuronal survival, if any, has yet to be reported.
  METHODOLOGY AND PRINCIPAL FINDINGS: We examined the effect of expressing each of the seven SIRT proteins in healthy cerebellar granule neurons (CGNs) or in neurons induced to die by low potassium (LK) treatment. We report that SIRT1 protects neurons from LK-induced apoptosis, while SIRT2, SIRT3 and SIRT6 induce apoptosis in otherwise healthy neurons. SIRT5 is generally localized to both the nucleus and cytoplasm of CGNs and exerts a protective effect. In a subset of neurons, however, SIRT5 localizes to the mitochondria and in this case it promotes neuronal death. Interestingly, the protective effect of SIRT1 in neurons is not reduced by treatments with nicotinamide or sirtinol, two pharmacological inhibitors of SIRT1. Neuroprotection was also observed with two separate mutant forms of SIRT1, H363Y and H355A, both of which lack deacetylase activity. Furthermore, LK-induced neuronal death was not prevented by resveratrol, a pharmacological activator of SIRT1, at concentrations at which it activates SIRT1. We extended our analysis to HT-22 neuroblastoma cells which can be induced to die by homocysteic acid treatment. While the effects of most of the SIRT proteins were similar to that observed in CGNs, SIRT6 was modestly protective against homocysteic acid toxicity in HT-22 cells. SIRT5 was generally localized in the mitochondria of HT-22 cells and was apoptotic.
  CONCLUSIONS/SIGNIFICANCE: Overall, our study makes three contributions - (a) it represents the first analysis of SIRT3-7 in the regulation of neuronal survival, (b) it shows that neuroprotection by SIRT1 can be mediated by a novel, non-catalytic mechanism, and (c) that subcellular localization may be an important determinant in the effect of SIRT5 on neuronal viability.
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• Lara, E., Mai, A., Calvanese, V., Altucci, L., Lopez-Nieva, P., Martinez-Chantar, M. L., Varela-Rey, M., Rotili, D., Nebbioso, A., Ropero, S., Montoya, G., Oyarzabal, J., Velasco, S., Serrano, M., Witt, M., Villar-Garea, A., Imhof, A., Mato, J. M., Esteller, M., Fraga, M. F., 2009. Salermide, a Sirtuin inhibitor with a strong cancer-specific proapoptotic effect. Oncogene 28, 781-791.
  Sirtuin 1 (Sirt1) and Sirtuin 2 (Sirt2) belong to the family of NAD⁺ (nicotinamide adenine dinucleotide-positive)-dependent class III histone deacetylases and are involved in regulating lifespan. As cancer is a disease of ageing, targeting Sirtuins is emerging as a promising antitumour strategy. Here we present Salermide (N-{3-[(2-hydroxy-naphthalen-1-ylmethylene)-amino]-phenyl}-2-phenyl-propio namide), a reverse amide with a strong in vitro inhibitory effect on Sirt1 and Sirt2. Salermide was well tolerated by mice at concentrations up to 100 µM and prompted tumour-specific cell death in a wide range of human cancer cell lines. The antitumour activity of Salermide was primarily because of a massive induction of apoptosis. This was independent of global tubulin and K16H4 acetylation, which ruled out a putative Sirt2-mediated apoptotic pathway and suggested an in vivo mechanism of action through Sirt1. Consistently with this, RNA interference-mediated knockdown of Sirt1, but not Sirt2, induced apoptosis in cancer cells. Although p53 has been reported to be a target of Sirt1, genetic p53 knockdowns showed that the Sirt1-dependent proapoptotic effect of Salermide is p53-independent. We were finally able to ascribe the apoptotic effect of Salermide to the reactivation of proapoptotic genes epigenetically repressed exclusively in cancer cells by Sirt1. Taken together, our results underline Salermide's promise as an anticancer drug and provide evidence for the molecular mechanism through which Sirt1 is involved in human tumorigenesis.
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• Jang, M., Cai, L., Udeani, G. O., Slowing, K. V., Thomas, C. F., Beecher, C. W. W., Fong, H. H. S., Farnsworth, N. R., Kinghorn, A. D., Mehta, R. G., Moon, R. C., Pezzuto, J. M., 1997. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275, 218-220.
  Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
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• Rezzi, S., Martin, F. P., Shanmuganayagam, D., Colman, R. J., Nicholson, J. K., Weindruch, R., 2009. Metabolic shifts due to long-term caloric restriction revealed in nonhuman primates. Experimental Gerontology 44, 356-362.
  The long-term health benefits of caloric restriction (CR) are well known but the associated molecular mechanisms are poorly understood despite increasing knowledge of transcriptional and related metabolic changes. We report new metabolic insights into long-term CR in nonhuman primates revealed by the holistic inspection of plasma (1)H NMR spectroscopic metabolic and lipoprotein profiles. The results revealed attenuation of aging-dependant alterations of lipoprotein and energy metabolism by CR, noted by relative increase in HDL and reduction in VLDL levels. Metabonomic analysis also revealed animals exhibiting distinct metabolic trajectories from aging that correlated with higher insulin sensitivity. The plasma profiles of insulin-sensitive animals were marked by higher levels of gluconate and acetate suggesting a CR-modulated increase in metabolic flux through the pentose-phosphate pathway. The metabonomic findings, particularly those that parallel improved insulin sensitivity, are consistent with diminished adiposity in CR monkeys despite aging. The metabolic profile and the associated pathways are compatible with our previous findings that CR-induced gene transcriptional changes in tissue suggest the critical regulation of peroxisome proliferator-activated receptors as a key mechanism. The metabolic phenotyping provided in this study can be used to define a reference molecular profile of CR-associated health benefits and longevity in symbiotic superorganisms and man.
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• Colman, R. J., Anderson, R. M., Johnson, S. C., Kastman, E. K., Kosmatka, K. J., Beasley, T. M., Allison, D. B., Cruzen, C., Simmons, H. A., Kemnitz, J. W., Weindruch, R., 2009. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201-204.
  Caloric restriction (CR), without malnutrition, delays aging and extends life span in diverse species; however, its effect on resistance to illness and mortality in primates has not been clearly established. We report findings of a 20-year longitudinal adult-onset CR study in rhesus monkeys aimed at filling this critical gap in aging research. In a population of rhesus macaques maintained at the Wisconsin National Primate Research Center, moderate CR lowered the incidence of aging-related deaths. At the time point reported, 50% of control fed animals survived as compared with 80% of the CR animals. Furthermore, CR delayed the onset of age-associated pathologies. Specifically, CR reduced the incidence of diabetes, cancer, cardiovascular disease, and brain atrophy. These data demonstrate that CR slows aging in a primate species.
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• Smith, J. J., Kenney, R. D., Gagne, D. J., Frushour, B. P., Ladd, W., Galonek, H. L., Israelian, K., Song, J., Razvadauskaite, G., Lynch, A. V., Carney, D. P., Johnson, R. J., Lavu, S., Iffland, A., Elliott, P. J., Lambert, P. D., Elliston, K. O., Jirousek, M. R., Milne, J. C., Boss, O., 2009. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Systems Biology 3
  Background: Calorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD⁺-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation. Results: Here we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet. Conclusion: CNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.
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• Feige, J. N., Lagouge, M., Canto, C., Strehle, A., Houten, S. M., Milne, J. C., Lambert, P. D., Mataki, C., Elliott, P. J., Auwerx, J., 2008. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metabolism 8, 347-358.
  The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.
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• Van Leeuwen, I, Lain, S., 2009, in: Advances in Cancer Research. Chapter 5: Sirtuins and p53,  edition 102, page 171-195.
  The role of sirtuins in cancer has recently stimulated both considerable interest and debate. It is becoming clear that some sirtuins deacetylate important tumor suppressors thereby impinging on their activity. Human SirT1, for instance, has been shown to deacetylate p53 in biochemical assays, and growing evidence indicates that it also performs this activity in cells. Since deacetylation of p53 correlates with a decreased p53 transcriptional function, it is conceivable that sirtuin inhibition could lead to improved tumor suppression. There are, however, still many open questions regarding, for example, whether sirtuins deacetylate those lysine residues in p53 that are critical for its activity. Preliminary observations also suggest that sirtuin-mediated modulation of p53 can also take place indirectly through changes in cellular processes (e.g., nucleolar function and p300 activity) known to affect p53. It also remains unclear whether depletion in the activity of a single sirtuin suffices to stabilize and activate p53 substantially or additional changes in other factors (including other sirtuins) are required. Finally, data from SIRT1-knockout mice demonstrate that sustained depletion of SirT1 can give rise to genomic instability and that, therefore, SirT1 acts as a tumor suppressor. This observation implies that the safety of therapeutic interventions based on SirT1 inhibition need to be evaluated. Here we review and examine the available data on the regulation of p53 by sirtuins and on the changes in sirtuin function in tumor cells, and discuss whether pharmacological inhibition of sirtuin activity constitutes an adequate approach for cancer treatment.
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• Chen, D., Bruno, J., Easlon, E., Lin, S. J., Cheng, H. L., Alt, F. W., Guarente, L., 2008. Tissue-specific regulation of SIRT1 by calorie restriction. Genes and Development 22, 1753-1757.
  Calorie restriction (CR) has been reported to increase SIRT1 protein levels in mice, rats, and humans, and elevated activity of SIRT1 orthologs extends life span in yeast, worms, and flies. In this study, we challenge the paradigm that CR induces SIRT1 activity in all tissues by showing that activity of this sirtuin in the liver is, in fact, reduced by CR and activated by a high-caloric diet. We demonstrate this change both by assaying levels of SIRT1 and its small molecule regulators, NAD⁺ and NADH, as well as assessing phenotypes of a liver-specific SIRT1 knockout mouse on various diets. Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined.
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• Vaziri, H., Dessain, S. K., Ng, E. E., Imai, S. I., Frye, R. A., Pandita, T. K., Guarente, L., Weinberg, R. A., 2001. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149-159.
  DNA damage-induced acetylation of p53 protein leads to its activation and either growth arrest or apoptosis. We show here that the protein product of the gene hSIR2(SIRT1), the human homolog of the S. cerevisiae Sir2 protein known to be involved in cell aging and in the response to DNA damage, binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue, modification of which has been implicated in the activation of p53 as a transcription factor. Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53. In contrast, expression of a catalytically inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity. We propose that hSir2 is involved in the regulation of p53 function via deacetylation.
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• Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., Geny, B., Laakso, M., Puigserver, P., Auwerx, J., 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127, 1109-1122.
  Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
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• Barger, J. L., Kayo, T., Vann, J. M., Arias, E. B., Wang, J., Hacker, T. A., Wang, Y., Raederstorff, D., Morrow, J. D., Leeuwenburgh, C., Allison, D. B., Saupe, K. W., Cartee, G. D., Weindruch, R., Prolla, T. A., 2008. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3, e2264-
  Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.
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• Barger, J. L., Kayo, T., Pugh, T. D., Prolla, T. A., Weindruch, R., 2008. Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Experimental Gerontology 43, 859-866.
  An active area of aging research is focused on identifying compounds having the ability to mimic the effects of caloric restriction (CR). From 2 to 5 months of age, we fed male B6C3F(1) mice either a 40% CR diet, a control diet supplemented with a commercially available nutraceutical mixture (NCM) containing resveratrol, quercetin and inositol hexaphosphate, or a diet supplemented with an equivalent dose of chemical-grade resveratrol (RES; 1.25 mg resveratrol kg(-1) day(-1)) from 2 to 5 months of age. Cardiac gene expression profiles were generated for the three groups of treated mice and compared to age-matched control (CO) mice. All three treatments were associated with changes in several cytoskeletal maintenance pathways, suggesting that RES and NCM are able to mimic short-term CR. CR uniquely affected several immune function pathways while RES uniquely affected multiple stress response pathways. Pathway analysis revealed that NCM (but not CR or RES) regulated multiple metabolic pathways that were also changed by long-term CR, including glucose and lipid metabolism, oxidative phosphorylation and chromatin assembly. Examination of key genes and pathways affected by NCM suggests that Foxo1 is a critical upstream mediator of its actions.
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