s i tifiscientific eide vidence in hlthh ealth and di di · pdf fileresveratrol and health...

RESVERATROLRESVERATROL"S i tifi E id i H lth d Di ""Scientific Evidence in Health and Disease"

Dr. Raúl Francisco PastorDr. Raúl Francisco Pastor4ª Cátedra de Medicina Interna4ª Cátedra de Medicina Interna

Hospital de ClínicasHospital de ClínicasHospital de ClínicasHospital de Clínicas“José de San Martín”“José de San Martín”

Universidad de Buenos Aires Universidad de Buenos Aires ArgentinaArgentinagg

EvidenceEvidence Based MedicineBased MedicineEvidenceEvidence‐‐Based MedicineBased Medicine

U ' id t th di l lit t II H tU ' id t th di l lit t II H t•• Users' guides to the medical literature. II. How to use an Users' guides to the medical literature. II. How to use an article about therapy or prevention. A. Are the results of article about therapy or prevention. A. Are the results of the study valid?the study valid? EvidenceEvidence‐‐Based Medicine Working Group.Based Medicine Working Group.Guyatt GH, Sackett DL, Cook DJ.JAMA. 1993 Dec 1;270(21): 2598‐601D f M di i M M U i i H il• Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

•• GlobaliseGlobalise the evidence, the evidence, localiselocalise the the decisióndecisiónJohn Eisemberg (1999) AHCPR (Agency for Health Care Policy and Research)

Resveratrol Resveratrol 3,5,4’‐trans‐trihidroxiestilbeno , ,

bioactivebioactive constituentconstituent, non, non‐‐nutritionalnutritional foodfood

Molecular Weight 228 24328 [g/mol]Molecular Weight 228.24328 [g/mol]

Roots

heléboroheléboro((VeratrumVeratrum

RootsPolygonumPolygonumCuspidatumCuspidatum(

Wine Wine CisCisResveratrol Resveratrol

Wine Wine PiceidosPiceidosResveratrolResveratrol

Wine Wine Trans Trans Resveratrol Resveratrol

Grapes Grapes VitisVitisViniferaVinifera

GrapesGrapesPiceidoPiceidoResveratrolResveratrol

grandiflorumgrandiflorumO. Loes) O. Loes) (Takaoka, 1940)

(Nonomura et al.,1963)

JeandetJeandet P. P. et al 1993 et al 1993

LamuelaLamuela‐‐RaventósRaventósR. 1995R. 1995

SiemmanSiemmanet al 1992et al 1992

ViniferaViniferaResveratolResveratolLangcakeLangcakeP. et al P. et al

Waterhouse Waterhouse A. A. LamuelaLamuela‐‐RaventósRaventós R. R. 1994199419761976 19941994

Vaccinium (arándanos)Rimando et

Cava Cava AndresAndres‐‐

ResorcinolVeratrumRimando et

al. 2004.LacuevaLacuevaet al. et al. 20012001

VeratrumOl oxhidrilo

CalorieCalorie RestrictionRestriction == ResveratrolResveratrolCalorieCalorie RestrictionRestriction = = ResveratrolResveratrol• McCay, et al 1935.

The effect of retarded growth upon the length of life and upon the ultimate body size. Journal of Nutrition 10, 63–79

• Howitz, K.T. 2003. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196.

• Jang M et al 1997Cancer Chemopreventive Activity of Resveratrol, a Natural Product Derived from Grapes Science 10 January Vol 275 no 5297 pp 218 220Grapes Science 10 January Vol. 275 no. 5297 pp. 218‐220

• Renaud SC, et al 1998Alcohol and mortality in middle aged men from eastern FranceAlcohol and mortality in middle‐aged men from eastern France.Epidemiology. Mar;9(2):184‐8.In the case of middle‐aged men from eastern France, a moderate daily intake of wine (22‐32 g of alcohol) was associated with a lower risk of death due to CVDswine (22 32 g of alcohol) was associated with a lower risk of death due to CVDs (40%), cancer (22%), other causes (42%), and all causes (33%).

CalorieCalorie RestrictionRestrictionCalorieCalorie RestrictionRestriction

Resveratrol and health – N° of Papers and trials

Jang M,et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes.S i 1997 J 10 275(5297) 218 20Science 1997 Jan 10;275(5297):218‐20.

Molecular Nutrition & Food ResearchVolume 55, Issue 8, pages 1129‐1141, 20 JUN 2011 DOI: 10.1002/mnfr.201100143http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201100143/full#fig1

CalorieCalorie RestrictionRestriction == ResveratrolResveratrol

d l d f l fd l d f l f

CalorieCalorie RestrictionRestriction = = ResveratrolResveratrol

•• Increased quality and span of lifeIncreased quality and span of life•• Reduced oxidative stressReduced oxidative stressReduced oxidative stressReduced oxidative stress•• Reduced risk of cancer Reduced risk of cancer •• Reduced neurodegenerative disorders Reduced neurodegenerative disorders •• Reduced autoimmune diseaseReduced autoimmune disease•• Reduced autoimmune diseaseReduced autoimmune disease•• Reduced cardiovascular disease Reduced cardiovascular disease •• Reduced Type II diabetes mellitusReduced Type II diabetes mellitus

Resveratrol content of selected fruits Resveratrol content of selected fruits and vegetablesand vegetablesand vegetablesand vegetables

Foods ResveratrolFoods Resveratrol cup serving in mgcup serving in mg

•• 1. Blueberry 1. Blueberry 32 32 ngng/gm/gm

•• 2. Bilberries 2. Bilberries 16 16 ngng/g/g

•• 3. Cranberry raw juice 3. Cranberry raw juice 0.2 mg/L0.2 mg/L

•• 4. Mulberry 4. Mulberry 0.00210.0021––0.0053 mg/g0.0053 mg/g

•• 5. Peanuts (raw) 5. Peanuts (raw) 0.010.01––0.26 (per serving of 146 g)0.26 (per serving of 146 g)

•• 6. Peanuts (boiled) 6. Peanuts (boiled) 0.320.32––1.281.28 (per serving of 180 g)(per serving of 180 g)p g gp g g

•• 7. Peanut butter 7. Peanut butter 0.040.04––0.13 (per serving of 258 g)0.13 (per serving of 258 g)

•• 8. Red grapes 8. Red grapes 0.240.24––1.251.25 (per serving of 160 g)(per serving of 160 g)g pg p (p g g)(p g g)

•• 9. Red grape juice (Spanish) 9. Red grape juice (Spanish) 0.170.17––1.301.30 (per serving of 150 ml)(per serving of 150 ml)

•• 10 . 10 . Black chocolateBlack chocolate 44 mg/Lmg/Lg/g/

•• 11. 11. Cocoa liquorCocoa liquor 5 5 mg/Lmg/L

Resveratrol content of winesResveratrol content of wines

Wi T t lWi T t l T t lT t l t lt lWines TotalWines Total TotalTotal resveratrolresveratrolresveratrol (mg/ L)resveratrol (mg/ L) 150ml glass (mg)150ml glass (mg)

•• 1. White wine1. White wine 0.05 0.05 ––1.80 1.80 0.010.01––0.270.27•• 2. Rose wine2. Rose wine 0.43 0.43 ––3.52 3.52 0.060.06––0.530.53•• 3. Red wine (Spanish) 3. Red wine (Spanish) 1.921.92––12.59 12.59 0.290.29––1.891.89•• 4. Red 4. Red winewine (Global) (Global) 1.98 1.98 ––7.13 7.13 0.300.30––1.071.07•• 5. Pinot noir 5. Pinot noir 0.0 0.0 ––2.0 2.0 0.060.06––0.300.30•• 6. Red 6. Red winewine ((ItalianItalian) ) 0.05 0.05 0.0080.008•• 7. Merlots wine (Chilean) 7. Merlots wine (Chilean) 2.25 2.25 0.350.35( )( )

ResveratrolResveratrol Natural SourcesNatural SourcesResveratrolResveratrol Natural SourcesNatural Sources

Resveratrol content of winesResveratrol content of wines

•• It is difficult to estimate the normal human It is difficult to estimate the normal human consumption of consumption of ResveratrolResveratrol as the intake of as the intake of ppred wine (verified main source of red wine (verified main source of ResveratrolResveratrol) ) differs greatly in the population and thediffers greatly in the population and thediffers greatly in the population and the differs greatly in the population and the content of content of

ff ll•• Average ofAverage of resveratrolresveratrol in winesin wines

mean 1.9mean 1.9 ±± 1.7 mg/L1.7 mg/Lmean 1.9 mean 1.9 ±± 1.7 mg/L 1.7 mg/L

•• consumption estimated dose may be up to consumption estimated dose may be up to

4 mg/person/day4 mg/person/day

Average values in wines of the isomers of Resveratrol and Piceído

7,55 mg/L7,55 mg/L2,15 mg/L2,15 mg/L,0,48 mg/L0,48 mg/L0,67 mg/L,0,67 mg/L,

ResveratrolResveratrolBi il bili d M b liBi il bili d M b li FF IIBioavailability and Metabolism Bioavailability and Metabolism ‐‐ FaseFase II

•• Resveratrol has a high absorptionResveratrol has a high absorption•• Reaches various organs Reaches various organs

•• Is metabolized mainly toIs metabolized mainly to glucuronideglucuronide and sulfate derivativesand sulfate derivatives•• Is metabolized mainly to Is metabolized mainly to glucuronideglucuronide and sulfate derivatives. and sulfate derivatives.

•• Has a significant role in intestinal Has a significant role in intestinal microfloramicroflora metabolite production metabolite production dihidroresveratroldihidroresveratrol

•• Resveratrol reaches peak plasma concentration peaks about 30 minutes Resveratrol reaches peak plasma concentration peaks about 30 minutes after intake, with the after intake, with the glucuronideglucuronide and sulfate, whose concentration and sulfate, whose concentration varies depending on the dosevaries depending on the dosevaries depending on the dosevaries depending on the dose

•• Mainly, elimination is by urine Mainly, elimination is by urine

((Sulfate derivatives 37%Sulfate derivatives 37% GlucuronideGlucuronide derivatives 19% Traces ofderivatives 19% Traces of((Sulfate derivatives 37%. Sulfate derivatives 37%. GlucuronideGlucuronide derivatives 19% Traces of derivatives 19% Traces of resveratrolresveratrol aglyconeaglycone). Total 56%.). Total 56%.

•• A high 44% Resveratrol whose fate is unknown ?A high 44% Resveratrol whose fate is unknown ?

•• Also, some metabolites remain unidentified ?Also, some metabolites remain unidentified ?

Mean total (free and conjugated)Mean total (free and conjugated) transtrans‐‐t l i f f bj t i 25t l i f f bj t i 25resveratrol in serum of four subjects given 25 resveratrol in serum of four subjects given 25

mg ofmg of transtrans‐‐resveratrol in various matrices.resveratrol in various matrices.

Mean plasma concentrations of resveratrol (A), resveratrol-4′-O-glucuronide (B), resveratrol-3-O-glucuronide (C), and resveratrol-3-O-sulfate (D) versus time in healthy volunteers after

the last of between 21 and 28 daily doses of resveratrol at either 0.5 ...y

Brown V A et al. Cancer Res 2010;70:9003-9011

Clinical trials of resveratrolResveratrol pharmacokinetics in healthy volunteersResveratrol pharmacokinetics in healthy volunteers

following multiple dosing.

Annals of the New York Academy of SciencesVolume 1215, Issue 1, pages 161‐169, 24 JAN 2011 DOI: 10.1111/j.1749‐6632.2010.05853.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1749‐6632.2010.05853.x/full#f1

ResveratrolResveratrolBioavailability and MetabolismBioavailability and Metabolism

•• HalfHalf‐‐life in blood of life in blood of resveratrolresveratrol´́ss metabolites metabolites h h d hh h d happroximates the 9 hours, indicating that exposure to approximates the 9 hours, indicating that exposure to

these derivatives is much higher than that due to these derivatives is much higher than that due to resveratrolresveratrol aglyconeaglyconeresveratrolresveratrol aglyconeaglycone..

•• Excretion in man with time depends on the Excretion in man with time depends on the concentration ofconcentration of resveratrolresveratrol in plasmain plasmaconcentration of concentration of resveratrolresveratrol in plasma.in plasma.

•• Therefore, when ingested small amounts of Therefore, when ingested small amounts of resveratrolresveratrol it is rapidly metabolized and eliminatedit is rapidly metabolized and eliminatedresveratrolresveratrol, it is rapidly metabolized and eliminated , it is rapidly metabolized and eliminated whereas if the amount ingested is large, then can be whereas if the amount ingested is large, then can be detected in tissues and can potentially enter the cells detected in tissues and can potentially enter the cells p yp yto display their action.to display their action.

‐‐

Resveratrolmg/day ‐

‐mg/day

‐‐‐

Intravascular IntracellularIntestinal

‐ ‐ ‐

Intravascularspace

Intracellular space

Intestinalspace

Meng et al., 2004).


I i i iI i i i i ii i h hh h•• In vivo activityIn vivo activity is sometimesis sometimes greater than that greater than that describeddescribed in vitro,in vitro, suggests that some form suggests that some form conjugateconjugate generatedgenerated in vivo,in vivo, is more potent is more potent than thethan the precursor (precursor (aglyconeaglycone)) ingested. ingested. p (p ( g yg y )) gg


•• It was shown that resveratrol accumulates in It was shown that resveratrol accumulates in LDL i l h l d h iLDL i l h l d h iLDL particles, may help reduce their LDL particles, may help reduce their susceptibility to oxidation and thus stressing susceptibility to oxidation and thus stressing a key step in a key step in atherogenesisatherogenesis. .

Diverse health benefits of Resveratrol Diverse health benefits of Resveratrol including including cardioprotectioncardioprotection

Resveratrol in Resveratrol in thethe healthhealth and and diseasedisease

•• CancerCancerResveratrol has shown much promise in treatingResveratrol has shown much promise in treatingcancer in laboratory animals and in vitro human cellcancer in laboratory animals and in vitro human cellstudies yet there is still a large void in human researchstudies yet there is still a large void in human researchstudies, yet there is still a large void in human research.studies, yet there is still a large void in human research.This may soon change, as six of the clinical trials currentlyThis may soon change, as six of the clinical trials currentlylisted for resveratrol on www.clinicaltrials.gov includelisted for resveratrol on www.clinicaltrials.gov includeggcancer patients as a target population.cancer patients as a target population.

ActsActs by inhibitingby inhibiting the 3 stagesthe 3 stages of carcinogenesisof carcinogenesis1) initiation1) initiation 2) promotion2) promotion 3) progression3) progression

Smoliga JM., Baur JA., Hausenblas HA., (2011) Resveratrol and health – Acomprehensive review of human clinical trials . M l N t F d R 55 1129 1141Mol. Nutr. Food Res. 55, 1129‐1141


•• Cardiovascular effectsCardiovascular effectsOne of the key One of the key cardioprotectivecardioprotective mechanisms ofmechanisms ofresveratrol stems from its ability toresveratrol stems from its ability to upregulateupregulateresveratrol stems from its ability to resveratrol stems from its ability to upregulateupregulateendothelial nitric oxide endothelial nitric oxide synthasesynthase ((eNOSeNOS) which) whichultimately increases nitric oxide (NO) mediatedultimately increases nitric oxide (NO) mediatedultimately increases nitric oxide (NO) mediatedultimately increases nitric oxide (NO) mediatedvasodilationvasodilation and increases blood and increases blood flowflow. .

Smoliga JM., Baur JA., Hausenblas HA., (2011) Resveratrol and health – Acomprehensive review of human clinical trials . Mol. Nutr. Food Res. 55, 1129‐1141


•• Oxidative stress and Oxidative stress and inflammationinflammationAtherosclerosis diabetes mellitus chronic obstructiveAtherosclerosis diabetes mellitus chronic obstructiveAtherosclerosis, diabetes mellitus, chronic obstructiveAtherosclerosis, diabetes mellitus, chronic obstructive

pulmonary disease, and cancer are examples of pulmonary disease, and cancer are examples of di i t d ith ROSdi i t d ith ROS i d d h ii d d h idiseases associated with ROSdiseases associated with ROS‐‐induced chronic induced chronic inflammationinflammation..

Smoliga JM., Baur JA., Hausenblas HA., (2011) Resveratrol and health – A

comprehensive review of human clinical trials .

Mol. Nutr. Food Res. 55, 1129‐1141


•• Obesity and diabetesObesity and diabetesMultiple mechanisms have been proposed to accountMultiple mechanisms have been proposed to accountMultiple mechanisms have been proposed to account Multiple mechanisms have been proposed to account for the insulinfor the insulin‐‐sensitizing effects of resveratrol, sensitizing effects of resveratrol, includingincluding antiinflammatoryantiinflammatory effectseffectsincluding including antiinflammatoryantiinflammatory effects.effects.

S li JM B JA H bl HA (2011) R t l d h lth ASmoliga JM., Baur JA., Hausenblas HA., (2011) Resveratrol and health – A

comprehensive review of human clinical trials .

Mol. Nutr. Food Res. 55, 1129‐1141Mol. Nutr. Food Res. 55, 1129 1141

Anti‐diabetic effects of ResveratrolAnti‐diabetic effects of Resveratrol

Annals of the New York Academy of SciencesVolume 1215, Issue 1, pages 34‐39, 24 JAN 2011 DOI: 10.1111/j.1749‐6632.2010.05844.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1749‐6632.2010.05844.x/full#f1


•• NeuroprotectiveNeuroprotective activity activity 250 mg trans250 mg trans‐‐resveratrol to increase cerebral bloodresveratrol to increase cerebral blood250 mg trans250 mg trans‐‐resveratrol to increase cerebral blood resveratrol to increase cerebral blood flowflow compared to placebo by FMDcompared to placebo by FMD


comprehensive review of human clinical trialscomprehensive review of human clinical trials .



•• LongevityLongevity•• LongevityLongevityResveratrol’sResveratrol’s ability to combat aging at the cellular levelability to combat aging at the cellular level

may ultimately lead to breakthroughs in geriatric andmay ultimately lead to breakthroughs in geriatric and

antianti‐‐aging medicine, but the data supporting this inaging medicine, but the data supporting this inantianti aging medicine, but the data supporting this inaging medicine, but the data supporting this in

humans are scant.humans are scant.


h i i f h li i l t i lcomprehensive review of human clinical trials .


Number of healthy volunteers who experienced Number of healthy volunteers who experienced adverse events deemed interventionadverse events deemed intervention‐‐related after related after

daily ingestion of resveratrol for 29 ddaily ingestion of resveratrol for 29 d

Recommendations for the use of Recommendations for the use of R t lR t l

Which relevant (overall) mechanisms of action of Which relevant (overall) mechanisms of action of R l h b d d?R l h b d d?

ResveratrolResveratrol

•• Modulation Modulation of cell proliferation and apoptosisof cell proliferation and apoptosis•• ModulationModulation of angiogenesisof angiogenesis

Resveratrol have been documented?Resveratrol have been documented?

•• Modulation Modulation of angiogenesisof angiogenesis•• Inhibition Inhibition of metastasisof metastasis•• Modulation Modulation of of redoxredox statusstatus•• Suppression Suppression of of adipogenesisadipogenesis and stimulation of and stimulation of adipocyteadipocyte

lipolysislipolysis•• StimulationStimulation ofof osteogenesisosteogenesis•• Stimulation Stimulation of of osteogenesisosteogenesis•• Modulation Modulation of mitochondria activityof mitochondria activity•• SuppressionSuppression of inflammationof inflammationSuppression Suppression of inflammationof inflammation•• Modulation Modulation of DNA damageof DNA damage•• Modulation Modulation of of xenobioticxenobiotic metabolismmetabolism•• Modulation Modulation of glutamate metabolismof glutamate metabolism•• Estrogenic Estrogenic activity/antiactivity/anti‐‐estrogenic estrogenic activityactivity

ResveratrolResveratrol45 45 Intervention StudiesIntervention Studies in Humansin Humans

ResveratrolResveratrol andand WineWineResveratrolResveratrol and and WineWine

•• Is important to note that the resveratrol Is important to note that the resveratrol concentrations in wine vary widely, evenconcentrations in wine vary widely, evenconcentrations in wine vary widely, even concentrations in wine vary widely, even within a given variety of grape or growing within a given variety of grape or growing

iiregion.region.

•• it is unclear if small doses of resveratrol onit is unclear if small doses of resveratrol onit is unclear if small doses of resveratrol on it is unclear if small doses of resveratrol on a regular basis (i.e. years of wine a regular basis (i.e. years of wine consumption) would have the same consumption) would have the same physiological effect as the highphysiological effect as the high CmaxCmaxphysiological effect as the high physiological effect as the high CmaxCmaxobserved from supplementation.observed from supplementation.

ConclusionConclusionConclusionConclusion

WW b lib li thth idid ii ffi i tlffi i tl tt tt•• WeWe believebelieve thethe evidenceevidence isis sufficientlysufficiently strongstrong totoconcludeconclude thatthat aa singlesingle dosedose ofof resveratrolresveratrol isis ableable totoInduceInduce beneficialbeneficial physiologicphysiologic responsesresponses andand thatthatInduceInduce beneficialbeneficial physiologicphysiologic responses,responses, andand thatthateithereither weeksweeks oror monthsmonths ofof resveratrolresveratrol supplementationsupplementationproducesproduces physiologicphysiologic changeschanges thatthat areare predictivepredictive ofofproducesproduces physiologicphysiologic changeschanges thatthat areare predictivepredictive ofofimprovedimproved health,health, especiallyespecially inin clinicalclinical populationspopulations withwithcompromisedcompromised healthhealthcompromisedcompromised healthhealth..

Resveratrol and health – A comprehensive review of humanclinical trials.James M. Smoliga, Joseph A. Baur and Heather A. Hausenblas.Mol Nutr Food Res 2011 55 1129 1141Mol. Nutr. Food Res. 2011, 55, 1129–1141

BibliografíaBibliografíaVV O Ah d NO Ah d N B ilB il CACA BB JA B K t l (2011) Wh t I N f OldJA B K t l (2011) Wh t I N f Old•• VangVang O, Ahmad N, O, Ahmad N, BaileBaile CA, CA, BaurBaur JA, Brown K, et al. (2011) What Is New for an Old JA, Brown K, et al. (2011) What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol. Molecule? Systematic Review and Recommendations on the Use of Resveratrol. PLoSPLoSONE 6(6): e19881.doi: 10.1371/journal.pone.0019881ONE 6(6): e19881.doi: 10.1371/journal.pone.0019881

•• MengMeng, X.F.,, X.F., MaliakalMaliakal, P., Lu, H., et al. (2004). Urinary and plasma levels of resveratrol, P., Lu, H., et al. (2004). Urinary and plasma levels of resveratrolMengMeng, X.F., , X.F., MaliakalMaliakal, P., Lu, H., et al. (2004). Urinary and plasma levels of resveratrol , P., Lu, H., et al. (2004). Urinary and plasma levels of resveratrol and and quercetinquercetin in humans, mice, and rats after ingestion of pure compounds and grape in humans, mice, and rats after ingestion of pure compounds and grape juice. Journal of Agricultural and Food Chemistry. 52. pp: 935juice. Journal of Agricultural and Food Chemistry. 52. pp: 935‐‐942.942.

•• ManachManach, C., , C., SclabertSclabert, A., et al. (2004). , A., et al. (2004). PolyphenolsPolyphenols: food sources and bioavailability. : food sources and bioavailability. A i J l f Cli i l N i i 79 727A i J l f Cli i l N i i 79 727 747747American Journal of Clinical Nutrition. 79. pp: 727American Journal of Clinical Nutrition. 79. pp: 727‐‐747.747.

• Informe del Comité Científico de la Agencia Española de Seguridad Alimentaria y Nutrición (AESAN) en relación con la aplicación de luz UVC para la inducción de compuestos bioactivos en uvas . Documento aprobado por el Comité Científico encompuestos bioactivos en uvas . Documento aprobado por el Comité Científico en sesión plenaria de 14 de noviembre de 2007. Revista del comité científico nº 7

• Smoliga JM., Baur JA., Hausenblas HA., (2011) Resveratrol and health – A comprehensive review of human clinical trials . Mol. Nutr. Food Res. 55, 1129–1141

• IR Pérez et al. ‐ Revista de Enología, 2001. Niveles de resveratrol y piceído en vinos y cavas

• www.clinicaltrials.gov

Thanks for your attentionThanks for your attention

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