RESVERATROL

"S i tifi E id
"ScientificEvidence
i H lth andDisease"
inHealth
d Di
"

Dr.RalFranciscoPastor
4CtedradeMedicinaInterna
Hospital de Clnicas
HospitaldeClnicas
JosdeSanMartn
UniversidaddeBuenosAires
Argentina
g

EvidenceBasedMedicine
Evidence
Based Medicine
Users'guidestothemedicalliterature.II.Howtousean
U
' id t th
di l lit t
II H
t
articleabouttherapyorprevention.A.Aretheresultsof
thestudyvalid? Evidence
EvidenceBasedMedicineWorkingGroup.
Guyatt GH, Sackett DL, CookDJ.
JAMA. 1993Dec1;270(21): 2598601
Departmentof
D
f Medicine,McMasterUniversity,Hamilton,
M di i
M M
U i
i H il
Ontario,Canada.

Globalise theevidence,localise
theevidence,localise thedecisin
thedecisin
JohnEisemberg (1999)
AHCPR(AgencyforHealthCarePolicyandResearch)

Resveratrol
3,5,4transtrihidroxiestilbeno
, ,
bioactive constituent,non
constituent,nonnutritional food
Molecular Weight 228 24328 [g/mol]
MolecularWeight228.24328[g/mol]

Roots

Roots

helboro

Polygonum
Cuspidatum

(Veratrum
grandiflorum
O.Loes)

((Nonomura et
al.,1963)

(Takaoka,1940)

Cava
Andres
Andres
Lacueva
etal.
2001

Vaccinium
(arndanos)
Rimando et
Rimandoet
al.2004.

Grapes
Vitis
Vinifera
Resveratol

Langcake
P.etal
1976

Wine

Wine

Grapes

Wine

Trans
Resveratrol

Cis
Resveratrol

Piceido
Resveratrol

Piceidos
Resveratrol

Jeandet P.
etal1993

Waterhouse
A.Lamuela
A.
Lamuela
Ravents R.
1994

Lamuela
Lamuela
Ravents
R.1995

Siemman
etal1992

Resorcinol
Veratrum
Ol oxhidrilo

Calorie Restriction =
= Resveratrol
=Resveratrol

McCay,etal1935.
Theeffectofretardedgrowthuponthelengthoflifeandupontheultimatebody
size. JournalofNutrition10,6379

Howitz,K.T.2003.
Smallmoleculeactivatorsofsirtuins extendSaccharomyces cerevisiae lifespan.
Nature425,191196.

JangMetal1997
CancerChemopreventive ActivityofResveratrol,aNaturalProductDerivedfrom
Grapes Science 10January
GrapesScience
10 January Vol.275
Vol 275 no.5297
no 5297 pp.218220
pp 218 220

Renaud SC, etal1998

Alcohol and mortality in middle aged men from eastern France
AlcoholandmortalityinmiddleagedmenfromeasternFrance.
Epidemiology.Mar;9(2):1848.
InthecaseofmiddleagedmenfromeasternFrance,amoderatedailyintakeof
wine (2232
wine(22
32gofalcohol)wasassociatedwithalowerriskofdeathduetoCVDs
g of alcohol) was associated with a lower risk of death due to CVDs
(40%),cancer(22%),othercauses(42%),andallcauses(33%).

Calorie Restriction

Resveratrolandhealth N ofPapersandtrials
JangM,etal.Cancerchemopreventive
activityofresveratrol,anaturalproduct
derivedfromgrapes.
S i
Science
1997 J 10 275(5297) 218 20
1997Jan10;275(5297):21820.

MolecularNutrition&FoodResearch
Volume55,Issue8,pages11291141,20JUN2011DOI:10.1002/mnfr.201100143
http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201100143/full#fig1

Calorie Restriction =
= Resveratrol
=Resveratrol

Increasedqualityandspanoflife
d
l
d
flf
Reduced oxidative stress
Reducedoxidativestress
Reducedriskofcancer
Reducedneurodegenerativedisorders
Reduced autoimmune disease
Reducedautoimmunedisease
Reducedcardiovasculardisease
ReducedTypeIIdiabetesmellitus

Resveratrolcontentofselectedfruits
and vegetables
andvegetables
FoodsResveratrol
1.Blueberry
2.Bilberries
3.Cranberryrawjuice
4.Mulberry
5.Peanuts(raw)
6.Peanuts(boiled)
7.Peanutbutter
g p
8.Redgrapes
9.Redgrapejuice(Spanish)
10.
10.Blackchocolate
Blackchocolate
11.Cocoaliquor
11.Cocoaliquor

cupservinginmg
32ng
32
ng/gm
/gm
16ng
16
ng/g
/g
0.2mg/L
0.00210.0053mg/g
0.0021
0.010.26(perservingof146g)
0.01
0.321.28 (perservingof180g)
0.32
p
g
g
0.040.13(perservingof258g)
0.04
0.241.25 (p
0.24
(perservingof160g)
g
g)
0.171.30 (perservingof150ml)
0.17
4 mg/L
g/
5mg/L
5
mg/L

Resveratrolcontentofwines
WinesTotal
Wi
T t l
resveratrol(mg/L)

1.Whitewine
0.05
0.051.80
2.Rosewine
0.43
0.433.52
3.Redwine(Spanish) 1.92
1.9212.59
4.Redwine
4.Red
wine (Global) 1.98
1.987.13
5.Pinotnoir
0.02.0
0.0
6.Redwine
6.Red
wine (Italian
Italian)
)
0.05
7.Merlotswine(Chilean)
(
)
2.25

TTotal
t l resveratrol
t l
150mlglass(mg)

0.010.27
0.01
0.060.53
0.06
0.291.89
0.29
0.301.07
0.30
0.060.30
0.06
0.008
0.35

Resveratrol NaturalSources
Natural Sources

Resveratrolcontentofwines
Itisdifficulttoestimatethenormalhuman
consumptionofResveratrol
p
Resveratrol astheintakeof
consumptionof
redwine(verifiedmainsourceofResveratrol
redwine(verifiedmainsourceof
Resveratrol)
)
differs
differsgreatlyinthepopulationandthe
greatly in the population and the
contentof
Averageoff resveratroll inwines
mean 1.9 1.7mg/L
mean1.9
mean1.9
1.7 mg/L
consumptionestimateddosemaybeupto
4mg/person/day

Averagevaluesinwinesoftheisomers
ofResveratrol andPicedo

0,67mg/L,

0,48mg/L

2,15mg/L
2,15mg/L,

7,55mg/L

Resveratrol
Bi
BioavailabilityandMetabolism
BioavailabilityandMetabolism
il bili
d M b li Fase
F
I
Resveratrolhasahighabsorption

Reachesvariousorgans
Is metabolized mainly to glucuronide andsulfatederivatives.
Ismetabolizedmainlytoglucuronide
Ismetabolizedmainlyto
and sulfate derivatives
Hasasignificantroleinintestinalmicroflora
Hasasignificantroleinintestinalmicroflora metaboliteproduction
dihidroresveratrol
Resveratrolreachespeakplasmaconcentrationpeaksabout30minutes
afterintake,withtheglucuronide
afterintake,withtheglucuronide andsulfate,whoseconcentration
varies
variesdependingonthedose
depending on the dose

Mainly,eliminationisbyurine
(Sulfatederivatives37%.
Sulfate derivatives 37% Glucuronide derivatives19%Tracesof
Sulfatederivatives37%.Glucuronide
derivatives 19% Traces of

resveratrol aglycone).Total56%.
aglycone).Total56%.
Ahigh44%Resveratrolwhosefateisunknown?
Also,somemetabolitesremainunidentified?

Meantotal(freeandconjugated) trans
trans
resveratrolinserumoffoursubjectsgiven25
t li
ff
bj t i
25
mgof trans
transresveratrolinvariousmatrices.

Mean plasma concentrations of resveratrol (A), resveratrol-4-O-glucuronide (B), resveratrol3-O-glucuronide (C), and resveratrol-3-O-sulfate (D) versus time in healthy volunteers after
the last of between 21 and 28 daily
y doses of resveratrol at either 0.5 ...

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

Clinicaltrialsofresveratrol
Resveratrolpharmacokineticsinhealthyvolunteers
Resveratrol
pharmacokinetics in healthy volunteers
followingmultipledosing.

AnnalsoftheNewYorkAcademyofSciences
Volume1215,Issue1,pages161169,24JAN2011DOI:10.1111/j.17496632.2010.05853.x
http://onlinelibrary.wiley.com/doi/10.1111/j.17496632.2010.05853.x/full#f1

Resveratrol
BioavailabilityandMetabolism
Half
Halflifeinbloodof
lifeinbloodofresveratrol
resveratrols metabolites
approximatesthe9hours,indicatingthatexposureto
h h
d
h
thesederivativesismuchhigherthanthatdueto
resveratrol aglycone
aglycone..
Excretioninmanwithtimedependsonthe
concentration of resveratrol inplasma.
concentrationofresveratrol
concentrationof
in plasma
Therefore,wheningestedsmallamountsof
resveratrol,itisrapidlymetabolizedandeliminated
resveratrol
,itisrapidlymetabolizedandeliminated
it is rapidly metabolized and eliminated
whereasiftheamountingestedislarge,thencanbe
p
y
detectedintissuesandcanpotentiallyenterthecells
todisplaytheiraction.

Resveratrol
mg/day

Intestinal Intravascular Intracellular

Intracellular
space
space
space
Mengetal.,2004).

Resveratrol
BioavailabilityandMetabolism
Invivoactivity
I i
i i issometimes
i
i
greaterthanthat
h
h
described invitro, suggeststhatsomeform
conjugate generated invivo, ismorepotent
precursor(
precursor(aglycone
(aglycone)
gy
) ingested.
g
thanthe p

Resveratrol
BioavailabilityandMetabolism

Itwasshownthatresveratrolaccumulatesin
LDL
LDLparticles,mayhelpreducetheir
i l
h l
d
h i
susceptibilitytooxidationandthusstressing
akeystepin
akeystepinatherogenesis
atherogenesis..

DiversehealthbenefitsofResveratrol
includingcardioprotection
including
cardioprotection

Resveratrolinthe
Resveratrolinthe health anddisease
anddisease
Cancer
Resveratrolhasshownmuchpromiseintreating
cancerinlaboratoryanimalsandinvitrohumancell
studies yet there is still a large void in human research
studies,yetthereisstillalargevoidinhumanresearch.
Thismaysoonchange,assixoftheclinicaltrialscurrently
g
listedforresveratrolonwww.clinicaltrials.govinclude
cancerpatientsasatargetpopulation.
Acts byinhibiting the3stages ofcarcinogenesis
1)initiation 2)promotion 3)progression
Smoliga JM.,Baur JA.,Hausenblas HA.,(2011)Resveratrol andhealth A
comprehensivereviewofhumanclinicaltrials.
M l N t F d R 55 1129 1141
Mol.Nutr.FoodRes.55,11291141

Resveratrolinthe
Resveratrolinthe health anddisease
anddisease

Cardiovasculareffects
Oneofthekeycardioprotective mechanismsof
Oneofthekeycardioprotective
resveratrol
resveratrolstemsfromitsabilitytoupregulate
resveratrolstemsfromitsabilityto
stems from its ability to upregulate
endothelialnitricoxide
endothelialnitricoxidesynthase
synthase (eNOS)which
eNOS)which
ultimately increases nitric oxide (NO) mediated
ultimatelyincreasesnitricoxide(NO)mediated
vasodilation andincreasesbloodflow
andincreasesbloodflow..
Smoliga JM.,Baur JA.,Hausenblas HA.,(2011)Resveratrol andhealth A
comprehensivereviewofhumanclinicaltrials.
Mol.Nutr.FoodRes.55,11291141

Resveratrolinthe
Resveratrolinthe health anddisease
anddisease
Oxidativestressandinflammation
Oxidativestressandinflammation
Atherosclerosis,diabetesmellitus,chronicobstructive
Atherosclerosis diabetes mellitus chronic obstructive
pulmonarydisease,andcancerareexamplesof
di
diseasesassociatedwithROS
diseasesassociatedwithROS
i t d ith ROSinducedchronic
i d d h i
inflammation..
inflammation
Smoliga JM.,Baur JA.,Hausenblas HA.,(2011)Resveratrol andhealth A
comprehensivereviewofhumanclinicaltrials.
Mol.Nutr.FoodRes.55,11291141

Resveratrolinthe
Resveratrolinthe health anddisease
anddisease
Obesityanddiabetes
Multiple
Multiplemechanismshavebeenproposedtoaccount
mechanisms have been proposed to account
fortheinsulin
fortheinsulinsensitizingeffectsofresveratrol,
including antiinflammatory effects.
includingantiinflammatory
including
effects
SSmoliga
li JM.,Baur
JM B
JA H
JA.,Hausenblas
bl HA.,(2011)Resveratrol
HA (2011) R
t l andhealth
d h lth A
comprehensivereviewofhumanclinicaltrials.
Mol. Nutr. Food Res. 55, 11291141
Mol.Nutr.FoodRes.55,1129
1141

Antidiabetic effects of Resveratrol

AntidiabeticeffectsofResveratrol

AnnalsoftheNewYorkAcademyofSciences
Volume1215,Issue1,pages3439,24JAN2011DOI:10.1111/j.17496632.2010.05844.x
http://onlinelibrary.wiley.com/doi/10.1111/j.17496632.2010.05844.x/full#f1

Resveratrolinthe
Resveratrolinthe health anddisease
anddisease
Neuroprotective activity
250mgtrans
250
250mgtrans
mg trans
transresveratroltoincreasecerebralblood
resveratrol to increase cerebral blood
flow comparedtoplacebobyFMD
Smoliga JM.,Baur JA.,Hausenblas HA.,(2011)Resveratrol andhealth A
comprehensive review of human clinical trials
comprehensivereviewofhumanclinicaltrials.
Mol.Nutr.FoodRes.55,11291141

Resveratrolinthe
Resveratrolinthe health anddisease
anddisease
Longevity
Resveratrols abilitytocombatagingatthecellularlevel
mayultimatelyleadtobreakthroughsingeriatricand
antiaging
anti
agingmedicine,butthedatasupportingthisin
medicine, but the data supporting this in
humansarescant.
Smoliga JM.,Baur JA.,Hausenblas HA.,(2011)Resveratrol andhealth A
comprehensivereviewofhumanclinicaltrials.
h i
i
fh
li i l t i l
Mol.Nutr.FoodRes.55,11291141

Numberofhealthyvolunteerswhoexperienced
adverseeventsdeemedinterventionrelatedafter
adverseeventsdeemedintervention
dailyingestionofresveratrolfor29d

Recommendationsfortheuseof
Resveratrol
R
t l
Whichrelevant(overall)mechanismsofactionof
Resveratrolhavebeendocumented?
R
lh
b
d
d?

Modulationofcellproliferationandapoptosis
Modulationofcellproliferationandapoptosis
Modulation ofangiogenesis
Modulationofangiogenesis
Modulation
of angiogenesis
Inhibitionofmetastasis
Inhibition
ofmetastasis
Modulationof
Modulation
ofredox
redox status
Suppressionof
Suppression
ofadipogenesis
adipogenesis andstimulationofadipocyte
andstimulationofadipocyte
lipolysis
Stimulation ofosteogenesis
Stimulationof
Stimulation
of osteogenesis
Modulationofmitochondriaactivity
Modulation
ofmitochondriaactivity
Suppression ofinflammation
Suppressionofinflammation
Suppression
of inflammation
ModulationofDNAdamage
Modulation
ofDNAdamage
Modulationof
Modulation
ofxenobiotic
xenobiotic metabolism
Modulationofglutamatemetabolism
Modulation
ofglutamatemetabolism
Estrogenicactivity/anti
Estrogenic
activity/antiestrogenic
estrogenicactivity
activity

Resveratrol
45InterventionStudies
45
InterventionStudies inHumans

Resveratrol and
and Wine
andWine
Isimportanttonotethattheresveratrol
concentrations in wine vary widely, even
concentrationsinwinevarywidely,even
withinagivenvarietyofgrapeorgrowing
region.
i
it
itisunclearifsmalldosesofresveratrolon
is unclear if small doses of resveratrol on
aregularbasis(i.e.yearsofwine
consumption)wouldhavethesame
physiological effect as the high Cmax
physiologicaleffectasthehighCmax
physiologicaleffectasthehigh
observedfromsupplementation.

Conclusion
We
W believe
b li
th evidence
the
id
i sufficiently
is
ffi i tl strong
t
t
to
conclude that a single dose of resveratrol is able to
Induce beneficial physiologic responses,
responses and that
either weeks or months of resveratrol supplementation
produces physiologic changes that are predictive of
improved health, especially in clinical populations with
compromised health
health..
Resveratrol andhealth Acomprehensivereviewofhuman
clinicaltrials.
JamesM.Smoliga,JosephA.Baur andHeatherA.Hausenblas.
Mol Nutr Food Res 2011 55 1129 1141
Mol.Nutr.FoodRes.2011,55,11291141

Bibliografa

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Nutricin(AESAN)enrelacinconlaaplicacindeluzUVCparalainduccinde
compuestos bioactivos enuvas.Documento
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Thanks foryourattention
for your attention