review article effect of antioxidants supplementation on...

Review ArticleEffect of Antioxidants Supplementation on Aging and Longevity

Izabela Sadowska-Bartosz1 and Grzegorz Bartosz12

1 Department of Biochemistry and Cell Biology University of Rzeszow Zelwerowicza Street 4 35-601 Rzeszow Poland2Department of Molecular Biophysics University of Łodz Pomorska 141143 90-236 Łodz Poland

Correspondence should be addressed to Izabela Sadowska-Bartosz isadowskapocztafm

Received 14 January 2014 Accepted 11 February 2014 Published 25 March 2014

Academic Editor Efstathios S Gonos

Copyright copy 2014 I Sadowska-Bartosz and G Bartosz This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

If aging is due to or contributed by free radical reactions as postulated by the free radical theory of aging lifespan of organismsshould be extended by administration of exogenous antioxidants This paper reviews data on model organisms concerningthe effects of exogenous antioxidants (antioxidant vitamins lipoic acid coenzyme Q melatonin resveratrol curcumin otherpolyphenols and synthetic antioxidants including antioxidant nanoparticles) on the lifespan of model organisms Mechanismsof effects of antioxidants often due to indirect antioxidant action or to action not related to the antioxidant properties of thecompounds administered are discussed The legitimacy of antioxidant supplementation in human is considered

1 Introduction

Aging is an unavoidable universal biological phenomenonaffecting all multicellular organisms (with few apparentexceptions) and probably common also among unicellularorganisms including protozoa yeast and bacteria [1 2]Although different hypotheses have been put forward toexplain the cellular and molecular mechanisms of agingrecent studies made it increasingly clear that aging is due toaccumulation of molecular damage giving rise to a unifiedtheory of aging [3ndash8] Among reactions contributing tothis damage reactions of free radicals and other reactiveoxygen species are the main reason apart from reactionsof metabolites such as sugars and reactive aldehydes andspontaneous errors in biochemical processes [9]

From a thermodynamic point of view all aerobic organ-isms are subject to the action of common oxidant that isoxygen The redox potential of the O

22H2O redox system

(approximately + 08V at pH 7) is more positive than those ofmost other biologically relevant redox systemsTherefore theoxidation by O

2of organic compounds will have a negative

free enthalpy and should proceed spontaneously In otherwords organic compounds and structures composed of themare thermodynamically unstable in an oxygen-containing

atmosphere Molecular oxygen in its triplet basal stateis rather unreactive due to the spin restriction Howeverformation of oxygen free radicals and other reactive oxygenspecies (ROS) opens the gate for potentially deleteriousoxidative reactions of oxygen [7] Seen from that perspectivethe ldquoFree Radical Theory of Agingrdquo (FRTA) [10] now morecommonly termed the oxidative damage theory of ageingseems to address a key facet of intrinsic biological instabilityof living systems [11 12] The basic idea of the FRTA isthat free radicals and other ROS formed unavoidably in thecourse of metabolism and arising due to the action of variousexogenous factors damage biomolecules and accumulationof this damage are the cause of age-related diseases and aging

If FRTA is true antioxidants should slow down agingand prolong lifespanThis apparently obvious conclusion hasstimulated enormous number of studies aimed at finding arelationship between levels of endogenous antioxidants andlifespan of various organisms on the effects of addition ofexogenous antioxidants on the course of aging and lifespanof model organisms Pubmed provides more than 13300 hitsfor conjunction of terms ldquoantioxidantrdquo and ldquoaging or ageingrdquoHowever in spite of the plethora of studies the answer to thequestion if exogenous antioxidants can prolong life is far frombeing clear

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 404680 17 pageshttpdxdoiorg1011552014404680

2 BioMed Research International

H3C

CH3

CH3

CH3CH3 CH3 CH3

CH3

HO

O

120572-tocopherol (vitamin E)

HO

HO

H

HO OH

O O

Ascorbic acid(vitamin C)

SS

O

OH

Lipoic acid

HO

OCH3

O O

H3CO

OH

HO

OH

O

OH

OH

OH

HO

OH

O

O

O

OH

OH

OH

OH

OH

OHEpigallocatechin gallate

CH3CH3O

CH3O

OH

OH

10

Ubiquinol (coenzyme Q10)

H3C O

O

HN HN CH3

Melatonin

HO

OH

Tyrosol

HO

OH

Quercetin

H3C

H3C

OH

OH SkQ1

HO

OH

OH

Resveratrol

H3C CH3

CH3

N+

Ominus

PBN

Catechin

Poplus

Curcumin

Figure 1 Some antioxidants studied as antiaging agents

2 Effect of AOs on the Lifespanof Model Organism

Many studies have addressed the question of supplementa-tion with antioxidant vitamins especially vitamins C and Eand synthetic compounds can prolong the lifespan of modelanimals Vitamin C (ascorbic acid) is the major hydrophilicantioxidant and a powerful inhibitor of lipid peroxidationIn membranes this molecule rapidly reduces 120572-tocopheroxylradicals and LDL to regenerate 120572-tocopherol and inhibitpropagation of free radicals Vitamin E (120572-tocopherol) isthe main hydrophobic antioxidant in cell membranes andcirculating lipoproteins Its antioxidant function is stronglysupported by regeneration promoted by vitamin C Vitamin

E is thought to prevent atherosclerosis through inhibition ofoxidative modification Coenzyme Q (ubiquinol CoQ) andlipoic acid in their reduced forms and melatonin (Figure 1)are also efficient antioxidants

Novel endogenous indole indolepropionamide anotherendogenous antioxidant is similar in structure to melatoninbinds to the rate-limiting component of oxidative phospho-rylation in complex I of the respiratory chain and acts asa stabilizer of energy metabolism thereby reducing ROSproduction [13]

Epitalon is a synthetic tetrapeptide Ala-Glu-Asp-Glyshowing antioxidant activity [14] (SS)-6-hydroxy-2578-tetramethylchroman-2-carbonyl-beta-alanyl-L-histidine (SS-Trolox-carnosine) is a synthetic analogue of carnosine

BioMed Research International 3

containing a Trolox (water-soluble analog of vitamin E)residue [15]

Recently the antiaging effect of resveratrol (RSV) hasbeen a hotly discussed topic RSV was first isolated from theroots of white hellebore (Veratrum grandiflorum O Loes) in1940 and later in 1963 from the roots of Polygonum cuspida-tum (or Fallopia japonica) a plant used in traditional Chineseand Japanese medicine [16] This polyphenolic compoundsare a phytoalexin that stimulates cell defenses in plants RSV issynthesized inmany plants such as peanuts blueberries pinenuts and grapes which protects them against fungal infec-tion and ultraviolet irradiation It mainly accumulates in aglycosylated state (piceid) SomedimethoxylatedRSVderiva-tives (pterostilbene) are also present as well as RSV oligomers(120576-viniferin a dimer and hopeaphenol a tetramer) Inter-estingly RSV plays a number of protective roles in animalsalthough it is rapidly metabolized in a conjugated form(glucorono- or sulfo-) [17] Since the early 1990s it has beensuggested that RSV could be the molecule responsible forthe French paradox that is the low occurrence of coronaryheart diseases and cardiovascular diseases in South-WesternFrance despite the consumption of a high saturated fat dietThe French paradox was correlated to some extent with theregular consumption of red wine which contains high levelsof RSV [18]

Curcumin [17-bis (4-hydroxy-3-methoxyphenyl)-16-heptadiene-35-dione] (diferuloylmethane CUR) the maincomponent of the yellow extract from the plant Curcumalonga (turmeric a popular Indian spice) is a main bio-active polyphenol which has been used widely as a spicefood additive and a herbal medicine in Asia [19] Tetrahy-drocurcumin (THC) is an active metabolite of CUR Orallyingested CUR is metabolized into THC by a reductase foundin the intestinal epithelium THC possesses extremely strongantioxidant activity compared to other curcuminoids Theantioxidant role of THC has been implicated in recoveryfrom renal injury inmice and in anti-inflammatory responses[20] Tyrosol is a main phenol present in extra virgin oliveoil [21]

Some researchers hope that development of new meansof introduction of antioxidants into cells or construction ofnew antioxidants can make a breakthrough in antioxidantmodulation of aging and longevity If mitochondria are themain source of ROS in the cell mitochondrially targetedantioxidants could be more effective than traditional onesThis idea was the basis of synthesis of positively chargedderivatives of plastoquinone and other antioxidants whichare retained in the mitochondria due to the high negativepotential at the inner mitochondrial membrane [22] SkQ1 isa mitochondria-targeted plastoquinone-containing [10-(61015840-plastoquinonyl) decyltriphenylphosphonium] [23]

Results of studies on the supplementation of modelorganisms with antioxidant vitamins and other antioxidantsare divergent Examples of recent studies devoted to thisquestion are summarized in Table 1 and these data are onlycommented in this section

Ascorbic acid partially rescued the lifespan of superoxidedismutase (SOD)-deficient yeast Saccharomyces cerevisiae

which was considerably reduced as a result of lack of thisvital antioxidant enzyme [12] However this effect shouldbe seen rather as a partial restoration of the redox sta-tus seriously deranged in these cells rat compared to lifeextension of normal yeast cells Another study using butD-erythroascorbic acid (ascorbic acid homologue producedin the yeast) showed little effect of this antioxidant on thereplicative lifespan of wild-type yeast [13] Similar reportshave been published for multicellular organisms in whichantioxidants had life-prolonging effects on mutants deficientin antioxidant defense or were subjected to oxidative stressbut did not affect the lifespan of healthy wild type animals

Supplementation of the growth medium of S cerevisiaewith the lipophilic antioxidants 120572-tocopherol and CoQ aloneor in combination with 120572-tocopherol increased oxidativestress and decreased cellular lifespan [24] It should berecalled however that S cerevisiae is unable to producepolyunsaturated fatty acids [25] so lipid oxidative damagemay be of lower importance and lack of protective effects ofhydrophobic antioxidants located mainly in cell membranes[24] maybe not surprising in this species

Effect of vitamin C on the lifespan of several multicel-lular model organisms (Caenorhabditis elegans Drosophilamelanogaster mice rats and guinea pigs) has been recentlyreviewed by Pallauf et al No consistent picture emerges fromthe summary of data some studies demonstrating prolonga-tion of lifespans and others showing no effect [26] Ernst etal conducted a comprehensive literature review regarding theeffect of vitamin E on lifespan in model organisms includingsingle-cell organisms rotifers C elegans D melanogasterand laboratory rodents The findings of their review suggestthat there is no consistent beneficial effect of vitamin E onlifespan in model organisms which corresponds to resultsof meta-analysis of mortality in human intervention studies[27]

While most of the studies concerning mammals havebeen done on mice an interesting study has addressed theeffect of dietary supplementation with either vitamin E orvitamin C (ascorbic acid) on a wild-derived animal short-tailed field vole (Microtus agrestis) Antioxidant supplemen-tation for nine months reduced hepatic lipid peroxidationbut DNA oxidative damage to hepatocytes and lymphocyteswas unaffected Surprisingly antioxidant supplementationsignificantly shortened lifespan in voles maintained underboth cold (7 plusmn 2∘C) and warm (22 plusmn 2∘C) conditions [28]

Hector et al (2012) quantified the current knowledge oflife extension of model organisms by RSV These authorsused meta-analysis techniques to assess the effect of RSV onsurvival using data from 19 published papers including sixspecies yeast nematodes mice fruit flies Mexican fruit fliesand turquoise killifish While the lifespan of the turquoisekillifish was positively affected by the RSV treatment resultsare less clear for flies and nematodes as there was importantvariability between the studies [29]

The rapid expansion of nanotechnology provided a hugeassortment of nanoparticles (NPs) that differ in chemicalcomposition size shape surface charge and chemistry andcoating and dispersion status Antioxidant delivery can be


Table 1 Effect of supplementation with natural and synthetic antioxidants on the lifespan of model organisms

Organism Additive Parameter studied Effect reported ReferenceSaccharomyces cerevisiaebudding yeast Ascorbic acid Replicative lifespan of SOD-1

deficient mutantPartial restoration of normalreplicative lifespan

[128]

Saccharomyces cerevisiae Erythroascorbic acid Replicative lifespan ofwild-type yeast Little effect [24]

Saccharomyces cerevisiae 120572-tocopherol CoQ aloneor with 120572-tocopherol Replicative lifespan Decrease increased

oxidative stress[24]

Paramecium tetraurelia Vitamin E Clonal lifespan Increase maximal (382 versus 256fissions) at 1000mgL medium

[129]

Paramecium tetraurelia Melatonin Clonal lifespan [130]Asplanchnabrightwelliirotifer Vitamin E (25 ugmL) Lifespan Increase limited to

the prereproductive stage [15][131]

Philodina acuticornisodiosa rotifer Indolepropionamide Lifespan Increase up to 3-fold [13]

Caenorhabditis elegansnematode

CoQVitamin E Lifespan Prolongation [132]

Caenorhabditis elegans 200 120583gmL vitamin Efrom hatching to day 3 Survival Increase (17ndash23) [133]

Caenorhabditis elegans 120574-Tocopherol Lifespan Slight extensionno effect of 120572-tocopherol

[134]

Caenorhabditis elegans 120574- or 120572-tocopherol Lifespan No effect [134]

Caenorhabditis elegans Polydatin resveratrol-3-O-120573-mono-D-glucoside Mean lifespan

Increase by up to 31 and 62under normal and acute stressconditions respectively

[56]

Caenorhabditis elegans Curcumin Lifespan Increase inmev-1and daf-16 mutants

[135]

Caenorhabditis elegansQuercetinisorhamnetinand tamarixetin

Lifespan Increase by 11ndash16 [136]

Caenorhabditis elegans Quercetin-3-O-glucoside Lifespan Increase by low concentrationsdecrease by high concentrations

[137]

Caenorhabditis elegansMyricetinquercetin kaempferoland naringenin

Lifespan Increase [90]

Caenorhabditis elegans Caffeic acid androsmarinic acid Lifespan Increase [138]

Caenorhabditis elegans Catechin Mean lifespan median lifespan Increase by 9 and 13respectively at 200 120583M

[86]

Caenorhabditis elegans (minus)-Epicatechin Lifespan No effect [87]

Caenorhabditis elegans Epigallocatechin gallate(220 nM) Mean lifespan Increase by 10 [139]

Caenorhabditis elegans Epigallocatechin gallate Mean lifespan Increase under stress conditionsbut not under normal conditions

[140]

Caenorhabditis elegans Ferulsinaic acid(05ndash100 120583M) Lifespan Increase [141]

Caenorhabditis elegans Procyanidins from apples(Malus pumila65 120583gmL) Mean lifespan Increase [87]

Caenorhabditis elegans Tyrosol Lifespan Increase [21]

Caenorhabditis elegansMn-NN1015840-bis(salicylidene)ethylenediamide chloride(EUK-8) an SOD mimetic

Lifespan Extension but only after specificculture conditions

[142]

Caenorhabditis elegans KPG-7 a herb complex Lifespan Prolongation [143]

Caenorhabditis elegans EGb 761 extract ofGinkgo biloba leaves Mean lifespan Prolongation [94]


Table 1 Continued

Organism Additive Parameter studied Effect reported ReferenceCaenorhabditis elegans Royal gelly Lifespan Prolongation [34]

Caenorhabditis elegans Pt nanoparticles(a SODCAT mimetic) Lifespan Prolongation [31]

Drosophila melanogaster Lipoic acid Lifespan Increase [144]Drosophila melanogaster Melatonin Lifespan Increase [145]Drosophila melanogaster Epitalon Lifespan Increase by 11ndash16 [14]

Drosophila melanogaster Carnosine Average lifespan Increase in malesno effect on females [15]

Drosophila melanogaster SS-Trolox-carnosine Average lifespan Increase in males (by 16)and in females (by 36) [15]

Drosophila melanogaster Curcumin 1mggof medium Lifespan Increase [146]

Drosophila melanogaster Curcumin 05 and10mgg Lifespan

Increase by 6 and26 in females and by16 and 13 in males

[65]

Drosophila melanogaster Curcumin Lifespan Extension gender- andgenotype-specific [64]

Drosophila melanogaster Aloe vera extract Lifespan Extension [147]Drosophila melanogaster Extract of black rice Lifespan Increase by ca 14 [89]Drosophila melanogaster Cacao Lifespan Increase [88]Drosophila melanogaster Black tea extract Mean lifespan Increase by 10 [148]

Drosophila melanogaster

EUK-8Mn 3-methoxy-NN1015840-bis(salicyldene)ethylenediamine chloride(EUK-134) mitoquinone

Lifespan No effect on wild type flies [149]

Anastrepha ludensMexican fruit fly 120574- or 120572-Tocopherol Lifespan No effect [134]

Mus musculus mousestrain C57BL6 Vitamin E lifelong Median lifespan Increase by 15 [150]

Mus musculus Vitamin E Lifespan No effect [151]Mus musculus C3HHeand LAF1 Vitamin E 025 ww Lifespan Increase in mean lifespan no

effect on maximum lifespan [152]

Mus musculus SAMP8(senescence-accelerationprone)

Lipoic acid Lifespan Decrease [45]

Mus musculus SAMP8 Melatonin Lifespan Increase [153]

Mus musculus Tetrahydrocurcumin02 from the age of 13m Average lifespan Increase [20]

Mus musculus males fromthe age of 12m

LGcombo complexmixture of botanicalextracts vitaminsand nutraceuticals

Lifespan No effect [33]

Mus musculus A fullerene mimetic of SOD Lifespan Prolongation [32]

Mus musculus Royal gelly Lifespan Increased mean lifespanno effect on maximal lifespan [35]

Rattus rattus rat Wistar Epigallocatechin gallate Median lifespan Increase by 8ndash12 weeks(control 105 weeks) [77]

Microtus agrestis field vole Vitamin C orvitamin E for 9m Lifespan Decrease [28]

Mus musculus Ellobiustalpinus (mole vole)Phodopus campbelli (dwarfhamster)

SkQ1 (mitochondriallytargeted plastoquinonederivative)

Survival Increase [23]


significantly improved using various NPs [30] some NPspossess antioxidant properties and are able to efficientlyattenuate oxidative stress by penetrating specific tissues ororgans even when administered at low concentrations andfound to increase the lifespan of model organisms [3132] Nevertheless there is an increasing concern about thetoxicity especially genotoxicity of NPs and this question fieldrequires thorough studies

It has been argued that antioxidant mixtures such asthose found in natural products are better than simpleantioxidant formulas that is due to synergism betweenantioxidants KPG-7 is a commercially available herbmixturecontainingThymus vulgaris Rosmarinus officinalis Curcumalonga Foeniculum vulgare Vitis vinifera (polyphenol) silkprotein Taraxacum officinale and Eleutherococcus senticosuswhich have been reported to include a variety of antioxidantantitumoral and anti-inflammatory bioactivities Positiveeffects of such extracts on the lifespan of model organismshave been reported but other studies showed no significanteffects For example administration of a complex mixture ofvitamins minerals botanical extracts and other nutraceu-ticals rich in antioxidants and anti-inflammatories to malemice starting from the age of 12m failed to affect theirlifespan [33]

In the honeybee Apis mellifera L queens live and repro-duce for 1ndash4 years but hive workers which are derivedfrom the same diploid genome live for only 3ndash6 weeksduring the spring and summer Queens are fed throughouttheir lives with royal jelly produced by the hypopharyngealpostcerebral and mandibular glands of the worker bees Incontrast workers are fed royal jelly for only a short period oftime during their larval stages It suggests that royal containslongevity-promoting agents for queens which may perhapsaffect the longevity of other species if it affects the ldquopublicrdquomechanisms of aging [34]However the effect of royal jelly onthe maximal lifespan of mice was rather disappointing [35]Moreover the action of complex preparations including plantextracts is difficult to interpret because apart from antiox-idants they contain various biologically active products[36]

3 Reversal of Age-RelatedChanges by Antioxidants

Apart from the effect of prolongation of lifespan by antioxi-dant administration throughout most of the lifetime (long-lasting experiments) another approach to study antiagingeffect of antioxidants consists in short-time experiments inwhich functional tests compare the status of experimentalanimals before and after supplementation An experimentof this type consisted in administration of N-tert-butyl-120572-phenylnitrone (PBN) to aged Mongolian gerbils for 2 weeksSuch a treatment reduced the amount of protein carbonylsin brain augmented the activity of glutamine synthetaseand decreased the number of errors in radial arm mazepatrolling behavior normalizing the values to those typicalfor young animals However these changes were reversibleafter cessation of PBN treatment [37] Similarly relatively oldmice (175months) fed high-CoQdiet (281mgg) for 15weeks

improved special performance in Morris water maze test andreduced protein oxidative damage [38]

4 How Do lsquolsquoAOsrsquorsquo (Do Not) ActPossible Explanations

Generally the effects of antioxidant supplementation inmodel organisms are disappointing Many studies showed noeffect or even negative effects on the lifespan Only in somecases considerable prolongation of lifespan was obtained andin organisms which are evolutionarily quite distant frommammals In some cases mean but not maximal lifespan wasaffected which may be caused by reduction of mortality dueto diseases rather than interference with the aging processitself An apparently obvious conclusion from the plethoraof studies could be that antioxidants cannot be expected toprolong significantly the lifespan especially of mammalswhich does not support the FRTA

However perhaps such a simple conclusion would beprecocious not taking into account experimental setupemployed in different studies One of the questions is therelevance of use of model organisms if understanding humanaging is aimed The basic biochemical mechanisms are socommon in all living world that there are good reasonsto expect that the mechanisms governing aging are alsouniversal It may not always be true It has been suggestedthat there are ldquopublicrdquo and ldquoprivaterdquo mechanisms of aging[39] Seemingly the mechanisms of aging of S cerevisiaeused as a model organism in biogerontology may be ratherprivate than public This refers to both ldquochronologicrdquo agingwhere yeast survival is limited by exhaustion of nutrientsandor accumulation of toxic products of metabolism and toldquoreplicativerdquo aging which seems to be a measure of fecundityrather than longevity and is limited by other factors comparedto those relevant to aging of multicellular organisms [40 41]Somatic cells of C elegans and D melanogaster are postmi-totic which only partly reflects the situation in mammaliantissues

It should be taken into account that ascorbic acidwhich is a vitamin for primates is synthesized by otherorganisms including mice and rats [42] It does not precludethe antioxidant action of ascorbate in these organisms butadministration of exogenous ascorbic acid may inhibit itsendogenous synthesis

Sometimes the administered antioxidants may be notfully taken up especially when added to complex mediaNumerous studies using C elegans have used a protocolin which chemicals are orally delivered by incorporatingthem into the nematode growth media or mixing with thefood bacteria However actual exposure levels are difficultto estimate The use of liposomes loaded with water-solublesubstances resulted in successful oral delivery of chemicalsinto the intestines of C elegans When using liposomesoral administration of hydrophilic antioxidants (ascorbicacid N-acetyl-cysteine reduced glutathione and thiopro-line) prolonged the lifespan of the nematodes whereas theconventional method of delivery showed no longevity effects[43] It is also difficult to estimate the amount of ingestedfood in many model organisms such as C elegans or D


melanogaster so the effects of admixture of high doses ofantioxidants may lead feeding rejection and thus starvation[44]

The life-prolonging effect of antioxidants may be limitedto a more or less narrow ldquotherapeutic windowrdquo This windowmay be different for various organisms that is due todifferences in the uptake rate and metabolism Not alwaysthe experimental conditions may hit the therapeutic window

Introduction of antioxidants in the diet may affect theendogenous antioxidant system and the effect is not alwaysadvantageous Farr et al reported that supplementation withlipoic acid reduced indices of oxidative stress increasingglutathione level and decreasing the concentration of lipidperoxidation products and glutathione peroxidase activityHowever this treatment actually decreased the lifespan ofSAMP8 mice [45]

The life-prolonging effect can be correlated withantioxidant properties of an additive in some but not inother cases For example onion flavonoids quercetinquercetin 31015840-O-120573-D-glucopyranoside and quercetin 3-O-120573-D-glucopyranoside-(4rarr 1)-120573-D-glucopyranoside increasedthe lifespan of C elegans but no direct correlation was foundbetween antioxidative activity and antiaging activity [46]Similarly no correlation was found between the antioxidantactivities of 6 plant extracts and their lifespan benefits in Celegans [47]

It should be remembered that (i) the effects of anantioxidantmay be not due to its direct antioxidant action butto its indirect antioxidant effects (induction of endogenousantioxidant mechanisms) and (ii) compound called ldquoantioxi-dantrdquo may have a plethora of other effects in vivo not relatedat all to its antioxidant action

Antioxidants can have deleterious effects on traits that asa consequence increase longevity For instance thioprolinewas reported to increase longevity of D melanogaster whichmight be ascribed to its direct antioxidant action howeverit decreased also the metabolic rate mean weight at eclosionand development speed of the fruit flies whichmight bemorerelevant for its life-prolonging effect [44]

Similarly RSV reduced acute oxidative damage howeverit did not extend the normal life span of C elegans indi-cating that antioxidant properties of this compound wereprobably not adequate to affect ageing [48] Howitz andcolleagues proposed that RSV is capable of increasing thedeacetylase activity of human sirtuin 1 (SIRT1) [49] SIRT1the closest homolog of the yeast silent information regulator(sir)2 protein functions as an NAD+-dependent histone andnonhistone protein deacetylase in several cellular processeslike energy metabolism stress responses and so forth Ithas been found that RSV activates SIRT1 by increasing itsbinding with lamin A thus aiding in the nuclear matrixlocalization of SIRT1 Ghosh et al suggested that rescueof adult stem cell decline in laminopathy-based prematureaging mice by RSV is SIRT1-dependent [50] Besides SIRT1activation RSV inhibits SIRT3 and it can mimic calorierestrictiondietary restriction (DR) effects [51] DR withadequate nutrition is the only nongenetic and the mostconsistent nonpharmacological intervention that extendslifespan in model organisms from yeast to mammals and

protects against the deterioration of biological functionsdelaying or reducing the risk of many age-related diseases Ithas already been known since the 1930s that a severe loweringof calorie intake dramatically slows the rate of ageing inmammals and lowers the onset of numerous age-relateddiseases including cancer cardiovascular disease diabetesand neurodegeneration It is found that DR induced an80 increase in the lifespan of unicellular organisms andsome invertebrates and a 20ndash40 increase in small mammals[52] The biological mechanisms of DRrsquos beneficial effectsinclude modifications in energy metabolism redox statusinsulin sensitivity inflammation autophagy neuroendocrinefunction and induction of hormesisxenohormesis responseThe molecular signalling pathways mediating the antiagingeffect of DR include not only sirtuins but also AMP-activatedprotein kinase (AMPK) insulininsulin growth factor-1 andtarget of rapamycin (TORmTOR) which form a complexinteracting network Rascon et al reported that the lifespanextension effects of RSV are conserved in the honeybee andmay be driven by a mechanism related to DR In contrasthyperoxic stress abolished the RSV life-extension response[53]

Although RSV has been found to extend the lifespanof many model organisms including yeast nematodes andfruit flies in the Sir2 or (Sirtuin 2)-dependent manner someother groups have questioned the importance of the Sir2pathway for ageing and could not confirm a beneficial effectof RSV on the lifespan of D melanogaster A Drosophilastrainwith ubiquitous overexpression of dSir2 using theUAS-GAL4 systemwas long-lived relative towild-type controls butwas neither long-lived relative to the appropriate transgeniccontrols nor a new line with stronger overexpression of dSir2These findings underscore the importance of controllingfor genetic background and for the mutagenic effects oftransgene insertions in studies of genetic effects on lifespan[48] Burnett et al found that DR increased fly lifespanindependently of dSir2 but these findings do not necessarilyrule out a role for sirtuins in determination of metazoanlifespan [54]

Marchal et al reviewed the beneficial effects of RSV in dif-ferentmammalian species including humans and concludedthat they generally reflect the effects observed during chronicDR without malnutrition Although most of these effectshave been observed in individuals without age-associatedpathology in those which were overweight or obese theyindicate the role of RSV in metabolic regulation and theantiaging efficacy of this intervention One explanation is thepositive and rapid changes induced by RSV which lead toadaptive metabolic response associated with an energy bal-ance regulation andmaintenance of overall health Moreoverdata on the effects of thismolecule on longevity in healthy butnonobese mammals are rare and these authors recommendthat longitudinal studies on experimental models close tohumans such as nonhuman primates multiply [18]

Recent studies have indicated that at equivalent and diet-achievable doses pterostilbene is a more potent modulatorof cognition and cellular stress than RSV likely driven byincreased peroxisome proliferator-activated receptor alphaexpression and increased lipophilicity due to substitution of


hydroxy with methoxy group in pterostilbene [55] Wen etal investigated polydatin and its role in extending lifespanimproving oxidative stress resistance and the possible reg-ulation mechanism involved in the insulinIGF-1 signaling(IIS) pathway Polydatin protected against oxidative stressIt improved the expression of the inducible oxidative stressprotein (GST-4) and corresponding stroke frequencies in thetransgenic CL2166 strain but not due to its direct antioxidantaction bymainly increased SOD-3GFP expression inCF1553worms and translocation of DAF-16 to the nucleus in wormcells [56]

Similarly although CUR is a directly acting antioxidantits lifespan-prolonging effects seem to be dependent mainlyon its indirect antioxidant action (induction of antioxidantproteins) or interference with cellular signaling CUR reg-ulates the expression of inflammatory cytokines (eg TNFIL-1) growth factors (eg VEGF EGF and FGF) growthfactor receptors (eg EGFR HER-2 and AR) enzymes (egCOX-2 LOX MMP9 MAPK mTOR and Akt) adhesionmolecules (eg ELAM-1 ICAM-1 and VCAM-1) apoptosisrelated proteins (eg Bcl-2 caspases DR and Fas) andcell cycle proteins (eg cyclin D1) CUR modulates theactivity of several transcription factors (eg NF-120581B AP-1 and STAT) and their signaling pathways [57] Recentstudies performed in both invertebrate and vertebratemodelshave been conducted to determine whether CUR was alsoneuroprotective [58] A compelling new body of literatureis also mounting to support the efficacy of CUR in stressandmood disorders Current understanding of the biologicalbasis for antidepressant-relevant biochemical and behavioralchanges shows convergence with some mechanisms knownfor standard antidepressants [59]

Recently Xiang et al reported that THC regulates theoxidative stress response and aging via the O-type forkheaddomain transcription factor (FOXO) In NIH3T3 cells THCinduced nuclear accumulation of FOXO4 a member of theFOXO family of transcription factors by inhibiting phospho-rylation of protein kinase B (PKB)Akt FOXO factors actas sensors in the insulinIGF-1 (IIS) pathway and influencemammalian longevity Overall the totality of the evidencesupports a potential role of FOXO3A in human health agingand longevity The association of FOXO with diverse agingphenotypes including insulin sensitivity CHD cancer type2 diabetes and longevity is suggestive of a ldquogatekeeperrdquo rolein the IIS pathway An important downstream mechanismwhereby FOXO3A might influence human aging is throughmodification of oxidative stress In D melanogaster THCattenuated the oxidative stress response an effect that wasblocked in a FOXO mutant background THC extended thelife span of Drosophila under normal conditions and lossof either FOXO or Sir2 activity eliminated this effect Basedon these results it seems that THC may regulate the agingprocess via an evolutionarily conserved signaling pathwaythat includes both FOXO and Sir2 [60]

Pu et al tested the hypothesis that dietaryCURwhich hasan antioxidant effect can improve aging-related cerebrovas-cular dysfunction via mitochondrial uncoupling protein 2UCP2 upregulation Dietary CUR administration for onemonth remarkably restored the impaired cerebrovascular

endothelium-dependent vasorelaxation in aging SpragueDawley rats In cerebral arteries from aging Sprague Dawleyrats and cultured endothelial cells CUR promoted eNOS andAMPK phosphorylation upregulated UCP2 and reducedROS production These effects of CUR were abolished byeither AMPK or UCP2 inhibition Chronic dietary CURsignificantly reduced ROS production and improved cere-brovascular endothelium-dependent relaxation in aging wildtype mice but not in aging UCP2minusminus mice CUR supplemen-tation ameliorated age-associated large elastic artery stiffen-ing nitric oxide-mediated vascular endothelial dysfunctionoxidative stress and increase in collagen and AGEs levels inmice [61]

Yanase et al examined the effects of PAK1-deficiency ordownregulation on a few selected functions of C elegansincluding reproduction expression of HSP162 gene andlifespan They found that PAK1 promotes reproductionwhereas it inactivates HSP162 gene and shortens lifespan asdo PI-3 kinase (AGE-1) TOR and insulin-like signallingILS(Daf-2) in this worm These findings not only support theldquotrade-offrdquo theory on reproduction versus lifespan but alsosuggest the possibility that the reduced reproduction (orHSP162 gene activation) of this worm could be used asthe first indicator of extended lifespan for a quick in vivoscreening for PAK1-blockers [62] Yu et al examined themodulation of oxidative-stress resistance and associated reg-ulatorymechanisms byCUR also in aC elegansmodel CUR-treated wild-type C elegans exhibited increased survivalduring juglone-induced oxidative stress compared to thecontrol treatment In addition CUR reduced the levels ofintracellular ROS in C elegans CUR induced the expressionof the gst-4 and hsp-162 stress response genes Lastly theirfindings from the mechanistic study in this investigationsuggest that the antioxidant effect of CUR is mediated viaregulation of age-1 akt-1 pdk-1 osr-1 unc-43 sek-1 skn-1sir-21 and mev-1 [63]

In D melanogaster CUR which extended the lifespanof D melanogaster also modulated the expression of severalaging-related genes including mth thor InR and JNK[64] Shen et al found that lifespan extension by CUR inDrosophila was associated with the upregulation of Mn-SOD and CuZn-SOD genes and the downregulation of dInRATTD Def CecB and DptB genes These authors suggestedthatCUR increasesmean lifespan ofDrosophila via regulatinggene expression of the key antioxidant enzyme SOD andreducing lipid peroxidation [65]

However not always overexpression of antioxidantenzymes may be relevant for the lifespan In particularthe overexpression of major antioxidant enzymes whichdecrease the steady-state level of ROS does not extend thelifespan of mice Overexpression of SODs protects againstoxidative stress but has little or no effect on the lifespan of Celegans [66 67] The lifespan of sod-2 mutant of C eleganswas not decreased but even extended suggesting that ROStoxicity does not play a major role in lifespan regulationin these animals [68] One possible explanation of whydeletion of individual SOD genes failed to shorten lifespanis compensation by additional SOD genes However a recent


report from the Hekimi lab demonstrates that worms lackingall five SODgenes are viable and have normal lifespan despitesignificantly increased sensitivity to multiple stresses [69]These observations indicate that oxidative damage causedby superoxide radical does not contribute to worm agingIt should be expected that species with weak antioxidantdefense accumulating oxidative damage should be shortlived which is definitely not true for the longest living rodentthe naked mole rat Heterocephalus glaber [70]

The term ldquogreen teardquo refers to the product manufacturedfrom fresh tea leaves by steaming or drying at elevatedtemperatures with the precaution to avoid oxidation of thepolyphenolic components known as catechins The naturalproduct EGCGaccounts for 50ndash80of catechins in green tearepresenting 200ndash300mg in a brewed cup of green tea Sev-eral other catechins such as (minus)-epicatechin-3-gallate (ECG)(minus)-epigallocatechin (EGC) and (minus)-epicatechin (EC) arefound in lower abundance in green tea EGCG is definedas a major green tea catechin that contributes to beneficialtherapeutic effects including antioxidant anti-inflammatoryanticancer and immunomodulatory effects [71]

EGCG binds strongly to many biological molecules andaffects a variety of enzyme activities and signal transductionpathways at micromolar or nanomolar levels [72] Most ofthe medicinal properties of green tea are associated withthe ldquoepicatechinsrdquo (2R 3R) rather than the catechins (2S3R) The green tea catechins have been shown to be moreeffective antioxidants than Vitamins C and E and theirorder of effectiveness as radical scavengers is ECG lt EGCGlt EGC lt EC lt catechin The metal-chelating propertiesof green tea catechins are believed to be also importantcontributors to their antioxidative activity [73] EGCG actsas a powerful hydrogen-donating radical scavenger of ROSand RNS and chelates divalent transition metal ions (Cu2+Zn2+ and Fe2+) thereby preventing the Fe2+-induced for-mation of free radicals in vitro Among 12 polyphenoliccompounds EGCG most potently inhibited Fe2+-mediatedDNA damage and iron ascorbate-promoted lipid peroxida-tion of brainmitochondrial membranes During ageing totalFe2+ concentration increases in some brain regions that areinvolved in the pathogenesis of degenerative diseases suchas Alzheimerrsquos Parkinsonrsquos and Huntingtonrsquos disease ThisFe2+ accumulation obviously fosters the production of thehighly reactive hydroxyl radicals (OHsdot) which attacks a largenumber of functional groups of the biomolecules in neuronsBy chelating redox-active transition metal ions the gallategroups of EGCG are thought to inhibit the Fenton-like-reaction mechanism [74] Thus the formation of OHsdot isinhibited Consequently polyunsaturated fatty acids in forexample mitochondrial membranes are protected from lipidperoxidation [75]

Results obtained byWeinreb et al shed some light on theantioxidative-iron chelating activities of EGCGunderlying itsneuroprotectiveneurorescue mechanism of action furthersuggesting a potential neurodegenerative-modifying effectfor EGCG Their study sought a deeper elucidation of themolecular neurorescue activity of EGCG in a progressiveneurotoxic model of long-term serum deprivation of human

SH-SY5Y neuroblastoma cells In this model proteomicanalysis revealed that EGCG (01ndash1120583M) affected the expres-sion levels of diverse proteins including proteins relatedto cytoskeletal components metabolism and heat shockEGCG induced the levels of cytoskeletal proteins such as betatubulin IV and tropomyosin 3 playing a role in facilitatingcell assembly Moreover EGCG increased the levels of thebinding protein 14-3-3 gamma involved in cytoskeletal regu-lation and signal transduction pathways in neurons EGCGdecreased protein levels and mRNA expression of the betasubunit of the enzyme prolyl 4-hydroxylase which belongsto a family of iron-oxygen sensors of hypoxia-induciblefactor (HIF) prolyl hydroxylases that negatively regulate thestability and degradation of several proteins involved in cellsurvival and differentiation Accordingly EGCG decreasedprotein levels of two molecular chaperones that were associ-ated with HIF regulation the immunoglobulin-heavy-chainbinding protein and the heat shock protein 90 beta [76]In vivo EGCG increased expression and activity of antiox-idant enzymes such as glutathione peroxidase glutathionereductase SOD and CAT and inhibited prooxidative onessuch as monoamine oxidase (MAO)-B The rat lifespanextension by EGCG was due to reduction of liver andkidney damage and improving age-associated inflammationand oxidative stress through the inhibition of transcriptionfactor NF-120581B signaling by activating the longevity factorsforkhead box class O 3A (FOXO3A) and SIRT1 [77] FOXOgenes are the closest human homologues of C elegansDAF-16 In C elegans DAF-16 increases the expression ofmanganese superoxide dismutase (SOD2) which convertssuperoxide to less damaging hydrogen peroxide and is apotent endogenous protector against free radicals amongother ldquoantiagingrdquo effects In vivo studies show that oxidativelesions in DNA proteins and other tissues accumulated withage and feeding calorically restricted diets (a potent insulinsensitizer) to rodents and humans mitigate this damage [78]Brown et al showed that 25120583M EGCG does not provokea significant change in the intracellular ROS level of daf-16mutant C elegans while in the wild type strain ROS levelsare significantly reduced by the flavonoid This indicates thatEGCG decreases ROS levels in the nematode in a DAF-16dependent manner [79]

Meng et al examined EGCG for its antiaging effect onhuman diploid fibroblasts Fibroblasts treated with EGCG at25 and 50 120583M for 24 h considerably increased CAT SOD1SOD2 and glutathione peroxidase gene expressions andtheir enzyme activities thus protecting the cells againstH2O2-induced oxidative damage accompanied by decreased

intracellular ROS accumulation and well-maintained mito-chondrial potentialMoreover fibroblasts treated with EGCGat 125 120583M for long term showed less intracellular ROS withhigher mitochondrial potential more intact mitochondrialDNA much elevated antioxidant enzyme levels and morejuvenile cell status compared to those of the untreated group[80] Davinelli et al investigated the combined effect ofL-carnosine and EGCG on the activation of two stress-responsive pathways heme oxygenase (HO)-1 andHsp72 (theinducible form of Hsp70) which play an important role incytoprotection against oxidative stress-induced cell damage


They demonstrated that the neuroprotective effects of EGCGand L-carnosine are achieved through the modulation ofHO-1Hsp72 systems Moreover the combined action ofboth compounds resulted in a synergistic increase of HO-1expression which suggests a crosstalk between the HO-1 andthe Hsp72-mediated pathways [81] Rodrigues et al analyzedthe neuroprotective effects of prolonged consumption of agreen tea extract rich in catechins but poor in EGCG andother green tea bioactive components that could also affordbenefit Theses authors demonstrated that the consumptionof an extract rich in catechins rather than EGCG protectedthe rat hippocampal formation from aging-related declinescontributing to improving the redox status and preventingthe structural damage observed in old animals with reper-cussions on behavioral performance [82] Feng et al investi-gated the protective effects of EGCG on hydrogen peroxide(H2O2)-induced oxidative stress injury in human dermal

fibroblasts The incubation of human dermal fibroblastswith EGCG markedly inhibited the human dermal fibrob-last injury induced by H

2O2 The assay for 22-diphenyl-

1-picrylhydrazyl radical scavenging activity indicated thatEGCG had a direct concentration-dependent antioxidantactivity Treatment of human dermal fibroblasts with EGCGsignificantly reversed the H

2O2-induced decrease of SOD

and glutathione peroxidase and the inhibition of malondi-aldehyde levels These authors suggested that EGCG shouldhave the potential to be used further in cosmetics and in theprevention of aging-related skin injuries [83]

In addition to the plethora of evidence that catechinsare cytoprotective via antioxidant and antiapoptotic effectsrecent observations suggest that the catechins may alsocontain prooxidant properties particularly at high concen-trations Thus at low concentrations in vitro (1ndash50120583M) theyare antioxidant and antiapoptotic whereas at higher con-centrations (100ndash500120583M) the reverse is true DNA isolatedfrom humans was exposed to 200120583M of EGC and EGCGwhich induced oxidative damage due to the production ofhydrogen peroxide Green tea extract (10ndash200120583gmL) andEGCG (20ndash200120583M) exacerbated oxidant activity oxidativestress genotoxicity and cytotoxicity induced by hydrogenperoxide in RAW 2647 macrophages [84] Catechins partic-ularly EGCG (100120583M) have also been shown to increase theoxidative damage incurred after exposure of DNA to 8-oxo-78-dihydro-21015840-deoxyguanosine [85]

The lifespan-prolonging effect of catechin in C elegansmay be related to a significant reduction in body lengthand modulation of energy-intensive stress response [86]Thelifespan extension of C elegans by apple procyanidins isdependent on SIR-21 as treatment with procyanidins hadno effect on the longevity of SIR-21 worms which lack theactivity of SIR-2 a member of the sirtuin family of NAD+-dependent protein deacetylases [87]

Extension of lifespan of D melanogaster by black teaextract seems to be at least partly due to increased expressionof SOD and catalase (CAT) [88]The analogous effect of blackrice extract is most likely due to upregulating the genes ofSOD1 SOD2 CAT Mth and Rpn11 at the transcriptionallevel [89] The effects of flavonoids (myricetin quercetinkaempferol and naringenin) on the lifespan of C elegans

involved an increased DAF-16 translocation and sod-3 pro-moter activity [90]

Longevity-promoting regimens including DR and inhi-bition of TORwith rapamycin RSV or the natural polyaminespermidine have often been associated with autophagy andin some cases were reported to require autophagy for theireffects Seemingly clearing cellular damage by autophagy is acommon denominator of many lifespan-extending manipu-lations [91]

Maintenance of optimal long-term health conditions isaccomplished by a complex network of longevity assuranceprocesses that are controlled by vitagenes a group of genesinvolved in preserving cellular homeostasis during stress-ful conditions Vitagenes encode for heat shock proteins(Hsp) Hsp32 Hsp70 the thioredoxin and the sirtuin proteinsystems Dietary antioxidants such as polyphenols havebeen demonstrated to be protective through the activationof hormetic pathways including vitagenes and proteasomalactivity degrading oxidatively modified proteins [92 93]

The life-prolonging effects of complex extracts are usuallyascribed to the antioxidants present in these extracts but theymay contain also toxins produced by plants against insectsand microorganisms which may induce a hormetic effect[36] Such a hormeticmechanism of action has been reportedfor the effects ofGinkgo biloba extract EGb 761 on the lifespanof C elegans [94] But perhaps antioxidants can also act viahormetic mechanisms and can belong to hormesis-inducingcompounds (hormetins) [93] Like toxins they act in someconcentration range their high concentrations being usuallytoxic A hormetic action of quercetin and other flavonoidson C elegans has been documented [95] It is debatablewhether hormesis which undoubtedly increases longevity ofinvertebrates can be of relevance as an aging-delaying factorin mammals and especially in human but there are reasons toassume that it modulates ldquopublicrdquo mechanisms of aging anddelay aging of mammals even if these effects are not of a largemagnitude [36]

Paradoxically the effect of hormesis may be mediated byincreased formation of ROS especially by the mitochondriabelieved to be the main source of ROS in the cell In theconcept ofmitochondrial hormesis (mitohormesis) increasedformation of ROS within the mitochondria evokes an adap-tive response that culminates in subsequently increased stressresistance assumed to ultimately cause a long-term reductionof oxidative stress Mitohormesis was claimed to providea common mechanistic denominator for the physiologicaleffects of physical exercise reduced calorie uptake andglucose restriction [96] This idea questions the FRTA andrather suggests that ROS act as essential signaling moleculesto promote metabolic health and longevity [97]

The glycolytic inhibitor lonidamine (5 120583M) was found toextend both median and maximum lifespan of C elegans by8 each This compound promotes mitochondrial respira-tion and increases formation of (ROS) Extension of lifespanis abolished by coapplication of an antioxidant indicatingthat increased ROS formation is required for the extension oflifespan by lonidamine [98]The same effectswere found inCelegans for low concentrations of arsenite [99] a cytotoxic and


antimalarial quassinoid glaucarubinone [100] and glucoserestriction [101]

In summary complex effects of exogenous antioxidantsin model organisms are compatible with the current under-standing of the role of ROS which are not only damagingagents but also take part in the signaling pathways andmay mediate beneficial response reactions on the basisof hormetic mechanisms [102ndash104] The direct antioxidantaction of antioxidant supplements seems thereby to be muchless important than induction of endogenous antioxidantsespecially via the Nrf-2 dependent pathway [105]

5 Antioxidant Supplementation in HumansDoes It Make Sense

Thechanges in the structure of contemporary human popula-tions are characterized by an increase in the fraction of peoplewho are 65 years and older a phenomenon of significantimportance from demographic political social and healthpoints of view [106] Nutrition has been recognized to havean important impact on overall mortality andmorbidity andits role in extending life expectancy has been the object ofextensive scientific research Dietary supplementation withantioxidants has become more and more popular Howevertheir biochemicalmechanisms of protection against oxidativestress and antiaging effects are not fully understood TheMediterranean diet (MeDi) a heart-healthy eating plan thatemphasizes fruits vegetables whole grains beans nutsseeds healthy fats and red wine consumption rich in antiox-idants like RSV which have been shown to have protectiveeffects against oxidative damage [107] The Mediterraneanlifestyle has been for many millennia a daily habit for peoplein Western civilizations living around the Mediterraneansea who worked intensively and survived with very fewseasonal foods A high adherence to the traditional MeDi isassociated with lowmortality (higher longevity) and reducedrisk of developing chronic diseases including cancer themetabolic syndrome depression and cardiovascular andneurodegenerative diseases [108] Recently several foodstuffshave been claimed as ldquoantiagingrdquo principally on the basis oftheir anti-inflammatory and antioxidative properties berriesdark chocolate beans (due to their high concentration inlow-fat protein protease inhibitors fibrins genistein andminerals) fish vegetables nuts whole grains garlic (due tothe high amount of garlic-derived polysulfides that undergocatabolism to hydrogen sulfide promoting vasodilatation)and avocados (as a great source of monounsaturated fatvitamins and antioxidants) [109]These authors reviewed thepathophysiological mechanisms that potentially link agingwith diet and the scientific evidence supporting the antiagingeffect of the traditional MeDi as well as of some specificfoods Recently five places [Okinawa (Japan) Sardinia (Italy)Loma Linda (California) Ikaria (Greece) and Nicoya (CostaRica)] have been recognized as having a very high prevalenceof octogenarians and have joined the Blue-Zones a NationalGeographic project Among the lifestyle habits that arecommon to those populations are high levels of daily physicalactivity (eg gardening and walking) positive attitude (egan ability to articulate a sense of purpose and enriching their

day with periods of calm and midday siesta) and a wisediet-high consumption of fruit wild plants and vegetableand low consumption of meat products That diet is similarto the MeDi [110] MeDi may not only reduce the risk forAlzheimerrsquos disease [111] but also lower mortality rates andspeed of disease progression in those already afflicted [112]On the other hand in a prospective cohort study of 1410older adults a higher adherence to MeDi did not lower therisk for incident dementia [113] In another study a higheradherence to MeDi failed to delay the transition from acognitively healthy status to mild cognitive impairment [114]Titova et al suggested that one possible reason for thesecontrasting findings could be that the MeDi score which iscommonly used to explore correlations between MeDi andhealth outcomes in elderly cohorts may mask health-relatedeffects of certain dietary components by including others thatare not relevant for the health domain of interest [115]

Most recently Bacalini et al discussed the potentialimpact of so-called ldquoepigenetic dietrdquo on age-related diseasesfocusing on cardiovascular disease highlighting the invo-lvement of epigenetic modifications rather than DNAmethy-lation such asmicroRNA [116] Epigeneticmodificationsmaydelay the aging process and impact diverse health benefitsby activating numerous intracellular pathways One leadingtheory suggests that bioactive phytochemicals including1-isothiocyanato-4-(methylsulfinyl) butane (sulforaphane)(2R 3R)-57-dihydroxy-2-(345-trihydroxyphenyl)-3-4-di-hydro-2H-chromen-3-yl 345-trihydroxybenzoate (epigal-locatechin gallate) RSV and CUR play significant roles asepigenetic modifiers [117 118]

In recent years the wealth of basic science researchsupporting RSVrsquos potential to treat delay and even pre-vent age-related chronic diseases has led to a number ofhuman clinical trials As research in nonclinical populationsbecomes more common disparity in dosing protocols andclinical endpoints will likely continue to cause conflictingfindings The range of daily RSV dosage used in clinicaltrials for healthy individuals (75 to 5000mg) [110] would beexpected to result in different clinical responses [119 120]Brown et al confirmed this demonstrating 2500mg to bemore effective than both lower (500mg and 1000mg) andhigher dosages (5000mg) in reducing plasma insulin-likegrowth factor-1 (IGF-1) concentrations [119]Though 1000mgRSV did not alter IGF-1 concentrations it was sufficient toreduce insulin-like growth factor binding protein-3 (IGFBP-3) concentrations This demonstrates that there may not bea single optimal dose of RSV but rather the ideal dose mayvary depending on the target outcomemeasures which is notuncommon for various drugs Further research is warrantedto increase our understanding of the physiological responsesof RSV before widespread use in humans can be promotedFurthermore chronic studies are an absolute must as it isstill unclear if RSV supplementation on the longer term isbeneficial for overall health status [111] A synthetic analogueof RSVHS-1793may be a new potent chemopreventive agentagainst human prostate and breast cancer cells [121 122] HS-1793 showedmore potent anticancer effects in several aspectscompared to RSV in MCF-7 (wild-type p53) and MDA-MB-231 (mutant p53) cells [122] Moreover HS-1793 may inhibit


human prostate cancer progression and angiogenesis byinhibiting the expression of hypoxic condition induced HIF-1120572 protein and vascular endothelial growth factor (VEGF)HS-1793 showed also more potent effects than RSV on thecytotoxic effects on PC-3 cells [120 122]

Gnetum gnemon is an arboreal dioecious plant that is cul-tivated in Indonesia The seeds of this species mainly containdimeric stilbenoid compounds [gnetin C gnemonoside Aand gnemonosideD along with trans-RSV] the active form ofRSV Recent data show showed that the ethanolic extract ofGgnemon seeds inhibits endothelial senescence suggesting thattrans-RSVplays a critical role in the prevention of endothelialsenescence [123] Fleenor et al suggested that gnetin may bea novel therapy for treating arterial aging in humans [124]

It should be noted that status elderly people are a very het-erogeneous groupThe nutrition situation of ldquoyoungrdquo seniorsdoes generally not differ from the situation of working-ageadults while institutionalized elderly people and those in needof care often show signs of a global malnutrition The criticalnutrients in the nutrition of the elderly particularly includevitamins B12 and D Six percent of all elderly have a manifestand 10 to 30 a functional vitamin B12 deficiency The maincause is vitamin B12 malabsorption resulting from a typeB atrophic gastritis The functional vitamin B12 deficiencyand the associated hyperhomocysteinemia are risk factors forneurodegenerative diseases and accelerate bone loss Withincreasing age the vitamin D status is deteriorating About50 of the elderly living in private households is deficient invitamin D in geriatrics vitamin D deficiency is more the rulethan an exception This is caused by a reduced endogenousbiosynthesis low UVB exposure and a diet low in vitaminD A vitamin D deficiency increases the risk for falls andfractures as well as the risk for neurodegenerative diseasesAlso the overall mortality is increased [125]

On the other hand up till now no prospective clinicalintervention studies have been able to show apositive associa-tion between antioxidant supplementation and increased sur-vival More studies are needed to understand the interactionsamong single nutrient modifications (eg proteinaminoacid fatty acids vitamins phytochemicals andminerals) thedegree of DR and the frequency of food consumption inmodulating antiagingmetabolic andmolecular pathways andin the prevention of age-associated diseases Meta-analysis ofmortality data from 57 trials with a supplementation periodof at least one year was published between 1988 and 2009with sample sizes ranging from 28 to 39876 (median =423) yielding 246371 subjects and 29295 all-cause deathsindicating that supplementation with vitamin E has no effecton all-cause mortality at doses up to 5500 IUd [79] The lastmeta-analysis of randomized controlled human trials andstudies performed with rodents also do not support the ideathat the consumption of dietary supplements can increase thelifespan of initially healthy individuals [91]

Most recently Macpherson et al reported that multivita-min-multimineral treatment has no effect on mortality risk[126] Bjelakovic et al noted that antioxidant supplementsdo not possess preventive effects and may be harmful withunwanted consequences to our health especially in well-nourished populations The optimal source of antioxidants

seems to come from our diet not from antioxidant supple-ments in pills or tablets Even more beta-carotene vitaminA and vitamin E may increase mortality Some recent largeobservational studies now support these findings [127]

In summary while beneficial effects of antioxidant sup-plements seem undoubtful in cases of antioxidant deficien-cies additional studies are warranted in order to designadapted prescriptions in antioxidant vitamins and mineralsfor healthy persons

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

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[2] K Ksiązek ldquoLetrsquos stop overlooking bacterial agingrdquo Biogerontol-ogy vol 11 no 6 pp 717ndash723 2010

[3] K A Hughes and R M Reynolds ldquoEvolutionary and mecha-nistic theories of agingrdquo Annual Review of Entomology vol 50pp 421ndash445 2005

[4] J Vina C Borras and J Miquel ldquoTheories of ageingrdquo IUBMBLife vol 59 no 4-5 pp 249ndash254 2007

[5] G J Brewer ldquoEpigenetic oxidative redox shift (EORS) theoryof aging unifies the free radical and insulin signaling theoriesrdquoExperimental Gerontology vol 45 no 3 pp 173ndash179 2010

[6] C A Cefalu ldquoTheories and mechanisms of agingrdquo Clinics inGeriatric Medicine vol 27 no 4 pp 491ndash506 2011

[7] P Zimniak ldquoRelationship of electrophilic stress to agingrdquo FreeRadical Biology and Medicine vol 51 no 6 pp 1087ndash1105 2011

[8] S I Rattan ldquoTheories of biological aging genes proteins andfree radicalsrdquo Free Radical Research vol 40 no 12 pp 1230ndash1238 2006

[9] S I Rattan V Kryzch S Schnebert E Perrier and C NizardldquoHormesis-based anti-aging products a case study of a novelcosmeticrdquo Dose-Response vol 11 no 1 pp 99ndash108 2013

[10] D Harman ldquoAging a theory based on free radical and radiationchemistryrdquo The Journal of Gerontology vol 11 no 3 pp 298ndash300 1956

[11] T B Kirkwood and A Kowald ldquoThe free-radical theory ofageingmdasholder wiser and still aliverdquo BioEssays vol 34 no 8 pp692ndash700 2012

[12] V N Gladyshev ldquoThe free radical theory of aging is dead Longlive the damage theoryrdquo Antioxidants amp Redox Signaling vol20 no 4 pp 727ndash731 2014

[13] B Poeggeler K Sambamurti S L Siedlak G Perry M ASmith andMA Pappolla ldquoA novel endogenous indole protectsrodent mitochondria and extends rotifer lifespanrdquo PLoS ONEvol 5 no 4 article e10206 2010

[14] V K Khavinson D M Izmaylov L K Obukhova and VV Malinin ldquoEffect of epitalon on the lifespan increase inDrosophila melanogasterrdquo Mechanisms of Ageing and Develop-ment vol 120 no 1ndash3 pp 141ndash149 2000

[15] S Stvolinsky M Antipin K Meguro T Sato H Abe and ABoldyrev ldquoEffect of carnosine and its trolox-modified deriva-tives on life span of Drosophila melanogasterrdquo RejuvenationResearch vol 13 no 4 pp 453ndash457 2010


[16] S Timmers J Auwerx and P Schrauwen ldquoThe journey ofresveratrol from yeast to humanrdquo Aging vol 4 no 3 pp 146ndash158 2012

[17] A Lancon J J Michaille and N Latruffe ldquoEffects of dietaryphytophenols on the expression of microRNAs involved inmammalian cell homeostasisrdquo Journal of the Science of Food andAgriculture vol 93 no 13 pp 3155ndash3164 2013

[18] J Marchal F Pifferi and F Aujard ldquoResveratrol in mammalseffects on aging biomarkers age-related diseases and life spanrdquoAnnals of theNewYorkAcademy of Sciences vol 1290 pp 67ndash732013

[19] L R Shen L D Parnell J M Ordovas and C Q LaildquoCurcumin and agingrdquo Biofactors vol 39 no 1 pp 133ndash1402013

[20] K Kitani T Osawa and T Yokozawa ldquoThe effects of tetrahy-drocurcumin and green tea polyphenol on the survival of maleC57BL6 micerdquo Biogerontology vol 8 no 5 pp 567ndash573 2007

[21] A Canuelo B Gilbert-Lopez P Pacheco-Linan E Martınez-Lara E Siles and A Miranda-Vizuete ldquoTyrosol a main phenolpresent in extra virgin olive oil increases lifespan and stressresistance inCaenorhabditis elegansrdquoMechanisms of Ageing andDevelopment vol 133 no 8 pp 563ndash574 2012

[22] V P Skulachev ldquoHow to clean the dirtiest place in the cellcationic antioxidants as intramitochondrial ROS scavengersrdquoIUBMB Life vol 57 no 4-5 pp 305ndash310 2005

[23] V N Anisimov M V Egorov M S Krasilshchikova et alldquoEffects of the mitochondria-targeted antioxidant SkQ1 onlifespan of rodentsrdquo Aging vol 3 no 11 pp 1110ndash1119 2011

[24] Y T Lam R Stocker and I W Dawes ldquoThe lipophilic antiox-idants 120572-tocopherol and coenzyme Q10 reduce the replicativelifespan of Saccharomyces cerevisiaerdquo Free Radical Biology andMedicine vol 49 no 2 pp 237ndash244 2010

[25] H Yazawa H Iwahashi Y Kamisaka K Kimura and HUemura ldquoProduction of polyunsaturated fatty acids in yeastSaccharomyces cerevisiae and its relation to alkaline pH toler-ancerdquo Yeast vol 26 no 3 pp 167ndash184 2009

[26] K Pallauf J K Bendall C Scheiermann et al ldquoVitamin C andlifespan in model organismsrdquo Food Chemistry and Toxicologyvol 58 pp 255ndash263 2013

[27] I M Ernst K Pallauf J K Bendall et al ldquoVitamin E supple-mentation and lifespan in model organismsrdquo Ageing ResearchReviews vol 12 no 1 pp 365ndash375 2013

[28] C Selman J S McLaren A R Collins G G Duthie and JR Speakman ldquoDeleterious consequences of antioxidant sup-plementation on lifespan in a wild-derived mammalrdquo BiologyLetters vol 9 no 4 Article ID 20130432 2013

[29] K L Hector M Lagisz and S Nakagawa ldquoThe effect ofresveratrol on longevity across species a meta-analysisrdquo BiologyLetters vol 8 no 5 pp 790ndash793 2012

[30] G Vecchio A Galeone V Brunetti et al ldquoConcentration-dependent size-independent toxicity of citrate capped AuNPsin Drosophila melanogasterrdquo PLoS ONE vol 7 no 1 articlee29980 2012

[31] J Kim M Takahashi T Shimizu et al ldquoEffects of a potentantioxidant platinum nanoparticle on the lifespan of Caeno-rhabditis elegansrdquoMechanisms of Ageing and Development vol129 no 6 pp 322ndash331 2008

[32] K L Quick S S Ali R Arch C Xiong D Wozniak and L LDugan ldquoA carboxyfullerene SOD mimetic improves cognitionand extends the lifespan of micerdquoNeurobiology of Aging vol 29no 1 pp 117ndash128 2008

[33] S R Spindler P L Mote and J M Flegal ldquoLifespan effects ofsimple and complex nutraceutical combinations fed isocalori-cally to micerdquo Age 2013

[34] Y Honda Y Fujita H Maruyama et al ldquoLifespan-extendingeffects of royal jelly and its related substances on the nematodeCaenorhabditis elegansrdquo PLoS ONE vol 6 no 8 article e235272011

[35] S Inoue S Koya-Miyata S Ushio K Iwaki M Ikeda andM Kurimoto ldquoRoyal Jelly prolongs the life span of C3HHeJmice correlation with reduced DNA damagerdquo ExperimentalGerontology vol 38 no 9 pp 965ndash969 2003

[36] E le Bourg ldquoHormesis aging and longevityrdquo Biochimica etBiophysica Acta vol 1790 no 10 pp 1030ndash1039 2009

[37] J M Carney P E Starke-Reed C N Oliver et al ldquoReversalof age-related increase in brain protein oxidation decreasein enzyme activity and loss in temporal and spatial memoryby chronic administration of the spin-trapping compoundN-tert-butyl-alpha-phenylnitronerdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 88 no9 pp 3633ndash3636 1991

[38] R A Shetty M J Forster and N Sumien ldquoCoenzyme Q(10)supplementation reverses age-related impairments in spatiallearning and lowers protein oxidationrdquo Age vol 35 no 5 pp1821ndash1834 2013

[39] L Partridge and D Gems ldquoMechanisms of ageing public orprivaterdquo Nature Reviews Genetics vol 3 no 3 pp 165ndash1752002

[40] T Bilinski R Zadrąg-Tęcza and G Bartosz ldquoHypertrophyhypothesis as an alternative explanation of the phenomenon ofreplicative aging of yeastrdquo FEMS Yeast Research vol 12 no 1pp 97ndash101 2012

[41] R Zadrag G Bartosz and T Bilinski ldquoIs the yeast a relevantmodel for aging of multicellular organisms An insight fromthe total lifespan of Saccharomyces cerevisiaerdquo Current AgingScience vol 1 no 3 pp 159ndash165 2008

[42] G Banhegyi L Braun M Csala F Puskas and J MandlldquoAscorbate metabolism and its regulation in animalsrdquo FreeRadical Biology and Medicine vol 23 no 5 pp 793ndash803 1997

[43] A Shibamura T Ikeda and Y Nishikawa ldquoA method fororal administration of hydrophilic substances toCaenorhabditiselegans effects of oral supplementation with antioxidants onthe nematode lifespanrdquoMechanisms of Ageing andDevelopmentvol 130 no 9 pp 652ndash655 2009

[44] E le Bourg ldquoOxidative stress aging and longevity inDrosophilamelanogasterrdquo FEBS Letters vol 498 no 2-3 pp 183ndash186 2001

[45] S A Farr T O Price W A Banks N Ercal and J E MorleyldquoEffect of alpha-lipoic acid on memory oxidation and lifespanin SAMP8 micerdquo Journal of Alzheimerrsquos Disease vol 32 no 2pp 447ndash455 2012

[46] Y L Xue T Ahiko T Miyakawa et al ldquoIsolation and Caeno-rhabditis elegans lifespan assay of flavonoids from onionrdquoJournal of Agricultural and Food Chemistry vol 59 no 11 pp5927ndash5934 2011

[47] P B Pun J Gruber S Y Tang et al ldquoAgeing in nematodesdo antioxidants extend lifespan in Caenorhabditis elegansrdquoBiogerontology vol 11 no 1 pp 17ndash30 2010

[48] W Chen L Rezaizadehnajafi and M Wink ldquoInfluence ofresveratrol on oxidative stress resistance and life span inCaenorhabditis elegansrdquo Journal of Pharmacy and Pharmacol-ogy vol 65 no 5 pp 682ndash688 2013


[49] K THowitz K J BittermanH Y Cohen et al ldquoSmallmoleculeactivators of sirtuins extend Saccharomyces cerevisiae lifespanrdquoNature vol 425 no 6954 pp 191ndash196 2003

[50] S Ghosh B Liu and Z Zhou ldquoResveratrol activates SIRT1 in aLamin A-dependent mannerrdquo Cell Cycle vol 12 no 6 pp 872ndash876 2013

[51] M Gertz G T Nguyen F Fischer et al ldquoA molecular mecha-nism for direct sirtuin activation by resveratrolrdquo PLoS ONE vol7 no 11 article e49761 Article ID e49761 2012

[52] D L Smith Jr T R Nagy andD B Allison ldquoCalorie restrictionwhat recent results suggest for the future of ageing researchrdquoEuropean Journal of Clinical Investigation vol 40 no 5 pp 440ndash450 2010

[53] B Rascon B P Hubbard D A Sinclair and G V AmdamldquoThe lifespan extension effects of resveratrol are conserved inthe honey bee and may be driven by a mechanism related tocaloric restrictionrdquo Aging vol 4 no 7 pp 499ndash508 2012

[54] C Burnett S Valentini F Cabreiro et al ldquoAbsence of effects ofSir2 overexpression on lifespan in C elegans and DrosophilardquoNature vol 477 no 7365 pp 482ndash485 2011

[55] J Chang A Rimando M Pallas et al ldquoLow-dose pterostilbenebut not resveratrol is a potent neuromodulator in aging andAlzheimerrsquos diseaserdquo Neurobiology of Aging vol 33 no 9 pp2062ndash2071 2012

[56] H Wen X Gao and J Qin ldquoProbing the anti-aging roleof polydatin in Caenorhabditis elegans on a chiprdquo IntegrativeBiology Quantitive Biosecences from Nano to Macro vol 6 no1 pp 35ndash43 2013

[57] S Shishodia ldquoMolecular mechanisms of curcumin action geneexpressionrdquo Biofactors vol 39 no 1 pp 37ndash55 2013

[58] A Monroy G J Lithgow and S Alavez ldquoCurcumin and neuro-degenerative diseasesrdquo Biofactors vol 39 no 1 pp 122ndash1322013

[59] J M Witkin and X Li ldquoCurcumin an active constiuent of theancient medicinal herb Curcuma longa L some uses and theestablishment and biological basis of medical efficacyrdquo CNS ampNeurological Disorders Drug Targets vol 12 no 4 pp 487ndash4972013

[60] L Xiang Y Nakamura Y M Lim et al ldquoTetrahydrocurcuminextends life span and inhibits the oxidative stress response byregulating the FOXO forkhead transcription factorrdquo Aging vol3 no 11 pp 1098ndash1109 2011

[61] Y Pu H Zhang P Wang et al ldquoDietary curcumin amelio-rates aging-related cerebrovascular dysfunction through theAMPKuncoupling protein 2 pathwayrdquo Cellular Physiology andBiochemistry vol 32 no 5 pp 1167ndash1177 2013

[62] S Yanase Y Luo and H Maruta ldquoPAK1-deficiencydown-regulation reduces brood size activates HSP162 gene andextends lifespan in Caenorhabditis elegansrdquo Drug Discoveries ampTherapeutics vol 7 no 1 pp 29ndash35 2013

[63] CW Yu C CWei andVH Liao ldquoCurcumin-mediated oxida-tive stress resistance in Caenorhabditis elegans is modulated byage-1 akt-1 pdk-1 osr-1 unc-43 sek-1 skn-1 sir-21 and mev-1rdquoFree Radical Research vol 48 no 3 pp 371ndash379 2014

[64] K-S Lee B-S Lee S Semnani et al ldquoCurcumin extendslife span improves health span and modulates the expressionof age-associated aging genes in Drosophila melanogasterrdquoRejuvenation Research vol 13 no 5 pp 561ndash570 2010

[65] L R Shen F Xiao P Yuan et al ldquoCurcumin-supplementeddiets increase superoxide dismutase activity and mean lifespanin Drosophilardquo Age vol 35 no 4 pp 1133ndash1142 2013

[66] R Doonan J J McElwee F Matthijssens et al ldquoAgainstthe oxidative damage theory of aging superoxide dismutasesprotect against oxidative stress but have little or no effect on lifespan in Caenorhabditis elegansrdquo Genes amp Development vol 22no 23 pp 3236ndash3241 2008

[67] V I Perez A Bokov H van Remmen et al ldquoIs the oxidativestress theory of aging deadrdquo Biochimica et Biophysica Acta vol1790 no 10 pp 1005ndash1014 2009

[68] J M van Raamsdonk and S Hekimi ldquoDeletion of the mito-chondrial superoxide dismutase sod-2 extends lifespan inCaenorhabditis elegansrdquo PLoS Genetics vol 5 no 2 articlee1000361 2009

[69] J M van Raamsdonk and S Hekimi ldquoSuperoxide dismutaseis dispensable for normal animal lifespanrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 109 no 15 pp 5785ndash5790 2012

[70] K A Rodriguez Y H Edrey P Osmulski M Gaczynskaand R Buffenstein ldquoAltered composition of liver proteasomeassemblies contributes to enhanced proteasome activity in theexceptionally long-lived naked mole-ratrdquo PLoS ONE vol 7 no5 article e35890 2012

[71] J W Gu K L Makey K B Tucker et al ldquoEGCG a major greentea catechin suppresses breast tumor angiogenesis and growthvia inhibiting the activation of HIF-1120572 and NF120581B and VEGFexpressionrdquo Vascular Cell vol 5 no 1 article 9 2013

[72] M J Lee P Maliakal L Chen et al ldquoPharmacokinetics of teacatechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans formation of different metabolites andindividual variabilityrdquo Cancer Epidemiology Biomarkers amp Pre-vention vol 11 no 10 part 1 pp 1025ndash1032 2002

[73] N T Zaveri ldquoGreen tea and its polyphenolic catechins medic-inal uses in cancer and noncancer applicationsrdquo Life Sciencesvol 78 no 18 pp 2073ndash2080 2006

[74] K Jomova D Vondrakova M Lawson and M Valko ldquoMetalsoxidative stress and neurodegenerative disordersrdquo Molecularand Cellular Biochemistry vol 345 no 1-2 pp 91ndash104 2010

[75] A Mahler S Mandel M Lorenz et al ldquoEpigallocatechin-3-gallate a useful effective and safe clinical approach for targetedprevention and individualised treatment of neurological dis-easesrdquoThe EPMA Journal vol 4 no 1 article 5 2013

[76] O Weinreb T Amit and M B Youdim ldquoA novel approachof proteomics and transcriptomics to study the mechanism ofaction of the antioxidant-iron chelator green tea polyphenol (-)-epigallocatechin-3-gallaterdquoFree Radical Biology andMedicinevol 43 no 4 pp 546ndash556 2007

[77] YNiu LNa R Feng et al ldquoThephytochemical EGCG extendslifespan by reducing liver and kidney function damage andimproving age-associated inflammation and oxidative stress inhealthy ratsrdquo Aging Cell vol 12 no 6 pp 1041ndash1049 2013

[78] B J Willcox T A Donlon Q He et al ldquoFOXO3A genotypeis strongly associated with human longevityrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 105 no 37 pp 13987ndash13992 2008

[79] M K Brown J L Evans and Y Luo ldquoBeneficial effects ofnatural antioxidants EGCG and 120572-lipoic acid on life span andage-dependent behavioral declines in Caenorhabditis elegansrdquoPharmacology Biochemistry andBehavior vol 85 no 3 pp 620ndash628 2006

[80] Q Meng C N Velalar and R Ruan ldquoEffects of epigallo-catechin-3-gallate on mitochondrial integrity and antioxidativeenzyme activity in the aging process of human fibroblastrdquo FreeRadical Biology andMedicine vol 44 no 6 pp 1032ndash1041 2008


[81] S Davinelli R di Marco R Bracale A Quattrone D Zellaand G Scapagnini ldquoSynergistic effect of L-Carnosine andEGCG in the prevention of physiological brain agingrdquo CurrentPharmaceutical Design vol 19 no 15 pp 2722ndash2727 2013

[82] J Rodrigues M Assuncao N Lukoyanov A Cardoso FCarvalho and J P Andrade ldquoProtective effects of a catechin-rich extract on the hippocampal formation and spatial memoryin aging ratsrdquo Behavioural Brain Research vol 246 pp 94ndash1022013

[83] B Feng Y Fang and S M Wei ldquoEffect and mechanismof epigallocatechin-3-gallate (EGCG) against the hydrogenperoxide-induced oxidative damage in human dermal fibrob-lastsrdquo Journal of Cosmetic Science vol 64 no 1 pp 35ndash44 2013

[84] L Elbling R M Weiss O Teufelhofer et al ldquoGreen tea extractand (-)-epigallocatechin-3-gallate the major tea catechin exertoxidant but lack antioxidant activitiesrdquoThe FASEB Journal vol19 no 7 pp 807ndash809 2005

[85] A Furukawa S Oikawa M Murata Y Hiraku and S Kawan-ishi ldquo(minus)-Epigallocatechin gallate causes oxidative damage toisolated and cellular DNArdquo Biochemical Pharmacology vol 66no 9 pp 1769ndash1778 2003

[86] N Saul K Pietsch R Menzel S R Sturzenbaum and C ESteinberg ldquoCatechin induced longevity in C elegans from keyregulator genes to disposable somardquoMechanisms of Ageing andDevelopment vol 130 no 8 pp 477ndash486 2009

[87] T Sunagawa T Shimizu T Kanda M Tagashira M Sami andT Shirasawa ldquoProcyanidins from apples (Malus pumila Mill)extend the lifespan of Caenorhabditis elegansrdquo Planta Medicavol 77 no 2 pp 122ndash127 2011

[88] S Bahadorani and A J Hilliker ldquoCocoa confers life spanextension in Drosophila melanogasterrdquo Nutrition Research vol28 no 6 pp 377ndash382 2008

[89] Y Zuo C Peng Y Liang et al ldquoBlack rice extract extends thelifespan of fruit fliesrdquo Food amp Function vol 3 no 12 pp 1271ndash1279 2012

[90] G Grunz K Haas S Soukup et al ldquoStructural featuresand bioavailability of four flavonoids and their implicationsfor lifespan-extending and antioxidant actions in C elegansrdquoMechanisms of Ageing and Development vol 133 no 1 pp 1ndash102012

[91] E L Abner F A Schmitt M S Mendiondo J L Marcumand R J Krysci ldquoVitamin E and all-cause mortality a meta-analysisrdquo Current Aging Science vol 4 no 2 pp 158ndash170 2011

[92] V Calabrese C Cornelius A T Dinkova-Kostova et al ldquoCel-lular stress responses hormetic phytochemicals and vitagenesin aging and longevityrdquo Biochimica et Biophysica Acta vol 1822no 5 pp 753ndash783 2012

[93] S I Rattan ldquoRationale and methods of discovering hormetinsas drugs for healthy ageingrdquo Expert Opinion on Drug Discoveryvol 7 no 5 pp 439ndash448 2012

[94] Z Wu J V Smith V Paramasivam et al ldquoGinkgo biloba extractEGb 761 increases stress resistance and extends life span ofCaenorhabditis elegansrdquo Cellular andMolecular Biology vol 48no 6 pp 725ndash731 2002

[95] A Kampkotter C G Nkwonkam R F Zurawski et al ldquoInves-tigations of protective effects of the flavonoids quercetin andrutin on stress resistance in themodel organismCaenorhabditiselegansrdquo Toxicology vol 234 no 1-2 pp 113ndash123 2007

[96] M Ristow and K Zarse ldquoHow increased oxidative stress pro-motes longevity andmetabolic health the concept ofmitochon-drial hormesis (mitohormesis)rdquo Experimental Gerontology vol45 no 6 pp 410ndash418 2010

[97] M Ristow and S Schmeisser ldquoExtending life span by increasingoxidative stressrdquo Free Radical Biology and Medicine vol 51 no2 pp 327ndash336 2011

[98] S Schmeisser K Zarse and M Ristow ldquoLonidamine extendslifespan of adult Caenorhabditis elegans by increasing theformation of mitochondrial reactive oxygen speciesrdquo Hormoneand Metabolic Research vol 43 no 10 pp 687ndash692 2011

[99] S Schmeisser K Schmeisser S Weimer et al ldquoMitochondrialhormesis links low-dose arsenite exposure to lifespan exten-sionrdquo Aging Cell vol 12 no 3 pp 508ndash517 2013

[100] K Zarse A Bossecker L Muller-Kuhrt et al ldquoThe phyto-chemical glaucarubinone promotes mitochondrial metabolismreduces body fat and extends lifespan of Caenorhabditis ele-gansrdquo Hormone and Metabolic Research vol 43 no 4 pp 241ndash243 2011

[101] T J Schulz K Zarse A Voigt N Urban M Birringer andM Ristow ldquoGlucose restriction extends Caenorhabditis eleganslife span by inducing mitochondrial respiration and increasingoxidative stressrdquo Cell Metabolism vol 6 no 4 pp 280ndash2932007

[102] G Bartosz ldquoReactive oxygen species destroyers or messen-gersrdquo Biochemical Pharmacology vol 77 no 8 pp 1303ndash13152009

[103] I Juranek D Nikitovic D Kouretas A W Hayes and A MTsatsakis ldquoBiological importance of reactive oxygen speciesin relation to difficulties of treating pathologies involvingoxidative stress by exogenous antioxidantsrdquo FoodChemistry andToxicology vol 61 pp 240ndash247 2013

[104] X Wang H Fang Z Huang et al ldquoImaging ROS signaling incells and animalsrdquo Journal of Molecular Medicine vol 91 no 8pp 917ndash927 2013

[105] H J Forman K J Davies and F Ursini ldquoHow do nutritionalantioxidants really work nucleophilic tone and para-hormesisversus free radical scavenging in vivordquo Free Radical Biology andMedicine vol 66 pp 24ndash35 2014

[106] I Sanchez Zaplana and E Maestre Gonzalez ldquo[Feeding andaging]rdquo Revista da Escola de Enfermagem vol 36 no 6 pp 8ndash15 2013

[107] S Dato P Crocco P DrsquoAquila et al ldquoExploring the role ofgenetic variability and lifestyle in oxidative stress response forhealthy aging and longevityrdquo International Journal of MolecularSciences vol 14 no 8 pp 16443ndash16472 2013

[108] P Chedraui and F R Perez-Lopez ldquoNutrition and health duringmid-life searching for solutions and meeting challenges for theaging populationrdquo Climacteric vol 16 supplement 1 pp 85ndash952013

[109] C Chrysohoou and C Stefanadis ldquoLongevity and diet Myth orpragmatismrdquoMaturitas vol 76 no 4 pp 303ndash307 2013

[110] C Chrysohoou J Skoumas C Pitsavos et al ldquoLong-termadherence to the Mediterranean diet reduces the prevalence ofhyperuricaemia in elderly individuals without known cardio-vascular disease the Ikaria studyrdquo Maturitas vol 70 no 1 pp58ndash64 2011

[111] N Scarmeas Y Stern R Mayeux J J Manly N Schupfand J A Luchsinger ldquoMediterranean diet and mild cognitiveimpairmentrdquo Archives of Neurology vol 66 no 2 pp 216ndash2252009

[112] N Scarmeas J A Luchsinger R Mayeux and Y SternldquoMediterranean diet and Alzheimer disease mortalityrdquo Neurol-ogy vol 69 no 11 pp 1084ndash1093 2007


[113] C Feart C Samieri V Rondeau et al ldquoAdherence to amediterranean diet cognitive decline and risk of dementiardquoThe Journal of the American Medical Association vol 302 no6 pp 638ndash648 2009

[114] N Cherbuin and K J Anstey ldquoThe mediterranean diet is notrelated to cognitive change in a large prospective investigationthe PATH Through Life Studyrdquo The American Journal of Geri-atric Psychiatry vol 20 no 7 pp 635ndash639 2012

[115] O E Titova E Ax S J Brooks et al ldquoMediterranean diet habitsin older individuals associations with cognitive functioningand brain volumesrdquo Experimental Gerontology vol 48 no 12pp 1443ndash1448 2013

[116] M G Bacalini S Friso F Olivieri et al ldquoPresent and futureof anti-ageing epigenetic dietsrdquo Mechanisms of Ageing andDevelopment 2014

[117] TMHardy and TO Tollefsbol ldquoEpigenetic diet impact on theepigenome and cancerrdquo Epigenomics vol 3 no 4 pp 503ndash5182011

[118] S L Martin T M Hardy and T O Tollefsbol ldquoMedicinalchemistry of the epigenetic diet and caloric restrictionrdquoCurrentMedicinal Chemistry vol 20 no 32 pp 4050ndash4059 2013

[119] V A Brown K R Patel M Viskaduraki et al ldquoRepeatdose study of the cancer chemopreventive agent resveratrol inhealthy volunteers safety pharmacokinetics and effect on theinsulin-like growth factor axisrdquo Cancer Research vol 70 no 22pp 9003ndash9011 2010

[120] J M Smoliga E S Colombo and M J Campen ldquoA healthierapproach to clinical trials evaluating resveratrol for primaryprevention of age-related diseases in healthy populationsrdquoAging vol 5 no 7 pp 495ndash506 2013

[121] D H Kim M A Hossain M Y Kim et al ldquoA novel resveratrolanalogueHS-1793 inhibits hypoxia-inducedHIF-1120572 andVEGFexpression and migration in human prostate cancer cellsrdquoInternational Journal of Oncology vol 43 no 6 pp 1915ndash19242013

[122] J A Kim D H Kim M A Hossain et al ldquoHS-1793 aresveratrol analogue induces cell cycle arrest and apoptotic celldeath in human breast cancer cellsrdquo International Journal ofOncology vol 44 no 2 pp 473ndash480 2014

[123] H Ota M Akishita H Tani et al ldquotrans-resveratrol inGnetumgnemon protects against oxidative-stress-induced endothelialsenescencerdquo Journal of Natural Products vol 76 no 7 pp 1242ndash1247 2013

[124] B S Fleenor A L Sindler N K Marvi et al ldquoCurcumin ame-liorates arterial dysfunction and oxidative stress with agingrdquoExperimental Gerontology vol 48 no 2 pp 269ndash276 2013

[125] A Strohle M Wolters and A Hahn ldquo[Food supplementsmdashpotential and limits part 3]rdquo Medizinische Monatsschrift furPharmazeuten vol 36 no 9 pp 324ndash340 2013

[126] H Macpherson A Pipingas and M P Pase ldquoMultivitamin-multimineral supplementation and mortality a meta-analysisof randomized controlled trialsrdquo The American Journal ofClinical Nutrition vol 97 no 2 pp 437ndash444 2013

[127] G Bjelakovic D Nikolova and C Gluud ldquoAntioxidant supple-ments and mortalityrdquo Current Opinion in Clinical Nutrition ampMetabolic Care vol 17 no 1 pp 40ndash44 2014

[128] A Krzepiłko A Swieciło J Wawryn et al ldquoAscorbate restoreslifespan of superoxide-dismutase deficient yeastrdquo Free RadicalResearch vol 38 no 9 pp 1019ndash1024 2004

[129] P JMinogue and J NThomas ldquoAn 120572-tocopherol dose responsestudy in Paramecium tetraureliardquo Mechanisms of Ageing andDevelopment vol 125 no 1 pp 21ndash30 2004

[130] J N Thomas and J Smith-Sonneborn ldquoSupplemental mela-tonin increases clonal lifespan in the protozoan Parameciumtetraureliardquo Journal of Pineal Research vol 23 no 3 pp 123ndash130 1997

[131] M Sawada and H E Enesco ldquoVitamin E extends lifespanin the short-lived rotifer Asplanchna brightwellirdquo ExperimentalGerontology vol 19 no 3 pp 179ndash183 1984

[132] N Ishii N Senoo-Matsuda K Miyake et al ldquoCoenzyme Q10can prolong C elegans lifespan by lowering oxidative stressrdquoMechanisms of Ageing and Development vol 125 no 1 pp 41ndash46 2004

[133] L A Harrington and C B Harley ldquoEffect of vitamin E on lifes-pan and reproduction in Caenorhabditis elegansrdquo Mechanismsof Ageing and Development vol 43 no 1 pp 71ndash78 1988

[134] S Zou J Sinclair M AWilson et al ldquoComparative approachesto facilitate the discovery of prolongevity interventions effectsof tocopherols on lifespan of three invertebrate speciesrdquoMech-anisms of Ageing and Development vol 128 no 2 pp 222ndash2262007

[135] V H Liao C W Yu Y J Chu W H Li Y C Hsieh and T TWang ldquoCurcumin-mediated lifespan extension in Caenorhab-ditis elegansrdquo Mechanisms of Ageing and Development vol 132no 10 pp 480ndash487 2011

[136] F Surco-Laos J Cabello E Gomez-Orte et al ldquoEffects ofO-methylated metabolites of quercetin on oxidative stressthermotolerance lifespan and bioavailability onCaenorhabditiselegansrdquo Food amp Function vol 2 no 8 pp 445ndash456 2011

[137] M Duenas F Surco-Laos S Gonzalez-Manzano et al ldquoDeg-lycosylation is a key step in biotransformation and lifespaneffects of quercetin-3-O-glucoside in Caenorhabditis elegansrdquoPharmacological Research vol 76 pp 41ndash48 2013

[138] K Pietsch N Saul S Chakrabarti S R Sturzenbaum RMenzel and C E Steinberg ldquoHormetins antioxidants andprooxidants defining quercetin- caffeic acid- and rosmarinicacid-mediated life extension in C elegansrdquo Biogerontology vol12 no 4 pp 329ndash347 2011

[139] S Abbas and M Wink ldquoEpigallocatechin gallate from greentea (Camellia sinensis) increases lifespan and stress resistance inCaenorhabditis elegansrdquo Planta Medica vol 75 no 3 pp 216ndash221 2009

[140] L Zhang G Jie J Zhang and B Zhao ldquoSignificant longevity-extending effects of EGCG on Caenorhabditis elegans understressrdquo Free Radical Biology andMedicine vol 46 no 3 pp 414ndash421 2009

[141] A A Sayed ldquoFerulsinaic acid attenuation of advanced glycationend products extends the lifespan of Caenorhabditis elegansrdquoJournal of Pharmacy and Pharmacology vol 63 no 3 pp 423ndash428 2011

[142] T Moriwaki S Kato Y Kato A Hosoki and Q M Zhang-Akiyama ldquoExtension of lifespan and protection against oxida-tive stress by an antioxidant herb mixture complex (KPG-7)in Caenorhabditis elegansrdquo Journal of Clinical Biochemistry andNutrition vol 53 no 2 pp 81ndash88 2013

[143] M Keaney andDGems ldquoNo increase in lifespan inCaenorhab-ditis elegans upon treatment with the superoxide dismutasemimetic EUK-8rdquo Free Radical Biology andMedicine vol 34 no2 pp 277ndash282 2003

[144] J H Bauer S Goupil G B Garber and S L Helfand ldquoAnaccelerated assay for the identification of lifespan-extendinginterventions in Drosophila melanogasterrdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 101 no 35 pp 12980ndash12985 2004


[145] D M Izmaylov and L K Obukhova ldquoGeroprotector effec-tiveness of melatonin investigation of lifespan of DrosophilamelanogasterrdquoMechanisms of Ageing and Development vol 106no 3 pp 233ndash240 1999

[146] B K Suckow and M A Suckow ldquoLifespan extension by theantioxidant curcumin in Drosophila melanogasterrdquo Interna-tional Journal of Biomedical Science vol 2 no 4 pp 402ndash4052006

[147] K T Chandrashekara andM N Shakarad ldquoAloe vera or resver-atrol supplementation in larval diet delays adult aging in thefruit fly Drosophila melanogasterrdquo The Journals of GerontologySeries A Biological Sciences and Medical Sciences vol 66 no 9pp 965ndash971 2011

[148] C Peng Y Zuo K M Kwan et al ldquoBlueberry extract prolongslifespan ofDrosophilamelanogasterrdquo Experimental Gerontologyvol 47 no 2 pp 170ndash178 2012

[149] TMagwere MWest K Riyahi M PMurphy R A Smith andL Partridge ldquoThe effects of exogenous antioxidants on lifespanand oxidative stress resistance in Drosophila melanogasterrdquoMechanisms of Ageing and Development vol 127 no 4 pp 356ndash370 2006

[150] R Banks J R Speakman and C Selman ldquoVitamin E sup-plementation and mammalian lifespanrdquoMolecular Nutrition ampFood Research vol 54 no 5 pp 719ndash725 2010

[151] A AMorley and K J Trainor ldquoLack of an effect of vitamin E onlifespan of micerdquo Biogerontology vol 2 no 2 pp 109ndash112 2001

[152] A D Blackett and D A Hall ldquoVitamin Emdashits significance inmouse ageingrdquo Age and Ageing vol 10 no 3 pp 191ndash195 1981

[153] M I Rodrıguez G Escames L C Lopez et al ldquoImprovedmitochondrial function and increased life span after chronicmelatonin treatment in senescent prone micerdquo ExperimentalGerontology vol 43 no 8 pp 749ndash756 2008

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


H3C

CH3

CH3

CH3CH3 CH3 CH3

CH3

HO

O

120572-tocopherol (vitamin E)

HO

HO

H

HO OH

O O

Ascorbic acid(vitamin C)

SS

O

OH

Lipoic acid

HO

OCH3

O O

H3CO

OH

HO

OH

O

OH

OH

OH

HO

OH

O

O

O

OH

OH

OH

OH

OH

OHEpigallocatechin gallate

CH3CH3O

CH3O

OH

OH

10

Ubiquinol (coenzyme Q10)

H3C O

O

HN HN CH3

Melatonin

HO

OH

Tyrosol

HO

OH

Quercetin

H3C

H3C

OH

OH SkQ1

HO

OH

OH

Resveratrol

H3C CH3

CH3

N+

Ominus

PBN

Catechin

Poplus

Curcumin

Figure 1 Some antioxidants studied as antiaging agents

2 Effect of AOs on the Lifespanof Model Organism

Many studies have addressed the question of supplementa-tion with antioxidant vitamins especially vitamins C and Eand synthetic compounds can prolong the lifespan of modelanimals Vitamin C (ascorbic acid) is the major hydrophilicantioxidant and a powerful inhibitor of lipid peroxidationIn membranes this molecule rapidly reduces 120572-tocopheroxylradicals and LDL to regenerate 120572-tocopherol and inhibitpropagation of free radicals Vitamin E (120572-tocopherol) isthe main hydrophobic antioxidant in cell membranes andcirculating lipoproteins Its antioxidant function is stronglysupported by regeneration promoted by vitamin C Vitamin

E is thought to prevent atherosclerosis through inhibition ofoxidative modification Coenzyme Q (ubiquinol CoQ) andlipoic acid in their reduced forms and melatonin (Figure 1)are also efficient antioxidants

Novel endogenous indole indolepropionamide anotherendogenous antioxidant is similar in structure to melatoninbinds to the rate-limiting component of oxidative phospho-rylation in complex I of the respiratory chain and acts asa stabilizer of energy metabolism thereby reducing ROSproduction [13]

Epitalon is a synthetic tetrapeptide Ala-Glu-Asp-Glyshowing antioxidant activity [14] (SS)-6-hydroxy-2578-tetramethylchroman-2-carbonyl-beta-alanyl-L-histidine (SS-Trolox-carnosine) is a synthetic analogue of carnosine


















[128]





[129]








[134]




[56]


[135]




[137]





[86]




[140]






[142]




Table 1 Continued









[65]



































































































References




































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































[128]





[129]








[134]




[56]


[135]




[137]





[86]




[140]






[142]




Table 1 Continued









[65]



































































































References




































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Table 1 Continued









[65]



































































































References




































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























































































References




































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















review article effect of antioxidants supplementation on...

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