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If aging is due to or contributed by free radical reactions, as postulated by the free radical theory of aging, lifespan of organisms should be extended by administration of exogenous antioxidants. This paper reviews data on model organisms concerning the effects of exogenous antioxidants (antioxidant vitamins, lipoic acid, coenzyme Q, melatonin, resveratrol, curcumin, other polyphenols, and synthetic antioxidants including antioxidant nanoparticles) on the lifespan of model organisms. Mechanisms of effects of antioxidants, often due to indirect antioxidant action or to action not related to the antioxidant properties of the compounds administered, are discussed. The legitimacy of antioxidant supplementation in human is considered.
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Review Article
Effect of Antioxidants Supplementation on Aging and Longevity
Izabela Sadowska-Bartosz1and Grzegorz Bartosz1,2
1Department of Biochemistry and Cell Biology, University of Rzesz´
ow,ZelwerowiczaStreet4,35-601Rzesz
´
ow, Poland
2Department of Molecular Biophysics, University of Ł´
od´
z, Pomorska 141/143, 90-236 Ł ´
od´
z, Poland
Correspondence should be addressed to Izabela Sadowska-Bartosz; isadowska@poczta.fm
Received  January ; Accepted  February ; Published  March 
Academic Editor: Efstathios S. Gonos
Copyright ©  I. Sadowska-Bartosz and G. Bartosz. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
If aging is due to or contributed by free radical reactions, as postulated by the free radical theory of aging, lifespan of organisms
should be extended by administration of exogenous antioxidants. is paper reviews data on model organisms concerning
the eects of exogenous antioxidants (antioxidant vitamins, lipoic acid, coenzyme Q, melatonin, resveratrol, curcumin, other
polyphenols, and synthetic antioxidants including antioxidant nanoparticles) on the lifespan of model organisms. Mechanisms
of eects of antioxidants, oen due to indirect antioxidant action or to action not related to the antioxidant properties of the
compounds administered, are discussed. e legitimacy of antioxidant supplementation in human is considered.
1. Introduction
Aging is an unavoidable, universal, biological phenomenon
aecting all multicellular organisms (with few apparent
exceptions) and probably common also among unicellular
organisms, including protozoa, yeast, and bacteria [,].
Although dierent hypotheses have been put forward to
explain the cellular and molecular mechanisms of aging,
recent studies made it increasingly clear that aging is due to
accumulation of molecular damage, giving rise to a unied
theory of aging []. Among reactions contributing to
this damage, reactions of free radicals and other reactive
oxygen species are the main reason, apart from reactions
of metabolites such as sugars and reactive aldehydes and
spontaneous errors in biochemical processes [].
From a thermodynamic point of view, all aerobic organ-
isms are subject to the action of common oxidant, that is,
oxygen. e redox potential of the O2/H2Oredoxsystem
(approximately+.VatpH)ismorepositivethanthoseof
most other biologically relevant redox systems. erefore, the
oxidation by O2of organic compounds will have a negative
free enthalpy and should proceed spontaneously. In other
words, organic compounds and structures composed of them
are thermodynamically unstable in an oxygen-containing
atmosphere. Molecular oxygen, in its triplet basal state,
is rather unreactive due to the spin restriction. However,
formation of oxygen free radicals and other reactive oxygen
species (ROS) opens the gate for potentially deleterious
oxidative reactions of oxygen []. Seen from that perspective,
the “Free Radical eory of Aging” (FRTA) [], now more
commonly termed the oxidative damage theory of ageing,
seems to address a key facet of intrinsic biological instability
of living systems [,]. e basic idea of the FRTA is
that free radicals and other ROS, formed unavoidably in the
course of metabolism and arising due to the action of various
exogenous factors, damage biomolecules, and accumulation
ofthisdamagearethecauseofage-relateddiseasesandaging.
If FRTA is true, antioxidants should slow down aging
and prolong lifespan. is apparently obvious conclusion has
stimulated enormous number of studies aimed at nding a
relationship between levels of endogenous antioxidants and
lifespan of various organisms on the eects of addition of
exogenous antioxidants on the course of aging and lifespan
of model organisms. Pubmed provides more than  hits
for conjunction of terms “antioxidant” and “aging or ageing.
However, in spite of the plethora of studies, the answer to the
question if exogenous antioxidants can prolong life is far from
being clear.
Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 404680, 17 pages
http://dx.doi.org/10.1155/2014/404680
BioMed Research International
H3C
CH3
CH3
CH3CH3CH3CH3
CH3
HO
O
𝛼-tocopherol (vitamin E)
HO
HO
H
HO OH
OO
Ascorbic acid
(vitamin C)
S
S
O
OH
Lipoic acid
HO
OCH3
OO
H3CO
OH
HO
OH
O
OH
OH
OH
HO
OH
O
O
O
OH
OH
OH
OH
OH
OH
Epigallocatechin gallate
CH3
CH3O
CH3O
OH
OH
10
Ubiquinol (coenzyme Q10)
H3CO
O
HN HN CH3
Melatonin
HO
OH
Tyr osol
HO
OH
Quercetin
H3C
H3C
OH
OH SkQ1
HO
OH
OH
Resveratrol
H3CCH3
CH3
N+
O
PBN
Catechin
P
Curcumin
F : Some antioxidants studied as antiaging agents.
2. Effect of AOs on the Lifespan
of Model Organism
Many studies have addressed the question of supplementa-
tion with antioxidant vitamins, especially vitamins C and E,
and synthetic compounds can prolong the lifespan of model
animals. Vitamin C (ascorbic acid) is the major hydrophilic
antioxidant and a powerful inhibitor of lipid peroxidation.
In membranes, this molecule rapidly reduces 𝛼-tocopheroxyl
radicals and LDL to regenerate 𝛼-tocopherol and inhibit
propagation of free radicals. Vitamin E (𝛼-tocopherol) is
the main hydrophobic antioxidant in cell membranes and
circulating lipoproteins. Its antioxidant function is strongly
supported by regeneration promoted by vitamin C. Vitamin
E is thought to prevent atherosclerosis through inhibition of
oxidative modication. Coenzyme Q (ubiquinol, CoQ) and
lipoic acid in their reduced forms and melatonin (Figure )
are also ecient antioxidants.
Novel endogenous indole, indolepropionamide, another
endogenous antioxidant, is similar in structure to melatonin,
binds to the rate-limiting component of oxidative phospho-
rylation in complex I of the respiratory chain, and acts as
a stabilizer of energy metabolism, thereby reducing ROS
production [].
Epitalon is a synthetic tetrapeptide Ala-Glu-Asp-Gly,
showing antioxidant activity []. (S,S)--hydroxy-,,,-
tetramethylchroman--carbonyl-beta-alanyl-L-histidine (S,
S-Trolox-carnosine) is a synthetic analogue of carnosine
BioMed Research International
containing a Trolox (water-soluble analog of vitamin E)
residue [].
Recently, the antiaging eect of resveratrol (RSV) has
been a hotly discussed topic. RSV was rst isolated from the
roots of white hellebore (Veratr u m g randio r u m, O. Lo e s )in
 and later in  from the roots of Polygonum cuspida-
tum (or Fallopia japonica), a plant used in traditional Chinese
and Japanese medicine []. is polyphenolic compounds
are a phytoalexin that stimulates cell defenses in plants. RSV is
synthesized in many plants, such as peanuts, blueberries, pine
nuts, and grapes, which protects them against fungal infec-
tion and ultraviolet irradiation. It mainly accumulates in a
glycosylated state (piceid). Some dimethoxylated RSV deriva-
tives (pterostilbene) are also present as well as RSV oligomers
(𝜀-viniferin, a dimer, and hopeaphenol, a tetramer). Inter-
estingly, RSV plays a number of protective roles in animals,
although it is rapidly metabolized in a conjugated form
(glucorono- or sulfo-) []. Since the early s, it has been
suggested that RSV could be the molecule responsible for
the French paradox, that is, the low occurrence of coronary
heart diseases and cardiovascular diseases in South-Western
France, despite the consumption of a high saturated fat diet.
e French paradox was correlated to some extent with the
regular consumption of red wine, which contains high levels
of RSV [].
Curcumin [,-bis (-hydroxy--methoxyphenyl)-,-
heptadiene-,-dione] (diferuloylmethane, CUR), the main
component of the yellow extract from the plant Curcuma
longa (turmeric, a popular Indian spice), is a main bio-
active polyphenol, which has been used widely as a spice,
food additive, and a herbal medicine in Asia []. Tetrahy-
drocurcumin (THC) is an active metabolite of CUR. Orally
ingested CUR is metabolized into THC by a reductase found
in the intestinal epithelium. THC possesses extremely strong
antioxidant activity compared to other curcuminoids. e
antioxidantroleofTHChasbeenimplicatedinrecovery
from renal injury in mice and in anti-inammatory responses
[]. Tyrosol is a main phenol present in extra virgin olive
oil [].
Some researchers hope that development of new means
of introduction of antioxidants into cells or construction of
new antioxidants can make a breakthrough in antioxidant
modulation of aging and longevity. If mitochondria are the
main source of ROS in the cell, mitochondrially targeted
antioxidants could be more eective than traditional ones.
is idea was the basis of synthesis of positively charged
derivatives of plastoquinone and other antioxidants which
are retained in the mitochondria due to the high negative
potential at the inner mitochondrial membrane []. SkQ is
a mitochondria-targeted, plastoquinone-containing [-(󸀠-
plastoquinonyl) decyltriphenylphosphonium] [].
Results of studies on the supplementation of model
organisms with antioxidant vitamins and other antioxidants
are divergent. Examples of recent studies devoted to this
questionaresummarizedinTable  and these data are only
commented in this section.
Ascorbic acid partially rescued the lifespan of superoxide
dismutase (SOD)-decient yeast Saccharomyces cerevisiae
which was considerably reduced as a result of lack of this
vital antioxidant enzyme []. However, this eect should
be seen rather as a partial restoration of the redox sta-
tus seriously deranged in these cells rat compared to life
extension of normal yeast cells. Another study, using but
D-erythroascorbic acid (ascorbic acid homologue produced
in the yeast) showed little eect of this antioxidant on the
replicative lifespan of wild-type yeast []. Similar reports
have been published for multicellular organisms, in which
antioxidants had life-prolonging eects on mutants decient
in antioxidant defense or were subjected to oxidative stress
but did not aect the lifespan of healthy wild type animals.
Supplementation of the growth medium of S. cerevisiae
with the lipophilic antioxidants 𝛼-tocopherol and CoQ alone,
or in combination with 𝛼-tocopherol, increased oxidative
stress and decreased cellular lifespan []. It should be
recalled, however, that S. cerevisiae is unable to produce
polyunsaturated fatty acids [] so lipid oxidative damage
may be of lower importance and lack of protective eects of
hydrophobic antioxidants, located mainly in cell membranes
[], maybe not surprising in this species.
Eect of vitamin C on the lifespan of several multicel-
lular model organisms (Caenorhabditis elegans, Drosophila
melanogaster, mice, rats, and guinea pigs) has been recently
reviewedbyPallaufetal.Noconsistentpictureemergesfrom
the summary of data, some studies demonstrating prolonga-
tion of lifespans and others showing no eect []. Ernst et
al. conducted a comprehensive literature review regarding the
eect of vitamin E on lifespan in model organisms including
single-cell organisms, rotifers, C. elegans,D. melanogaster,
and laboratory rodents. e ndings of their review suggest
that there is no consistent benecial eect of vitamin E on
lifespan in model organisms, which corresponds to results
of meta-analysis of mortality in human intervention studies
[].
While most of the studies concerning mammals have
been done on mice, an interesting study has addressed the
eect of dietary supplementation with either vitamin E or
vitamin C (ascorbic acid) on a wild-derived animal, short-
tailed eld vole (Microtus agrestis). Antioxidant supplemen-
tation for nine months reduced hepatic lipid peroxidation,
but DNA oxidative damage to hepatocytes and lymphocytes
was unaected. Surprisingly, antioxidant supplementation
signicantly shortened lifespan in voles maintained under
both cold (7±2
C) and warm (22 ± 2C) conditions [].
Hector et al. () quantied the current knowledge of
life extension of model organisms by RSV. ese authors
used meta-analysis techniques to assess the eect of RSV on
survival, using data from  published papers, including six
species: yeast, nematodes, mice, fruit ies, Mexican fruit ies,
and turquoise killish. While the lifespan of the turquoise
killish was positively aected by the RSV treatment, results
are less clear for ies and nematodes, as there was important
variability between the studies [].
e rapid expansion of nanotechnology provided a huge
assortment of nanoparticles (NPs) that dier in chemical
composition, size, shape, surface charge and chemistry, and
coating and dispersion status. Antioxidant delivery can be
BioMed Research International
T : Eect of supplementation with natural and synthetic antioxidants on the lifespan of model organisms.
Organism Additive Parameter studied Eect reported Reference
Saccharomyces cerevisiae,
budding yeast Ascorbic acid Replicative lifespan of SOD-
decient mutant
Partial restoration of normal
replicative lifespan []
Saccharomyces cerevisiae Erythroascorbic acid Replicative lifespan of
wild-type yeast Little eect []
Saccharomyces cerevisiae 𝛼-tocopherol, CoQ alone,
or with 𝛼-tocopherol Replicative lifespan Decrease increased
oxidative stress []
Paramecium tetraurelia Vitamin E Clonal lifespan Increase maximal ( versus 
ssions) at   mg/L medium []
Paramecium tetraurelia Melatonin Clonal lifespan []
Asplanchna
brightwellii,rotifer Vitamin E ( ug/mL) Lifespan Increase limited to
the prereproductive stage [][]
Philodina acuticornis
odiosa,rotifer Indolepropionamide Lifespan Increase up to -fold []
Caenorhabditis elegans,
nematode
CoQ
Vitamin E Lifespan Prolongation []
Caenorhabditis elegans  𝜇g/mL vitamin E
from hatching to day  Survival Increase (–%) []
Caenorhabditis elegans 𝛾-Tocopherol Lifespan Slight extension,
no eect of 𝛼-tocopherol []
Caenorhabditis elegans 𝛾-, or 𝛼-tocopherol Lifespan No eect []
Caenorhabditis elegans Polydatin, resveratrol--O-
𝛽-mono-D-glucoside Mean lifespan
Increase by up to % and %
under normal and acute stress
conditions, respectively
[]
Caenorhabditis elegans Curcumin Lifespan Increase in mev-
and daf- mutants []
Caenorhabditis elegans
Quercetin,
isorhamnetin,
and tamarixetin
Lifespan Increase by –% []
Caenorhabditis elegans Quercetin--O-glucoside Lifespan Increase by low concentrations,
decrease by high concentrations []
Caenorhabditis elegans
Myricetin,
quercetin, kaempferol,
and naringenin
Lifespan Increase []
Caenorhabditis elegans Caeic acid, and
rosmarinic acid Lifespan Increase []
Caenorhabditis elegans Catechin Mean lifespan, median lifespan Increase by  and %,
respectively, at   𝜇M[]
Caenorhabditis elegans ()-Epicatechin Lifespan No eect []
Caenorhabditis elegans Epigallocatechin gallate
( nM) Mean lifespan Increase by % []
Caenorhabditis elegans Epigallocatechin gallate Mean lifespan Increase under stress conditions
but not under normal conditions []
Caenorhabditis elegans Ferulsinaic acid
(.– 𝜇M) Lifespan Increase []
Caenorhabditis elegans Procyanidins from apples
(Malus pumila, 𝜇g/mL) Mean lifespan Increase []
Caenorhabditis elegans Tyrosol Lifespan Increase []
Caenorhabditis elegans
Mn-N,N󸀠-bis(salicylidene)
ethylenediamide chloride
(EUK-), an SOD mimetic
Lifespan Extension but only aer specic
culture conditions []
Caenorhabditis elegans KPG-, a herb complex Lifespan Prolongation []
Caenorhabditis elegans EGb , extract of
Ginkgo biloba leaves Mean lifespan Prolongation []
BioMed Research International
T  : C o n t i n u e d.
Organism Additive Parameter studied Eect reported Reference
Caenorhabditis elegans Royal gelly Lifespan Prolongation []
Caenorhabditis elegans Pt nanoparticles
(a SOD/CAT mimetic) Lifespan Prolongation []
Drosophila melanogaster Lipoic acid Lifespan Increase []
Drosophila melanogaster Melatonin Lifespan Increase []
Drosophila melanogaster Epitalon Lifespan Increase by –% []
Drosophila melanogaster Carnosine Average lifespan Increase in males,
no eect on females []
Drosophila melanogaster S,S-Trolox-carnosine Average lifespan Increase in males (by %)
and in females (by %) []
Drosophila melanogaster Curcumin,  mg/g
of medium Lifespan Increase []
Drosophila melanogaster Curcumin, . and
. mg/g Lifespan
Increase by % and
% in females and by
%and%inmales
[]
Drosophila melanogaster Curcumin Lifespan Extension, gender- and
genotype-specic []
Drosophila melanogaster Aloe vera extract Lifespan Extension []
Drosophila melanogaster Extract of black rice Lifespan Increase by ca % []
Drosophila melanogaster Cacao Lifespan Increase []
Drosophila melanogaster Black tea extract Mean lifespan Increase by % []
Drosophila melanogaster
EUK-
Mn -methoxy-N,N󸀠-
bis(salicyldene)
ethylenediamine chloride
(EUK-), mitoquinone
Lifespan No eect on wild type ies []
Anastrepha ludens,
Mexican fruit y 𝛾-, or 𝛼-Tocoph erol Lif esp an No ee ct []
Mus musculus,mouse,
strain CBL/ Vitamin E, lifelong Median lifespan Increase by % []
Mus musculus Vitamin E Lifespan No eect []
Mus musculus,CH/He
and LAF Vitamin E, .% w/w Lifespan Increase in mean lifespan, no
eect on maximum lifespan []
Mus musculus,SAMP
(senescence-acceleration
prone)
Lipoic acid Lifespan Decrease []
Mus musculus, SAMP Melatonin Lifespan Increase []
Mus musculus Tetrahydrocurcumin,
.% from the age of  m Average lifespan Increase []
Mus musculus,malesfrom
the age of m
LGcombo, complex
mixture of botanical
extracts, vitamins,
and nutraceuticals
Lifespan No eect []
Mus musculus A fullerene mimetic of SOD Lifespan Prolongation []
Mus musculus Royal gelly Lifespan Increased mean lifespan,
no eect on maximal lifespan []
Rattus rattus, rat, Wistar Epigallocatechin gallate Median lifespan Increase by – weeks
(control:  weeks) []
Microtus agrestis,eldvole Vitamin C or
vitamin E, for  m Lifespan Decrease []
Mus musculus, Ellobius
talpinus (mole vole),
Phodopus campbelli (dwarf
hamster)
SkQ (mitochondrially
targeted plastoquinone
derivative)
Survival Increase []
BioMed Research International
signicantly improved using various NPs []; some NPs
possess antioxidant properties and are able to eciently
attenuate oxidative stress by penetrating specic tissues or
organs, even when administered at low concentrations and
foundtoincreasethelifespanofmodelorganisms[,
]. Nevertheless, there is an increasing concern about the
toxicity, especially genotoxicity of NPs, and this question eld
requires thorough studies.
It has been argued that antioxidant mixtures, such as
those found in natural products, are better than simple
antioxidant formulas, that is, due to synergism between
antioxidants. KPG- is a commercially available herb mixture
containing ymus vulgaris,Rosmarinus ocinalis,Curcuma
longa,Foeniculum vulgare,Vitis v inife ra (polyphenol), silk
protein, Tar a x ac u m o c i n ale , and Eleutherococcus senticosus,
which have been reported to include a variety of antioxidant,
antitumoral, and anti-inammatory bioactivities. Positive
eects of such extracts on the lifespan of model organisms
have been reported but other studies showed no signicant
eects. For example, administration of a complex mixture of
vitamins, minerals, botanical extracts, and other nutraceu-
ticals, rich in antioxidants and anti-inammatories, to male
mice starting from the age of  m, failed to aect their
lifespan [].
In the honeybee Apis mellifera L., queens live and repro-
duce for – years but hive workers, which are derived
fromthesamediploidgenome,liveforonlyweeks
during the spring and summer. Queens are fed throughout
their lives with royal jelly, produced by the hypopharyngeal,
postcerebral, and mandibular glands of the worker bees. In
contrast,workersarefedroyaljellyforonlyashortperiodof
time during their larval stages. It suggests that royal contains
longevity-promoting agents for queens which may perhaps
aect the longevity of other species if it aects the “public”
mechanisms of aging []. However, the eect of royal jelly on
the maximal lifespan of mice was rather disappointing [].
Moreover, the action of complex preparations including plant
extracts is dicult to interpret because, apart from antiox-
idants, they contain various biologically active products
[].
3. Reversal of Age-Related
Changes by Antioxidants
Apart from the eect of prolongation of lifespan by antioxi-
dant administration throughout most of the lifetime (long-
lasting experiments), another approach to study antiaging
eect of antioxidants consists in short-time experiments, in
which functional tests compare the status of experimental
animals before and aer supplementation. An experiment
of this type consisted in administration of N-tert-butyl-𝛼-
phenylnitrone (PBN) to aged Mongolian gerbils for  weeks.
Such a treatment reduced the amount of protein carbonyls
in brain, augmented the activity of glutamine synthetase,
and decreased the number of errors in radial arm maze
patrolling behavior, normalizing the values to those typical
for young animals. However, these changes were reversible
aer cessation of PBN treatment []. Similarly, relatively old
mice (. months) fed high-CoQ diet (. mg/g) for  weeks
improved special performance in Morris water maze test and
reduced protein oxidative damage [].
4. How Do ‘‘AOs’’ (Do Not) Act?
Possible Explanations
Generally, the eects of antioxidant supplementation in
model organisms are disappointing. Many studies showed no
eect or even negative eects on the lifespan. Only in some
cases considerable prolongation of lifespan was obtained and
in organisms which are evolutionarily quite distant from
mammals. In some cases, mean but not maximal lifespan was
aected,whichmaybecausedbyreductionofmortalitydue
to diseases rather than interference with the aging process
itself. An apparently obvious conclusion from the plethora
of studies could be that antioxidants cannot be expected to
prolong signicantly the lifespan, especially of mammals,
which does not support the FRTA.
However, perhaps such a simple conclusion would be
precocious, not taking into account experimental setup
employed in dierent studies. One of the questions is the
relevance of use of model organisms if understanding human
aging is aimed. e basic biochemical mechanisms are so
common in all living world that there are good reasons
to expect that the mechanisms governing aging are also
universal. It may not always be true. It has been suggested
that there are “public” and “private” mechanisms of aging
[]. Seemingly, the mechanisms of aging of S. cerevisiae,
used as a model organism in biogerontology, may be rather
private than public. is refers to both “chronologic” aging
where yeast survival is limited by exhaustion of nutrients
and/or accumulation of toxic products of metabolism and to
“replicative” aging which seems to be a measure of fecundity
rather than longevity and is limited by other factors compared
to those relevant to aging of multicellular organisms [,].
Somatic cells of C. elegans and D. melanogaster are postmi-
totic, which only partly reects the situation in mammalian
tissues.
It should be taken into account that ascorbic acid,
which is a vitamin for primates, is synthesized by other
organisms including mice and rats []. It does not preclude
the antioxidant action of ascorbate in these organisms but
administration of exogenous ascorbic acid may inhibit its
endogenous synthesis.
Sometimes the administered antioxidants may be not
fully taken up especially when added to complex media.
Numerous studies using C. elegans have used a protocol,
in which chemicals are orally delivered by incorporating
them into the nematode growth media or mixing with the
food bacteria. However, actual exposure levels are dicult
to estimate. e use of liposomes loaded with water-soluble
substances resulted in successful oral delivery of chemicals
into the intestines of C. elegans. When using liposomes,
oral administration of hydrophilic antioxidants (ascorbic
acid, N-acetyl-cysteine, reduced glutathione, and thiopro-
line) prolonged the lifespan of the nematodes, whereas the
conventional method of delivery showed no longevity eects
[]. It is also dicult to estimate the amount of ingested
food in many model organisms, such as C. elegans or D.
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melanogaster, so the eects of admixture of high doses of
antioxidants may lead feeding rejection and thus starvation
[].
e life-prolonging eect of antioxidants may be limited
to a more or less narrow “therapeutic window”. is window
may be dierent for various organisms, that is, due to
dierences in the uptake rate and metabolism. Not always,
the experimental conditions may hit the therapeutic window.
Introduction of antioxidants in the diet may aect the
endogenous antioxidant system and the eect is not always
advantageous. Farr et al. reported that supplementation with
lipoic acid reduced indices of oxidative stress increasing
glutathione level and decreasing the concentration of lipid
peroxidation products and glutathione peroxidase activity.
However, this treatment actually decreased the lifespan of
SAMP mice [].
e life-prolonging eect can be correlated with
antioxidant properties of an additive in some but not in
other cases. For example, onion avonoids, quercetin,
quercetin 󸀠-O-𝛽-D-glucopyranoside, and quercetin -O-𝛽-
D-glucopyranoside-( )-𝛽-D-glucopyranoside increased
the lifespan of C. elegans butnodirectcorrelationwasfound
between antioxidative activity and antiaging activity [].
Similarly, no correlation was found between the antioxidant
activities of  plant extracts and their lifespan benets in C.
elegans [].
It should be remembered that (i) the eects of an
antioxidantmaybenotduetoitsdirectantioxidantactionbut
to its indirect antioxidant eects (induction of endogenous
antioxidant mechanisms) and (ii) compound called “antioxi-
dant” may have a plethora of other eects in vivo,notrelated
at all to its antioxidant action.
Antioxidants can have deleterious eects on traits that, as
a consequence, increase longevity. For instance, thioproline
was reported to increase longevity of D. melanogaster which
might be ascribed to its direct antioxidant action; however,
it decreased also the metabolic rate, mean weight at eclosion,
anddevelopmentspeedofthefruitieswhichmightbemore
relevant for its life-prolonging eect [].
Similarly, RSV reduced acute oxidative damage; however,
it did not extend the normal life span of C. elegans indi-
cating that antioxidant properties of this compound were
probably not adequate to aect ageing []. Howitz and
colleagues proposed that RSV is capable of increasing the
deacetylase activity of human sirtuin  (SIRT) []. SIRT,
the closest homolog of the yeast silent information regulator
(sir) protein, functions as an NAD+-dependent histone and
nonhistone protein deacetylase in several cellular processes,
like energy metabolism, stress responses, and so forth. It
hasbeenfoundthatRSVactivatesSIRTbyincreasingits
binding with lamin A, thus aiding in the nuclear matrix
localization of SIRT. Ghosh et al. suggested that rescue
of adult stem cell decline in laminopathy-based premature
aging mice by RSV is SIRT-dependent []. Besides SIRT
activation, RSV inhibits SIRT, and it can mimic calorie
restriction/dietary restriction (DR) eects []. DR with
adequate nutrition is the only nongenetic and the most
consistent nonpharmacological intervention that extends
lifespan in model organisms from yeast to mammals and
protects against the deterioration of biological functions,
delaying or reducing the risk of many age-related diseases. It
has already been known since the s that a severe lowering
of calorie intake dramatically slows the rate of ageing in
mammals and lowers the onset of numerous age-related
diseases, including cancer, cardiovascular disease, diabetes
and neurodegeneration. It is found that DR induced an
% increase in the lifespan of unicellular organisms and
some invertebrates and a –% increase in small mammals
[]. e biological mechanisms of DR’s benecial eects
include modications in energy metabolism, redox status,
insulin sensitivity, inammation, autophagy, neuroendocrine
function, and induction of hormesis/xenohormesis response.
e molecular signalling pathways mediating the antiaging
eectofDRincludenotonlysirtuins,butalsoAMP-activated
protein kinase (AMPK), insulin/insulin growth factor-, and
target of rapamycin (TOR/mTOR), which form a complex
interacting network. Rasc´
on et al. reported that the lifespan
extension eects of RSV are conserved in the honeybee and
maybedrivenbyamechanismrelatedtoDR.Incontrast,
hyperoxic stress abolished the RSV life-extension response
[].
Although RSV has been found to extend the lifespan
of many model organisms including yeast, nematodes, and
fruit ies in the Sir or (Sirtuin )-dependent manner, some
other groups have questioned the importance of the Sir
pathway for ageing and could not conrm a benecial eect
of RSV on the lifespan of D. melanogaster. ADrosophila
strain with ubiquitous overexpression of dSir using the UAS-
GAL system was long-lived relative to wild-type controls but
was neither long-lived relative to the appropriate transgenic
controls nor a new line with stronger overexpression of dSir.
ese ndings underscore the importance of controlling
for genetic background and for the mutagenic eects of
transgene insertions in studies of genetic eects on lifespan
[]. Burnett et al. found that DR increased y lifespan
independently of dSir but these ndings do not necessarily
rule out a role for sirtuins in determination of metazoan
lifespan [].
Marchal et al. reviewed the benecial eects of RSV in dif-
ferent mammalian species, including humans, and concluded
that they generally reect the eects observed during chronic
DR without malnutrition. Although most of these eects
have been observed in individuals without age-associated
pathology, in those, which were overweight or obese, they
indicate the role of RSV in metabolic regulation and the
antiaging ecacy of this intervention. One explanation is the
positive and rapid changes induced by RSV, which lead to
adaptive metabolic response associated with an energy bal-
ance regulation and maintenance of overall health. Moreover,
data on the eects of this molecule on longevity in healthy but
nonobese mammals are rare, and these authors recommend
that longitudinal studies on experimental models close to
humans, such as nonhuman primates, multiply [].
Recent studies have indicated that at equivalent and diet-
achievable doses pterostilbene is a more potent modulator
of cognition and cellular stress than RSV, likely driven by
increased peroxisome proliferator-activated receptor alpha
expression and increased lipophilicity due to substitution of
BioMed Research International
hydroxywithmethoxygroupinpterostilbene[]. Wen et
al. investigated polydatin and its role in extending lifespan,
improving oxidative stress resistance and the possible reg-
ulation mechanism involved in the insulin/IGF- signaling
(IIS) pathway. Polydatin protected against oxidative stress.
It improved the expression of the inducible oxidative stress
protein (GST-) and corresponding stroke frequencies in the
transgenic CL strain but not due to its direct antioxidant
action by mainly increased SOD-::GFP expression in CF
wormsandtranslocationofDAF-tothenucleusinworm
cells [].
Similarly, although CUR is a directly acting antioxidant,
its lifespan-prolonging eects seem to be dependent mainly
on its indirect antioxidant action (induction of antioxidant
proteins) or interference with cellular signaling. CUR reg-
ulates the expression of inammatory cytokines (e.g., TNF,
IL-), growth factors (e.g., VEGF, EGF, and FGF), growth
factor receptors (e.g., EGFR, HER-, and AR), enzymes (e.g.,
COX-, LOX, MMP, MAPK, mTOR, and Akt), adhesion
molecules (e.g., ELAM-, ICAM-, and VCAM-), apoptosis
related proteins (e.g., Bcl-, caspases, DR, and Fas), and
cellcycleproteins(e.g.,cyclinD).CURmodulatesthe
activity of several transcription factors (e.g., NF-𝜅B, AP-
, and STAT) and their signaling pathways []. Recent
studies performed in both invertebrate and vertebrate models
have been conducted to determine whether CUR was also
neuroprotective []. A compelling new body of literature
is also mounting to support the ecacy of CUR in stress
and mood disorders. Current understanding of the biological
basis for antidepressant-relevant biochemical and behavioral
changes shows convergence with some mechanisms known
for standard antidepressants [].
Recently,Xiangetal.reportedthatTHCregulatesthe
oxidativestressresponseandagingviatheO-typeforkhead
domain transcription factor (FOXO). In NIHT cells, THC
induced nuclear accumulation of FOXO, a member of the
FOXO family of transcription factors, by inhibiting phospho-
rylation of protein kinase B (PKB)/Akt. FOXO factors act
as sensors in the insulin/IGF- (IIS) pathway and inuence
mammalian longevity. Overall, the totality of the evidence
supports a potential role of FOXOA in human health, aging,
and longevity. e association of FOXO with diverse aging
phenotypes, including insulin sensitivity, CHD, cancer, type
 diabetes, and longevity, is suggestive of a “gatekeeper” role
in the IIS pathway. An important downstream mechanism
whereby FOXOA might inuence human aging is through
modication of oxidative stress. In D. melanogaster,THC
attenuated the oxidative stress response, an eect that was
blocked in a FOXO mutant background. THC extended the
life span of Drosophila under normal conditions, and loss
of either FOXO or Sir activity eliminated this eect. Based
on these results, it seems that THC may regulate the aging
process via an evolutionarily conserved signaling pathway
that includes both FOXO and Sir [].
Pu et al. tested the hypothesis that dietary CUR, which has
an antioxidant eect, can improve aging-related cerebrovas-
cular dysfunction via mitochondrial uncoupling protein 
UCP upregulation. Dietary CUR administration for one
month remarkably restored the impaired cerebrovascular
endothelium-dependent vasorelaxation in aging Sprague
Dawley rats. In cerebral arteries from aging Sprague Dawley
rats and cultured endothelial cells, CUR promoted eNOS and
AMPK phosphorylation, upregulated UCP, and reduced
ROS production. ese eects of CUR were abolished by
either AMPK or UCP inhibition. Chronic dietary CUR
signicantly reduced ROS production and improved cere-
brovascular endothelium-dependent relaxation in aging wild
type mice but not in aging UCP−/− mice. CUR supplemen-
tation ameliorated age-associated large elastic artery stien-
ing, nitric oxide-mediated vascular endothelial dysfunction,
oxidativestress,andincreaseincollagenandAGEslevelsin
mice [].
Yanase et al. examined the eects of PAK-deciency or
downregulation on a few selected functions of C. elegans,
including reproduction, expression of HSP. gene, and
lifespan. ey found that PAK promotes reproduction,
whereas it inactivates HSP. gene and shortens lifespan, as
do PI- kinase (AGE-), TOR, and insulin-like signalling/ILS
(Daf-) in this worm. ese ndings not only support the
“trade-o ” theory on reproduction versus lifespan, but also
suggest the possibility that the reduced reproduction (or
HSP.geneactivation)ofthiswormcouldbeusedas
the rst indicator of extended lifespan for a quick in vivo
screening for PAK-blockers []. Yu et al. examined the
modulation of oxidative-stress resistance and associated reg-
ulatory mechanisms by CUR also in a C. elegans model. CUR-
treated wild-type C. elegans exhibited increased survival
during juglone-induced oxidative stress compared to the
control treatment. In addition, CUR reduced the levels of
intracellular ROS in C. elegans. CUR induced the expression
of the gst- and hsp-. stress response genes. Lastly, their
ndings from the mechanistic study in this investigation
suggest that the antioxidant eect of CUR is mediated via
regulation of age-, akt-, pdk-, osr-, unc-, sek-, skn-,
sir-., and mev- [].
In D. melanogaster, CUR, which extended the lifespan
of D. melanogaster, also modulated the expression of several
aging-related genes, including mth, thor, InR, and JNK
[]. Shen et al. found that lifespan extension by CUR in
Drosophila was associated with the upregulation of Mn-
SOD and CuZn-SOD genes and the downregulation of dInR,
ATTD, Def, CecB, and DptB genes. ese authors suggested
that CUR increases mean lifespan of Drosophila via regulating
gene expression of the key antioxidant enzyme SOD and
reducing lipid peroxidation [].
However, not always overexpression of antioxidant
enzymes may be relevant for the lifespan. In particular,
the overexpression of major antioxidant enzymes, which
decrease the steady-state level of ROS, does not extend the
lifespan of mice. Overexpression of SODs protects against
oxidative stress but has little or no eect on the lifespan of C.
elegans [,]. e lifespan of sod- mutant of C. elegans
was not decreased but even extended suggesting that ROS
toxicity does not play a major role in lifespan regulation
in these animals []. One possible explanation of why
deletion of individual SOD genes failed to shorten lifespan
is compensation by additional SOD genes. However, a recent
BioMed Research International
report from the Hekimi lab demonstrates that worms lacking
all ve SOD genes are viable and have normal lifespan, despite
signicantly increased sensitivity to multiple stresses [].
ese observations indicate that oxidative damage caused
by superoxide radical does not contribute to worm aging.
It should be expected that species with weak antioxidant
defense, accumulating oxidative damage, should be short
lived, which is denitely not true for the longest living rodent,
the naked mole rat Heterocephalus glaber [].
e term “green tea” refers to the product manufactured
from fresh tea leaves by steaming or drying at elevated
temperatures with the precaution to avoid oxidation of the
polyphenolic components known as catechins. e natural
product EGCG accounts for –% of catechins in green tea,
representing – mg in a brewed cup of green tea. Sev-
eral other catechins such as ()-epicatechin--gallate (ECG),
()-epigallocatechin (EGC), and ()-epicatechin (EC) are
found in lower abundance in green tea. EGCG is dened
as a major green tea catechin that contributes to benecial
therapeutic eects, including antioxidant, anti-inammatory,
anticancer, and immunomodulatory eects [].
EGCGbindsstronglytomanybiologicalmoleculesand
aects a variety of enzyme activities and signal transduction
pathways at micromolar or nanomolar levels []. Most of
themedicinalpropertiesofgreenteaareassociatedwith
the “epicatechins” (R, R) rather than the catechins (S,
R). e green tea catechins have been shown to be more
eective antioxidants than Vitamins C and E, and their
order of eectiveness as radical scavengers is ECG <EGCG
<EGC <EC <catechin. e metal-chelating properties
of green tea catechins are believed to be also important
contributors to their antioxidative activity []. EGCG acts
as a powerful hydrogen-donating radical scavenger of ROS
and RNS and chelates divalent transition metal ions (Cu2+,
Zn2+ and Fe2+), thereby preventing the Fe2+-induced for-
mation of free radicals in vitro. Among  polyphenolic
compounds, EGCG most potently inhibited Fe2+-mediated
DNA damage and iron ascorbate-promoted lipid peroxida-
tion of brain mitochondrial membranes. During ageing, total
Fe2+ concentration increases in some brain regions that are
involved in the pathogenesis of degenerative diseases, such
as Alzheimer’s, Parkinson’s, and Huntingtons disease. is
Fe2+ accumulation obviously fosters the production of the
highly reactive hydroxyl radicals (OH), which attacks a large
number of functional groups of the biomolecules in neurons.
By chelating redox-active transition metal ions, the gallate
groups of EGCG are thought to inhibit the Fenton-like-
reaction mechanism [ ]. us, the formation of OHis
inhibited. Consequently, polyunsaturated fatty acids in, for
example, mitochondrial membranes are protected from lipid
peroxidation [].
Results obtained by Weinreb et al. shed some light on the
antioxidative-iron chelating activities of EGCG underlying its
neuroprotective/neurorescue mechanism of action, further
suggesting a potential neurodegenerative-modifying eect
for EGCG. eir study sought a deeper elucidation of the
molecular neurorescue activity of EGCG in a progressive
neurotoxic model of long-term serum deprivation of human
SH-SYY neuroblastoma cells. In this model, proteomic
analysis revealed that EGCG (.– 𝜇M) aected the expres-
sion levels of diverse proteins, including proteins related
to cytoskeletal components, metabolism, and heat shock.
EGCG induced the levels of cytoskeletal proteins, such as beta
tubulin IV and tropomyosin , playing a role in facilitating
cell assembly. Moreover, EGCG increased the levels of the
binding protein -- gamma, involved in cytoskeletal regu-
lation and signal transduction pathways in neurons. EGCG
decreased protein levels and mRNA expression of the beta
subunit of the enzyme prolyl -hydroxylase, which belongs
to a family of iron-oxygen sensors of hypoxia-inducible
factor (HIF) prolyl hydroxylases that negatively regulate the
stability and degradation of several proteins involved in cell
survival and dierentiation. Accordingly, EGCG decreased
proteinlevelsoftwomolecularchaperonesthatwereassoci-
ated with HIF regulation, the immunoglobulin-heavy-chain
binding protein, and the heat shock protein  beta [].
In vivo, EGCG increased expression and activity of antiox-
idant enzymes, such as glutathione peroxidase, glutathione
reductase, SOD, and CAT and inhibited prooxidative ones,
such as monoamine oxidase (MAO)-B. e rat lifespan
extension by EGCG was due to reduction of liver and
kidney damage and improving age-associated inammation
and oxidative stress through the inhibition of transcription
factor NF-𝜅B signaling by activating the longevity factors:
forkheadboxclassOA(FOXOA)andSIRT[]. FOXO
genesaretheclosesthumanhomologuesofC. elegans
DAF-. In C.elegans, DAF- increases the expression of
manganese superoxide dismutase (SOD), which converts
superoxide to less damaging hydrogen peroxide and is a
potent endogenous protector against free radicals, among
other “antiaging” eects. In vivo studies show that oxidative
lesionsinDNA,proteins,andothertissuesaccumulatedwith
age and feeding calorically restricted diets (a potent insulin
sensitizer) to rodents and humans mitigate this damage [].
Brown et al. showed that  𝜇MEGCGdoesnotprovoke
a signicant change in the intracellular ROS level of daf-16
mutant C. elegans, while in the wild type strain ROS levels
are signicantly reduced by the avonoid. is indicates that
EGCG decreases ROS levels in the nematode in a DAF-
dependent manner [].
Meng et al. examined EGCG for its antiaging eect on
human diploid broblasts. Fibroblasts treated with EGCG at
 and  𝜇M for  h considerably increased CAT, SOD,
SOD, and glutathione peroxidase gene expressions and
their enzyme activities, thus protecting the cells against
H2O2-induced oxidative damage, accompanied by decreased
intracellular ROS accumulation and well-maintained mito-
chondrial potential. Moreover, broblasts treated with EGCG
at . 𝜇M for long term showed less intracellular ROS with
higher mitochondrial potential, more intact mitochondrial
DNA, much elevated antioxidant enzyme levels, and more
juvenile cell status compared to those of the untreated group
[]. Davinelli et al. investigated the combined eect of
L-carnosine and EGCG on the activation of two stress-
responsivepathways:hemeoxygenase(HO)-andHsp(the
inducible form of Hsp), which play an important role in
cytoprotection against oxidative stress-induced cell damage.
 BioMed Research International
ey demonstrated that the neuroprotective eects of EGCG
and L-carnosine are achieved through the modulation of
HO-/Hspsystems.Moreover,thecombinedactionof
both compounds resulted in a synergistic increase of HO-
expression which suggests a crosstalk between the HO- and
the Hsp-mediated pathways []. Rodrigues et al. analyzed
the neuroprotective eects of prolonged consumption of a
green tea extract rich in catechins but poor in EGCG and
other green tea bioactive components that could also aord
benet. eses authors demonstrated that the consumption
of an extract rich in catechins rather than EGCG protected
the rat hippocampal formation from aging-related declines
contributing to improving the redox status and preventing
thestructuraldamageobservedinoldanimals,withreper-
cussions on behavioral performance []. Feng et al. investi-
gated the protective eects of EGCG on hydrogen peroxide
(H2O2)-induced oxidative stress injury in human dermal
broblasts. e incubation of human dermal broblasts
with EGCG markedly inhibited the human dermal brob-
last injury induced by H2O2. e assay for ,-diphenyl-
-picrylhydrazyl radical scavenging activity indicated that
EGCG had a direct, concentration-dependent antioxidant
activity. Treatment of human dermal broblasts with EGCG
signicantly reversed the H2O2-induced decrease of SOD
and glutathione peroxidase and the inhibition of malondi-
aldehyde levels. ese authors suggested that EGCG should
have the potential to be used further in cosmetics and in the
prevention of aging-related skin injuries [].
In addition to the plethora of evidence that catechins
are cytoprotective via antioxidant and antiapoptotic eects,
recent observations suggest that the catechins may also
contain prooxidant properties, particularly at high concen-
trations. us, at low concentrations in vitro (– 𝜇M), they
are antioxidant and antiapoptotic, whereas at higher con-
centrations (– 𝜇M), the reverse is true. DNA isolated
from humans was exposed to  𝜇M of EGC and EGCG,
which induced oxidative damage due to the production of
hydrogen peroxide. Green tea extract (– 𝜇g/mL) and
EGCG (– 𝜇M) exacerbated oxidant activity, oxidative
stress, genotoxicity, and cytotoxicity induced by hydrogen
peroxide in RAW . macrophages []. Catechins, partic-
ularly EGCG ( 𝜇M), have also been shown to increase the
oxidative damage incurred aer exposure of DNA to -oxo-
,-dihydro-󸀠-deoxyguanosine [].
e lifespan-prolonging eect of catechin in C. elegans
may be related to a signicant reduction in body length
and modulation of energy-intensive stress response []. e
lifespan extension of C. elegans by apple procyanidins is
dependent on SIR-. as treatment with procyanidins had
no eect on the longevity of SIR-. worms, which lack the
activity of SIR-, a member of the sirtuin family of NAD+-
dependent protein deacetylases [].
Extension of lifespan of D. melanogaster by black tea
extract seems to be at least partly due to increased expression
of SOD and catalase (CAT) []. e analogous eect of black
rice extract is most likely due to upregulating the genes of
SOD, SOD, CAT, Mth, and Rpn at the transcriptional
level []. e eects of avonoids (myricetin, quercetin,
kaempferol, and naringenin) on the lifespan of C. elegans
involved an increased DAF- translocation and sod- pro-
moter activity [].
Longevity-promoting regimens, including DR and inhi-
bition of TOR with rapamycin, RSV, or the natural polyamine
spermidine, have oen been associated with autophagy and
in some cases were reported to require autophagy for their
eects. Seemingly, clearing cellular damage by autophagy is a
common denominator of many lifespan-extending manipu-
lations [].
Maintenance of optimal long-term health conditions is
accomplished by a complex network of longevity assurance
processes that are controlled by vitagenes, a group of genes
involved in preserving cellular homeostasis during stress-
ful conditions. Vitagenes encode for heat shock proteins
(Hsp) Hsp, Hsp the thioredoxin and the sirtuin protein
systems. Dietary antioxidants, such as polyphenols, have
been demonstrated to be protective through the activation
of hormetic pathways, including vitagenes and proteasomal
activity degrading oxidatively modied proteins [,].
e life-prolonging eects of complex extracts are usually
ascribed to the antioxidants present in these extracts but they
may contain also toxins produced by plants against insects
and microorganisms which may induce a hormetic eect
[]. Such a hormetic mechanism of action has been reported
for the eects of Ginkgo biloba extract EGb  on the lifespan
of C. elegans []. But perhaps antioxidants can also act via
hormetic mechanisms and can belong to hormesis-inducing
compounds (hormetins) []. Like toxins, they act in some
concentration range, their high concentrations being usually
toxic. A hormetic action of quercetin and other avonoids
on C. elegans has been documented []. It is debatable
whether hormesis, which undoubtedly increases longevity of
invertebrates, can be of relevance as an aging-delaying factor
in mammals and especially in human but there are reasons to
assume that it modulates “public” mechanisms of aging and
delay aging of mammals even if these eects are not of a large
magnitude [].
Paradoxically, the eect of hormesis may be mediated by
increased formation of ROS, especially by the mitochondria
believedtobethemainsourceofROSinthecell.Inthe
concept of mitochondrial hormesis (mitohormesis), increased
formation of ROS within the mitochondria evokes an adap-
tive response that culminates in subsequently increased stress
resistance assumed to ultimately cause a long-term reduction
of oxidative stress. Mitohormesis was claimed to provide
a common mechanistic denominator for the physiological
eects of physical exercise, reduced calorie uptake, and
glucose restriction []. is idea questions the FRTA and
rather suggests that ROS act as essential signaling molecules
to promote metabolic health and longevity [].
e glycolytic inhibitor lonidamine ( 𝜇M) was found to
extend both median and maximum lifespan of C. elegans by
% each. is compound promotes mitochondrial respira-
tion and increases formation of (ROS). Extension of lifespan
is abolished by coapplication of an antioxidant, indicating
that increased ROS formation is required for the extension of
lifespan by lonidamine []. e same eects were found in C.
elegans for low concentrations of arsenite [], a cytotoxic and
BioMed Research International 
antimalarial quassinoid glaucarubinone [], and glucose
restriction [].
In summary, complex eects of exogenous antioxidants
in model organisms are compatible with the current under-
standingoftheroleofROS,whicharenotonlydamaging
agentsbutalsotakepartinthesignalingpathwaysand
may mediate benecial response reactions on the basis
of hormetic mechanisms []. e direct antioxidant
action of antioxidant supplements seems thereby to be much
less important than induction of endogenous antioxidants,
especially via the Nrf- dependent pathway [].
5. Antioxidant Supplementation in Humans:
Does It Make Sense?
e changes in the structure of contemporary human popula-
tions are characterized by an increase in the fraction of people
who are  years and older, a phenomenon of signicant
importance from demographic, political, social, and health
points of view []. Nutrition has been recognized to have
an important impact on overall mortality and morbidity; and
its role in extending life expectancy has been the object of
extensive scientic research. Dietary supplementation with
antioxidants has become more and more popular. However,
their biochemical mechanisms of protection against oxidative
stress and antiaging eects are not fully understood. e
Mediterranean diet (MeDi), a heart-healthy eating plan that
emphasizes fruits, vegetables, whole grains, beans, nuts,
seeds, healthy fats, and red wine consumption rich in antiox-
idants like RSV which have been shown to have protective
eects against oxidative damage []. e Mediterranean
lifestyle has been for many millennia a daily habit for people
in Western civilizations living around the Mediterranean
sea who worked intensively and survived with very few
seasonal foods. A high adherence to the traditional MeDi is
associated with low mortality (higher longevity) and reduced
risk of developing chronic diseases, including cancer, the
metabolic syndrome, depression, and cardiovascular and
neurodegenerative diseases []. Recently, several foodstus
have been claimed as “antiaging”, principally on the basis of
their anti-inammatory and antioxidative properties: berries;
dark chocolate; beans (due to their high concentration in
low-fat protein, protease inhibitors, brins, genistein, and
minerals); sh; vegetables; nuts; whole grains; garlic (due to
the high amount of garlic-derived polysuldes that undergo
catabolism to hydrogen sulde promoting vasodilatation);
and avocados (as a great source of monounsaturated fat,
vitamins, and antioxidants) []. ese authors reviewed the
pathophysiological mechanisms that potentially link aging
with diet and the scientic evidence supporting the antiaging
eect of the traditional MeDi, as well as of some specic
foods. Recently, ve places [Okinawa (Japan), Sardinia (Italy),
Loma Linda (California), Ikaria (Greece), and Nicoya (Costa
Rica)] have been recognized as having a very high prevalence
of octogenarians and have joined the Blue-Zones, a National
Geographic project. Among the lifestyle habits that are
common to those populations are high levels of daily physical
activity (e.g., gardening and walking), positive attitude (e.g.,
an ability to articulate a sense of purpose and enriching their
day with periods of calm and midday siesta), and a wise
diet-high consumption of fruit, wild plants and vegetable,
and low consumption of meat products. at diet is similar
to the MeDi []. MeDi may not only reduce the risk for
Alzheimer’s disease [],butalsolowermortalityratesand
speed of disease progression in those already aicted [].
On the other hand, in a prospective cohort study of 
older adults, a higher adherence to MeDi did not lower the
risk for incident dementia []. In another study, a higher
adherencetoMeDifailedtodelaythetransitionfroma
cognitively healthy status to mild cognitive impairment [].
Titova et al. suggested that one possible reason for these
contrasting ndings could be that the MeDi score, which is
commonly used to explore correlations between MeDi and
health outcomes in elderly cohorts, may mask health-related
eects of certain dietary components by including others that
are not relevant for the health domain of interest [].
Most recently, Bacalini et al. discussed the potential
impact of so-called “epigenetic diet” on age-related diseases,
focusing on cardiovascular disease, highlighting the invo-
lvementofepigeneticmodicationsratherthanDNAmethy-
lation, such as microRNA []. Epigenetic modications may
delay the aging process and impact diverse health benets
by activating numerous intracellular pathways. One leading
theory suggests that bioactive phytochemicals including
-isothiocyanato--(methylsulnyl) butane (sulforaphane),
(R, R)-,-dihydroxy--(,,-trihydroxyphenyl)---di-
hydro-H-chromen--yl, ,,-trihydroxybenzoate (epigal-
locatechin gallate), RSV, and CUR play signicant roles as
epigenetic modiers [,].
In recent years, the wealth of basic science research
supporting RSV’s potential to treat, delay, and even pre-
vent age-related chronic diseases has led to a number of
human clinical trials. As research in nonclinical populations
becomes more common, disparity in dosing protocols and
clinical endpoints will likely continue to cause conicting
ndings. e range of daily RSV dosage used in clinical
trials for healthy individuals ( to mg) []wouldbe
expected to result in dierent clinical responses [,].
Brown et al. conrmed this, demonstrating  mg to be
more eective than both lower ( mg and  mg) and
higher dosages ( mg) in reducing plasma insulin-like
growth factor- (IGF-) concentrations [].ough  mg
RSV did not alter IGF- concentrations, it was sucient to
reduce insulin-like growth factor binding protein- (IGFBP-
) concentrations. is demonstrates that there may not be
a single optimal dose of RSV, but rather the ideal dose may
vary depending on the target outcome measures, which is not
uncommon for various drugs. Further research is warranted
to increase our understanding of the physiological responses
of RSV before widespread use in humans can be promoted.
Furthermore, chronic studies are an absolute must, as it is
still unclear if RSV supplementation on the longer term is
benecial for overall health status []. A synthetic analogue
of RSV, HS-, may be a new potent chemopreventive agent
against human prostate and breast cancer cells [,]. HS-
 showed more potent anticancer eects in several aspects
compared to RSV in MCF- (wild-type p) and MDA-MB-
 (mutant p) cells []. Moreover, HS- may inhibit
 BioMed Research International
humanprostatecancerprogressionandangiogenesisby
inhibiting the expression of hypoxic condition induced HIF-
𝛼protein and vascular endothelial growth factor (VEGF).
HS- showed also more potent eects than RSV on the
cytotoxic eects on PC- cells [,].
Gnetum gnemon is an arboreal dioecious plant that is cul-
tivatedinIndonesia.eseedsofthisspeciesmainlycontain
dimeric stilbenoid compounds [gnetin C, gnemonoside A,
and gnemonoside D along with trans-RSV] the active form of
RSV. Recent data show showed that the ethanolic extract of G.
gnemon seeds inhibits endothelial senescence, suggesting that
trans-RSV plays a critical role in the prevention of endothelial
senescence [].Fleenoretal.suggestedthatgnetinmaybe
a novel therapy for treating arterial aging in humans [].
It should be noted that status elderly people are a very het-
erogeneous group. e nutrition situation of “young” seniors
does generally not dier from the situation of working-age
adults while institutionalized elderly people and those in need
of care oen show signs of a global malnutrition. e critical
nutrients in the nutrition of the elderly particularly include
vitamins B and D. Six percent of all elderly have a manifest
and  to % a functional vitamin B deciency. e main
cause is vitamin B malabsorption resulting from a type
B atrophic gastritis. e functional vitamin B deciency
and the associated hyperhomocysteinemia are risk factors for
neurodegenerative diseases and accelerate bone loss. With
increasing age, the vitamin D status is deteriorating. About
% of the elderly living in private households is decient in
vitamin D; in geriatrics vitamin D, deciency is more the rule
than an exception. is is caused by a reduced endogenous
biosynthesis, low UVB exposure, and a diet low in vitamin
D. A vitamin D deciency increases the risk for falls and
fractures as well as the risk for neurodegenerative diseases.
Also the overall mortality is increased [].
On the other hand, up till now no prospective clinical
intervention studies have been able to show a positive associa-
tion between antioxidant supplementation and increased sur-
vival. More studies are needed to understand the interactions
among single nutrient modications (e.g., protein/amino
acid, fatty acids, vitamins, phytochemicals, and minerals), the
degreeofDR,andthefrequencyoffoodconsumptionin
modulating antiaging metabolic and molecular pathways and
in the prevention of age-associated diseases. Meta-analysis of
mortality data from  trials with a supplementation period
of at least one year was published between  and ,
with sample sizes ranging from  to . (median =
), yielding . subjects, and . all-cause deaths
indicating that supplementation with vitamin E has no eect
on all-cause mortality at doses up to . IU/d []. e last
meta-analysis of randomized controlled human trials, and
studies performed with rodents also do not support the idea
that the consumption of dietary supplements can increase the
lifespan of initially healthy individuals [].
Most recently, Macpherson et al. reported that multivita-
min-multimineral treatment has no eect on mortality risk
[]. Bjelakovic et al. noted that antioxidant supplements
do not possess preventive eects and may be harmful with
unwanted consequences to our health, especially in well-
nourished populations. e optimal source of antioxidants
seems to come from our diet, not from antioxidant supple-
ments in pills or tablets. Even more, beta-carotene, vitamin
A, and vitamin E may increase mortality. Some recent large
observational studies now support these ndings [].
In summary, while benecial eects of antioxidant sup-
plements seem undoubtful in cases of antioxidant decien-
cies, additional studies are warranted in order to design
adapted prescriptions in antioxidant vitamins and minerals
for healthy persons.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
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... Clinical trials with the supplementation of antioxidants did not prove beneficial in reducing ageing-associated disease or improving life expectancy. Further complicating the picture, it has been shown that the prolonged exposure to the exogenous antioxidants could have deleterious effects on the endogenous antioxidant systems, and some studies have shown that the long-term introduction of antioxidants in the diet actually reduced the overall lifespan [143,144]. ...
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The United States is undergoing a demographic shift towards an older population with profound economic, social, and healthcare implications. The number of Americans aged 65 and older will reach 80 million by 2040. The shift will be even more dramatic in the extremes of age, with a projected 400% increase in the population over 85 years old in the next two decades. Understanding the molecular and cellular mechanisms of ageing is crucial to reduce ageing-associated disease and to improve the quality of life for the elderly. In this review, we summarized the changes associated with the ageing of hematopoietic stem cells (HSCs) and what is known about some of the key underlying cellular and molecular pathways. We focus here on the effects of reactive oxygen species and the thioredoxin redox homeostasis system on ageing biology in HSCs and the HSC microenvironment. We present additional data from our lab demonstrating the key role of thioredoxin-1 in regulating HSC ageing.
... There is no clear evidence in human studies to support the beneficial effect of these supplements in relation to all-cause mortality, cardiovascular disease, cancer, or cognitive function [58]. In animal studies using mammalian models, many studies have shown that treatment with antioxidant supplements, when aimed at extending lifespan, result in no overt effect or even can have a negative effect [59]. ...
... Antioxidant-rich diets have also been considered for a series of clinical trials with the goal of minimizing the elevated levels of oxidative stress that correlates with age. Unfortunately, many of these trials and experiments did not observe a positive effect with increasing dietary antioxidant supplements with regard to onset prevention or reducing symptoms of age-related diseases (Figure 3) (Sadowska-Bartosz and Bartosz, 2014;Conti et al., 2016;Gutteridge and Halliwell, 2018). In fact, administering large doses of antioxidant not only has demonstrated in many cases no therapeutic effect, but it has also been associated with worsening pathological outcomes in human subjects. ...
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The process of aging strongly correlates with maladaptive architectural, mechanical, and biochemical alterations that contribute to the decline in cardiac function. Consequently, aging is a major risk factor for the development of heart disease, the leading cause of death in the developed world. In this review, we will summarize the classic and recently uncovered pathological changes within the aged heart with an emphasis on the mitochondria. Specifically, we describe the metabolic changes that occur in the aging heart as well as the loss of mitochondrial fitness and function and how these factors contribute to the decline in cardiomyocyte number. In addition, we highlight recent pharmacological, genetic, or behavioral therapeutic intervention advancements that may alleviate age-related cardiac decline.
... There is no clear evidence in human studies to support the beneficial effect of these supplements in relation to all-cause mortality, cardiovascular disease, cancer, or cognitive function [58]. In animal studies using mammalian models, many studies have shown that treatment with antioxidant supplements, when aimed at extending lifespan, result in no overt effect or even can have a negative effect [59]. ...
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Background The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Methods Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. Results Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. Conclusions Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.
... In order to restore the oxidative balance, many antioxidant supplementation therapies (e.g., antioxidant vitamins, coenzyme Q, resveratrol, curcumin) have been implemented. However, tests of the effectiveness of such treatments in humans have raised contrasting results [199][200][201]. Some NRF2-activating compounds have been described as potential senotherapeutic drugs. ...