Feuillet_Anti Age.indd

Transcription

La protéine qui nourrit votre beauté
Renverser les effets du temps
Boisson concentrée collagène enrichie d’anti-oxydants
• Améliore la texture de la peau
• Réduit les rides et ridules
• Augmente l’élasticité de la peau
• Régénère les tissus
Thé vert et canneberges
Boisson concentré anti-âge
Inovacure
En prenant un supplément d’antioxydant, comme
la boisson anti-âge d’Inovacure, vous vous assurez
d’une bonne protection contre un surplus de
radicaux libres.
La boisson Inovacure anti-âge est un moyen naturel
de rester en forme, en santé et physiquement
autonome le plus longtemps possible.
Les antioxydants contenues dans la boisson antiâge sont :
La vitesse du vieillissement varie d’une personne à
une autre. En effet, l’âge chronologique, celui que
l’on fête à chaque année, peut être différent de
notre âge physiologique. Voici 3 raisons qui explique
le vieillissement physiologique :
1. La vitamine C comme antioxydant est très bien
documenté. De plus, elle rends service à d’autres
vitamines antioxydantes, comme la vitamine E et
le bêta-carotène. Elle leur redonne leur pouvoir
antioxydant (jusqu’à 18% pour la vitamine E et 13%
pour le bêta-carotène).
1.Des attaques des radicaux libres;
2.Des modifications dans notre système immunitaire;
3.La baisse des antioxydants protecteurs.
Aussi, la vitamine C est bénéfique à différents
systèmes du corps, notamment à la régénération
de la peau, des ligaments, des cartilages, des os,
des dents et des gencives, car elle intervient dans
la formation du collagène. La vitamine C favorise
aussi un bon système immunitaire et accélère la
cicatrisation.
La théorie des radicaux libres comme explication
du vieillissement et de l’augmentation des maladies
reliées à l’âge a commencé à être acceptée dans
les années 1980 par les scientifiques et dans les
années 1990 par le public.
2. La vitamine E est un puissant antioxydant.
Elle joue un rôle essentiel dans la protection des
membranes qui entourent les cellules du corps.
Les effets néfastes des radicaux libres sont nombreux.
En voici des exemples :
La vitamine E a d’autres propriétés qui ne sont
pas reliés à son activité antioxydantes, mais qui
sont très important au niveau cardioprotecteur
(propriétés anti-inflammatoires, anti-plaquettaires
et vasodilatatrices). De plus, elle est utile pour
renforcir le système immunitaire.
•Ils accélèrent le vieillissement;
•Ils affaiblissent le système immunitaire;
•Ils entretiennent l’inflammation;
•Ils sont impliqués dans le développement de nombreuses maladies : maladies dégénératives (sclérose en plaques, Alzheimer), maladies cardiovasculaires, diabète, maladies articulaires, cancers (sein, poumon, estomac, côlon,…), douleur, fibromyalgie, syndrome de fatigue chronique,…
De plus, les vitamines E et C pourraient procurer
une protection contre la maladie d’Alzheimer
lorsque pris ensemble. Ces antioxydants aideraient
à protéger le cerveau contre l’agression des
radicaux libres associés à la maladie d’Alzheimer et
au vieillissement.
Les antioxydants ont la capacité de diminuer
le processus des radicaux libres. En fait, les
antioxydants protègent les cellules de notre corps
contre la dégradation causée par l’agression des
radicaux libres.
Certaines études monte donc que la vitamine E a
un potentiel thérapeutique plus élevé lorsqu’elle
est associée à d’autres antioxydants comme la
vitamine C, la vitamine A et le bêta-carotène.
2
3. Les flavonoïdes contenues dans l’extrait de
pépins de raisins est un puissant antioxydant. Leurs
activités antioxydantes sont de 20 à 50 fois plus
importantes que celles des vitamines C et E.
cellules des tissus conjonctifs que l’on retrouve
dans les muscles, les tendons, les ligaments, le
cartilage, les os, les poumons et la peau. Le
collagène représente environ 80% du poids des
tissus conjonctifs et 30% à 35% des protéines totales
de l’organisme.
Ces flavonoïdes ont d’autres allégations reliées au
vieillissement, comme celle de protéger contre
la résistance à l’insuline qui apparaît souvent
avec l’âge, de réduire les risques de cancers, de
stimuler la flexibilité des articulations, de diminuer
l’inflammation dans l’arthrite, d’atténuer la
détérioration mentale, d’augmenter la résistance
du système immunitaire et de diminuer les désordres
de la rétines comme la dégénérescence maculaire.
Nous savons que le corps fabrique son propre
collagène chaque jour et que cette production
diminue avec l’âge. À partir de 25 ans, le taux de
collagène diminue dans le corps, laissant apparaître
les premiers signes du vieillissement. À l’âge de 70
ans, le perte de collagène s’élève à plus de 30%.
Un des premiers signe de la diminution de la
production de collagène est l’apparition des
rides. Un supplément de collagène peut aider
grandement à la régénérescence des tissus de la
peau et ainsi contribuer à ralentir le processus de
vieillissement. Le collagène aidera à raffermir, à
tonifier et à hydrater la peau, tout en augmentant
son élasticité, ce qui aidera à réduire les rides et
ridules.
4. Le bêta-carotène est bien reconnu par ses
propriétés antioxydantes puissantes pour la
protection de la peau, des yeux, des cheveux, du
foie et des poumons. Le bêta-carotène est aussi
largement reconnu pour son rôle dans le maintien
de la santé cardiovasculaire. Il a un rôle antiplaquettaire, car en tant qu’antioxydant, il aide à
prévenir l’oxydation des LDL (« mauvais cholestérol
») De plus, le bêta-carotène joue aussi un rôle sur le
système immunitaire.
Pour terminer, la boisson anti-âge d’Inovacure
contient
également
des
FOS
(fructooligosaccharides). Les FOS ont plusieurs fonctions.
Ils agissent comme un prébiotique en nourrissent
les bifidobactéries (bactéries bénéfiques de la flore
intestinale), ce qui supporte le système immunitaire.
En améliorant la flore intestinale, ils exercent une
influence majeure sur la résistance aux maladies,
tels les cancers ou des pathologies inflammatoires.
5. Le coenzyme Q10 est un puissant antioxydant
moins connu. À l’âge de 50 ans, une personne en
bonne santé en produit 25% de moins qu’à l’âge
de 20 ans. Le coenzyme Q10 protège la structure
de nombreuses molécules comme la vitamine
E et les lipides. De plus, elle a d’autres rôles très
importants comme, par exemple, elle diminue les
risques de caillots sanguins, facilite la normalisation
de la glycémie des diabétiques, aide à abaisser la
pression artérielle et réduit la profondeur des rides.
Les FOS ont aussi une influence bénéfique sur
le profil lipidique. Ils ont des effets au niveau
de la cholestérolémie totale et sur les LDL tout
en diminuant les triglycérides. De plus, une
consommation chronique de FOS favorise une
réduction de la production hépatique de glucose à
jeun, ce qui réduit la glycémie à jeun chez les sujets
diabétiques. Pour terminer, une supplémentation
en FOS renforcent l’absorption du magnésium et du
calcium. Ce qui améliore la densité des os.
Il est important de noter que les antioxydants n’ont
pas tous la même action. Pour une protection la
plus large possible, il ne faut pas se contenter d’un
seul antioxydant, mais de les consommer tous.
La boisson anti-âge Inovacure contient également
du collagène. Le collagène est la protéine la plus
abondante de l’organisme. Il est secrété par les
3
Les rôles de la boisson anti-âge
recherchons à l’intérieur du corps. Par contre, sous
certaines conditions (ex : la chaleur, la lumière, la
cuisson, l’entreposage prolongé…), cette réaction
dans les aliments peut se produire avant que
l’aliment soit consommé. L’antioxydant devient
donc oxydé trop rapidement et l’aliment devient
inefficace comme antioxydant. En prenant un
supplément d’antioxydant sous la forme d’un
supplément, vous vous assurez d’une bonne
protection contre un surplus de radicaux libres.
La boisson anti-âge est un moyen naturel de rester
en forme, en santé et physiquement autonome le
plus longtemps possible. De nombreuses études
ont démontrées qu’il est possible de ralentir notre
vieillissement.
Nous savons que la vitesse du vieillissement varie
d’une personne à une autre. En effet, l’âge
chronologique, celui que l’on fête à chaque année,
peut être différent de notre âge physiologique. Voici
3 raisons qui explique le vieillissement physiologique :
Quels sont les effets néfastes des radicaux libres?
•Ils accélèrent le vieillissement;
1.Des modifications dans notre système immunitaire
2.Des attaques des radicaux libres
3.La baisse des antioxydants protecteurs
•Ils affaiblissent le système immunitaire;
•Ils entretiennent l’inflammation;
•Ils sont impliqués dans le développement de nombreuses maladies : maladies dégénératives (sclérose en plaques, Alzheimer), maladies cardiovasculaires, diabète, maladies articulaires, cancers (sein, poumon, estomac, côlon,…), douleur, fibromyalgie, syndrome de fatigue chronique,…
Que sont les radicaux libres?
La théorie des radicaux libres comme explication
du vieillissement et de l’augmentation des maladies
reliées à l’âge a commencé à être acceptée dans
les années 1980 par les scientifiques et dans les
années 1990 par le public.
Quels sont les facteurs favorisant la formation des
radicaux libres?
Les radicaux libres sont des substances incomplètes
et très instables, car ils comprennent des électrons
non appariées (célibataires). Ces électrons ont
tendance à chercher à se stabiliser avec un
électron appartenant à une autre molécule. En se
complétant, les radicaux libres déstabilisent donc
une molécule voisine et entraînent une réaction
en chaîne causant des destructions au niveau
cellulaire. Les problèmes surviennent lorsque les
radicaux libres sont trop abondants soit par manque
d’antioxydants, soit par une surcharge de facteurs
favorisant leur production. Les antioxydants ont la
capacité d’arrêter ce processus de réactions en
chaîne.
•L’alimentation pauvre en antioxydants
(en fruits, en légumes et en grains entiers);
•Les excès d’alcool (plus de 1 consommation par jour chez les femmes et plus de 2 chez les hommes)
•Les excès de viande rouge comme le bœuf, le porc et l’agneau (plus de 500g par semaine)
•Les poissons et les viandes fumées
•Les aliments modifiés, transgéniques ou les viandes provenant d’animaux nourrit d’hormones
•Les nitrites contenus dans les charcuteries et les viandes froides
•Les gras rancis, frits ou brûlé (ex : viandes carbonisées (barbecue), beurre noirci dans la poêle, huile dont la date est périmée)
Un antioxydant est une substance relativement
instable pour pouvoir céder un électron afin de
neutraliser un radical libre. C’est ce que nous
4
• l’excès de poids, surtout au niveau de la taille,
car il augmente la production d’hormones de
croissance, qui dans des quantités élevées,
augmente le risque de certains cancers
(ex : sein)
personnes qui consomment plusieurs portions de
fruits et légumes par jour sont moins susceptibles de
souffrir de maladies reliées au stress oxydatif telles
que : les maladies cardiovasculaires, le cancer, la
démence, le diabète, les maladies dégénératives
des yeux (ex : cataracte, dégénérescence de la
macula), la maladie de parkinson,…
• les pesticides
• la fumée du tabac : plus de 4000 produits
toxiques contenues dans les cigarettes sont
sources de radicaux libres
À quoi servent les antioxydants?
• les excès de rayons ultraviolets
• ils assurent la protection des cellules, des
gras insaturés, des protéines, de l’Adn et du
cholestérol ldl en neutralisant la formation des
radicaux libres.
• les stress émotionnels
• les polluants
Qu’est-ce qu’un antioxydant?
• ils jouent un rôle dans la prévention de
certaines maladies.
les antioxydants protègent les cellules de notre
corps contre l’oxydation ou la dégradation causée
par l’agression des radicaux libres. la popularité
des antioxydants s’explique par le fait que de
nombreuses études ont démontrées que les
• ils renforcent le système immunitaire.
5
La vitamine C et la boisson anti-âge
les apports nutritionnels quotidiens recommandés
pour les adultes de 19 ans et plus sont de 75mg pour
les femmes et de 90mg pour les hommes. puisque le
tabagisme augmente le stress oxydatif et le taux de
renouvellement métabolique de la vitamine c, le
besoin en vitamine c est accru de 35mg/jour chez
les fumeurs. les femmes enceintes ont besoin de
85mg et celles qui allaitent 120mg.
la vitamine c, qui a comme nom chimique l’acide
ascorbique, est un nutriment hydrosoluble (qui est
soluble dans l’eau). un des rôles importants de la
vitamine c est son effet antioxydant qui protège
les cellules contre les dommages causés par les
radicaux libres. elle éteint les « feux allumés » par les
radicaux libres avant qu’ils aient causé des dégâts.
Une petite expérience qui explique le pouvoir
antioxydant de la vitamine C
de plus, la vitamine c rends service à d’autres
vitamines antioxydantes, comme la vitamine e
et le bêta-carotène. lorsque ces vitamines sont
bloquées parce qu’elles ont déjà neutralisé un
radical libre, la vitamine c leur redonne leur pouvoir
antioxydant (jusqu’à 18% pour la vitamine e et 13%
pour le bêta-carotène).
coupez une pomme en deux. prenez une des
moitié et ajoutez-y du jus de citron, d’orange ou de
pamplemousse. par la suite, laissez les deux moitiés
de pommes à l’air libre. Vous allez constater que
la chair de la moitié de pomme qui n’a pas été
enduite de jus s’est noircie sous l’effet de l’oxygène
tandis que l’autre moitié a été protégé par le
rôle antioxydant de la vitamine c. tout comme la
vitamine c a protégé la pomme des méfaits de
l’oxygène, elle vous protégera à l’intérieur de votre
corps.
de plus, la vitamine c est bénéfique à différents
systèmes du corps, notamment à la régénération
de la peau, des ligaments, des cartilages, des os,
des dents et des gencives, car elle intervient dans
la formation du collagène. la vitamine c favorise
aussi un bon système immunitaire et accélère la
cicatrisation.
6
La vitamine E et la boisson anti-âge
vitamine C, la vitamine A et le bêta-carotène
(provitamine A).
La vitamine E est un nutriment liposoluble (qui est
soluble dans les tissus adipeux). Elle peut donc être
emmagasinée. La vitamine E est un antioxydant
majeur.
Le puissant rôle antioxydant de la vitamine E
s’explique de la manière suivante : la vitamine E joue
un rôle essentiel dans la protection des membranes
qui entourent les cellules du corps en brisant les
réactions en chaîne des radicaux libres. Elle ralenti
donc le vieillissement prématuré. La vitamine E est
le meilleur antioxydant pour ce travail puisqu’elle
est soluble dans les lipides, or les membranes des
cellules sont faites de molécules graisseuses.
La vitamine E a d’autres propriétés qui ne sont
pas reliés à son activité antioxydantes, mais qui
sont très important au niveau cardioprotecteur
(propriétés anti-inflammatoires, antiplaquettaires et
vasodilatatrices). De plus, elle est utile pour renforcir
le système immunitaire.
La vitamine E a aussi des effets sur la peau. Elle
augmente la capacité de rétention d’eau de la
peau, ce qui diminue l’amplitudes des rides.
La dose et la nature de la vitamine E pourraient être
important dans son efficacité. Certaines études
montrent que les tocotriénols seraient plus actif que
les tocophérols. Par contre, les tocotriénols sont
beaucoup plus dispendieux. De plus, la vitamine
E naturelle semble préférable à la vitamine E
synthétique. Nous remarquons donc que plusieurs
études manquent afin de bien comprendre les
effets de la vitamine E. Par contre, il est quand
même intéressant d’en avoir dans la Boisson antiâge.
La vitamine E participe également à la protection
des globules rouges et des tissus du corps. De plus,
elle aide à diminuer les maladies cardiovasculaires
en ayant des propriétés anti-inflammatoires et
vasodilatatrices et en réduisant l’oxydation des
lipoprotéines de faible densité (LDL : souvent appelé
« mauvais cholestérol). Les LDL sont une cible de
choix pour les radicaux libres. Une fois oxydés, ils
participent à l’athérosclérose (dépôt de graisse
dans les artères). L’attaque des LDL par les radicaux
libres se fait en 2 parties : la 1ère par des radicaux
libres liposolubles et la 2e par des radicaux libres
hydrosolubles. C’est pourquoi il y a nécessité d’une
action synergique d’antioxydants liposolubles (ex
: la vitamine E) et d’antioxydants hydrosolubles
(ex : la vitamine C).
Les apports nutritionnels quotidiens recommandés
pour les femmes et les hommes de 14 ans et plus
sont de 15mg (22.5UI). Les femmes enceintes ont
aussi besoin de 15mg tandis que celles qui allaitent
de 19mg.
C’est un peu la même chose pour la maladie
d’Alzheimer. Les vitamines E et C pourraient procurer
une protection contre la maladie d’Alzheimer
lorsque pris ensemble. Ces antioxydants aideraient
à protéger le cerveau contre l’agression des
radicaux libres associés à la maladie d’Alzheimer et
au vieillissement.
Certaines études monte donc que la vitamine E a
un potentiel thérapeutique plus élevé lorsqu’elle
est associée à d’autres antioxydants comme la
7
peuvent aggraver le processus de carcinogénèse).
Le bêta-carotène est bien reconnu par ses
propriétés antioxydantes puissantes pour la
protection de la peau, des yeux, des cheveux, du
foie et des poumons. Il défend donc les cellules
contre les radicaux libres. Le bêta-carotène est
aussi largement reconnu pour son rôle dans le
maintien de la santé cardiovasculaire. Il a un rôle
antiplaquettaire, car en tant qu’antioxydant, il aide
à prévenir l’oxydation des LDL.
La vitamine A, le bêta-carotène et
la boisson anti-âge
De plus, le bêta-carotène joue aussi un rôle sur le
système immunitaire.
La vitamine A est une vitamine liposoluble (qui est
soluble dans les tissus adipeux). Elle peut donc être
emmagasinée. Elle se présente dans l’organisme
sous différentes formes : rétinol, rétinal, acide
rétinoïque ou palmitate de rétinyle. Au niveau du
vieillissement , la vitamine A joue un rôle important
dans la vision (surtout dans la vision nocturne). Elle
aide aussi à la régulation du système immunitaire et
contribue à la santé de la peau.
Vitamine A dans des multivitmines (antioxydantes)
Marque
Vitamine
A (UI
equivalent)
Bêtacarotène (UI
equivalent)
0
5 000
2 000
1 500
Pure essence,
Longevity, anti-aging
0
10 000
L’organisme peut transformer certains caroténoïdes,
les provitamines A, en vitamine A dans la mesure
où l’organisme en a besoin. Le bêta-carotène est
la provitamine A la plus importante.
Garden of Life,
living multi
0
10 000
Nature’s Way, Alive!
1 500
1 000
Source Naturals,
Life force multi
2 500
10 000
Note : L’automédication en vitamine A n’est
pas recommandée puisqu’il y a des dangers de
malformations congénitales et des possibilités
d’ostéoporose. De plus, la vitamine A est de moins
en moins reconnue comme un antioxydants
majeur, mais le bêta-carotène, lui, est reconnu
comme un puissant antioxydant. De plus, il n’y a
pas d’inconvénients de prendre des suppléments
de bêta-carotène, sauf si à long terme et à très
hautes doses ( ex : 20mg à 30mg de bêta-carotène
pourraient augmenter légèrement l’incidence du
cancer du poumon Le bêta-carotène est sensible
à l’oxydation causée par la fumée de cigarette.
Comme l’organisme des fumeurs n’a plus la
capacité de recycler les sous-produits de carotène
oxydé, ces derniers deviennent pro-oxydants et
Nature’s Answer,
antioxydant supreme
0
0
Nature’s Plus,
Source of life
0
15 000
Thorne Research,
Anti-Oxidant
0
0
Jamieson
Bêta-carotène avec
vitamines C et E
0
25 000
Now, Super
Antioxydants
0
12 500
Natural Factors, La
beauté de l’intérieur
(pour 4 capsules)
0
2 500
SISU Optimal Health
Multi 2 (antioxydant)
Swiss Total One
anti-oxidant
Note : Bien qu’il n’y ait pas de doses quotidienne officiellement recommandée
de bêta-carotène, dans la pratique, le dosage varie habituellement entre
5 000 et 25 000UI.
8
L’extrait de pépins de raisins et la
boisson anti-âge
vaisseaux sont donc renforcés, plus élastiques et
moins perméables. l’efficacité de la circulation
sanguine en est augmentée.
les oligo-proanthocyanidines (opc) sont le sous
groupe de flavonoïdes le plus puissant. ces
flavonoïdes sont concentrés surtout dans les pépins
de raisin. leurs puissantes propriétés antioxydantes
ont fait l’objet de plusieurs études ces dernières
études. leurs activités antioxydantes est de 20 à
50 fois plus importantes que celles des vitamines c
et e. de plus, les opc sont à la fois hydrosolubles
et liposolubles. elles ont donc des propriétés
antioxydantes dans un milieu acqueux ou lipidique.
les opc ont un effet positif sur plusieurs facteurs
des maladies cardiovasculaires. par exemple, elles
réduisent le taux de ldl, empêchent l’agrégation
des plaquettes sanguines et diminuent les effets
néfastes des radicaux libres. les opc ont d’autres
allégations reliées au vieillissement, comme celle
de protéger contre la résistance à l’insuline qui
apparaît souvent avec l’âge, de réduire les
risques de cancers, de stimuler la flexibilité des
articulations, de diminuer l’inflammation dans
l’arthrite, d’atténuer la détérioration mentale,
d’augmenter la résistance du système immunitaire
et de diminuer les désordres de la rétines comme
la rétinopathie diabétique et la dégénérescence
maculaire.
les opc ont une affinité avec le collagène. l’effet
antioxydant des opc est efficace pour protéger le
collagène. elles se lient au collagène et contribue
à préserver la structure des tissus conjonctifs. ce qui
aide à réduire les indices visibles du vieillissement
prématuré comme les rides et la peau flasque.
leur affinité pour le collagène leur procure aussi,
une capacité de régénération des tissus internes
notamment l’intérieur des vaisseaux sanguins. les
puisque les opc ne sont pas considérées comme
des nutriments essentiels, il n’y a pas d’apport
nutritionnel recommandé.
9
Le collagène et la boisson anti-âge
Aussi, les modifications hormonales de la
ménopause agissent sur la peau des femmes. Nous
remarquons alors que la peau s’amincit un peu plus
et tend à se dessécher davantage. Par la suite, la
peau change de couleur et de pigmentation, et on
voit apparaître des taches brunes.
C’est avec grand plaisir qu’Inovacure vous présente
l’ajout d’une boisson supplémentée en collagène
dans nos kits Mode de vie et Fitness.
Le collagène est la protéine la plus abondante de
l’organisme. Il est secrété par les cellules des tissus
conjonctifs que l’on retrouve dans les muscles,
les tendons, les ligaments, le cartilage, les os, les
poumons et la peau.
Nous pouvons aider à la régénération des tissus
de votre peau avec notre boisson enrichie en
collagène. Notre boisson aide à nourrir la peau
de l’intérieur. Cette méthode que l’on nomme la
nutricosmétique ou cosmétofood se définie par
manger des aliments enrichis en principes actifs.
La nutricosmétique ou cosmétofood est une
orientation qui est en pleine croissance en Europe
et au Japon.
Les tissus conjonctifs constituent la majorité de la
masse du corps. Ils représentent environ 65% du
volume total chez l’homme. Pour vous expliquer
l’importance du collagène, il est important de
mentionner qu’il représente environ 80% du poids
des tissus conjonctifs et 30% des protéines de
l’organisme.
Comme la santé commence à l’intérieur du corps,
notre boisson enrichie en collagène agit à la
source du problème. Un supplément de collagène
peut aider grandement à la régénérescence des
tissus de la peau et ainsi contribuer à ralentir le
processus de vieillissement. Le collagène va donc
aider à raffermir et tonifier la peau. Il aidera aussi à
augmenter l’élasticité de la peau, ce qui aidera à
réduire les rides et ridules.
Du latin, le collagène, «colla» et «genmen», veut dire
produire la colle. Donc, par définition, le collagène
est à la fois le matériel et la colle qui tiennent notre
corps ensemble.
Nous savons que le corps fabrique son propre
collagène chaque jour et que cette production
diminue avec l’âge. Un des premiers signe de
la diminution de la production de collagène est
l’apparition des rides. La peau retient moins d’eau,
s’amincit et commence à rider. Ce processus
commencent dès l’âge de vingt-cinq ans et
s’accélère dans la quarantaine et la cinquantaine.
Le collagène est la protéine la plus abondante de
l’organisme. Il est secrété par les cellules des tissus
conjonctifs que l’on retrouve dans les muscles,
les tendons, les ligaments, le cartilage, les os, les
poumons et la peau.
10
et commence à rider. ce processus commencent
dès l’âge de vingt-cinq ans et s’accélère dans
la quarantaine et la cinquantaine. de plus, les
modifications hormonales de la ménopause
agissent sur la peau des femmes. nous remarquons
alors que la peau s’amincit un peu plus et tend
à se dessécher davantage. par la suite, la peau
change de couleur et de pigmentation, et on voit
apparaître des taches brunes.
les tissus conjonctifs constituent la majorité de la
masse du corps. ils représentent environ 65% du
volume total chez l’homme. pour vous expliquer
l’importance du collagène, il est important de
mentionner qu’il représente environ 80% du poids
des tissus conjonctifs et 30% à 35% des protéines
totales de l’organisme.
du latin, le collagène, «colla» et «genmen», veut dire
produire la colle. donc, par définition, le collagène
est à la fois le matériel et la colle qui tiennent notre
corps ensemble. nous savons que le corps fabrique
son propre collagène chaque jour et que cette
production diminue avec l’âge. À partir de 25 ans,
le taux de collagène diminue dans le corps, laissant
apparaître les premiers signes du vieillissement. À
l’âge de 70 ans, le perte de collagène s’élève à
plus de 30%. un des premiers signe de la diminution
de la production de collagène est l’apparition
des rides. la peau retient moins d’eau, s’amincit
un supplément de collagène peut aider
grandement à la régénérescence des tissus de la
peau et ainsi contribuer à ralentir le processus de
vieillissement. le collagène aidera à raffermir, à
tonifier et à hydrater la peau, tout en augmentant
son élasticité, ce qui aidera à réduire les rides et
ridules. le collagène peut contribuer à rétablir
les tissus du derme en fournissant les protéines
essentielles pour mouler son armature originelle.
11
Les FOS et la boisson anti-âge
Les effets des fructooligosaccharides (FOS) sur le
vieillissement son nombreux. Les FOS ont plusieurs
fonctions. Des études démontrent un effet
bénéfique sur le système immunitaire. Les FOS
agissent aussi comme un prébiotique en nourrissent
les bifidobactéries (bactéries bénéfiques de la flore
intestinale), ce qui supporte le système immunitaire.
En améliorant la flore intestinale, ils exercent une
influence majeure sur la résistance aux maladies,
tels les cancers ou des pathologies inflammatoires.
Les FOS ont aussi une influence bénéfique sur le
profil lipidique. La croissance des bonnes bactéries
lactiques qui provoque une production d’acides
à chaîne courte (acide lactique, propionique...) a
des effets au niveau de la cholestérolémie totale et
sur les LDL tout en diminuant même les triglycérides.
De plus, une consommation chronique de FOS
favorise une réduction de la production hépatique
de glucose à jeun chez des sujets sains, ce qui réduit
la glycémie à jeun chez des sujets diabétiques.
Pour terminer, une supplémentation en FOS
renforcent l’absorption du magnésium et du
calcium. Ce qui améliore la densité minérale
osseuse.
12
Les fructo-oligosaccharides (Fos), le nouveau
supplément de fibres d’Inovacure
lorsque vous allez suggérer les Fos à vos clients(es),
il est important de mentionner qu’il est préférable
d’augmenter la consommation progressivement,
car la capacité d’absorption varie d’une personne
à une autre. certains individus ont même de la
difficulté à absorber plus de 1 gramme à la fois! ces
clients(es) pourraient souffrir de symptômes digestifs,
tels que : douleurs et crampes abdominales,
ballonnements, flatulences, accroissement des
borborygmes (bruits intestinaux), constipation et/ou
diarrhée. par contre, chez la majorité des gens, il
n’y a pas d’effet indésirable jusqu’à 20g/jour. les
Fos en suppléments ne devraient pas dépasser la
dose de 30g/jour.
les Fos font partie des polysaccharides non
assimilables, que l’on nomme habituellement les
fibre alimentaires. les Fos qui sont utilisés à des
fins commerciales proviennent habituellement de
la racine de chicorée. non digérés à l’intérieur de
l’intestin grêle les Fos aboutissent dans le côlon.
les propriétés d’une consommation quotidienne
d’au moins 2,5g de Fos (inovafibre contient 5g par
portion) ont été démontrées dans plusieurs études.
Voici donc un résumé des fonctions des Fos :
Annie Jolicoeur
, dt.p
1. en étant un prébiotique, les Fos nourrissent
les bactéries intestinales bénéfiques
(probiotiques). de cette façon, la prolifération
de bactéries pathogènes est limitée.
2. les Fos ont une influence bénéfique sur
le profil lipidique. les ldl (mauvais cholestérol)
et les triglycérides sont diminués.
3. les Fos renforcent l’absorption du magnésium
et du calcium, ce qui améliore la densité
osseuse.
4. les Fos un effet bénéfique sur le système
immunitaire. en améliorant la flore intestinale,
les Fos ont une influence positive sur la
résistance aux maladies.
5. les Fos favorisent une réduction de la
production hépatique de glucose à jeun,
ce qui réduit le taux de sucre chez les
personnes diabétiques.
13
Articles
scientifiques
Review
Skin aging
Skin aging
N. Puizina-Ivi}
S
U M M A R Y
There are two main processes that induce skin aging: intrinsic and extrinsic. A stochastic process that
implies random cell damage as a result of mutations during metabolic processes due to the production
of free radicals is also implicated. Extrinsic aging is caused by environmental factors such as sun exposure, air pollution, smoking, alcohol abuse, and poor nutrition.
Intrinsic aging reflects the genetic background and depends on time. Various expressions of intrinsic
aging include smooth, thinning skin with exaggerated expression lines. Extrinsically aged skin is characterized by photo damage as wrinkles, pigmented lesions, patchy hypopigmentations, and actinic keratoses.
Timely protection including physical and chemical sunscreens, as well as avoiding exposure to intense
UV irradiation, is most important. A network of antioxidants such as vitamins E and C, coenzyme Q10,
alpha-lipoic acid, glutathione, and others can reduce signs of aging. Further anti-aging products are
three generations of retinoids, among which the first generation is broadly accepted. A diet with lot of
fruits and vegetables containing antioxidants is recommended as well as exercise two or three times a
week.
K
E
Y Skin aging
WORDS
Life expectancy is continuously rising in developed
skin aging,
damage,
extrinsic aging,
intrinsic aging,
stochastic
damage,
prevention
countries, but the mystery of aging remains partially
unresolved. The prevalence of mental and physical disability and diseases related to aging has increased. In
many countries a demographic transition is occurring,
involving aging of the population and reduced birthrates,
as well as large-scale migrations. Advances in medical
care have brought about a significant increase in life
expectancy, especially throughout the 20th century. In
the next 50 years, about one-third of women will be
Acta Dermatoven APA Vol 17, 2008, No 2
15
menopausal, and anti-aging medicine will gain importance.
Skin aging is particularly important because of its
social impact. It is visible and also represents an ideal
model organ for investigating the aging process (1). The
“biological clock” affects both the skin and the internal
organs in a similar way, causing irreversible degeneration (2, 3). However, Nicholas Perricone, a prominent
American dermatologist, begins his book with the words
“Wrinkled, sagging skin is not the inevitable result of
47
Skin aging
getting older. It’s a disease, and you can fight it” (4). The
five top cosmetic non-surgical procedures are botulinum
toxin injection, microdermabrasion, filler injection, laser hair removal, and chemical peeling, whereas important cosmetic surgical procedures include liposuction,
breast augmentation, eyelid surgery, nose reshaping, and
breast reduction.
The factors that play a role in the aging process are
genetic, extrinsic, and stochastic damage.
Intrinsic aging
Intrinsic aging depends on time. The changes occur
partially as the result of cumulative endogenous damage due to the continuous formation of reactive oxygen species (ROS), which are generated by oxidative
cellular metabolism. Despite a strong antioxidant defense system, damage generated by ROS affects cellular constituents such as membranes, enzymes, and DNA
(5, 6). It has a genetic background, but is also due to
decreased sex hormone levels. The telomere, a terminal portion of the eukaryotic chromosome, plays an
important role. With each cell division, the length of the
human telomere shortens. Even in fibroblasts of quiescent skin more than 30% of the telomere length is lost
during adulthood (7). Telomeres are short sequences
of bases in all mammals, and are arranged in the same
mode (TTAGGG). The enzyme telomerase is responsible for its maintenance. It seems that telomeres are
responsible for longevity (8). The progressive erosion
of the telomere sequence (50–100 bp per mitosis)
through successive cycles of replication eventually precludes protection of the ends of the chromosomes, thus
preventing end-to-end fusions, which is incompatible
with normal cell function. The majority of cells have the
capacity for about 60 to 70 postnatal doublings during
their lifecycles, and thereafter they reach senescence,
remaining viable but incapable of proliferation. This
event facilitates end-to-end chromosomal fusions resulting in karyotype disarray with subsequent apoptosis,
thus serving as the “biological clock” (9).
Skin aging is affected by growth factor modifications and hormone activity that declines with age. The
best-known decline is that of sex steroids such estrogen, testosterone, dehydroepiandrosterone (DHEA),
and its sulfate ester (DHEAS) (10–12). Other hormones
such as melatonin, insulin, cortisol, thyroxine, and growth
hormone decline too. At the same time, induced levels
of certain signaling molecules such as cytokines and
chemokines decline as well, leading to the deterioration of several skin functions (13). Also, the levels of
their receptors decline as well (14). At the same time,
48
Review
some signaling molecules increase with age. One of
these is a cytokine called transforming growth factorbeta1, which induces fibroblast senescence. Cellular
senescence is a result of molecular alterations in the
cellular milieu as well as in DNA and proteins within the
cell. All of these changes gradually lead to aberrant cellular response to environmental factors, which can decrease viability and lead to cell death (15).
Clinical manifestations of aged skin are xerosis, laxity, wrinkles, slackness, and the occurrence of benign
neoplasms such as seborrheic keratoses and cherry angiomas. There are histological features that accompany
these changes. In the epidermis, there is no alteration
in the stratum corneum and epidermal thickness,
keratinocyte shape, and their adhesion, but a decreased
number of melanocytes and Langerhans cells is evident
(6). The most obvious changes are at the epidermaldermal junction: flattening of the rete ridges with reduced surface contact of the epidermis and dermis. This
results in a reduced exchange of nutrients and metabolites between these two parts. In the dermis several
fibroblasts may be seen, as well as a loss of dermal volume (6, 16). A decrease in blood supply due to a reduced number of blood vessels also occurs. There is
also a depressed sensory and autonomic innervation of
epidermis and dermis. Cutaneous appendages are affected as well. Terminal hair converts to vellus hair. As
melanocytes from the bulb are lost, hairs begin to gray.
Further reasons for graying are decreased tyrosinase
activity, less efficient melanosomal transfer and migration, and melanocyte proliferation (17).
Factors that contribute to wrinkling include changes
in muscles, the loss of subcutaneous fat tissue, gravitational forces, and the loss of substance of facial bones
and cartilage. Expression lines appear as result of repeated tractions caused by facial muscles that lead to
formation of deep creases over the forehead and between eyebrows, and in nasolabial folds and periorbital
areas. Repeated folding of the skin during sleeping in
the same position on the side of the face contributes to
appearance of “sleeping lines.” Histologically, thick connective tissue strands containing muscle cells are present
beneath the wrinkle (18). In the muscles an accumulation of lipofuscin (the “age pigment”), a marker of cellular damage, appears. The deterioration of neuromuscular control contributes to wrinkle formation (19). The
constant gravitational force also acts on the facial skin,
resulting in an altered distribution of fat and sagging.
Skin becomes lax and soft tissue support is diminished.
Gravitational effects with advanced years play an important role and contribute to advanced sagging. This
factor is particularly prominent in the upper and lower
eyelids, on the cheeks, and in the neck region.
16
Review
Skin aging
Table 1. Glogau’s photoaging classification (5, 31).
Type
Characteristics
1: No wrinkles
Typical age 20s to 30s
Early photoaging
Mild pigmentary changes
No keratosis
No or minimal wrinkles
2: Wrinkles
in motion
Typical ages late 30s to 40s
Early to moderate photoaging
Early senile lentigines
Palpable but not visible keratoses
Parallel smile lines beginning to
appear laterally to mouth
3: Wrinkles at rest Typical age 50 or older
Advanced photoaging
Obvious dyschromias,
telangiectasias
Visible keratoses
4: Only wrinkles
Typical age 60 or older
Severe photoaging
Yellow-gray skin
Precancerous lesions
No normal skin
Fat depletion and accumulation at unusual sites contributes to the altered appearance of the face (20). It
affects the forehead, periorbital, and buccal areas, the
inner line of nasolabial folds, and the temporal and perioral regions. At the same time it accumulates
submentally, around the jaws, at outer lines of nasolabial folds and at lateral malar areas. In contrast to the
young, in whom fat tissue is diffusely distributed, in aged
skin fat tends to accumulate in pockets, which droop
and sag due to the force of gravity (20, 21). The mass of
facial bones and skeletal bones reduces with age. Resorption affects the mandible, maxilla, and frontal bones.
This loss of bone enhances facial sagging and wrinkling
with obliteration of the demarcation between the jaw
and neck that is so distinct in young persons (22). Steven
Hoefflin states that in the aging face the quantity and
position of subcutaneous fat makes the difference. It
also seems that estrogen and progesterone contribute
to elastic fiber maintenance (23).
Extrinsic aging
Extrinsic aging develops due to several factors: ionizing radiation, severe physical and psychological stress,
17
alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation. Among all
these environmental factors, UV radiation contributes
up to 80%. It is the most important factor in skin aging,
especially in premature aging. Both UVB (290–320 nm),
and UVA (320–400 nm) are responsible, and the skin
alterations caused by UV radiation depend upon the
phenotype of photoexposed skin (5, 24).
UVB induces alterations mainly at the epidermal
level, where the bulk of UVB is absorbed. It damages
the DNA in keratinocytes and melanocytes, and induces
production of the soluble epidermal factor (ESF) and
proteolytic enzymes, which can be found in the dermis
after UV exposure. UVB is responsible for appearance
of thymidine dimers, which are also called “UV fingerprints.” That is, after UVB exposure, a strong covalent
bond between two thymidines occurs. With aging, this
bond cannot be dissolved quickly, and accumulation of
mutations occurs. Affected cells appear as sunburn cells
8 to 12 hours after exposure. Reduced production of
DNA can be observed during the next 12 hours. Actinic
keratoses, lentigines, carcinomas, and melanomas represent delayed effects. A mnemonic for UVB is B as in
burn or bad.
UVA penetrates more deeply into the dermis and
damages both the epidermis and dermis. The amount
of UVA in ambient light exceeds the UVB by 10 to 100
times, but UVB has biological effects 1,000 times stronger than UVA. It is accepted that UVA radiation plays an
important role in the pathogenesis of photoaging, so
the mnemonic for UVA is A as in aging (24). The exact
mechanism of how UV radiation causes skin aging is not
clear. The dermal extracellular matrix consists of type I
and III collagens, elastin, proteoglycans, and fibronectin,
and collagen fibrils strengthen the skin. Photoaged skin
is characterized by alterations in dermal connective tissue. The amount and structure of this tissue seems to
be responsible for wrinkle formation. In photoaged skin,
collagen fibrils are disorganized and elastin-containing
material accumulates (25). Levels of precursors as well
as cross-links between type I and III collagens are reduced, whereas elastin is increased (26, 27). UV radiation increases the production of collagen-degrading
enzymes, matrix metalloproteinases (MMPs), and the
xeroderma pigmentosum factor (XPF), which can also
be found in the epidermis. XPF induces epidermal-dermal invagination, representing the beginning of wrinkle
formation. At the base of wrinkles, less type IV and VII
collagen is found. This instability deepens the wrinkles.
Each MMP degrades a different dermal matrix protein;
for example, MMP-1 cleaves collagen types I, II, and III,
and MMP-9 (gelatinase) degrades type IV and V and
49
Skin aging
Revie
gelatin. Under normal conditions, MMPs are part of a
coordinated network and are regulated by their endogenous inhibitors (TIMPs). The imbalance between activation and inhibition can lead to proteolysis (28). The
activation of MMPs can be triggered by UVA and UVB,
but molecular mechanisms differ depending upon the
type of radiation. UVA radiation can generate ROS that
affect lipid peroxidation and generate DNA strand
breaks (29). On the other hand, within minutes after
exposure UVB radiation causes MMP activity and DNA
damage. These effects can be observed after exposing
human skin to one-tenth of the minimal erythema dose.
Topical pretreatment with tretinoin inhibits activation of
MMPs in UVB-exposed skin (30). The degree of skin damage following long-lasting UV irradiation also depends on
the skin phototype according to Fitzpatrick. In lighter
complexes (types I and II) more serious degenerative
changes are elicited than in types III and IV, in which
melanosomes in the upper epidermal layer serve as relatively good UVA and UVB protection. Glogau developed
a photoaging scale that is used to clinically classify the
extent of photodamage (Table 1) (5, 31). It has been
stated that the number of melanocytes decreases by 8 to
20% every 10 years.
Another environmental factor contributing to premature aging is smoking. “Smoker’s face” or “cigarette skin”
are characteristic, implying increased facial wrinkling and
an ashen and gray skin appearance (32, 33). A prematurely old appearance is a symptom of long-term smokers. Yellow and irregularly thickened skin is result of elastic tissue breakdown due to smoking (34) or to UV. Premature facial wrinkling is not reduced in women on hormone replacement therapy (35). Genetic predisposition
may also influence the development of facial wrinkling
(36). It seems that cigarette smoking induces the activation of MMPs in the same mode as in persons with significant sun exposure (37). Smoking also reduces facial stratum corneum moisture as well as vitamin A levels, which
is important in reducing the extent of collagen damage
(5). The photochemical activity of smog is due to the
reduction of air pollutants such as nitrogen oxides and
volatile organic compounds created from fossil fuel combustion in the presence of sunlight. Emission from factories and motor vehicle exhaust are primary sources of
these compounds. The major targets of ozone in the skin
are the superficial epidermal layers; this results in the
depletion of antioxidants such as alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) in the superficial
epidermal layers (38).
As stochastic damage is explained, the damage is initiated by random cosmic radiation and triggered by free
radicals during cell metabolism, which damages cell lipid
compounds, especially membrane structures. The free
50
18
radical theory is one of the most widely accepted theories to explain the cause of skin aging. These compounds
are formed when oxygen molecules combine with other
molecules, yielding an odd number of electrons. That is,
an oxygen molecule with paired electrons is stable, but
one with an unpaired electron is very reactive and it takes
electrons from other vital components. As result, cell death
or mutation appear (4, 5).
Protection of the skin
The skin is equipped with two photoprotective
mechanisms: the melanin in the lower layer of epidermis,
and the urocanic acid barrier of the stratum corneum,
which reflects and absorbs a significant amount of UVB
radiation. The thickness of the stratum corneum appears
to be highly significant for photoprotection (39).
Antioxidants provide protection against UVB-induced
oxidative stress, especially in stratum corneum lipids. Even
systemically applied antioxidants accumulate in the stratum corneum and play an important role against UV-induced skin damage (40, 41).
The body has developed further defense mechanisms
that protect against UV radiation and dangerous free radicals. Antioxidants naturally occurring in the skin are superoxide dismutase, catalase, alpha-tocopherol, ascorbic
acid, ubiquinone, and glutathione. Many of them are inhibited by UV and visible light (42). The antioxidant program consists of a diet containing large amounts of vitamins A, E, and C, grape-seed extracts, coenzyme Q10,
and alpha-lipoic acid (4). The most highly recommended
foods include: avocados, berries, dark green leafy vegetables, orange-colored vegetables and fruits, pineapples,
salmon, and tomatoes.
The mainstay in the prevention of skin aging is
photoprotection. UV filters are now present in cosmetic
products for daily use, such as makeup, creams, lotions,
and hair sprays. The general requirements are that modern sunscreens should protect against UVA and UVB rays
and be photo-stable and water resistant.
Chemical UV filters have the capacity to absorb shortwavelength UV and transform photons into heat-emitting long-wavelength (infrared) radiation. Most of them
absorb a small wavelength range. They can be divided
into three groups. The first group consists of molecules
that primarily absorb the UVB spectrum (p-aminobenzoic acid derivatives and zincacid esters), and second of
molecules that primarily absorb the UVA spectrum (butyl-methoxydibenzoylmethane). The third group consists
of molecules that absorb UVA and UVB photons (benzophenone). A combination of different filters in the same
product renders the whole filter system photo-unstable.
Review
Skin aging
That means that UV exposure causes photochemical reactions that generate ROS with subsequent phototoxic
and photoallergic reactions. Great efforts have been made
to stabilize molecules in UV filters, which has improved
the efficacy of photoprotection with chemical UV filters.
Today there is a growing need for standardization and
evaluation of UVA photoprotection, while for UVB there
is already consensus on the international level (1, 43).
The use of physical filters is encouraged. The most
frequently used of these are microparticles of zinc oxide and titanium dioxide with diameters in the range of
10 to 100 nm. They are capable of reflecting a broad
spectrum of UVA and UVB rays. They do not penetrate
into the skin and thus have low potential for developing toxic or allergic effects. Today they are increasingly
being used in combination with chemical filters. One
disadvantage of the inorganic micropigments is that
they reflect visible light, creating a “ghost” effect. This
is one reason such sunscreens are often rejected by
consumers (5, 43, 44).
Conclusion
This overview shows that, during the human life
cycle, the skin is exposed to a number of unavoidable
as well as avoidable damaging factors. Genetics also
play a highly important role. In addition to all the conditions mentioned above, further processes pertaining to
oxygenation and reduction are active in skin aging.
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A U T H O R S '
A D D R E S S E S
54
Neira Puizina-Ivi}, MD, PhD, Asst. Professor, Laboratory of
Dermatopathology, Department of Dermatovenerology, Split Clinical
Hospital Center, [oltanska 1, 21 000 Split, Croatia,
E-mail: neiraradogost.com
21
22
23
24
25
26
27
28
29
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American Journal of Epidemiology
Copyright ª 2005 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved; printed in U.S.A.
Vol. 163, No. 1
DOI: 10.1093/aje/kwj007
Advance Access publication November 23, 2005
Original Contribution
Serum Antioxidants, Inflammation, and Total Mortality in Older Women
J. Walston1, Q. Xue1, R. D. Semba1, L. Ferrucci2, A. R. Cappola3, M. Ricks1, J. Guralnik1, and
L. P. Fried1
1
School of Medicine, Johns Hopkins University, Baltimore, MD.
National Institute of Aging, Baltimore, MD.
3
School of Medicine, University of Pennsylvania, Philadelphia, PA.
2
The inflammatory cytokine interleukin-6 (IL-6) has been linked to poor health outcomes in older adults. Oxidative
stress triggers the production of IL-6, and antioxidant micronutrients play a critical role in decreasing this inflammatory response. The authors sought to identify the relations between serum levels of antioxidant nutrients and IL-6
and mortality in older women. Levels of a- and b-carotene, lycopene, lutein/zeaxanthin, a-cryptoxanthin, total
carotenoids, retinol, a-tocopherol, zinc, and selenium were measured at baseline in 619 participants in Women’s
Health and Aging Study I (Baltimore, Maryland, 1992–1998). IL-6 was measured at baseline and at follow-up 1 and
2 years later, and all-cause mortality was determined over a 5-year period. Participants with the highest serum
levels of a-carotene, total carotenoids, and selenium were significantly less likely to be in the highest tertile of serum
IL-6 at baseline (p < 0.0001). Those with the lowest levels of a- and b-carotene, lutein/zeaxanthin, and total
carotenoids were significantly more likely to have increasing IL-6 levels over a period of 2 years. Those with the
lowest selenium levels had a significantly higher risk of total mortality over a period of 5 years (hazard ratio ¼ 1.54,
95% confidence interval: 1.03, 2.32). These findings suggest that specific antioxidant nutrients may play an important role in suppressing IL-6 levels in disabled older women.
aging; antioxidants; carotenoids; inflammation; interleukin-6; mortality; selenium
Abbreviations: CI, confidence interval; OR, odds ratio; SD, standard deviation; WHAS I, Women’s Health and Aging Study I.
known to enhance proinflammatory nuclear factor-jB signal
transduction pathways and hence interleukin-6 production
(6, 10).
Prior studies have suggested that several categories of
dietary antioxidants, including the carotenoids, retinol, atocopherol, zinc, and selenium, may be effective in suppressing
activation of these proinflammatory pathways through the
quenching of free radical molecules (11, 12). Few studies
have investigated the cross-sectional and longitudinal relations between specific antioxidants and inflammation, as
measured by serum interleukin-6 level, and ultimately mortality in older adults. Therefore, we studied the relations of
Older adults with the highest serum levels of interleukin-6
are more likely to develop disability and worsening chronic
disease and are more likely to be frail and to die earlier than
those with the lowest levels (1–5). These poor health outcomes are probably directly mediated by elevated interleukin-6 concentrations, which can induce muscle and bone
loss, anemia, immune dysfunction, and altered production
and function of multiple hormones (6–9). The etiology of
chronic interleukin-6 elevations in older adults is multifactorial, with declines in sex steroid hormones, increased prevalence of inflammatory disease, increased fat mass, and
increased generation of free radicals of oxygen all being
Reprint requests to Dr. Jeremy D. Walston, Johns Hopkins University School of Medicine, John R. Burton Pavilion, 5505 Hopkins Bayview
Circle, Baltimore, MD 21224 (e-mail: [email protected]).
18
43
Am J Epidemiol 2006;163:18–26
Downloaded from http://aje.oxfordjournals.org/ by guest on January 13, 2012
Received for publication March 11, 2005; accepted for publication July 19, 2005.
Antioxidants, Inflammation, and Mortality in Older Women 19
MATERIALS AND METHODS
Human subjects
Women’s Health and Aging Study I (WHAS I) is a
longitudinal cohort study of the one third most disabled
community-dwelling older women in Baltimore, Maryland.
Subjects were women aged �65 years residing in 12 contiguous zip code areas in Baltimore who were recruited from
a random sample of the Health Care Financing Administration’s Medicare enrollment file (N ¼ 32,538 women). An
age-stratified (65–74, 75–84, and �85 years) sample of these
women was randomly selected. Of those, 5,316 were eligible
for screening, 4,135 were screened for disability, 1,409 met
the study criteria, 1,002 agreed to participate in the study,
and 783 agreed to have blood drawn starting in 1992 (13, 14).
Of these 783 persons, 619 had stored serum samples and data
on all reported variables recorded in the database. This left
383 WHAS I participants who were not included in these
analyses.
Study participants received an extensive interview and
examination in their homes at baseline and every 6 months
for 3 years, for a total of seven examinations. Physical activity was measured by participant report, with persons who
walked more than eight blocks per week being deemed active and those who walked less than eight blocks deemed
inactive, as validated in prior WHAS I studies (15). Smoking status was analyzed by dividing pack-years into four
categories: none, mild (1–30 pack-years), moderate (31–
56 pack-years), and heavy (>56 pack-years) (16). Blood
was drawn at baseline and at 1-year intervals. Information
on physician diagnosis of 16 major chronic diseases was
obtained at each examination, and the presence/absence of
each disease was adjudicated by trained physicians using
abstracted medical records and following standardized
state-of-the-art algorithms (13). Information on vital status
was obtained through follow-up interviews with proxies,
obituaries, and matching with the National Death Index over
a 5-year period. The Johns Hopkins University Institutional
Review Board approved the study, and all participants gave
informed consent.
Statistical analysis
Baseline demographic and health-related characteristics
for the 619 WHAS I women with complete outcome and
covariate information were compared by tertile of interleukin-6 values, using the v2 test for categorical variables and
analysis of variance for continuous variables. We calculated
summary statistics for micronutrients, including means,
medians, standard deviations (SDs), and ranges, and compared the log-transformed micronutrient values by tertile of
interleukin-6 using analysis of variance. Sequential logistic
regressions for being in the highest interleukin-6 tertile compared with the lowest two tertiles were fitted against each of
the micronutrients, with adjustment for age, Black race, years
of education, pack-years of smoking, body mass index
(weight (kg)/height (m)2), and physical activity. In addition,
adjustments were made in the final model for four prevalent
chronic diseases known to be associated with inflammation:
chronic obstructive pulmonary disease, peripheral arterial
disease, angina, and diabetes mellitus. Micronutrient values
were logarithmically transformed to approximate normality
in all regression models. To validly assess the relative
strength of associations between interleukin-6 and micronutrients, we calculated odds ratios and 95 percent confidence intervals associated with a 1-SD increase in log
micronutrient values. A random-effects model was used to
examine both population-averaged and individual changes
in log interleukin-6 levels over time while accounting for
between-person heterogeneity in baseline interleukin-6 levels and individual rate of change over time.
To determine whether low levels of specific micronutrients at baseline predicted a significant increase in
interleukin-6 over time, we divided subjects with nutrient
measurements into tertiles, and the percentages of those who
had a 0.5-SD increase in interleukin-6 level over 1-year and
2-year spans were determined. We selected the 0.5-SD increment to achieve a balance between sample size limitation
Laboratory analyses
Blood samples were obtained by venipuncture, and serum was separated by centrifugation and stored at –70C
until analysis. Levels of serum a-carotene, b-carotene,
b-cryptoxanthin, lycopene, lutein/zeaxanthin (not separated
with this procedure), and a-tocopherol were determined by
high performance liquid chromatography (17). The internal
standards used were tocol (Hoffmann-LaRoche, Inc., Nutley,
New Jersey) at 320 nm and all-trans-ethyl-b-apo-8#carotenoate (purified sample, courtesy of Dr. Fred Khachik,
University of Maryland) at 450 nm. Within-run and betweenrun coefficients of variation for pooled standards were 10.7
44
percent and 23.9 percent for a-carotene, 7.0 percent and
19.1 percent for b-carotene, 4.7 percent and 8.5 percent
for b-cryptoxanthin, 4.1 percent and 4.6 percent for lutein/
zeaxanthin, and 4.1 percent and 9.7 percent for a-tocopherol,
respectively. Total cholesterol was measured using an automated enzymatic method, and the values were used to
compute the a-tocopherol:cholesterol ratio (18). Serum selenium and zinc levels were measured by graphite furnace
atomic absorption spectrometry using a Perkin Elmer
Analyst 600 with Zeeman background correction (Perkin
Elmer Corporation, Norwalk, Connecticut). Within-run and
between-run coefficients of variation were 5.8 percent and
4.8 percent for selenium and 2.8 percent and 3.9 percent for
zinc, respectively. Plasma interleukin-6 was measured using
an enzyme-linked immunosorbent assay (Quantikine human
interleukin-6; R&D Systems, Inc., Minneapolis, Minnesota). Quality control was assessed by repeated analysis of
standard reference material (SRMb; National Institute of
Standards and Technology, Gaithersburg, Maryland) and
pooled reference standards. All samples were analyzed in
a masked fashion.
dietary carotenoids, retinol, a-tocopherol, zinc, and selenium with interleukin-6 and mortality in a cohort of older
women.
20
Walston et al.
TABLE 1. Demographic and health-related characteristics of 619* study participants with measurements
of interleukin-6 and antioxidant nutrient levels, by tertile of interleukin-6 at baseline, Women’s Health and
Aging Study I, Baltimore, Maryland, 1992–1993
Tertile of interleukin-6
Total
�2.80 pg/ml
(n ¼ 208)
Mean age (years)
77.3 (7.8)z
76.7 (7.8)
77.5 (7.9)
77.6 (7.6)
0.45
Black race (%)
27.3
23.1
26.3
32.7
0.09
Mean years of education
9.9 (4.9)
>2.80–�4.81 pg/ml
(n ¼ 209)
10.5 (6.7)
9.9 (3.5)
>4.81 pg/ml
(n ¼ 202)
9.3 (3.4)
Level of smoking and pack-years (%)
0.08
<0.01
None: 0
52.3
64.3
48.8
43.5
Mild: 1–30
27.0
24.2
30.4
26.5
Moderate: 31–56
11.1
7.2
12.1
14.0
9.6
4.3
8.7
Heavy: >56
p valuey
16.0
28.8 (6.8)
27.3 (5.3)
29.2 (7.2)
29.8 (7.6)
<0.01
Ability to walk �8 blocks (%)
31.1
40.5
32.0
20.4
<0.01
Prevalent chronic diseases (%)
Cardiovascular disease
23.6
22.7
34.5
37.6
Peripheral arterial disease
20.2
17.3
15.8
28.7
0.003
Chronic obstructive pulmonary
disease
15.0
12.0
17.2
15.8
0.30
Diabetes mellitus
16.2
9.1
15.8
23.8
<0.01
<0.01
* All participants with baseline data on serum carotenoid levels, corrected interleukin-6 level, age, race, education, pack-years of smoking, body mass index, chronic obstructive pulmonary disease, peripheral arterial disease,
cardiovascular disease, and diabetes.
y p value for comparison between the three interleukin-6 tertiles.
z Numbers in parentheses, standard deviation.
§ Weight (kg)/height (m)2.
able longitudinal interleukin-6 measurements together and
modeling log interleukin-6 as a continuous outcome in order to explicitly model the effect of baseline micronutrient
levels in tertiles on individual rate of change in log interleukin-6 levels over time. Cox proportional hazards regression models were used to determine the relations between
and clinical significance. Crude incidence rates for having
a greater than 0.5-SD increase in interleukin-6 were plotted
by micronutrient tertile; logistic regression analyses were
used to calculate the adjusted odds ratios, with the highest
tertiles of micronutrients being used as reference groups.
We also applied random-effects models by pooling all avail-
TABLE 2. Summary data on levels of micronutrients and interleukin-6 among 619 participants at baseline,
Women’s Health and Aging Study I, Baltimore, Maryland, 1992–1993*
Median
Minimum
Maximum
a-Carotene (lmol/liter)
Micronutrient
Mean
0.09
Standard deviation
0.09
0.07
0.00
0.93
b-Carotene (lmol/liter)
0.44
0.38
0.31
0.03
3.34
Lycopene (lmol/liter)
0.56
0.31
0.51
0.02
2.00
Lutein/zeaxanthin (lmol/liter)
0.38
0.20
0.35
0.04
1.72
1.41
b-Cryptoxanthin (lmol/liter)
0.14
0.15
0.1
0.01
Total carotenoids (lmol/liter)
1.60
0.73
1.5
0.13
4.49
Retinol (lmol/liter)
2.60
0.93
2.4
0.67
7.16
21.83
8.90
19.7
5.05
66.53
4.23
1.65
3.8
0.90
12.39
a-Tocopherol (lmol/liter)
a-Tocopherol:cholesterol ratio (mg/g)
Zinc (lg/liter)
889.7
229.8
854.4
188.2
Selenium (lg/liter)
118.2
19.2
116.4
58.2
Interleukin-6 (pg/ml)
5.51
12.69
3.70
0.66
2,661.5
245.8
289.72
* n ¼ 619 for all analyses except a-tocopherol:cholesterol ratio (n ¼ 605), zinc (n ¼ 615), and selenium (n ¼ 591).
45
Body mass index§
TABLE 3. Odds ratios (cross-sectional association) for being in the highest tertile of
interleukin-6 level as compared with the two lowest tertiles, according to micronutrient
intake at baseline, Women’s Health and Aging Study I, Baltimore, Maryland, 1992–1993*
Odds ratioy
95% confidence interval
p value
Micronutrient
0.65
0.53, 0.80
<0.0001
0.72
0.59, 0.87
0.001
0.75
0.63, 0.91
0.003
0.72
0.59, 0.89
0.004
0.77
0.63, 0.94
0.016
0.038
0.87
0.72, 1.05
0.91
0.74, 1.11
0.5
a-Tocopherol:cholesterol ratio (mg/g)
1.01
0.82, 1.24
0.777
0.65
0.53, 0.79
<0.0001
Selenium (lg/liter)
0.65
0.52, 0.80
<0.0001
Zinc (lg/liter)
0.99
0.82, 1.20
0.948
Given that there were 383 WHAS I participants with missing data, we compared demographic characteristics in persons with blood values and those without blood values. We
found that, compared with the 383 persons who did not have
blood information available for analysis, persons with data
on all blood variables were younger (77.3 years (SD, 7.8) vs.
80.0 years (SD, 8.3); p < 0.01), had a higher body mass
index (28.8 (SD, 6.8) vs. 27.5 (SD, 6.6); p < 0.01), and had
higher levels of physical activity (31.1 percent vs. 19.3
percent; p < 0.01), as measured by the percentage in each
group who had walked more than eight blocks in the past
week. To explore the impact of these differences on our
inference, we stratified the results shown in table 3 by
age, body mass index, and physical activity and calculated
the micronutrients with the strongest inverse association
with interleukin-6 and mortality.
RESULTS
Demographic and health-related characteristics of the 619
WHAS I participants with complete blood measurements are
displayed in table 1 by interleukin-6 tertile (�2.80 pg/ml,
>2.80–�4.81 pg/ml, and >4.81 pg/ml). Mean and median
nutrient and interleukin-6 values for these 619 participants are displayed in table 2. Persons in the highest tertile
of interleukin-6 were more likely to be smokers, to have a
greater body mass index, to have peripheral arterial disease,
diabetes, or cardiovascular disease, and to be inactive (table 1).
FIGURE 1. Crude incidence rate for an increase of more than 0.5 standard deviation (3.21 pg/ml) in interleukin-6 level, by micronutrient tertile and
duration of follow-up, Women’s Health and Aging Study I, Baltimore, Maryland, 1992–1998. The lowest, middle, and highest tertiles are
distinguished by bars with diagonal lines, bars with horizontal lines, and black bars, respectively. The differences in 1-year incidence rates by
a-carotene tertile were significant at the 0.01 level; the differences in 2-year incidence rates by a-carotene and total carotenoid tertiles were
significant at the 0.05 level.
46
* n ¼ 619 for all analyses except a-tocopherol:cholesterol ratio (n ¼ 605), zinc (n ¼ 615), and
selenium (n ¼ 591).
y Calculated for a one-standard-deviation increase in log-transformed micronutrient level in
a logistic regression model with adjustment for age, race, years of education, smoking status,
body mass index, chronic obstructive pulmonary disease, peripheral arterial disease, angina,
diabetes, physical activity, and incident cardiovascular disease.
22
Walston et al.
TABLE 4. Adjusted odds ratio for having an interleukin-6 level that increased longitudinally by more than
0.5 standard deviation (3.21 pg/ml) over a 2-year period, with the highest tertile of each micronutrient at
baseline used as the reference group, Women’s Health and Aging Study I, Baltimore, Maryland, 1992–1995
Baseline nutrient tertile
Year 1
No.
ORy,z
Year 2
95% CIy
No.
ORz
95% CI
0.039
>0.039, 0.094
>0.094
146
2.48
1.05, 5.88*
112
7.99
2.27, 28.21**
126
1.49
0.60, 3.72
111
7.12
2.08, 24.38**
155
1
119
1
138
141
1.68
0.96
115
108
4.09
3.52
148
1
119
1
0.23
>0.23, 0.45
>0.45
0.74, 3.84
0.42, 2.21
1.38, 12.11*
1.19, 10.39 *
0.38
>0.38, 0.64
1.01
0.44, 2.31
109
1.71
0.63, 4.62
1.40
0.63, 3.09
118
2.14
0.83, 5.52
155
1
115
1
132
144
1.12
1.34
105
114
5.57
3.18
151
1
123
1
0.27
>0.27, 0.41
>0.41
0.46, 2.74
0.61, 2.94
1.74, 17.80**
1.08, 9.39*
0.074
>0.074, 0.14
>0.14
129
1.58
0.69, 3.62
102
2.00
0.75, 5.37
147
1.40
0.63, 3.11
118
1.71
0.67, 4.39
151
1
122
1
148
143
0.70
0.70
111
121
0.48
0.66
136
1
110
1
2.13
>2.13, 2.90
>2.90
0.31, 1.56
0.31, 1.59
0.19, 1.23
0.27, 1.61
17.43
>17.43, 23.08
>23.08
138
0.46
0.18, 1.13
116
1.00
0.37, 2.72
141
1.00
0.46, 2.18
106
2.17
0.86, 5.47
148
1
120
1
a-Tocopherol:cholesterol ratio
(lmol/liter)
3.31
>3.31, 4.47
>4.47
141
0.84
0.35, 2.02
109
1.05
0.38, 2.94
131
1.23
0.54, 2.81
105
1.70
0.64, 4.52
134
1
112
1
1.17
132
2.05
0.86, 4.91
113
3.98
1.51, 10.49**
142
153
1.94
1
0.83, 4.52
103
126
1.40
1
0.47, 4.14
110.00
131
0.53
0.23, 1.27
99
0.94
0.36, 2.45
138
0.76
0.34, 1.68
115
0.81
0.32, 2.03
>122.90
140
1
122
1
135
0.94
0.39, 2.26
103
1.05
0.38, 2.94
147
145
1.76
1
0.81, 3.85
124
119
1.70
1
0.64, 4.52
>1.17, 1.80
>1.80
Selenium (lg/liter)
>110.00, 122.90
Zinc (lg/liter)
770.85
>770.85, 938.68
>938.68
* p 0.05; **p 0.01.
y OR, odds ratio; CI, confidence interval.
z Adjusted for age, Black race, years of education, smoking status, body mass index, baseline cardiovascular
disease, chronic obstructive pulmonary disease, diabetes, peripheral vascular disease, physical activity, incident
cardiovascular disease, and baseline interleukin-6 level.
47
>0.64
134
138
TABLE 5. Mortality hazard over a 5-year period in relation to baseline levels of three micronutrients in a Cox proportional hazards
model, Women’s Health and Aging Study I, Baltimore, Maryland, 1992–1998
No. of deaths
over 5 years
Unadjusted
HRy
95% CIy
Age- and raceadjusted HR
�0.040
71
1.19
0.85, 1.68
1.44*
1.02, 2.04
1.06
0.70, 1.59
73
1.21
0.86, 1.69
1.30
0.92, 1.82
1.19
0.81, 1.74
>0.094
62
1
�1.167
75
1.23
0.88, 1.72
1.32
0.95, 1.85
1.07
0.72, 1.58
67
1.03
0.73, 1.45
1.09
0.78, 1.54
1.02
0.69, 1.50
>1.806
64
1
�109.9
78
1.66*
1.17, 2.37
1.48*
1.03, 2.13
1.54*
1.03, 2.32
68
1.40
0.98, 2.02
1.24
0.86, 1.79
1.30
0.86, 1.96
>122.8
51
1
Micronutrient
95% CI
Fully
adjusted HRz
95% CI
>0.040, �0.094
1
1
>1.167, �1.806
1
1
Selenium (lg/liter)
>109.9, �122.8
1
1
2 years (figure 1). The associations between increasing
interleukin-6 and a-carotene remained significant in the
fully adjusted model for year 1 (OR ¼ 2.48, p < 0.05). For
year 2, the associations remained significant for a-carotene
(OR ¼ 7.99, p < 0.01), b-carotene (OR ¼ 4.09, p <
0.05), lutein/zeaxanthin (OR ¼ 5.57, p < 0.01), and total
carotenoids (OR ¼ 3.98, p < 0.01) (table 4). Selenium
levels were unrelated to interleukin-6 increase in both
models (table 4), probably partly because of the large
number of subjects in the lowest selenium tertile who
did not return for follow-up visits in this longitudinal
study. Further investigation of the potential reasons why
many persons in the lowest selenium tertile at baseline
were missing from subsequent analyses showed that those
participants had a significantly greater risk of all-cause mortality over a 5-year period than participants in the other
tertiles (hazard ratio ¼ 1.54, 95 percent CI: 1.03, 2.32;
p < 0.05), even in unadjusted and fully adjusted models
(table 5). We identified no significant increase in 5-year
cardiovascular disease mortality hazard in the two lower
tertiles of selenium in relation to the highest tertile (data
not shown). We also identified an increased risk of mortality for persons with the lowest levels of a-carotene in
the model adjusted for age and race, but we identified no
increased mortality risk in persons with the lowest baseline levels of a-carotene or total carotenoids over 5 years
in the fully adjusted model (table 5). No other cause-ofdeath grouping was large enough for analysis of differences between groups.
coefficients for the relations between micronutrients and log
interleukin-6 levels. We found that associations and correlations were generally higher for older women, women with
a higher body mass index, and women with lower physical
activity than for women without these risk factors (data not
shown).
In the cross-sectional analysis adjusting for multiple confounders, we identified highly significant inverse relations
between serum interleukin-6 levels and a-carotene (odds
ratio (OR) ¼ 0.65, 95 percent confidence interval (CI): 0.53,
0.80), total carotenoids (OR ¼ 0.65, 95 percent CI: 0.53, 0.79),
and selenium (OR ¼ 0.65, 95 percent CI: 0.52, 0.80) (p <
0.0001 for each)—a 35 percent reduction in risk of being in
the highest interleukin-6 tertile for every 1-SD increase in
log nutrient value (table 3). Persons with the highest levels
of b-carotene, lycopene, lutein/zeaxanthin, b-cryptoxanthin,
and retinol were also significantly less likely to be in the
highest interleukin-6 tertile (table 3). There was no identifiable relation between serum levels of zinc, a-tocopherol, or
a-tocopherol:cholesterol ratio and serum interleukin-6 in
these analyses (table 3).
We found an increasing but not statistically significant
time trend in the population mean interleukin-6 level using
the random-effects model. There was substantial betweenperson heterogeneity in the rate of change (i.e., time slope)
in interleukin-6 levels over time (p < 0.01; data not shown),
suggesting that any population-average approach in this
case could underestimate critical changes in interleukin-6
on an individual level. Therefore, we examined the longitudinal effect of baseline micronutrient levels on individuallevel changes in serum interleukin-6. The percentage increase
of more than 0.5 SD in interleukin-6 values (3.21 pg/ml)
over 1-year and 2-year periods significantly increased as the
a-carotene level decreased (figure 1). A similar finding was
observed among the total carotenoid groups over a period of
DISCUSSION
These findings demonstrate robust inverse cross-sectional
relations between the potent inflammatory cytokine interleukin-6 and several antioxidant carotenoids and selenium.
48
* p � 0.05.
y HR, hazard ratio; CI, confidence interval.
z Adjusted for age (years), Black race, years of education, current smoking, body mass index, chronic obstructive pulmonary disease,
peripheral arterial disease, angina, diabetes, and physical activity at baseline.
24
Walston et al.
The increased 5-year mortality in persons with the lowest
selenium levels was identified after we found that many persons in the lowest selenium tertile did not return for subsequent study visits. Selenium deficiency is associated with a
host of inflammatory tissue responses and with disease progression, including myocarditis related to Coxsackievirus
and human immunodeficiency virus, thyroid dysfunction,
arthritis, cancer, depression, and cardiovascular disease
(27, 32). This selenium deficiency-related acceleration of
many disease processes may partly explain the association
between mortality and lower selenium levels observed in this
population. Further exploration of the specific etiology of
mortality beyond cardiovascular disease may help add biologic and tissue specificity to this finding.
It is not clear why we did not identify a relation between
the carotenoids and mortality. Although we cannot rule out
residual confounding, other plausible explanations exist.
First, the set of micronutrients included in this study comprises only a small part of a large family of antioxidants and
nutrients. It may well be that other nutrients and biomediators that we did not measure (e.g., vitamin C) can modulate
interleukin-6 as well, thereby independently contributing to
mortality. Second, we had hypothesized that micronutrients
represent more distal correlates relative to interleukin-6 in
relation to mortality; therefore, the effects are more likely to
be indirect. Third, WHAS I was designed to study the one
third most disabled older women, which could have resulted
in limited variability of micronutrient levels—that is, a flooring effect—in the study population. Finally, since we do not
have longitudinal data on serum antioxidants because of the
prohibitive cost, we are not able to confirm a causal relation
without taking into account the changes in carotenoid levels
over time.
A number of questions remained unanswered in this
study. First, it is unclear whether low dietary intake, high
oxidative stress, or both contributed to the observed lower
antioxidant levels. Although inflammation has minimal impact on selenium levels, serum carotenoid levels are modestly decreased by inflammatory processes in younger and
older adults (33, 34). Second, although we adjusted for diseases known to trigger inflammation, it was not possible
to characterize all clinical and subclinical inflammationinducing conditions and hence capture all potentially confounding variables in this population. Third, although there
is some knowledge of specificity in function of antioxidant
nutrients and enzymes, many studies have been performed in
in-vitro systems, making any findings regarding specificity
of function of individual nutrients less than conclusive.
Fourth, we had 383 missing data points because of lack of
or insufficient amounts of serum for measuring the relevant
variables. Given that persons with insufficient data were
older, less obese, and less physically active, we would hypothesize that our findings would have been even stronger if
we had had those missing data. Finally, we did not have
longitudinal measurements of antioxidant levels for this
analysis, which, combined with longitudinal interleukin-6
measurements, might help determine directionality and
the utility of specific antioxidant nutrient interventions in
suppressing elevated interleukin-6 levels in at-risk older
adults.
49
No relations were demonstrated between a-tocopherol or
zinc levels and serum interleukin-6. Importantly, longitudinal analyses demonstrated that baseline levels of a-carotene,
b-carotene, lutein/zeaxanthin, and total carotenoids were
significantly associated with increasing levels of interleukin-6 over a period of 2 years and that low levels of selenium
were associated with increased risk of all-cause mortality
over a period of 5 years. The identification of differences in
relations between individual antioxidant micronutrients and
interleukin-6 may provide specific clues as to which oxidative pathways most contribute to the inflammatory characteristics observed in frail and disabled older adults (1, 3, 19).
Additional longitudinal nutritional data and analyses may
help in determining which serum antioxidant measurements
might be useful guides in the suppression of oxidative
stress-induced inflammation.
Dietary carotenoids are powerful antioxidants that are
embedded within lipid bi-layers (the two lipid layers that
make up cell membranes) and function to quench free radicals generated by intracellular oxidative processes (20).
Although all of the individual carotenoids analyzed for
this study showed significant relations with interleukin-6,
b-carotene and (especially) a-carotene demonstrated the most
robust cross-sectional and longitudinal relations. Lower
levels of a-carotene have been linked to atherosclerotic
processes in older adults, and low levels of a-carotene and
b-carotene correlate with a higher risk of coronary artery
disease in adult women (21, 22). This may be partly because
a- and b-carotene constitute a major benign sink for oxidation in lipid particles; hence, lower levels of these carotenoids could lead to more oxidized lipids and increased
activation of inflammatory pathways (23–25). Although deficiencies in lutein/zeaxanthin have most often been linked to
macular degeneration, studies also show a strong relation
between low levels of these nutrients and cardiovascular
disease (26). Thus, our longitudinal findings suggest that
low levels of a- and b-carotene, lutein/zeaxanthin, and total
carotenoids may drive interleukin-6 increases, perhaps
through decreased availability of these antioxidants for
quenching free radicals in the cardiovascular system.
Selenium is a critical constituent of glutathione peroxidase, the major reducing enzyme for both hydrogen peroxide
and lipid peroxides (27). Zinc, like selenium, is an important
component of a cytosolic antioxidant enzyme, copper-zinc
superoxide dismutase (28). Although we found a strong relation between low selenium and high interleukin-6, we found
no relation between zinc and interleukin-6. Superoxide molecules are converted to hydrogen peroxide by copper-zinc
superoxide dismutase, which in turn activates inflammatory
pathways (25). Elevation of copper-zinc superoxide dismutase to selenium-dependent glutathione peroxidase activity
has been demonstrated to correlate with increased lipid peroxidation and nuclear factor-jB activation through increased
hydrogen peroxide activity (29, 30). This evidence from
prior studies, along with our findings of a strong relation
between selenium and interleukin-6 and no relation between
zinc and interleukin-6, suggests that oxidative processes
driven by increased hydrogen peroxide and lipid peroxides
rather than superoxide radicals may partly drive generation
of interleukin-6 in older adults (31).
In summary, in this study, we identified robust inverse
cross-sectional and longitudinal relations between several
specific carotenoids and serum interleukin-6. We identified
a robust cross-sectional inverse relation between selenium
and interleukin-6 and increased mortality among persons with
lower selenium levels. These findings suggest that specific
antioxidant nutrients, which act mechanistically to decrease
levels of hydrogen peroxide and lipid peroxides, may play an
important role in suppressing expression of interleukin-6 in
disabled older women.
ACKNOWLEDGMENTS
This research was supported by National Institutes of
Health contract N01-AG12112, National Institutes of
Health grant R37 AG19905, Older American Independence
Center grant P30 AG021334, and General Clinical Research Center–National Center for Research Resources
grant M01-RR0000052.
Conflict of interest: none declared.
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51
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The Journal of Experimental Biology 203, 1513–1521 (2000)
Printed in Great Britain © The Company of Biologists Limited 2000
JEB2594
REVIEW
SURFACE OXIDASE AND OXIDATIVE STRESS PROPAGATION IN AGING
DOROTHY M. MORRÉ1,*, GIORGIO LENAZ2 AND D. JAMES MORRÉ3
of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA, 2Departimento di
Biochimica, Bologna, Italy and 3Department of Medicinal Chemistry and Molecular Pharmacology,
Purdue University, West Lafayette, IN 47907, USA
1Department
*e-mail: [email protected]
Accepted 23 February; published on WWW 18 April 2000
Summary
activity has been shown to be necessary to maintain the
This report summarizes new evidence for a plasmaNAD+/NADH homeostasis essential for survival. Our
membrane-associated hydroquinone oxidase designated
as CNOX (constitutive plasma membrane NADH
findings demonstrate that the hyperactivity of the PMOR
oxidase) that functions as a terminal oxidase for a
system results in an NADH oxidase (NOX) activity
plasma membrane oxidoreductase (PMOR) electron
capable of generating reactive oxygen species at the cell
transport chain to link the accumulation of lesions in
surface. This would serve to propagate the aging cascade
mitochondrial DNA to cell-surface accumulations of
both to adjacent cells and to circulating blood
reactive oxygen species. Previous considerations of
components. The generation of superoxide by NOX forms
plasma membrane redox changes during aging have
associated with aging is inhibited by coenzyme Q and
lacked evidence for a specific terminal oxidase to catalyze
provides a rational basis for the anti-aging activity of
a flow of electrons from cytosolic NADH to molecular
circulating coenzyme Q.
oxygen (or to protein disulfides). Cells with functionally
deficient mitochondria become characterized by an
Key words: hydroquinone (NADH) oxidase, mitochondria, ageing,
cell surface, plasma membrane, electron transport, coenzyme Q,
anaerobic metabolism. As a result, NADH accumulates
oxidative stress.
from the glycolytic production of ATP. Elevated PMOR
A plasma membrane redox system essential to survival of
mitochondrial-deficient cells during aging
A consistent characteristic of aging cells is the accumulation
of somatic mutations of mitochondrial DNA (mtDNA) leading
to defective oxidative phosphorylation through alterations that
affect exclusively the four mitochondrial complexes involved
in proton translocation (Harman, 1956, 1972; Miquel et al.,
1980; Linnane et al., 1989; Arnheim and Cortopassi, 1992;
Ozawa, 1995; de Grey, 1997, 1998; Lenaz et al., 1997, 1998).
A major piece of the puzzle missing from our information is
how mitochondrial lesions are propagated to adjacent cells and
blood components during the aging cascade. Progress towards
understanding how this might occur is provided by the studies
of de Grey (1997, 1998), in which a largely hypothetical
plasma membrane oxidoreductase (PMOR) system has been
suggested to augment survival of mitochondrially deficient
cells through the regeneration of oxidized pyridine nucleotide
required to sustain glycolytic ATP production in the presence
of diminished respiratory chain activity (Yoneda et al., 1995;
Schon et al., 1996; Ozawa, 1997; Lenaz, 1998).
In this report, we describe a newly discovered cell-surface
protein with hydroquinone (NADH) oxidase activity
(designated NOX) (Kishi et al., 1999) that functions as a
terminal oxidase of the PMOR system together with a complete
electron transport chain involving a cytosolic hydroquinone
reductase, plasma-membrane-located quinones and the NOX
protein (Morré, 1998). This system, described in detail since
the studies of de Grey (1997, 1998) appeared, provides a
rational basis for the operation of the mitochondrial theory of
aging and for the propagation of aging-related mitochondrial
lesions, including a decline in mitochondrial ATP synthetic
capacity (Boffoli et al., 1996) and other energy-dependent
processes (Lenaz et al., 1998) during aging.
Alterations in mitochondrial DNA (mtDNA) are by far the
most common sources of genetic lesions associated with cell
aging and senescence. It has been widely noted that mtDNAs
are located at the inner mitochondrial membrane near sites
where highly reactive oxygen species and their products
might be formed. Several subunits of the electron transport
chain together with components of the ATP synthase and
mitochondrial tRNAs and rRNAs are encoded by the
mitochondrial genome. The flow of electrons through the
52
1514
D. M. MORRÉ, G. LENAZ AND D. J. MORRÉ
mitochondrial electron transport chain is not fully efficient,
and up to 2–4 % of the oxygen metabolized by mitochondria
has been estimated to be converted to oxygen radicals
(Boveris et al., 1972; Richter et al., 1988). A major tenet of
the mitochondrial theory of aging is that mtDNA may be
unable to counteract the damage inflicted by oxygen radicals
and their products because of a lack of excision and
recombination repair mechanisms (Miquel, 1992). This has
been demonstrated in cultured cells in which damage to
mtDNA resulting from oxidase stress is not only greater but
persists longer than does damage to nuclear DNA (Yakes and
Van Houten, 1997). Using the amount of 8-oxo-2′deoxyguanosine formed by the reaction of hydroxyl free
radicals with guanine in mtDNA as a biomarker of oxidative
DNA damage, the steady-state level of oxidative changes in
mtDNA was found to be approximately 10–16 times greater
than that of changes in nuclear DNA (Richter et al., 1988;
Shigenaga et al., 1994). Even lipid peroxidation of
mitochondrial membranes seems to lead to damage to
mtDNA (Balcavage, 1982).
Despite this overwhelming mass of evidence, alterations
to mtDNA per se and other forms of cellular and tissue
changes related to aging have been difficult to link. Chief
among these is the oxidation of low-density lipoproteins
(LDLs) and its implications as causal to atherogenesis
(Steinberg, 1997).
A model to link accumulation of lesions in mtDNA to an
extracellular response such as the oxidation of lipids in LDLs
and the attendant arterial changes was first proposed by de
Grey (1997, 1998) on the basis of the observations of Larm
et al. (1994) and Lawen et al. (1994) with Namalwa ρ0 cells.
These cells lack mtDNA and are unable to carry out oxidative
phosphorylation. Larm et al. (1994) and Lawen et al. (1994)
first demonstrated that the plasma membrane PMOR system
actually functions to regenerate NAD+ from NADH. In the
absence of a functional mitochondrial respiratory chain,
NADH accumulates as the result of glycolytic production of
ATP (Fig. 1). The ρ0 cells lacking functional mitochondria
apparently survive through enhanced electron flow to
molecular oxygen via PMOR. In addition, it may be possible
that aging cells over-express PMOR when mitochondrial
functions are depressed. Unpublished data from the
laboratory of G. Lenaz (Table 1) has demonstrated that, in
lymphocytes from insulin-dependent diabetic subjects, the
mitochondrial membrane potential exhibits increased
sensitivity to uncouplers as a result of decreased electron
input from the respiratory chain. PMOR is accordingly overexpressed in these cells. Oxidative stress and LDL oxidation
are common complicating features in diabetics (Kennedy and
Lyons, 1998).
The capacity of cells to generate ATP is determined either
by reoxidation of NADH by mitochondrial respiratory
mechanisms (reduction of oxygen to water) or by cytosolic
glycolytic mechanisms (reduction of pyruvate to lactate). If
sufficient pyruvate and uridine are provided, cells can grow
without a functional mitochondrial electron transport chain and
Table 1. Bioenergetic parameters in peripheral lymphocytes
from patients with insulin-dependent diabetes mellitus
Patients
Controls
P
Site I
respiration*
Site II
respiration*
Sensitivity
to FCCP‡
PMOR
activity§
(nmol min−1
10−6 cells−1)
0.12±0.05
0.26±0.12
0.08±0.08
0.21±0.07
19.7±7.5
5.2±1.9
2.7±0.6
1.9±0.5
<0.02
<0.01
<0.001
<0.005
Values are means ± S.E.M. (N=14 for patients and 13 for controls).
*O2 uptake with glutamate/malate (site I) and with succinate/
glycerol 3-phosphate (site II) are normalized to cytochrome c
oxidase activity (the ratio of activity measured to cytochrome
oxidase activity measured by ascorbate/N,N,N′,N′-tetramethyl-pphenylenediamine (TMPD) oxidation). The measurements were
performed in digitonin-permeabilized lymphocytes.
‡Slope of the green to red fluorescence ratio of 5,5′,6,6′tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine
iodide
(JC1) measured in flow cytometry after addition of increasing
concentrations
of
the
uncoupler
4-trifluoromethoxycarbonylcyanidephenylhydrazone (FCCP) (expressed in arbitrary
units).
§Dichlorophenolindophenol (DCIP) reduction by endogenous
NADH in intact lymphocytes.
PMOR, plasma membrane oxidoreductase activity.
oxidative phosphorylation. As shown by Vaillant et al. (1996),
transformed human cells in culture provided with excess
pyruvate grow anaerobically on a glucose medium because
NAD+ is regenerated from the NADH that is produced during
glycolysis. This continual regeneration of NAD+, including
that generated by the PMOR, ensures that the glycolytic
pathway will provide sufficient ATP to sustain cell growth and
viability.
Glucose
Plasma
membrane
ADP
Glycolysis
NAD +
ATP
NADH
+ H+
AH2
PMOR
A
Pyruvate
Fig. 1. Relationship between the plasma membrane oxidoreductase
(PMOR) system and the regeneration of NAD+ from NADH formed
during glycolysis. A is the external acceptor.
53
1515
Surface oxidase and oxidative stress propagation during aging
oxidase protein, designated NOX, capable of oxidizing
hydroquinones (Kishi et al., 1999). This protein, which is
located at the exterior of the cell (Morré, 1995; DeHahn et al.,
1997), appears to be multifunctional but may have a major
function as a terminal oxidase of the PMOR system. These
findings make it possible, for the first time, to delineate a
complete electron transfer chain in the plasma membrane
capable of transferring electrons from NADH to an external
electron acceptor via a reduced quinone intermediate.
Mammalian plasma membranes are enriched in coenzyme Q
(ubiquinone) (Table 3). The plasma membrane at the cytosolic
surface contains a quinone reductase capable of oxidizing
NADH and reducing coenzyme Q. The electron acceptor at the
external cell surface is either molecular oxygen or, under
certain conditions, both molecular oxygen and protein
disulfides (Morré, 1994; Chueh et al., 1997; Morré et al.,
1998). The enzyme can alternate between the two acceptors
(Morré, 1998). Hormones and growth factors stimulate NADH
oxidation and favor protein disulfide reduction at the expense
of oxygen consumption (Brightman et al., 1992; Morré, 1994;
Chueh et al., 1997). Chueh et al. (1997) demonstrated
stoichiometric relationships among protein disulfide reduction,
NADH oxidation and protein-thiol formation using isolated
plasma membranes from a plant source stimulated by an auxin
Glycolysis
Glucose
Pyruvate
Mitochondrial
DNA mutations
Anaerobic
cell
Glucose
ADP
NAD+
Glycolysis
New evidence for a plasma membrane oxidoreductase chain
important to aging
As demonstrated with ρ0 cells, a functional PMOR is
essential to aging cells expressing mitochondrial lesions.
Mitochondrial DNA encodes respiration and oxidative
phosphorylation enzymes exclusively, so that cells with
functionally deficient mitochondria become metabolically
anaerobic. In such cells, the PMOR could regenerate sufficient
reducing equivalents to maintain NAD+/NADH homeostasis
and ensure the survival even of cells completely deficient in
aerobic respiratory capacity.
Our work demonstrates that, in cells in which the PMOR is
over-expressed/activated, electrons are transferred from
NADH to external acceptors via a recently defined electron
transport chain in the plasma membrane (Kishi et al., 1999).
The resultant transfer of electrons could result subsequently in
the generation of superoxide and ultimately other reactive
oxygen species (ROS) at the cell surface (Table 2). Such cellsurface-generated ROS would then be capable of propagating
an aging cascade originating in mitochondria both to adjacent
cells and to circulating blood components such as LDLs and
to the vasculature (Fig. 2).
Work done in collaboration with Professor T. Kishi, KobeGakuin University, Japan, has described a cell-surface NADH
AT P
NADH
+ H+
ATP production
by glycolysis
Pyruvate
NAD +
A
PMOR
NADH
+ H+
Enhanced PMOR activity
to oxidize NADH
Adjacent cells
Fig. 2. Hypothesis to explain the
mechanism whereby anaerobiosis
resulting from mitochondrial lesions,
the resultant stimulation of glycolysis
and the enhancement of the plasma
membrane oxidoreductase (PMOR)
system result in the formation of
reactive oxygen species (ROS) at the
cell surface that can be propagated and
affect both adjacent cells and
circulating blood components. LDL,
low-density lipoprotein.
LDL
2H+
+
2e−
GO 2
Atherosclerosis
H 2O
O 2.
H 2O 2
Oxidised
LDL
OH−
Generation of
ROS at plasma membrane
54
Propagation
of response
AH2
1516
plant growth factor 2,4-dichlorophenoxyacetic acid (2,4-D). A
similar stoichiometry has been demonstrated for NADH
oxidation in HeLa cells (Morré et al., 1998).
As a terminal oxidase of the PMOR electron transport chain,
the NOX protein may be responsible not only for maintaining
NAD+/NADH homeostasis in metabolically anaerobic cells
but may also play a role in the enhanced generation of ROS in
aged cells expressing mitochondrial mutations that lead to
impaired oxidative phosphorylation. Since oxygen appears to
be the principal natural electron acceptor for the PMOR
electron transport chain, a number of factors, including metals
(iron or copper), could interrupt the orderly two-electron flow
to molecular oxygen that ordinarily forms water and initiates
a one-electron process producing superoxide (O2• or O2−) (Fig.
2). Superoxide then probably initiates a reaction that generates
H2O2 and other aggressive oxidants such as the hydroxyl
radical (OH•) (Papa and Skulachev, 1997). These ROS then
would be released into the environment to react with
neighboring cells and circulating molecules such as LDL
(Steinberg, 1997).
1992; Morré and Morré, 1995; Morré et al., 1995a,b, 1996a,
1997c).
Because the NOX protein is located at the external plasma
membrane surface and is not a transmembrane protein (Morré,
1994; DeHahn et al., 1997), a functional role as an NADH
oxidase is not considered likely (Morré, 1998). Although the
oxidation of NADH provides a basis for a convenient method
to assay the activity, the ultimate physiological electron donors
are most probably hydroquinones (Kishi et al., 1999), as
depicted in Fig. 3, with specific activities for hydroquinone
oxidation being greater than or equal to those of NADH
oxidation and/or protein-disulfide–thiol interchange.
The NOX protein partially purified from the surface of HeLa
cells also exhibits ubiquinol oxidase activity (Kishi et al.,
1999). These preparations completely lack NADH:ubiquinone
reductase activity and oxidize the dihydroquinone Q10H2 at a
rate of 3–6 nmol min−1 mg−1 protein. The Km for Q10H2 is
30 µmol l−1. Activities are inhibited competitively by the
cancer-cell-specific NADH oxidase inhibitors capsaicin (8methyl-N-vanillyl-6-noneamide) (Morré et al., 1995a, 1996a)
and the antitumor sulfonylurea N-(4-methylphenylsulfonyl)N′-(4-chlorophenyl)urea (LY181984) (Morré et al., 1995b).
The oxidation of Q10H2 proceeds with what appears to be a
normal two-electron transfer, in keeping with the participation
of the plasma membrane NADH oxidase as a terminal oxidase
of plasma membrane electron transport from cytosolic
NAD(P)H via coenzyme Q to acceptors at the cell surface, as
depicted in Fig. 3.
The NOX protein is distinguished from other oxidase
activities by differential susceptibility of the activity to several
common oxidoreductase inhibitors (Morré and Brightman,
1991) and to thiol reagents (Morré and Morré, 1994). In
addition, the activity of tNOX correlates with the growth of
transformed cells (Morré et al., 1995a, 1996a; Ozawa, 1995).
When inhibited by tNOX-specific vanilloids or antitumor
sulfonylureas, the cells initially divide normally, and DNA and
protein synthesis is not inhibited, but the cells fail to enlarge
(Morré and Morré, 1995; Morré et al., 1995a). The resultant
small cells, however, fail to divide and, after a few days, begin
to undergo apoptotic cell death (Morré and Morré, 1995; Morré
et al., 1995a; DeHahn et al., 1997). Two monoclonal antibodies
directed against tNOX, designated MAB 12.1 and MAB 12.5,
were generated and were shown also to be inhibitory to cell
enlargement in cancer cells but not in normal cells and to
induce apoptotic cell death even more efficiently than did the
drug inhibitors of tNOX (Morré, 1998).
In cancer cells, the tumor-associated (tNOX) activity was
constitutively activated (Morré et al., 1995a) and inhibited by
retinoids (Dai et al., 1997) and by other potential quinone-siteinhibitory drugs, such as the antitumor sulfonylurea LY181984
(Morré et al., 1995b) and capsaicin (Morré et al., 1995a), but
was no longer hormone- or growth-factor responsive (Bruno et
al., 1992; Morré et al., 1995a). The ability to oxidize NADH
was reflected in the ability of the protein to function as an
NADH:protein disulfide reductase or protein-disulfide–thiol
oxidoreductase with protein-disulfide–thiol interchange
Plasma membrane hydroquinone (NADH) oxidase (NOX)
The plasma membrane NADH oxidase (NOX) is a unique
cell-surface protein with hydroquinone (NADH) oxidase and
protein-disulfide–thiol interchange activities that normally
respond to hormones and growth factors (Brightman et al.,
1992; Morré, 1994, 1998). A hormone-insensitive and drugresponsive form of the activity designated tNOX also has
been described that is specific for cancer cells (Bruno et al.,
2O2 .
Plasma membrane
Outside
Inside
NOX
2O2
Q10
H2 O
GO2
Protein
S
S
Protein
SH
SH
Q10 H 2
Quinone
reductase
NAD(P)H
+ H+
NAD(P) +
Fig. 3. Diagram showing the spatial relationships between the
intracellular NAD(P)H:quinone reductase, the membrane pool of
coenzyme Q (Q10) and the external NADH oxidase (NOX) protein
across the plasma membrane. In this manner, the NOX protein could
function as a terminal oxidase of plasma membrane electron
transport, donating electrons from cytosolic NADH either to
molecular oxygen or to protein disulfides as electron acceptors.
55
1517
activity (Morré et al., 1997b). The latter may be related to low
levels of a protein disulfide isomerase-like activity reported at
the cell surface (Mandel et al., 1993). The protein is associated
with the enlargement phase of cell growth (Morré, 1998).
When NOX activity is inhibited, growth is also inhibited. In
the presence of capsaicin (Morré et al., 1995a), the antitumor
sulfonylurea LY181984 (Morré and Morré, 1995) and NOXinhibitory retinoids (Dai et al., 1997), the inhibited cells fail to
enlarge, division ceases and apoptotic cell death is the ultimate
fate of the inhibited cells.
CNOX was originally defined as a drug-indifferent
constitutive NADH oxidase activity associated with the plasma
membrane of non-transformed cells that was the normal
counterpart to tNOX. Indeed, a 36 kDa protein isolated from
rat liver and from plants has NOX activity that is unresponsive
to tNOX inhibitors.
While cancer cells exhibit both drug-responsive and
hormone- and growth-factor-indifferent (tNOX) as well as
drug-inhibited and hormone- and growth-factor-dependent
(CNOX) activities, non-transformed cells exhibit only the
drug-indifferent, hormone- and drug-responsive CNOX.
Among the first descriptions of the so-called constitutive or
CNOX activity of non-transformed cells and tissues was that
in rat liver plasma membranes, in which the activity was
stimulated by the growth factor diferric transferrin (Sun et al.,
1987). Subsequent work demonstrated that this NADH
oxidation was catalyzed by a unique enzyme exhibiting
responsiveness to several hormones and growth factors (Bruno
et al., 1992). Unlike mitochondrial oxidases, the hormonestimulated NADH oxidase activity of rat liver plasma
membranes was not inhibited by cyanide. The enzyme was also
distinguished from other oxidase activities by its response to
several common oxidoreductase inhibitors (i.e. catalase, azide
and chloroquine) and to various detergents (i.e. sodium
cholate, Triton X-100 and Chaps) (Morré and Brightman,
1991; Morré et al., 1997c). Like the tNOX of cancer cells,
CNOX is a unique membrane-associated protein that is capable
of oxidizing NADH, but its activity is modulated by hormones
and growth factors.
Table 2 presents evidence that NOX proteins under certain
conditions are capable of the production of ROS. We have used
ultraviolet light as a source of oxidative stress in cultured cells
to initiate superoxide generation (Morré et al., 1999). Such
generation is presumably due to the NADH oxidase because in
cell lines (HeLa, a human cervical carcinoma, and BT-20, a
human mammary carcinoma) that contain a capsaicinresponsive NADH oxidase, the response to ultraviolet light is
inhibited by capsaicin. In the MCF-10A cell line (a human
mammary epithelium), lacking tNOX activity and not
cancerous, the ultraviolet-light-induced generation of
superoxide is unaffected by capsaicin and, presumably, the
resultant effect of ultraviolet light on the plasma membrane
CNOX (Table 2).
The switch whereby the oxidase may reduce oxygen by
either a one-electron or a four-electron mechanism is not
understood at present, but it may reside in a delicate redox
Table 2. Reduction of cytochrome c as a measure of
superoxide production by cell lines in response to ultraviolet
irradiation and inhibition by superoxide dismutase and by
capsaicin
Rate of reduction of cytochrome c
(mol min−1 106 cells−1)
After ultraviolet treatment2
Cell
line1
HeLa S
BT-20
MCF-10A
Initial rate
No addition
+SOD3
+Capsaicin4
0.8±0.16
0.7±0.2
1.5±0.2
4.0±1.0
5.1±2.1
7.2±0.1
1.1
–0.1
–0.7
0.8
–3.7
7.2
Values are means ± S.D., N=3.
1HeLa S, human cervical carcinoma; BT-20, human mammary
adenocarcinoma; MCF-10A, human mammary epithelium (noncancer).
2Treatment for 10 min with short-wavelength ultraviolet light.
3Treatment with 7.5 µg ml−1 superoxide dismutase (SOD) (Sigma).
4Treatment with 2.5 µmol l−1 capsaicin in dimethylsulfoxide
(DMSO). Rates were corrected for a DMSO blank.
The generation of superoxide radical was determined by assaying
the rate of SOD-inhibitable cytochrome c reduction (Mayo and
Curnutte, 1990; McCord and Fridovich, 1968). The cytochrome c
was from horse heart mitochondria (type VI, Sigma) and was
dissolved in PBSG buffer (138 mmol l−1 NaCl, 2.7 mmol l−1 KC1,
8.1 mmol l−1 Na2HPO4 and 1.47 mmol l−1 KH2PO4, final
pH 7.37–7.42, then supplemented with 0.9 mmol l−1 CaCl2,
0.5 mmol l−1 MgCl2 and 7.5 mmol l−1 glucose) to make a solution
with a final concentration of 1 mg ml−1. Air-saturated reaction
mixtures of 100 µl of cytochrome c stock solution and 50 µl of cell
suspension (suspended in PBSG buffer) with a concentration of
approximately 5×106 cells ml−1 were added to 2 ml of PBSG buffer .
The formation of reduced cytochrome c was measured in the
presence and absence of 5 µl of SOD or capsaicin (in 1 mmol l−1 in
DMSO) by comparing the absorbance of the mixture at 550 and
540 nm. The SOD was obtained from Sigma, and a stock solution of
3 mg protein ml−1 H2O was prepared and stored at 4 °C. Superoxide
radical formation was stimulated by using a hand-held ultraviolet
light (short-wavelength). Plastic cuvettes were used to allow the light
to penetrate and reach the cells. The extent of cytochrome c
reduction was monitored spectrophotometrically at 550 nm every
10 s, with gentle mixing between readings. Data were analyzed from
the slope of the change in the difference in absorbance between 550
and 540 nm before and after ultraviolet treatment and then again after
SOD or capsaicin treatment.
Results are expressed as nmol superoxide 106 cells−1, using a value
of Em550nm of 2.1×103 l mol−1 cm−1 (Butler et al., 1982).
balance between the carriers involved. Such a balance may be
broken by oxidative stress or cell damage. Metal ions such as
iron and copper, released by tissue damage (Hershko, 1992),
may also play a role.
Plasma membrane levels of coenzyme Q
In the model depicted in Fig. 3, plasma membrane ubiquinone
or coenzyme Q is a major player in the PMOR system that we
56
1518
Table 3. The distribution of ubiquinone in subcellular
fractions from rat liver
Fraction
Homogenate
Golgi apparatus
Lysosomes
Mitochondria
Inner mitochondrial membranes
Microsomes
Peroxisomes
Plasma membranes
Supernatant
superoxide production and its inhibition by coenzyme Q in
serum from young (21–46 years old) and aged (76–95 years
old) individuals
[Ubiquinone-9]
(µg mg−1 protein)
(nmol min−1 ml−1 serum)
0.79±0.08
2.62±0.15
1.86±0.18
1.40±0.16
1.86±0.13
0.15±0.02
0.29±0.04
0.74±0.07
0.02±0.004
Group
N
21–46 years
76–82 years
83–95 years
16
15
15
No addition +0.1 mmol l−1 Q10
0.02±0.1
1.5±0.9
3.9±1.6
–
0.6±0.2
2.5±1.4
Values are means ± S.D.
Q10, ubiquinone-10 (CoQ10).
The values are means ± S.E.M. of seven experiments (see Kalén et
al., 1987).
The predominant coenzyme Q species isolated from rat liver
has nine isoprenoid units; hence, ubiquinone-9 or CoQ9. The
predominant coenzyme Q species from most other mammalian
species has 10 isoprenoid units; hence, ubiquinone-10 or CoQ10.
hepatocytes (Beyer et al., 1996), the anti-cancer quinone
glycoside adriamycin induced oxidative stress by enhancing
ROS production. Exogenous addition of coenzyme Q
prevented this ROS production and concomitantly protected
the cells from oxidative damage. We have observed similar
effects of exogenous coenzyme Q on NOX-mediated ROS
production (Table 4). Such an antioxidant effect at the plasma
membrane may very well ameliorate LDL oxidation by
scavenging ROS through the PMOR produced at the cell
surface (Fig. 2) (Thomas et al., 1997).
Some studies have shown that coenzyme Q levels decrease
with age (Beyer et al., 1985; Kalén et al., 1990; Genova et al.,
1995). However, this is not true for all tissues and especially
for the brain, where high levels of coenzyme Q are maintained
throughout aging (Söderberg et al., 1990; Battino et al., 1995).
However, most important would be circulating levels of
coenzyme Q that could come into contact with an overactive
or aberrant cell surface PMOR system or with circulating NOX
isoforms that may also play roles in aging related to oxidative
stress.
postulate as being responsible for the propagation of oxidative
stress to the extracellular environment. Ubiquinone or coenzyme
Q occurs ubiquitously among tissues. In rat liver, the highest
levels are found in the Golgi apparatus (Crane and Morré, 1977),
but it is also concentrated in the plasma membrane (Table 3)
(Kalén et al., 1987). The ubiquinone content of plasma
membrane is 2–5 times that of microsomes and only
approximately half that of mitochondria.
Ubiquinone has long been considered to have both pro- and
antioxidant roles (Ernster and Dallner, 1995) in addition to its
more conventional role in mediating electron transport
between NADH and succinic dehydrogenase and the
cytochrome system of mitochondria (Crane and Barr, 1985).
Both pro- and antioxidant and electron transport roles may now
be considered for ubiquinone in the plasma membrane.
Coenzyme Q is normally a product of cellular biosynthesis
(Andersson et al., 1994; Appelkvist et al., 1994) and provides
a potentially important source of one-electron pro-oxidant
oxygen reduction. In its reduced hydroquinone form
(ubiquinol), it is a powerful antioxidant acting either directly
on superoxide or indirectly on lipid radicals (Crane and Barr,
1985; Beyer and Ernster, 1990; Beyer, 1994) either alone or
together with vitamin E (α-tocopherol) (Kagan et al., 1990;
Ernster et al., 1992).
The antioxidant action of ubiquinol normally yields the
ubisemiquinone radical. The latter is converted back to
ubiquinol by re-reduction through the electron transfer chain
in mitochondria or by various quinone reductases in various
cellular compartments (Takahashi et al., 1995, 1996; Beyer et
al., 1996, 1997) including the plasma membrane (Navarro et
al., 1995; Villalba et al., 1995, 1997; Arroyo et al., 1999).
Thus, ubiquinone may transform from a beneficial one- or twoelectron carrier to a superoxide generator if the ubisemiquinone
anion becomes protonated (Nohl et al., 1996).
In perfused rat liver (Valls et al., 1994) and in isolated rat
CNOX is shed by cells and circulates – preliminary
evidence for an aging-related CNOX protein
The NOX protein is bound at the outer leaflet of the plasma
membrane (Morré, 1995; DeHahn et al., 1997), and NOX
activity has been shown to be shed in soluble form from the
cell surface (Morré et al., 1996b). The presence of the activity
in culture medium conditioned by the growth of cells
prompted a search for a comparable shed activity in the serum
of cancer patients. Serum from healthy volunteers or from
cancer patients does contain NADH oxidase activities with
properties similar, if not identical, to those of CNOX and
tNOX, respectively, found at the cell surface (Morré and
Reust, 1997; Morré et al., 1997a). The presence of the shed
form in the circulation provides an opportunity to use serum
from cancer patients as a source of the NOX protein for largescale isolation and characterization studies and to examine
NOX activity in the serum of subjects of advanced age in a
simple and non-invasive procedure that permits side-by-side
comparisons with serum from young adults. In this manner,
57
The original findings reported from the laboratory of G.
Lenaz was supported by a PRIN ‘Bioenergetics and
Membrane Transport’ from MURST, Rome.
superoxide production by buffy coats from the blood of aged
individuals and inhibition by coenzyme Q
(nmol min−1 106 cells−1)
Group
N
35–65 years
80–89 years
90–94 years
5
6
6
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60
See related article on page 826
How to Prevent Photoaging?
Leslie Baumann
Department of Dermatology, University of Miami, Miami, Florida, USA
There are several theories on photoaging and its etiology. At
this time, however, the only defenses commonly believed to
prevent photoaging are the use of sunscreens to reduce the
amount of ultraviolet (UV) that reaches the skin, the use of
retinoids to prevent production of collagenase and stimulate
collagen production, and the use of antioxidants to reduce
and neutralize free radicals. The Pinnell paper in this issue of
the Journal of Investigative Dermatology that examines ferulic acid combined with vitamins C and E shows that this
formulation seems to provide two of the above defenses: a
sunscreen effect, and an antioxidant effect. Not all sunscreens confer an antioxidant effect and not all antioxidants
yield a sunscreen effect (Pinnell et al, 2005b). For example,
Kang et al (2003) showed that although genistein and Nacetyl cysteine exhibit antioxidant activity, they produced
no effect on ultraviolet-induced erythema.
UV exposure results in skin damage through several
mechanisms including sunburn cell development, thymine
dimer formation, collagenase production, and the provocation of an inflammatory response. Sunburn cells, or UV-induced apoptotic cells, have long been used to assess skin
damage due to ultraviolet exposure. UV-induced apoptosis
is mediated by caspase-3 (Lin et al, 2005). Activation occurs
in a pathway that involves caspase-7 (Pinnell et al, 2005a). It
is believed that capsase-3 levels are good indicators of the
presence of cellular apotosis (Kang et al, 2003; Philips et al,
2003; Lin et al, 2005; Yao et al, 2005). Theoretically, the
fewer sunburn cells present, less the ‘‘skin damage’’ from
UV exposure. At this time, sun avoidance and use of sunscreens are the only defenses against sunburn cell formation. Sunscreens and sun avoidance can also protect
against thymine dimer formation.
Antioxidants protect the skin from free radicals through
several mechanisms in the early stages of elucidation. Free
radicals can act directly on growth factors and cytokine receptors in keratinocytes and dermal cells, leading to skin
inflammation. Kang et al have shown that free radical activation of the mitogen-activated protein (MAP) kinase pathways results in production of collagenase, which leads to
degradation of collagen (Saliou et al, 2001; Greul et al, 2002;
Kang et al, 2003; Papucci et al, 2003; Passi et al, 2003;
Middelkamp-Hup et al, 2004a, b; Sime and Reeve, 2004;
Katiyar, 2005). Blocking these pathways with antioxidants is
thought to prevent photoaging by preventing the production
of collagenase. This theory has been buttressed by re-
search on human skin performed by Kang et al. In this
study, investigators showed that when human skin was
pretreated with the antioxidants genistein and N-acetyl
cysteine, the UV induction of the cJun-driven enzyme collagenase was inhibited.
Many antioxidants are now available in oral and topical
preparations. Studies such as the one by Pinnell suggest that combinations of various antioxidants may have
synergistic effects, yielding formulations with greater efficacy than any of the individual antioxidant compounds used
alone. Each antioxidant is endowed with various properties
that distinguish it from other antioxidants. Some examples
of popular antioxidants and their characteristics will be
briefly discussed.
Pycnogenol is a trademark name for a standardized extract of the bark of the French maritime pine plant, which is
rich in procyanidins, also called proanthocyanidins. These
potent free-radical scavengers can also be found in grape
seed, grape skin, bilberry, cranberry, black currant, green
tea, black tea, blueberry, blackberry, strawberry, black
cherry, red wine, and red cabbage. In one study (Sime
and Reeve, 2004), Pycnogenol concentrations of 0.05%–
0.2% were applied to the irradiated dorsal skin of Skh:hr
hairless mice exposed daily to minimally inflammatory solarsimulated UV radiation. Mice pretreated with Pycnogenol
demonstrated a concentration-dependent reduction of the
inflammatory sunburn reaction (edema). In a study (Saliou
et al, 2001) evaluating the capacity of pine bark extract
to protect human skin against erythema induced by solar
radiation, 21 volunteers received oral supplementation of
Pycnogenol. During supplementation, the UVR level necessary to reach one minimal erythema dose (MED) was significantly elevated, suggesting that oral pine bark extract
supplementation mitigates the effects of UV radiation on the
skin, lowering erythema. The mechanism of action of
Pycnogenol may transcend its free-radical scavenging activities, as suggested by its anti-inflammatory effects, which
are partially ascribed to the fact that Pycnogenol inhibits
IFN-g-induced expression of ICAM-1 (Bito et al, 2000).
Silymarin is a naturally occurring polyphenolic flavonoid
compound or flavonolignans antioxidant derived from the
seeds of the milk thistle plant Silybum marianu. The beneficial effects of silymarin are primarily the result of its main
active constituent silybin, which was shown to be bioavailable in the skin and other tissues following systemic administration (Zhao and Agarwal, 1999). Topical application
of silybin before or immediately after UV irradiation has been
found to impart strong protection against UV-induced dam-
Abbreviations: CoQ10, coenzyme Q10; UV, ultraviolet
Copyright r 2005 by The Society for Investigative Dermatology, Inc.
xii
61
125 : 4 OCTOBER 2005
HOW TO PREVENT PHOTOAGING?
age in epidermal tissue by a reduction in thymine dimerpositive cells (Dhanalakshmi et al, 2004). A wide range of
in vivo animal studies suggests that silymarin possesses antioxidant, anti-inflammatory, and immunomodulatory
properties that may help prevent skin cancer as well as
photoaging (Katiyar, 2005).
Coenzyme Q10 (CoQ10) or ubiquinone is a naturally occurring antioxidant found in fish, shellfish, spinach, and
nuts. It is a fat-soluble compound also present in all human
cells as part of the electron transportation chain responsible
for energy production that has been recently found to exhibit antiapoptotic activity (Papucci et al, 2003). Researchers have identified an age-related decline of CoQ10 levels in
animals and humans (Beyer and Ernster, 1990). UV light
depletes vitamin E, vitamin C, glutathione, and CoQ10 from
the dermis as well as epidermis of the skin; however, CoQ10
is consistently found to be the first antioxidant depleted in
the skin.
Polypodium leucotomos (PL) extract is derived from
tropical fern and has demonstrated potent antioxidant activity. Orally administered PL was recently shown to decrease the incidence of phototoxicity in subjects receiving
PUVA treatment and in normal healthy subjects (Middelkamp-Hup et al, 2004a). UV-exposed keratinocytes and
fibroblasts treated with PL have also exhibited significantly
improved membrane integrity, reduced lipid peroxidation,
enhanced elastin expression, and inhibited matrix metalloproteinases-1 (MMP-1) expression (Philips et al, 2003).
Using antioxidants in combination is likely to impart
synergistic benefits. A randomized, double-blind, parallel
group, placebo-controlled study (Greul et al, 2002) examining the effects of an antioxidant preparation containing
vitamins E and C, carotenoids, selenium, and proanthocyanidins orally administered to subjects and then
exposed to UVB showed a difference in MMP-1 production
between the treatment and placebo groups (po0.05). The
assessment of MED of the skin, however, did not reveal any
statistically significant differences between the oral antioxidant group and the placebo group.
Although copious data have shown that both topical application and oral administration of individual antioxidants
impart benefits to the skin, it is reasonable to investigate a
cumulative or additive benefit derived from using oral and
topical antioxidant products in combination. In a study
(Passi et al, 2003) evaluating two groups of individuals,
Group A was treated daily with a base cream containing
0.05% ubiquinone, 0.1% vitamin E, and 1% squalene. In
addition, 50 mg of CoQ10 þ 50 mg of d-RRR-a-tocopheryl
acetate þ 50 mg of selenium were administered orally.
Group B was treated with the base cream alone. Sebum,
stratum corneum, and plasma levels of CoQ10, vitamin E,
and squalene were measured every 15 d. The patients
treated only with the topical antioxidant formulation showed
a significant increase of CoQ10, d-RRR-a-tocopherol, and
squalene in the sebum, with no significant changes observed in their stratum corneum or plasma concentrations.
Those treated with concomitant oral administration also
exhibited elevated levels of vitamin E and CoQ10 in the
stratum corneum.
xiii
Antioxidants clearly play an important role in the prevention of aging. It is unknown as to which antioxidants are the
most effective. Combining them both topically and orally
will likely be the leading therapeutic approach in the near
future. Antioxidants should be used in combination with sunscreens and retinoids to enhance their protective effects.
DOI: 10.1111/j.0022-202X.2005.23810.x
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 
 
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 
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 
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 INTRODUCTION - ANTIOXIDANTS & AGING, FREE RADICAL
CENEGENICS NEWSLETTER
NOV 2010
THEORY OF AGING (Pg. 1)
For any questions or recommendations please contact:
MEDICAL EDITOR
Michale J. Barber, M.D.
843-577-8484
[email protected]
PHARMACY
1-888-222-2956
[email protected]
 ANTIOXIDANTS 101 &
ANTIOXIDANT NUTRITION (Pg. 2)

REFERENCES
(Pg. 3)
PHARMACY
DISCUSSING RELEVANT ISSUES PERTAINING TO THE WORLD OF COMPOUNDING
PHARMACY
Introduction - Antioxidants & Aging
focus
How do you prevent accelerated aging? While there may not be a specific antidote or fountain of youth,
lifestyle habits, genetics, and free radical accumulation may all be associated with how well you age.
Specifically, antioxidants can discourage the aging process by deterring the progression of free radicals.
Free radicals are unstable molecules that cause destructive reactions in the body by damaging cellular
health. They are not in short supply and are a primary cause of accelerated aging.
Environmental toxins, stress, infections, poor nutrition, intensive exercise training, and smoking can all
lead to the accumulation of free radicals in the body. Furthermore, everyday metabolic processes, such as
breathing and eating, form free radicals. The proliferation of these highly reactive molecules can cause
a rapid decline in health, leading to cardiovascular disease, Alzheimer’s, arthritis, macular degeneration,
cancer, and other age-related ailments.
Antioxidants stabilize free radicals by adding an electron to the unbalanced molecule. While certain
antioxidants, including coenzyme Q10, superoxide dismutase, catalase, and glutathione peroxidase,
are naturally produced in the body, levels can decline with age. This leads to more oxidative stress
that can damage DNA, proteins, and mitochondria. Through weight management, a diet rich in fruits
and vegetables, and nutritional supplementation, antioxidant levels can be restored and destructive free
radicals can be thwarted.
This month, we look at the basic concepts surrounding free radicals, antioxidants, and aging. An
introduction on the free radical theory of aging and the role antioxidants may play in diminishing the
aging process is reviewed. Antioxidant-rich nutrients, including alpha lipoic acid, garlic, grape seed
extract and resveratrol, are also discussed to provide considerations for nutritional supplementation.
Free Radical Theory of Aging
As one of the most widely accepted theories on aging, the free radical theory of aging finds that cells constantly produce free radicals through normal metabolic
processes, ultraviolet light, and environmental toxins. Free radicals generate a chemical process known as oxidation, which causes cellular degeneration. This is
considered a major contributor to the aging process.
The free radical theory of aging was first identified over fifty years ago by Denham Harman, PhD. Since then, scientists have added to Dr. Harman’s theory and
questioned its relation to the aging process. Supporters of the theory advocate calorie restriction, a reduction in copper and iron intake, a decrease in polyunsaturated
fats, and an increase in antioxidant consumption can moderate free radical proliferation. Those opposed to the theory find that reactive oxygen species (ROS) have
minimal influence on aging. They suggest a certain amount of free radicals are needed for cellular signaling. While some critics oppose the free radical theory of
aging, more studies suggest lower levels of oxidative stress and higher levels of antioxidants can be related to longevity.
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ANTIOXIDANTS 101
Grape Seed Extract
Grape seed extract is rich in flavonoids, known as proanthocyanidins. As
a strong antioxidant compound, proanthocyanidins can protect the body
from a variety of free radicals and decrease lipid peroxidation in the cells.
Its antioxidant potential is considered stronger than vitamins C and E, and
beta-carotene. Researchers gave 300 mg of grape seed extract to 20 young
volunteers for five days finding that serum antioxidant levels increased
among those taking grape seed extract. Grape seed extract was given to
young and aged rats for 15 to 30 days, finding that it restored cellular
activity and membrane integrity. This suggests it can delay the aging
process by maintaining normal cellular function. Furthermore, grape seed
extract can reduce oxidative stress and free radical damage associated with
myocardial ischemia-reperfusion injuries.
Several forms of free radicals exist in our environment making it
essential to receive a variety of antioxidants. The body naturally
produces certain types of antioxidants, including glutathione, uric acid,
coenzyme Q10, and lipoic acid. Other antioxidants need to be obtained
through diet, such as vitamins C and E, selenium, and phytochemicals.
Free radicals can be formed in lipid or aqueous areas of the body. This
makes it essential to receive both fat and water-soluble antioxidants
to neutralize different oxidative intruders. Vitamin C, glutathione,
and lipoic acid are examples of water-soluble antioxidants,
while vitamins A and E are considered fat-soluble antioxidants.
A high consumption of antioxidant-rich fruits and vegetables can
significantly improve antioxidant levels in the body. Carotenoids, flavonoids,
polyphenols, lutein, and lycopene are antioxidant compounds found in several
fruits and vegetables. Carotenoids are commonly found in produce with
red, orange or yellow pigment (carrots, squash, sweet potatoes, cantaloupe,
peaches, etc.) Flavonoids and polyphenols can be found in pomegranate,
cranberries, tea, concord grapes, soy, and red wine. Dark green vegetables,
including broccoli, kale, spinach, and brussels sprouts contain lutein.
Tomatoes, pink grapefruit, and watermelon are good sources for lycopene.
Lutein
Lutein, a yellow pigment in the carotenoid family, has antioxidant
properties that are particularly important to ocular health. Lutein is one
of the most abundant carotenoids in the eye, as it filters out high-energy
blue light that can create free radical damage in the macular region of
the eye. Lutein can protect vision from cataracts and age-related macular
degeneration, as low levels have been related to vision ailments. Twoyear lutein supplementation (15 mg, 3x/week) was given to patients with
cataracts, finding long-term use improved visual acuity and had no side
effects. A twelve-month study gave 91 patients with macular degeneration
10 mg of lutein, which improved optical density, contrast sensitivity, glare
recovery, and vision acuity.
Endogenous antioxidants, including coenzyme Q10, superoxide dismutase,
catalase, and glutathione peroxidase, are abundant in youth. However,
these levels decrease with age. This decline can lead to mitochondrial
dysfunction. Restoring antioxidant levels can promote a life of health and
longevity, as research has shown centenarians have higher antioxidant
levels in their blood, in comparison to their younger counterparts..
N-Acetyl-L-Cysteine
N-Acetyl-L-Cysteine (NAC), also known as L-cysteine, is a sulfurcontaining amino acid that is vital to glutathione production. By increasing
glutathione levels, NAC lessens the development of oxidative stress. NAC’s
antioxidant activity has been shown to protect liver cells from oxidative
stress that can accumulate during exposure to arsenic, lead, and electric
fields. NAC’s ability to increase glutathione production may be the reason
for its protective cellular effects.
ANTIOXIDANT NUTRITION
Alpha Lipoic Acid
Alpha Lipoic Acid (ALA) is a “universal antioxidant”, as it is able to
protect the body from a wide range of free radicals. It is a fat and watersoluble antioxidant, making it a protectant against water and lipid based
free radicals. ALA deters the development of vascular oxidative stress
and inflammation that increase with age. A combination of ALA and
acetyl-l-carnitine was given to aged rats, finding the nutrients reduced
mitochondrial decay that leads to accelerated aging. Another study found
that ALA increased neurotransmitter levels in the brain, including serotonin,
dopamine, and norepinephrine. The study concluded that ALA could be a
beneficial treatment for reducing oxidative stress in the central nervous
system.
Pine Bark Extract
Pine bark extract is a rich source of procyanidin oligomers, which increase
antioxidant activity. It improves glutathione levels and restores other
antioxidants, such as vitamins C and E. Pine bark’s properties help to
reduce inflammation throughout the body. Researchers gave 25 subjects
pine bark extract (150 mg/day) for six weeks finding the extract improved
antioxidant activity and cholesterol levels.
Quercetin
Found in apples and onions, quercetin is a phytochemical with high
antioxidant activity that has been shown to benefit cardiovascular function.
Quercetin can inhibit platelet aggregation and aid blood pressure levels,
as well as increase nitric oxide activity and improve endothelial function.
Quercetin (150 mg/day) was given to 93 overweight subjects to determine
the effects on cardiovascular health. Those taking the nutrient had a
reduction in systolic blood pressure and oxidized LDL cholesterol.
CoQ10
Coenzyme Q10 is naturally produced in the body, but levels decline with
age. This antioxidant is necessary for cellular health and energy production.
It neutralizes free radicals and aids mitochondrial function. CoQ10
deficiencies are related to a higher amount of oxidative stress, reactive
oxygen species, and cellular death. CoQ10 was shown to reduce ECTONOX activity, an age-related indicator, in female subjects (45 to 55 years
old) taking CoQ10 supplements (180 mg/day) for 28 days. A single dose of
CoQ10 (200 mg) increased CoQ10 levels and lowered oxidative stress in
the muscle of 22 aerobically-trained and 19 untrained subjects. Similarly,
energy and workout capacity increased among subjects taking CoQ10 (200
mg/day) for fourteen-days.
Resveratrol
Found in grapes and red wine, resveratrol is a potent antioxidant with
polyphenol compounds. A higher intake of resveratrol has been associated
with an increase in nitric oxide activity and improvement in endothelial
function. Resveratrol has also been shown to reduce inflammation and
oxidative stress, which can significantly benefit cardiovascular health.
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Miquel J. Can antioxidant diet supplementation protect against age-related
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Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative
diseases of aging. Proc Natl Acad Sci USA. 1993; 90(17):7915-7922.
Montenegro MF, Neto-Neves EM, Dias-Junior CA, Ceron CS, et al. Quercetin
restores plasma nitrite and nitroso species levels in renovascular hypertension.
Naunvn Schmied Arch Pharm. 2010; 382(4):293-301.
Ames BN, Liu J. Delaying the mitochondrial decay of aging with acetylcarnitine. Ann
NY Acad Sci. 2004 Nov; 1033:108-116.
Morre DM, Morre DJ, Rehmus W, Kern D. Supplementation with CoQ10 lowers
age-related (ar) NOX levels in healthy subjects. Biofactors. 2008; 32(1-4):221-230.
Arivazhagan P, Panneerselvam C. Neurochemical changes related to ageing in the rat
brain and the effect of DL-alpha-lipoic acid. Exp Gerontol. 2002 Dec; 37(12):14891494.
Nuttall SL, Kendall MJ, Bombardelli E, Morazzoni P. An evaluation of the
antioxidant activity of a standardized grape seed extract, Leucoselect. J Clin Pharm
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Bagchi D, Bagchi M, Stohs SJ, et al. Free radicals and grape seed proanthocyanidin
extract: importance in human health and disease prevention. Toxicology. 2000 Aug 7;
148(2-3): 187-197.
Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol,
supplementation improves visual function in patients with age-related cataracts: a
2-y double-blind, placebo-controlled pilot study. Nutrition. 2003 Jan; 19(1):21-24.
Bagchi D, Ray SD, Patel D, Bagchi M. Protection against drug- and chemical-induced
multiorgan toxicity by a novel IH636 grape seed proanthocyanidin extract. Drugs Exp
Clin Res. 2001; 27(1): 3-15.
Perez VI, Bokov A, Van Remmen H, Mele J, et al. Is the oxidative stress theory of
aging dead? Biochim Biophys Acta. 2009 Oct; 1790(10):1005-1014.
Quinzii CM, Lopez LC, Gilkerson RW, Dorado B, et al. Reactive oxygen species,
oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J.
2010 Oct; 24(10):3733-3743.
Beckman K, Ames B. The free radical theory of aging matures. Physiol Rev. 1998;
78: 548-581.
Bernstein PS, Zhao DY, Sharifzadeh M, Ermakov IV, Gellerman W. Resonance Raman
measurement of macular carotenoids in the living human eye. Arch Biochem Biophys.
2004 Oct 15; 430(2):163-169.
Borek C. Antioxidants and radiation therapy. J Nutr. 2004 Nov; 134:3207S-3209S.
Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized
trial of Lutein and antioxidant supplementation in the intervention of atrophic
age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant
Supplementation Trial). Optometry. 2004 Apr; 75(4):216-230.
Cooke M, Iosia M, Buford T, et al. Effects of acute and 14-day coenzyme Q10
supplementation on exercise performance in both trained and untrained individuals. J
Int Soc Sports Nutr. 2008 Mar; 5:8.
Rimbach G, Virgili F, Park YC, Packer L. Effect of procyanidins from Pinus maritima
on glutathione levels in endothelial cells challenged by 3-morpholinosydnonimine or
activated macrophages. Redox Rep. 1999; 4(4): 171-177.
De Magalhaes JP, Church GM. Cells discover fire: employing reactive oxygen species
in development and consequences for aging. Exp Gerontol. 2006 Jan; 41(1):1-10.
Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a
herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther.
2002 Apr; 40(4): 158-168.
Devaraj S, Vega-López S, Kaul N, et al. Supplementation with a pine bark extract rich
in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein
profile. Lipids. 2002 Oct; 37(10): 931-934.
Sangeetha P, Balu M, Haripriya D, Panneerselvam C. Age associated changes
in erythrocyte membrane surface charge: Modulatory role of grape seed
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Edwards RL, Lyon T, Litwin SE, Rabovsky A, et al. Quercetin reduces blood pressure
in hypertensive subjects. J Nutr. 2007; 137(11):2405-2411.
Santra A, Chowdhury A, Ghatak S, et al. Arsenic induces apoptosis in mouse liver
is mitochondria dependent and is abrogated by N-acetylcysteine. Toxicol Appl
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Egert S, Bosy-Westphal A, Seiberl J, Kurbitz C, et al. Quercetin reduces systolic blood
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subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebocontrolled cross-over study. Br J Nutr. 2009; 102(7):1065-1074.
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Ann NY Acad Sci. 2004 Jun; 1019:260-264.
Fisher-Posovszky P, Kukulus V, Tews D, Unterkircher T, et al. Resveratrol regulates
human adipocyte number and function in a Sirt1-dependent manner. Amer J of Clin
Nutr. 2010; 92:5-15.
Yedjou CG, Tchounwou PB. N-acetyl-l-cysteine affords protection against leadinduced cytotoxicity and oxidative stress in human liver carcinoma (HepG2) cells.
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Ghanim H, Sia CL, Abuaysheh S, Korzeniewski K, et al. An antiinflammatory and
reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum
containing resveratrol. J Clin Endocrin Metab. 2010; 95(9):E1-E8.
Guachalla LM, Rudolph KL. ROS induced DNA damage and checkpoint responses:
influences on aging? Cell Cycle. 2010 Oct 15; 9(20):4058-4060.
Guler G, Turkozer Z, Tomruk A, Seyhan N. The protective effects of N-acetyl-Lcysteine and Epigallocatechin-3-gallate on electric field-induced hepatic oxidative
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Harman D. Aging: Phenomena and theories. Ann NY Acad Sci. 1998; 854:1-7.
Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits
platelet aggregation and essential components of the collagen-stimulated platelet
activation pathway in humans. J Thromb Haemost. 2004; 2(12):2138-2145.
Johnson EJ, Hammond BR, Yeum KJ, et al. Relation among serum and tissue
concentrations of lutein and zeaxanthin and macular pigment density. Am J Clin Nutr.
2000 Jun; 71(6):1555-1562.
Li L, Smith A, Hagen TM, Frei B. Vascular oxidative stress and inflammation increase
with age: ameliorating effects of alpha-lipoic acid supplementation. Ann NY Acad Sci.
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Mecocci P, Polidori MC, Troiano L, et al. Plasma antioxidants and longevity: a study
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Coenzyme Q10
AT A GLANCE
Introduction
Coenzyme Q10 is a fat-soluble compound that can be synthesized by the human body and hence cannot be
considered a vitamin. Coenzyme Q10 is a member of the ‘ubiquinone’ family, referring to the ubiquitous
presence of these compounds in living organisms. Coenzyme Q10 is also consumed in the diet.
Coenzyme Q10 is primarily found in the energy-producing center of the cell known as the ‘mitochondria’.
Therefore, the organs with the highest energy requirements, such as the heart and the liver, have the highest
coenzyme Q10 concentrations.
Health Functions
A sufficient intake of coenzyme Q10 (ubiquinone) is important as it helps the body to
•
•
convert energy from carbohydrates and fats to the form of energy used by the cells
protect, as an ‘antioxidant’, cells, tissues and organs against the damaging effects of free radicals,
believed to contribute to the aging process as well as the development of a number of health problems
including heart disease and cancer.
Disease Risk Reduction
Aging
As an antioxidant, coenzyme Q10 helps to neutralize harmful free radicals, which are one of the causes of
aging. Various factors, such as aging and stress, can lower the levels of coenzyme Q10 in the body and as a
result the ability of cells to withstand stress and regenerate declines. The levels of coenzyme Q10 in the body
almost inevitably decline with age.
In some animal studies, rodents treated with supplemental coenzyme Q10 lived longer than their untreated
counterparts. The effects of coenzyme Q10 supplements on human longevity remain unknown.
Heart disease
A symptom of many diseases involving the heart and blood vessels is atherosclerosis, the condition in which
an artery wall thickens as the result of a build-up of fatty materials such as cholesterol. As an antioxidant,
coenzyme Q10 can potentially inhibit damaging effects contributing to the development of atherosclerosis.
Coenzyme Q10 supplementation has shown promising effects in inhibiting atherosclerosis; more research is
needed to determine its role in disease prevention.
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Other Applications
Please note:
Any dietary or drug treatment with high-dosed micronutrients needs medical supervision.
Genetic mitochondrial disorders
Coenzyme Q10 supplementation has shown to be beneficial in individuals with inherited abnormalities in the
function of mitochondrial energy generation. In those rare patients with genetic defects in the body’s own
coenzyme Q10 production, supplementation has resulted in substantial improvement.
Heart disease
Research suggests that the beneficial effect of coenzyme Q10 in the prevention and treatment of heart
disease is mainly due to its ability to act as an antioxidant.
One clinical study, for example, found that people who received daily coenzyme Q10 supplements within
three days of a heart attack were significantly less likely to experience subsequent heart attacks and chest
pain. In addition, these same patients were less likely to die of heart disease than those who did not receive
the supplements.
Heart failure
Levels of coenzyme Q10 are low in people with congestive heart failure, a debilitating disease that occurs
when the heart is not able to pump blood effectively. This can cause blood to pool in parts of the body, such
as the lungs and legs.
Results from several clinical studies suggest that coenzyme Q10 supplements help to reduce swelling in the
legs, enhance breathing by reducing fluid in the lungs, and increase exercise capacity in people with heart
failure; other studies have not shown such effects.
High blood pressure
Several clinical studies involving small numbers of people suggest that coenzyme Q10 may lower blood
pressure.
More research with greater numbers of people is needed to assess the value of coenzyme Q10 in the
treatment of high blood pressure (‘hypertension’).
High cholesterol
Levels of coenzyme Q10 tend to be lower in people with high cholesterol compared to healthy individuals of
the same age. In addition, certain cholesterol-lowering drugs called ‘statins’ appear to deplete natural levels
of coenzyme Q10 in the body.
Taking coenzyme Q10 supplements has shown to correct the deficiency caused by statin medications without
affecting the medication's positive effects on cholesterol levels.
Heart surgery
Clinical research indicates that introducing coenzyme Q10 prior to heart surgery, including bypass surgery
and heart transplantation, can reduce damage caused by free radicals, strengthen heart function, and lower
the incidence of irregular heart beat (‘arrhythmias’) during the recovery phase.
Diabetes
High blood pressure, high cholesterol, and heart disease are all common problems associated with diabetes.
Research indicates that coenzyme Q10 supplements may improve heart health and blood sugar and may
help manage high cholesterol and high blood pressure in individuals with diabetes.
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Despite some concern that coenzyme Q10 may cause a sudden and dramatic drop in blood sugar
(‘hypoglycemia’), two clinical studies of people with diabetes given coenzyme Q10 showed no such adverse
effect. Thus, it has been concluded that coenzyme Q10 supplements could be used safely in diabetic patients
as adjunct therapy for cardiovascular diseases.
Parkinson’s disease
In Parkinson's disease, decreased activity of elements involved in energy production in mitochondria and
increased oxidative stress in a special part of the brain are thought to play a role. As part of the energyproducing process and antioxidant coenzyme Q10 might be beneficial in the treatment of Parkinson’s
disease.
A study in patients with early Parkinson's disease showed that supplementation with coenzyme Q10 was
associated with slower deterioration of brain function compared to placebo. These promising findings need to
be confirmed in larger clinical trials.
Breast cancer
Although a few case reports suggest that coenzyme Q10 supplementation may be beneficial as an additional
treatment to conventional therapy for breast cancer, the lack of controlled clinical trials makes it presently
impossible to determine the potential effects of coenzyme Q10 supplementation in cancer patients.
Periodontal (gum) disease
Gum disease is a widespread problem that is associated with swelling, bleeding, pain, and redness of the
gums. Clinical studies have reported that people with gum disease tend to have low levels of coenzyme Q10
in their gums.
In a few clinical studies involving small numbers of subjects, coenzyme Q10 supplements caused faster
healing and tissue repair.
Additional studies in humans are needed to evaluate the effectiveness of coenzyme Q10 when used together
with traditional therapy for periodontal disease.
Other disorders
Preliminary clinical studies also suggest that coenzyme Q10 may boost athletic performance, improve
immune function in individuals with immune deficiencies such as AIDS, improve symptoms of tinnitus, and
may be beneficial in cosmetics for healthy skin.
Intake Recommendations
Presently, health authorities have not established specific dietary intake recommendations for coenzyme
Q10.
Some researchers suggest daily doses of 30–200 mg coenzyme Q10 for adults 19 years and older.
As coenzyme Q10 is fat-soluble, it should be taken with a meal containing fat for optimal absorption.
Supply Situation
The average daily intake of coenzyme Q10 from food is estimated to be around 10 mg in several European
countries.
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Deficiency
It is generally assumed that with a varied diet, the body’s own production provides sufficient coenzyme Q10
for healthy individuals.
Decreased blood levels of coenzyme Q10 have been observed in individuals with diabetes, cancer, and
congestive heart failure, and in people taking lipid lowering medications (see Safety).
No coenzyme Q10 deficiency symptoms have been reported in the general population.
Sources
Primary dietary sources of coenzyme Q10 include oily fish (such as salmon and tuna), organ meats (such as
liver), and whole grains.
Safety
To date, there have been no reports of significant adverse side effects of coenzyme Q10 supplementation at
doses as high as 1,200 mg/day.
Some people have experienced gastrointestinal symptoms (e.g., nausea, diarrhea, appetite suppression,
and heartburn) when taking high doses of coenzyme Q10 supplements.
Because controlled safety studies in pregnant and breast-feeding women are not available, the use of
coenzyme Q10 supplements by such women should be avoided.
Drug interactions
Please note:
Because of the potential for interactions, dietary supplements should not be taken with medication without
first talking to an experienced healthcare provider.
www.nutri-facts.org
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Coenzyme Q10 (CoQ10)
TRADE NAMES




DESCRIPTION
























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




ACTIONS AND PHARMACOLOGY
ACTIONS


MECHANISM OF ACTION














PHARMACOKINETICS


76











INDICATIONS AND USAGE









RESEARCH SUMMARY












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


CONTRAINDICATIONS, PRECAUTIONS, ADVERSE
REACTIONS
CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS


78









ADVERSE REACTIONS



INTERACTIONS
DRUGS

















DOSAGE AND ADMINISTRATION




79








HOW SUPPLIED






LITERATURE















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

80









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





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


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



82
Q10
Indication principale : prévention des rides
ACTIF PUR A01
Synthèse bibliographique
4Nom INCI : UBIQUINONE
4Molécule pure à plus de 97%
obtenue par biotechnologie
Le Q10 également connu sous le nom de coenzyme Q10 ou encore sous le nom d’ubiquinone, est une substance similaire à une
vitamine.
Le Q10, naturellement présent dans la peau, est vital pour le bon fonctionnement du corps humain.
Cette molécule est présente dans la peau à l’état naturel pour protéger les lipides du sébum contre le stress oxydatif. Cependant,
la concentration intrinsèque de la peau en Q10 diminue considérablement avec l’âge, ce qui rend la peau plus sensible aux
attaques des UV notamment.
Le Q10 est l’un des rares antioxydants à être lipophiles.
Egalement très utilisé dans l’industrie pharmaceutique, le Q10 est efficace contre l’hypertension artérielle, l’insuffisance cardiaque,
la migraine, les maladies parodontales…
4MECANISMES D’ACTION / PREUVES D’EFFICACITE
Des études récentes in vitro et in vivo montrent que l’utilisation du Q10 serait efficace pour prévenir l’apparition des premiers signes
de l’âge.
Grâce à son action antiradicalaire, le Q10 protège les cellules et le tissu cutané vis-à-vis du stress oxydatif généré par une irradiation
UV [1]. Le Q10 permet également de protéger les constituants de la matrice dermique (collagène, élastine, acide hyaluronique…)
en limitant significativement l’expression de collagénases [1] et des MMP-1 (métalloprotéinases) [2]. De plus, il stimule la prolifération
des GAG (glycoaminoglycanes), aidant ainsi au maintien de la densité dermique [1].
En diminuant la synthèse de médiateurs pro-inflammatoires tel que l’IL-6, le Q10 apaise la peau [2]. Par ailleurs, il possède une action
énergisante en stimulant la glycolyse par accumulation de glucose dans les kératinocytes [3]. Enfin, les mêmes études montrent que
l’application régulière sur le long terme d’un produit contenant du Q10 permet de réduire la profondeur des rides [1].
4L’AVIS DE NOTRE EXPERT
Le Q10, encore appelé ubiquinone, est une molécule dérivée de la quinone. La présence d’une chaine latérale hydrophobe lui confère
une bonne affinité pour les structures lipophiles comme les membranes cellulaires. La forme réduite est l’ubiquinol. Les formes oxydées
et réduites sont alternativement régénérées dans les transferts électroniques nécessaires qui conduisent à la phosphorylation de l’ADP
en ATP (très énergétique).
Le coenzyme Q10 possède des caractéristiques d’anti-oxydant (maximum sous sa forme quinol). Il se trouve être un co-facteur
enzymatique absolument nécessaire dans des chaines métaboliques où il favorise des réactions d’oxydo-réduction grâce à sa structure
permettant la circulation d’électrons. C’est un élément indispensable au métabolisme énergétique.
Son taux semble diminuer avec l’âge et son apport exogène favoriserait le métabolisme cellulaire, tout en apportant une défense
anti-radicalaire. De nombreuses études, in vitro, montrent des effets sur la diminution des facteurs de dégradation du collagène
(collagénase et MMP).
Il est à noter que la prise de statine peut diminuer les quantités de Q10 synthétisé par l’organisme. Il n’y a toutefois pas à notre connaissance de corrélation établie avec des troubles dermatologiques.
Contrairement aux vitamines dont on doit assurer un apport exogène, le coenzyme Q10 est synthétisé à partir de la tyrosine et de la
chaine polyisoprénique. Ceci fait intervenir les enzymes du métabolisme du cholestérol. On peut penser que certaines compétitions
métaboliques et contrôles s’effectuent dans la peau.
La dose n’est pas établie clairement in vivo, on peut estimer que les besoins sont variables en fonction de l’âge. Nous ne pouvons que
conseiller la dose maximale, à notre connaissance, utilisée dans les études cliniques, soit 0,3%.
La large utilisation et communication sur cet actif en cosmétique devrait inciter les chercheurs en dermatologie à explorer encore plus
largement cette molécule.
e t a t p u r. c o m
83
4DOSE EFFICACE
L’ensemble des publications et études scientifiques, les usages habituels de cet actif et l’avis de notre expert ont conclu à utiliser l’Actif
pur Q10 à la dose de 40 mg par flacon.
4REFERENCES BIBLIOGRAPHIQUES
[1] Coenzyme Q10, a cutaneous antioxidant and energizer. Hoppe U, Bergemann et al., Biofactors. 9(2-4):371-8. 1999.
[2] Mechanisms of inhibitory effects of CoQ10 on UVB-induced wrinkle formation in vitro and in vivo. Inui M et al., Biofactors. 32
(1-4):237-43. 2008.
[3] Aging skin is functionally anaerobic: importance of coenzyme Q10 for anti aging skin care. Prahl S et al., Biofactors. 32(1-4):245-55.
2008.
Ces informations sont données à titre informatif, elles ne sauraient en aucun cas constituer une information médicale, ni engager notre
responsabilité. La copie et la reproduction de ces documents ne peuvent être faites qu’à des fins exclusives d’information pour un
usage personnel et privé. Toute utilisation de copie ou reproduction utilisée à d’autres fins est expressément interdite et engagerait la
responsabilité de l’utilisateur au sens de l’article L 122-3 du Code de la Propriété Intellectuelle.
e t a t p u r. c o m
84
■ Anti-âge
Les sources ali
de coenzym
L’alimentation pe
une partie de c
en consommant ré
les aliments s
Du poisson et la sardin
(de 0,5 à 3 mg
de la vian
(agneau: 3,5, bœuf: 3, pou
Certaines hu
poissons, noix
Certains légum
brocolis, épin
Des noix et des
Des algue
Dans la population gé
la viande rouge et
qui apportent l’e
de la coenzym
Notre organisme en a besoin
La coenzyme Q10,
une des stars anti-âge!
Il y a quelques années,
cette molécule au nom
barbare faisait la une
des publicités de produits
cosmétiques, juste le temps
d’une campagne
de marketing.
10
Ce n’est en fait qu’avec l’apparition des
effets toxiques des statines (médicaments
contre le cholestérol) qu’elle a lentement
gagné le cœur des personnes soucieuses
de conserver la pleine possession de leurs
moyens tout en vivant plus longtemps: non
seulement, elle réduisait significativement
voire totalement leurs douleurs musculaires invalidantes, mais de plus, elle leur
redonnait un bon tonus et le sentiment de
rajeunir.
Malgré cela, cette molécule naturellement
produite par notre organisme, essentielle
par nombreuses de ses fonctions, reste
inconnue de la plupart des médecins,
«bien» formatés par l’industrie pharmaceutique.
Parmi ses innombrables
interventions, en voici
quelques-unes:
Quelques mots
de physiologie
Présente uniquement dans les membranes des cellules, elle transporte l’hydrogène
et facilite l’action de nombreuses enzymes,
notamment l’action de celles impliquées
dans la production d’énergie. Elle participe
ainsi à la régénération du tissu musculaire
et donc du premier d’entre eux, le cœur!
Puissant anti-oxydant, elle réduit la toxicité du fer et protège la structure de nombre
de molécules, notamment la vitamine E et
les lipides.
Également puissant anti-agrégant plaquettaire, elle diminue les risques de
caillots sanguins.
Les réserves de l’organisme avoisinent les
2 grammes. Chaque jour, le quart environ
en est renouvelé. Que ce cycle de régénération diminue et le vieillissement s’accélère.
La co-enzyme Q10 est également connue
sous les noms d’ubiquinone et d’ubidécarénone. C’est une substance grasse dont
la structure chimique est proche de celle
des vitamines E et K. Présente partout dans
l’organisme, elle est produite de façon
croissante jusqu’aux environs des 20 ans,
puis lentement, de moins en moins: A 50
ans, une personne en bonne santé et sans
antécédent notable en produit 25% de
moins que 30 ans plus tôt.
La coenzyme Q10 est indispensable au
fonctionnement de certaines enzymes. Sans
elle, de nombreuses réactions chimiques
seraient moins performantes.
10 Alternatif-Bien-être No66 ■ Décembre 2008, janvier, février 2009
85
Que peut-on cr
en cas de manq
coenzyme Q 10
Les conséquences d’une ca
zyme Q10 sont encore mal
il est aujourd’hui certain
d’accidents cardiaques sévè
plus élevé que le déficit en
est important (1).
Certaines de ces complic
être déduites des effets b
complémentation nutritionn
ple la coenzyme Q10 réd
tensionnels des personne
et permet de réduire sign
posologie des médicaments
Les mieux connues de t
complications musculaires
les personnes prenant de
contre le cholestérol. Peu
les fibrates, elles ne cess
tiplier avec l’usage de plu
des statines et à des doses
élevées.
Quand la
complémentatio
en coenzyme Q
est-elle souhait
Comme nous venons de l’
certains traitements médic
devrait être systématique a
esoin
0,
i-âge!
ses innombrables
ntions, en voici
es-unes:
nte uniquement dans les membracellules, elle transporte l’hydrogène
e l’action de nombreuses enzymes,
ent l’action de celles impliquées
production d’énergie. Elle participe
a régénération du tissu musculaire
du premier d’entre eux, le cœur!
ant anti-oxydant, elle réduit la toxier et protège la structure de nombre
cules, notamment la vitamine E et
es.
ment puissant anti-agrégant pla, elle diminue les risques de
sanguins.
rves de l’organisme avoisinent les
mes. Chaque jour, le quart environ
nouvelé. Que ce cycle de régénérainue et le vieillissement s’accélère.
Santé
Les sources alimentaires
de coenzyme Q10
L’alimentation peut combler
une partie de ce manque
en consommant régulièrement
les aliments suivants:
Du poisson et la sardine en particulier
(de 0,5 à 3 mg/100 g),
de la viande
(agneau: 3,5, bœuf: 3, poulet: 1,7, porc: 1,4).
Certaines huiles:
poissons, noix, soja.
Certains légumes verts:
brocolis, épinards.
Des noix et des amandes.
Des algues.
Dans la population générale, ce sont
la viande rouge et les volailles
qui apportent l’essentiel
de la coenzyme Q10.
Que peut-on craindre
en cas de manque en
coenzyme Q 10?
Les conséquences d’une carence en coenzyme Q10 sont encore mal connues, mais
il est aujourd’hui certain que le risque
d’accidents cardiaques sévères est d’autant
plus élevé que le déficit en coenzyme Q10
est important (1).
Certaines de ces complications peuvent
être déduites des effets bénéfiques de la
complémentation nutritionnelle, par exemple la coenzyme Q10 réduit les chiffres
tensionnels des personnes hypertendues
et permet de réduire significativement la
posologie des médicaments de synthèse.
Les mieux connues de toutes sont les
complications musculaires observées chez
les personnes prenant des médicaments
contre le cholestérol. Peu fréquentes avec
les fibrates, elles ne cessent de se multiplier avec l’usage de plus en plus large
des statines et à des doses de plus en plus
élevées.
Quand la
complémentation
en coenzyme Q 10
est-elle souhaitable?
Comme nous venons de l’évoquer lors de
certains traitements médicamenteux. Elle
devrait être systématique afin de compen-
Comment vient-on
à manquer de
coenzyme Q10?
Les raisons sont nombreuses:
L’avancée en âge:
la production de l’organisme
diminue, l’appétit pour
les viandes diminue.
Des apports alimentaires
insuffisants.
La baisse de la production
de Q10 de l’organisme
par la prise de certains
médicaments:
les anti-cholestérol, certains
bêtabloquants, les antidépresseurs
tricycliques (imipramine et
apparentés), certains antipsychotiques (phénotiazine et apparentés)...
Et peut-être bien d’autres encore!
Une utilisation excessive
des réserves comme lors d’un
entraînement intensif ou lors de
certaines maladies: hyperthyroïdie,
affections rénales.
Souvent, la combinaison de
ces différents facteurs.
ser l’effet toxique de ces substances. La
dose quotidienne est comprise entre 50 et
100 mg/j. Les gélules sont prises au cours
des repas, en présence de graisses afin que
la coenzyme Q10 soit le mieux assimilée
possible.
Mais aussi, à partir d’un certain âge (70
ans, parfois plus tôt), dès que la diminution
de la force musculaire commence à réduire
l’autonomie. Même dose que précédemment.
Au cours des maladies
cardiovasculaires
En cas d’hypertension artérielle, la
coenzyme Q 10 fait baisser les chiffres de
façon significative chez une personne sur
deux. Afin d’éviter la survenue d’éventuels
malaises en lien avec une baisse trop
rapide, la posologie est augmentée de
façon progressive en même temps que la
posologie des médicaments allopathiques
est diminuée par le médecin.
En cas d’insuffisance coronarienne
(de l’angine de poitrine aux suites d’infarctus du myocarde), la prise de coenzyme
Q10 réduit significativement au bout de
seulement 4 semaines, le taux de la Lp(a),
marqueur du risque d’infarctus. De plus,
elle permet de prévenir les accidents qui
surviennent parfois dans les suites immédiates d’un pontage. Dose: 100 mg/j (en
association avec un magnésium soluble
dans les graisses (StressNut 3 gl/j) afin
de réduire encore le risque de troubles du
rythme.
Quelle que soit la cause d’une insuffisance cardiaque, la carence en coenzyme
Q10 est toujours sévère. À la posologie
de 100 mg/j en continu, non seulement
la fonction cardiaque s’améliore mais les
palpitations, la gêne respiratoire, la fati-
Décembre 2008, janvier, février 2009 ■ No66 Alternatif-Bien-être 11
86
11
■ Anti-âge
gue diminuent. Les traitements allopathiques retrouvent plus d’efficacité: la tension
artérielle s’abaisse un peu plus, les taux
sanguins de glucose et de triglycérides se
normalisent, le taux de HDL cholestérol (le
«bon») augmente. Associez au coenzyme
Q10 du sélénium pour son action sur le
muscle cardiaque.
La complémentation aurait des effets favorables quel que soit le stade de l’insuffisance cardiaque, même au stade terminal
dans l’attente d’une greffe cardiaque.
Dans la perspective d’une chirurgie cardiaque: à la dose de 100 mg/j pendant les
2 semaines qui précèdent l’intervention et
les 4 suivantes, la coenzyme Q10 améliore
considérablement le pronostic post-opératoire. La pompe cardiaque est améliorée,
le temps de récupération est sensiblement
raccourci et le nombre de complications est
également diminué.
Au cours de certaines maladies
métaboliques
Au cours du diabète, la coenzyme Q10
est souvent déficitaire, parfois de façon
sévère. Dans tous les cas, elle améliore
le métabolisme des sucres et facilite la
normalisation de la glycémie.
En cas de surpoids, une complémen-
tation à la dose de 100 mg par jour facilite la perte pondérale, et ce d’autant plus
qu’une activité physique est régulièrement
pratiquée.
Au cours de certaines myopathies
métaboliques liées à un déficit congénital
de production de la coenzyme Q10: la
prise conjuguée - d’abord à fortes doses
puis de façon moindre mais continue - de
coenzyme Q10 et de riboflavine (vitamine
B2) permet souvent de faire disparaître
complètement cette symptomatologie. La
posologie est dans ce cas du ressort strict
d’un médecin.
12
Au cours des parodontopathies, (ces
atteintes des gencives qui ont tendance
à durer malgré de nombreux traitements
locaux), une cure de 3 semaines associant
50 mg/j de coenzyme Q10 et 100 mg/j de
vitamine C (soit un comprimé d’acérola à
500 mg) permet d’obtenir une nette amélioration, voire la guérison des phénomènes
inflammatoires et dégénératifs qui touchent
les gencives et les autres tissus de soutien
de la dent.
Quel Coen
choisir?
Il existe différ
Naturels, sem
Ceux qui sont bon m
et les semi synthétiq
Il à noter qu’il faut le
des traces d’impuret
Deux associations fortement recommandées
Coenzyme et oméga 3 à longue chaîne (EPA, DHA (4)) sont déficitaires chez les per-
sonnes qui présentent une hypertension artérielle, une dyslipidémie (trop de cholestérol
ou/et de triglycérides), un diabète ou une insuffisance coronarienne (angine de poitrine,
infarctus).
Il est donc judicieux que celles-ci prennent ces deux types de compléments, mais pas
sous une forme les réunissant dans une même capsule. En effet, la vitamine E est systématiquement associée aux omégas 3 pour les protéger du phénomène d’oxydation. Oxydée,
elle cherche alors à se régénérer, ce qu’elle fait si dans la même capsule, elle se trouve en
présence et aux dépens de la coenzyme Q10.
Coenzyme Q10 + magnésium au cours des affections cardiaques caractérisées par
des troubles du rythme cardiaque. Certes l’arythmie ne sera pas guérie, mais réduite. Ses
conséquences seront donc moins graves.
Quelles dose
En prévention de l’éclampsie. Les
femmes enceintes dont les chiffres tensionnels s’élèvent au fil de la grossesse, sont
fortement exposées à ce type particulier
d’épilepsie. Leur taux de coenzyme Q10 est
significativement abaissé par rapport aux
autres femmes enceintes (2). Aussi, paraîtil justifié de complémenter toute femme
enceinte qui présente une hypertension,
une albuminurie ou un diabète. Dose entre
50 et 100 mg/j.
Anecdotique: au cours de la maladie
de Parkinson. Des posologies atteignant
1.200 mg/j ont été utilisées pendant 16
mois chez des personnes dont la maladie
s’était déclarée moins de 3 ans auparavant
et qui n’avaient pas encore reçu de levodopa. Les patients traités par 300 ou 600 mg/j
présentaient une tendance à l’amélioration.
Seules les personnes traitées par 1.200
mg/j montraient une amélioration significative tant au niveau des performances
12 Alternatif-Bien-être No66 ■ Décembre 2008, janvier, février 2009
87
physiques que des capacités intellectuelles
et de l’humeur (3).
Enfin en cosmétologie, un traitement
buccal ou/et percutané pendant 6 mois
réduit significativement la profondeur des
rides.
Dr Naïma Ananda Bauplé
[email protected]
Voir carnet d’adresses D.Plantes page 4
(1) CF « Journal of American College of Cardiology
», 2008 ; 52 : pp. 1435-1441.
(2) E. Teran, M. Racines-Orbe, S. Vivero, C.
Escudero, G. Molina, A. Calle: « Preeclampsia is
associated with a decrease in plasma coenzyme
Q10 levels” in “Free Radic. Biol. Med”, 2003 (dec),
1;35 (11): 1453-1456. (Experimental Pharmacology
and Cellular Metabolism Unit, Biomedical Center,
Central University of Ecuador, Quito, Ecuador.
CE: HYPERLINK «mailto:[email protected]»
[email protected])
(3) CF ‘’Le Quotidien du Médecin’’, n° 7.198 du
15.10 2002, page 10.
(4) OGA3 concentré, DHA2.
La posologie varie
indication à l’autre g
par jour.
Biodisponibi
Nous le rappelons, l
d’huile ou de graisse
contient des lipides.
Effets second
Ils sont essentiellem
traitements: perte d’a
Il est cepend
certaines pré
• Du fait de la resse
et la vitamine K, la
avec la prise de
• Chez l’insuffisan
d’une obstruction
• A éviter chez le
de médicaments h
• En cas de compl
l’augmentation du
de la participation
quand elle vient d’
Santé
Quel Coenzyme
choisir?
Il existe différents types de coenzyme:
Naturels, semi synthétique, synthétique.
Ceux qui sont bon marché sont les synthétiques
et les semi synthétiques beaucoup moins efficaces.
Il à noter qu’il faut les éviter d’autant plus que l’on trouve quelquefois
des traces d’impuretés sans caractère de dangerosité toutefois.
ommandées
Préférez toujours
les coenzymes
naturels
d’extraction
sont déficitaires chez les perlipidémie (trop de cholestérol
onarienne (angine de poitrine,
Les médicaments anti-cholestérol,
médicaments dangereux
et probablement inutiles...
Pendant longtemps on a cru que le cholestérol
était l’ennemi n° 1 de nos artères.
Aujourd’hui, il est prouvé que le faire baisser,
notamment par la prise de statines,
ne réduit en rien le risque cardiovasculaire :
les accidents mortels ne diminuent pas.
s de compléments, mais pas
ffet, la vitamine E est systémaénomène d’oxydation. Oxydée,
ême capsule, elle se trouve en
cardiaques caractérisées par
pas guérie, mais réduite. Ses
e des capacités intellectuelles
r (3).
cosmétologie, un traitement
Quelles doses prendre?
La posologie varie considérablement d’une personne à l’autre, d’une
indication à l’autre globalement il est conseillé de prendre 2 fois 50mg
par jour.
Biodisponibilité
percutané pendant 6 mois
cativement la profondeur des
Nous le rappelons, la co-enzyme Q10 est mieux absorbée en présence
d’huile ou de graisse. Donc, elle doit être prise au cours d’un repas qui
contient des lipides.
Dr Naïma Ananda Bauplé
[email protected]
et d’adresses D.Plantes page 4
Ils sont essentiellement d’ordre digestifs et concernent moins de 1% des
traitements: perte d’appétit, nausées, diarrhée, dyspepsie acide.
of American College of Cardiology
. 1435-1441.
Racines-Orbe, S. Vivero, C.
lina, A. Calle: « Preeclampsia is
decrease in plasma coenzyme
ree Radic. Biol. Med”, 2003 (dec),
1456. (Experimental Pharmacology
abolism Unit, Biomedical Center,
y of Ecuador, Quito, Ecuador.
«mailto:[email protected]»
edu.ec)
dien du Médecin’’, n° 7.198 du
e 10.
ntré, DHA2.
Effets secondaires d’une complémentation
Il est cependant indispensable de connaître
certaines précautions d’emploi
• Du fait de la ressemblance de structure entre la coenzyme Q10
et la vitamine K, la complémentation ne doit pas être concomitante
avec la prise de warfarine (Coumadine®, anti-vitamine K).
• Chez l’insuffisant hépatique ou la personne porteuse
d’une obstruction des voies biliaires.
• A éviter chez le diabétique lors de la prescription concomitante
de médicaments hypoglycémiants.
• En cas de complémentation en vitamine E à des taux élevés,
l’augmentation du taux de co-enzyme Q10 sera plus lente du fait
de la participation de celui-ci à la régénération de la vitamine E
quand elle vient d’être oxydée.
De plus, ces molécules qui réduisent considérablement le
renouvellement physiologique de la coenzyme Q 10, exposent
à des complications parfois redoutables :
1: Une baisse du pouvoir anti-oxydant, avec pour conséquence une accélération du vieillissement, notamment
vasculaire.
2: Une fatigabilité croissante pouvant aller jusqu’à l’abandon
de toute activité physique et l’installation dans un syndrome
dépressif réactionnel grave.
3: Des douleurs musculaires dont le bilan revient négatif et
que rien ne soulage, des douleurs qui peuvent se compliquer
de destruction aiguë d’une ou plusieurs loges musculaires
(rhabdomyolyse), d’insuffisance rénale aiguë voire de décès
dans d’horribles souffrances.
4: Une baisse des fonctions cognitives, plus particulièrement
chez les femmes.
Le Dr Michel de Lorgeril - un des deux signataires de la
fameuse étude de Lyon qui a mis en évidence la supériorité
écrasante du régime méditerranéen sur tout autre attitude - a
écrit deux livres(*) sur ce sujet dans lesquels il dénonce les
manipulations dont le corps médical a été victime de la part
des grands laboratoires pharmaceutiques. Les médecins
ignorent non seulement qu’ils ont été dupés, mais plus grave
encore, ils ne connaissent pas aujourd’hui encore les effets
secondaires potentiellement gravissimes de ces produits.
(*)En 2007 : « Dites à votre médecin que le cholestérol est innocent, il vous
soignera sans médicament », puis en 2008: «Cholestérol, mensonges et
propagande», tous deux aux éditions Thierry Souccar.
Décembre 2008, janvier, février 2009 ■ No66 Alternatif-Bien-être 13
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Preparation and Properties of Coenzyme Q10 Nanoemulsions
Authors: Fred Zülli*, Esther Belser, Daniel Schmid, Christina Liechti and Franz Suter, Mibelle AG Biochemistry, CH
Abstract
Since every cell consumes energy and needs antioxidant
Coenzyme Q10 (CoQ10), also known as ubiquinone, is used
protection, CoQ10 is present in all cellular membranes of every
for energy production within cells and acts as an anti-oxidant.
single cell of the body. Caused by this ubiquitous presence in
Due to this dual function CoQ10 finds its application in
the body, as well as in the rest of nature, CoQ10 is also known
different commercial branches such as drugs, food supplements,
as ubiquinone. However, deficiencies of CoQ10 in the human
or cosmetics.
body have been reported to occur frequently. In addition, CoQ10
Since CoQ10 is highly lipophilic, the topical and oral
levels decline rapidly under stress or with advancing age. In
bioavailability is very low. Several attempts have been made
case of deficiency CoQ10 has to be supplemented to guarantee
to improve absorption. Latest technical developments reveal
the body’s energy production and its essential antioxidant
that encapsulation of CoQ10 in nanoemulsions results in a
protection. (1,2)
significantly enhanced bioavailability. In addition, multiple
Use of CoQ10 as a drug, food supplement
and cosmetic ingredient
nanoemulsions prepared according to a patented process even
allow the administration of several incompatible substances at
the same time.
Although CoQ10 can be synthesized in the human body, it can
happen that the body’s synthetic capacity is not sufficient to meet
This article gives an overview of current key developments of
the required amount of CoQ10. Cases of deficiencies of CoQ10
the encapsulation of CoQ10 in nanoemulsions. It highlights
are reported in a variety of diseases, e.g. cardiovascular disorders.
how encapsulation upgrades the bioavailability of CoQ10 and
A randomized, double-blind clinical trial assessing 49 patients
with this the efficacy of CoQ10. In addition, this article presents
who experienced cardiac arrest (heart attack or accident), revealed
latest in vitro tests demonstrating the influence of CoQ10 on
the synthesis of collagen I and on the activity of mitochondria
and their resistance against stress of dermal fibroblasts and
keratinocytes, respectively.
that after an immediate treatment with a CoQ10 nanoemulsion
such as described in this paper the survival rate increased more
than 100 % versus placebo after 90 days. (3) Beside these life
saving properties, CoQ10 also shows positive effects in migraine
Introduction
and Parkinson treatments. Latest clinical research resulted in
Everyone requires energy to live. This energy is produced by
an excellent positive effect on attack frequencies, headache
combustion of carbohydrates or fats with oxygen. However, the
days and days with nausea in migraine patients. (4) In different
use of oxygen will always also generate reactive oxygen species
research programs for Parkinson’s disease the efficacy of CoQ10
(ROS) which will damage the cells and therefore reduce the
is now under investigation. Further interest in CoQ10 application
activity of cells. This will cause a general ageing process of cells
was reported for gastric ulcer, muscle dystrophy, allergy and even
and the whole body. Thanks to a compound named coenzyme
cancer or AIDS. (1)
Q10 (CoQ10) the human body possesses a pivotal player in
energy synthesis. In mitochondria CoQ10 helps to build up
CoQ10 found its uses not only as a remedy but also as a food
adenosine triphosphate (ATP), the body’s major form of stored
supplement and a cosmetic. Since the synthesis of CoQ10 in the
energy. A second task of CoQ10 is the activity as an essential
body weakens in correlation with advancing age, daily dietary
regenerating antioxidant scavenging free radicals such as ROS.
supplementation provides the required compensation for energy
B
Cosmetic Science Technology 2006
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Natural Ingredients
and health. Additionally, poor nutritional habits or mental and
to modify the molecular structure or change the compositions
physical stress may render CoQ10 supplementation advisable
of the CoQ10 preparations to improve the bioavailability. As a
as well. (5) To give an example, the integrity of mitochondria is
matter of fact, the investigation of both structure modifications
essential for the health of cells and organs. Mitochondrial DNA
and delivery systems revealed that bioavailability of CoQ10 after
repeatedly undergoes mutations caused by oxidative stress. In
oral application can be significantly enhanced choosing a proper
comparison to nuclear DNA having a SOS DNA repair system,
formulation. (13,14)
the mitochondrial DNA has no effective repair system to fight
Modern research now shows that CoQ10 nanoemulsions
such mutations. Therefore, all mutations will accumulate during
strikingly improve the bioavailability of the substance after oral
time and reduce the vitality of the cell. Hence, CoQ10 is an
application. (15) Daily application of 300 mg of powdered
essential antioxidant for mitochondria to protect the integrity of
CoQ10 results only in a serum concentration of 1.8 µg/ml after
its own DNA as good as possible. (6)
16 months. Thanks to encapsulation into nanoemulsions, the
As a cosmetic ingredient CoQ10 mainly acts as an antioxidant
same daily dosage of CoQ10 enhanced serum concentration up
to protect the cells against the ageing process induced by free
to 5.2 µg/ml after only 6 weeks. (16,17)
radicals. Oxidative stress caused by free radicals or UV-irradiation
These nanoemulsions improve dermal bioavailability as well.
plays a significant role in skin ageing. UV radiation is known
It is known that encapsulation of drugs in nanoemulsions and
to induce the formation of reactive oxygen species which are
liposomes enhance the drugs' concentrations in the dermis
implicated as toxic intermediates in the development of photo-
compared to conventional formulations. (18) Figure 1 shows
ageing. (7) The antioxidant activity of CoQ10 prevents untimely
the penetration of nanoparticles (nanoemulsion droplets) into
skin ageing and photo-ageing by enhancing the resistance of the
the skin and the release of the encapsulated material (CoQ10)
skin and scavenging radicals. (8,9) A German research group
(Figure 1).
found that CoQ10 also suppresses collagenase, an enzyme
Features of nanoemulsions
which causes damage of the connective tissue of the skin. The
group additionally showed that CoQ10 is effective against UV
mediated oxidative stress. (10) Taken together, these findings
turn CoQ10 into a unique cosmetic substance which protects
the skin from early ageing, wrinkle formation and loss of
cell activity.
Chemistry and bioavailability of Q10, and the
principle of nanoemulsions
CoQ10 belongs to the group of quinones. It is composed of a
p-benzoquinone ring system and a polyisoprenoid side-chain.
The length of the side-chain is responsible for the lipophilicity
of the molecule. The side-chain in CoQ10 consists of ten
isoprene units. This makes the molecule highly lipophilic. (11)
Therefore CoQ10 can freely move within the cellular membranes.
Unfortunately, the bioavailability of CoQ10 is very low in the
intestines after oral application. (12)
Several attempts have been made in the last few years to improve
the intestinal absorption of CoQ10. Researchers either tried
Figure 1:
Schematic illustration of the penetration of nanoemulsion droplets into the
stratum corneum of the skin. After the release of the encapsulated material the
substances can penetrate into deeper layers of the skin.
C
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Natural Ingredients
Figure 2:
Structure of a nanoemulsion droplet. Phospholipids are arranged according
their lipophilicity in the border area of the liquid oil droplet
Nanoemulsions (also named nanoparticles) are oil-in-water
emulsions having a small droplet size (30 – 300 nm). Figure 2
illustrates the structure of a nanoemulsion droplet (figure 2).
Phospholipids build the border area of the droplet and separate
the oily phase from the aqueous phase. Figure 3 shows an
electron microscope picture of a nanoemulsion containing CoQ10
(figure 3). The oil droplets containing CoQ10 are dispersed in the
water phase and have a diameter of about 50 nm. The small size
of the droplets is achieved through high pressure homogenization.
(19) A notable advantage of a nanoemulsion is its outstanding
stability, even at high temperatures up to 120 ºC.
Figure 4:
Nanoemulsions containing CoQ10. 1: 7% CoQ10, 2: 0.7% CoQ10, 3: 0.07%
CoQ10. The droplet size of all preparations is around 50 nm.
Figure 3:
Particle size of Q10 nanoparticles (around 50 nm) visualized by a TEM
(transmission electron microscope).
Of special interest is also the preparation of transparent CoQ10
nanoemulsions. These preparations can be obtained if a droplet
Figure 5:
Correlation between particle size and transparency. 1: 54 nm, 2: 79 nm,
3: 90 nm, 4: 102 nm, 5: 116 nm, 6: 197 nm.
size of less than 60 nm can be achieved. This small droplet size
Nanoemulsions containing droplets above 100 nm look white
will no longer scatter the light. However, CoQ10 will still absorb
where as dispersions around 70 – 100 nm appear opaque and
light and therefore this preparation looks orange (figure 4).
below that become transparent (figure 5).
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Novel CoQ10 nanoemulsions
The use of nanoemulsions in cell culture systems offers new
In this article we will present a novel CoQ10 double nanoemulsion
opportunities. Due to the small size these nanodroplets are easily
with special properties manufactured according to a patented
absorbed by cells by means of endocytosis. This technique is
procedure. (20) The preparation consists of two different
described in the US patent US 6,265,180 B1 and can be applied
nanoemulsions. These individual nanoemulsions can now
as a novel nutritional delivery system in cell cultures. Several
contain lipophilic compounds which are not compatible with
studies revealed that nanoemulsions containing CoQ10 in cell
each other such as vitamin E and Coenzyme Q10 (figure 6)
cultures reduce the need for blood serum, enhance the growth
which will form a dark complex when mixed together.
rate of the cells, and increase the production of antibodies. In
one study the production of antibodies in hybridoma cells was
enhanced by 42%. (21)
Use of CoQ10 nanoemulsions in cosmetics
CoQ10 encapsulated in the described nanoemulsions increases
the synthesis of collagen I in fibroblasts. This effect was recently
shown using normal human dermal fibroblasts (NHDF) and a
CoQ10 nanoemulsion at a concentration of 0.1%. Cells first
were cultured at standard conditions without CoQ10 during
Figure 6:
Illustration of a multiple nanoemulsion containing two different inner phases.
The substances of the two inner phases are not compatible with each other.
24 hours. Then the CoQ10 nanoemulsion was added and cells
were incubated for 72 hours.
CoQ10 is obtained in its oxidized form and must therefore be
The effect of CoQ10 was evaluated by visualization of the
reduced in the cell to act as an antioxidant. To facilitate this
protein using a polyclonal antibody anti-collagen I and a
reaction the reducing capacity of the cell has to be enhanced by
fluorescent
adding vitamin E (natural tocopherol). The double nanoemulsion
Results were photographed applying microscopy observation.
containing CoQ10 and tocopherol in individual droplets is
The photographs show an increased secretion of collagen I
therefore a very smart solution to activate the cell vitality in an
compared to the control. (figure 7)
efficient manner. Since both individual nanoemulsions are based
second
antibody
anti-immunglobuline-FITC.
This result demonstrates that CoQ10 encapsulated in nanodroplets
on a droplet size of around 50 nm the mixed preparation is
positively influences the expression of collagen I by fibroblasts.
transparent and has a high bioavailability.
In a second in vitro assay the influence of CoQ10 on the activity
The preparation of nanosize oil droplets offers another feature
of mitochondrial dehydrogenase in keratinocytes was assessed.
to overcome a limitation of CoQ10. The solubility of CoQ10 in
Cells (human adult low calcium high temperature cells, HaCaT)
oil is quite low. However, the solubility is enhanced at elevated
temperature. We therefore prepared saturated CoQ10 solutions at
were cultured according to standard procedures and incubated
60 ºC and used these solutions to manufacture nanoemulsions
for 72 hours with 0.1% of a CoQ10 nanoemulsion. In a further
at the same temperature. Due to the small droplet size these
step cells were incubated with sodium dodecylsulfate (SDS,
saturated CoQ10 oil solutions remained solutions even after
2µg/ml) for 24 hours to stress the cells.
the temperature has been reduced to room temperature.
The mitochondrial dehydrogenase activity was analyzed using
These supersaturated CoQ10 nanoemulsions can be stored at
the MTT test. The application of the CoQ10 nanoemulsion
refrigerated temperatures for many months without crystallization
enhanced the activity of the unstressed keratinocytes to 116.8%
of CoQ10 and are therefore very interesting products for the
application in cosmetics, food supplements and cell culture
+/-3.2% compared to the control 100.0% +/-1.3%. The SDS
systems.
treatment decreased the cell activity to 67.1% +/-4.1%.
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Figure 7:
Comparison of collagen I secretion by fibroblasts after incubation with CoQ10 (left) and control (right).
Pre-treatment with encapsulated CoQ10 downsized the
Since CoQ10 has a low bioavailability, strong endeavours have
damageing effect of SDS and the cell activity analyzed by the
been made to develop efficient delivery systems. Latest research
MTT test only decreased to 80.2% +/-1.6%. (figure 8)
established the encapsulation of CoQ10 in nanoemulsions. Data
The assessment reveals that CoQ10 nanoemulsions enhance the
mitochondrial activity of keratinocytes and protect them against
using nanoemulsions. This results in much higher CoQ10 serum
levels after oral application which is of great importance for the
necrotic stress factors.
treatment of different diseases.
The application of CoQ10 has been further improved by the
140
p<0.01
p<0.01
development of novel CoQ10 double nanoemulsions containing
p<0.01
120
Dehydrogenase activity %
show that the CoQ10 bioavailability is significantly enhanced by
tocopherol and CoQ10 in individual nanodroplets. In addition the
100
CoQ10 concentration in these nanoemulsions could be increased
80
by the development of a supersaturated CoQ10 nanoemulsion.
60
Cell Culture studies based on skin fibroblasts and keratinocytes
40
using these novel CoQ10 nanoemulsions revealed that
20
encapsulated CoQ10 supports the secretion of collagen I and
0
CoQ10
control
SDS
SDS + CoQ10
stimulates the mitochondrial cell activity. In addition a significant
control
protection against necrotic stress factors could also be shown.
Figure 8:
Activity of dehydrogenase. Left: Influence of CoQ10 compared to control;
right: influence of CoQ10 on necrotic activity of SDS.
References
Summary
CoQ10 proved to be a unique substance providing different
possibilities of application. In medicine, CoQ10 is used for
prevention and therapy of a variety of diseases. In nutrition,
CoQ10 finds its advantages as a food supplement. And, as a
cosmetic, CoQ10 becomes an indispensable ingredient as an
antioxidant and protective agent preventing skin ageing and
photo-ageing.
F
1. Gaby AR
The role of coenzyme Q10 in clinical medicine: Part 1,
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2. Grane FL
Biochemical functions of coenzyme Q10
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2004;110:3011-3016
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Neurology. 2005 Feb 22;64(4):713-5.
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Nano-encapsulation of azole antifungals: Potential applications to improve oral drug delivery.
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5. Hojerova J et al.
Coenzyme Q10--its importance, properties and use in
nutrition and cosmetics
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6. Wei YH et al.
Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in ageing.
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16. Shults CW et al.
Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.
Arch Neurol. 2002;59:1541-1550
17. Kohlert F et al.
Bioavailability of Q10 as powder vs Q10 in nanoparticles
Publication in preparation
18. Mezel M
Biodisposition of liposome-encapsulated active ingredients
applied on the skin
in O. Braun-Falco, H. C. Korting, and H. I. Maibach, eds,
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species for the induction of chronic cutaneous photodamage.
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8. Blatt T et al.
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Preparation and properties of small nanoparticles for skin
and hair care
SOFW 1997;123(13):880-5
9. Emerit I
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EXS. 1992;62:328-41.
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Mibelle AG, EP 1 516 662 A1, Patentblatt 2005/12
10. Hoppe U et al.
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Biofactors. 1999;9(2-4):371-8.
21. Zuelli F et al.
Nanoemulsions for delivering lipophilic substances
into cells
Mibelle AG, US 6 265 180 B1, Jul. 24, 2001
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Ubiquinones: stereochemistry and biological implications.
Membr Biochem. 1981;4(2):105-18.
12. Wils P et al.
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coenzyme q10 preparations.
Ann Nutr Metab. 2003;47(1):16-21.
Primary Authors Biography
Dr. Zülli obtained Ph.D. in Biochemistry from the Swiss Federal
Institute of Technology Zürich. His studies focused on structure
function analysis of enzymes using methods based on molecular biology. He worked in a postdoctoral position at the Nestlé
Research Center in the development of efficient expression
systems of recombinant DNA in yeast.
He is presently Head of Mibelle AG Biochemistry, a business
unit of Mibelle AG Cosmetics, the largest producer of cosmetic
products in Switzerland. In this position he is responsible for
the development, production and sale of active ingredients for
skin care.
14. Kommuru TR et al.
Self-emulsifying drug delivery systems (SEDDS) of coenzyme Q10: formulation development and bioavailability
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94
Mitochondrion 7S (2007) S34–S40
www.elsevier.com/locate/mito
The importance of plasma membrane coenzyme Q in aging
and stress responses
Plácido Navas
a,*
, José Manuel Villalba b, Rafael de Cabo
c
a
Centro Andaluz de Biologı́a del Desarrollo, Universidad Pablo de Olavide-CSIC, 41013 Sevilla, Spain
Departamento de Biologı́a Celular, Fisiologı́a e Inmunologı́a, Universidad de Córdoba, 14071 Córdoba, Spain
Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224-6825, USA
b
c
Received 26 October 2006; received in revised form 26 January 2007; accepted 3 February 2007
Available online 16 March 2007
Abstract
The plasma membrane of eukaryotic cells is the limit to interact with the environment. This position implies receiving stress signals
that affects its components such as phospholipids. Inserted inside these components is coenzyme Q that is a redox compound acting as
antioxidant. Coenzyme Q is reduced by diverse dehydrogenase enzymes mainly NADH-cytochrome b5 reductase and NAD(P)H:quinone
reductase 1. Reduced coenzyme Q can prevent lipid peroxidation chain reaction by itself or by reducing other antioxidants such as atocopherol and ascorbate. The group formed by antioxidants and the enzymes able to reduce coenzyme Q constitutes a plasma membrane redox system that is regulated by conditions that induce oxidative stress. Growth factor removal, ethidium bromide-induced q
cells, and vitamin E deficiency are some of the conditions where both coenzyme Q and its reductases are increased in the plasma membrane. This antioxidant system in the plasma membrane has been observed to participate in the healthy aging induced by calorie restriction. Furthermore, coenzyme Q regulates the release of ceramide from sphingomyelin, which is concentrated in the plasma membrane.
This results from the non-competitive inhibition of the neutral sphingomyelinase by coenzyme Q particularly by its reduced form. Coenzyme Q in the plasma membrane is then the center of a complex antioxidant system preventing the accumulation of oxidative damage
and regulating the externally initiated ceramide signaling pathway.
2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
Keywords: Coenzyme Q; Plasma membrane; Aging; Oxidative stress
can be driven either by the simultaneous transfer of two
electrons in a single step, or by two sequential steps of
one electron transfer through a partially reduced semiquinone intermediate. These redox forms allow CoQ to act
as antioxidant but also as pro-oxidant mainly through
the semiquinone intermediate (Nakamura and Hayashi,
1994).
CoQ is the only lipid antioxidant that is synthesized in
mammals by all cells, and its biosynthesis is a very complex
process which involves the participation of at least nine
gene products in all the species studied (Johnson et al.,
2005; Tzagoloff and Dieckmann, 1990). Most of the proteins encoded by these genes have not yet been purified
and the regulation of this biosynthesis pathway is still largely unknown (Rodriguez-Aguilera et al., 2003; Turunen
et al., 2004).
1. Introduction
Coenzyme Q or ubiquinone (CoQ) is constituted by a
benzoquinone ring and a lipid side chain constructed with
several isoprenoid units, the number of units being species
specific. Saccharomyces cerevisiae has six isoprene units
(CoQ6), Caenorhabditis elegans CoQ isoform contains nine
isoprenoid units (CoQ9), and mammalian species have different proportions of CoQ9 and CoQ10. Redox functions of
CoQ are due to its ability to exchange two electrons in a
redox cycle between the oxidized (ubiquinone, CoQ) and
the reduced form (ubiquinol, CoQH2). This redox reaction
*
Corresponding author. Tel.: +34 95 434 9385; fax: +34 95 434 9376.
E-mail address: [email protected] (P. Navas).
1567-7249/$ - see front matter 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
doi:10.1016/j.mito.2007.02.010
95
P. Navas et al. / Mitochondrion 7S (2007) S34–S40
CoQ transports electrons from mitochondrial respiratory chain complexes I and II to complex III and acts as
antioxidant as well (Crane and Navas, 1997; Turunen
et al., 2004). In addition, it functions as a cofactor for
uncoupling proteins (Echtay et al., 2000), regulates the permeability transition pore opening (Fontaine et al., 1998),
and it is required for the biosynthesis of pyrimidine nucleotides because it is the natural substrate of dihydroorotate
dehydrogenase, an enzyme located at the inner mitochondrial membrane (Jones, 1980). CoQ also enhances survival
of chemotherapy-treated cells (Brea-Calvo et al., 2006) and
is required for the stabilization of complex III in mitochondria (Santos-Ocana et al., 2002). Since the application of
the two-phase partition method to isolate high-purity
plasma membrane fractions from mammal cells (Navas
et al., 1989), it was confirmed that CoQ is present in all
the cellular membranes including plasma membrane
(Kalen et al., 1987; Mollinedo and Schneider, 1984). The
presence of CoQ in non-mitochondrial membranes suggests not only an important role for CoQ in each membrane but also the existence of specific mechanisms for its
distribution since the final reactions of CoQ biosynthesis
pathway are located exclusively at the mitochondria in
yeast (Jonassen and Clarke, 2000) and mammal cells (Fernandez-Ayala et al., 2005). CoQ is then driven to the
plasma membrane by the brefeldin A-sensitive endomembrane pathway (Fernandez-Ayala et al., 2005).
CoQ contributes to stabilize the plasma membrane,
regenerates antioxidants such as ascorbate and a-tocopherol, and regulates the extracellulary-induced ceramidedependent apoptosis pathway (Arroyo et al., 2004; Kagan
et al., 1996; Navas and Villalba, 2004; Turunen et al.,
2004). NAD(P)H-dependent reductases act at the plasma
membrane to regenerate CoQH2, contributing to maintain
its antioxidant properties (Navas et al., 2005). As a whole,
both CoQ and its reductases constitute a trans-plasma
membrane antioxidant system responsible of the above
described functions (Villalba et al., 1998).
This review will focus on the functions of CoQ and its
reductases in the plasma membrane, and its regulation
under aging and stress conditions. We will also emphasize
on the role of plasma membrane CoQ in the regulation of
stress-induced apoptosis.
S35
signal of its free radical (Kagan et al., 1998). An interchange of electrons could be possible between CoQ and
other redox compounds such as ascorbate (Roginsky
et al., 1998), DHLA (Nohl et al., 1997) and superoxide
(Kagan et al., 1998) leading to regenerate CoQH2, but
the major source of electrons comes from different
NAD(P)H-dehydrogenases (Beyer et al., 1996; Nakamura
and Hayashi, 1994; Navarro et al., 1995; Takahashi
et al., 1996). It has been demonstrated that the incubation
of liver plasma membranes with NADH increases CoQH2
levels with the concomitant decrease in oxidized CoQ
(Arroyo et al., 1998), which acts through semiquinone radicals and also recycles vitamin E homologue in a superoxide-dependent reaction (Kagan et al., 1998). CoQ, but not
the intermediate form of CoQ biosynthesis, is also reduced
by NADH-dependent dehydrogenases in plasma membrane of C. elegans (Arroyo et al., 2006).
Several enzymes have been reported to function as CoQ
reductases. These include the NADH-cytochrome b5 reductase (Constantinescu et al., 1994) (Navarro et al., 1995;
Villalba et al., 1995) and NADPH-cytochrome P450 reductase (Kagan et al., 1996), which are one-electron CoQreductases (Nakamura and Hayashi, 1994); and
NAD(P)H:quinone reductase 1 (NQO1, formerly DTdiaphorase) (Beyer et al., 1996; Landi et al., 1997) and a
distinct NADPH-CoQ reductase that is separate from
NQO1 (Takahashi et al., 1992, 1996), which are cytosolic
two-electron CoQ-reductases.
Both NADH-cytochrome b5 reductase and NQO1 were
demonstrated to act at the plasma membrane to reduce
CoQ (De Cabo et al., 2004; Navarro et al., 1995). The
NADH-cytochrome b5 reductase has been found in the
cytosolic side of the plasma membrane, where it is attached
through a myristic acid and a hydrophobic stretch of
aminoacids located at its N-terminus (Borgese et al.,
1982; Navarro et al., 1995). As a CoQ-reductase, the solubilized enzyme displays maximal activity with CoQ0, a
CoQ analogue which lacks the isoprenoid tail, whereas
reduction of CoQ10 requires reconstitution into phospholipids (Arroyo et al., 1998, 2004; Navarro et al., 1995).
NQO1 catalyses the reduction of CoQ to CoQH2 through
a two-electron reaction (Ernster et al., 1962). This enzyme
is mostly located in the cytosol with a minor portion associated to the membranes, including plasma membrane,
where has been recognized to be of importance to maintain
the antioxidant capacity of membranes (Navarro et al.,
1998; Olsson et al., 1993). It has been shown that this
enzyme can generate and maintain the reduced state of
ubiquinones such as CoQ9 and CoQ10 in membrane systems and liposomes, thereby promoting their antioxidant
function (Beyer et al., 1996; Landi et al., 1997).
These two enzymes would contribute to the transplasma membrane redox system providing the electrons
that are required to maintain its antioxidant properties
(Villalba et al., 1998). NADH-ascorbate free radical reductase, a trans-oriented activity shows a strong dependency
on the CoQ status of liver plasma membrane (Arroyo
2. The antioxidant system of the plasma membrane
2.1. CoQ is reduced at the plasma membrane by NAD(P)Hoxidoreductases
The plasma membrane delimites the cell and different
insults from the environment, like oxidative stress, can
attack this structure. Diverse antioxidants are protecting
the cell under these conditions, particularly ascorbate at
the hydrophilic cell surface and both CoQ and a-tocopherol in the hydrophobic phospholipid bilayer. The analysis
of CoQ at the plasma membrane has shown that both its
reduced and oxidized forms can be detected, and also the
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S36
et al., 2004) and NQO1 also contribute to the plasma membrane antioxidant system in different conditions such as
oxidative stress and aging (De Cabo et al., 2004, 2006;
López-Lluch et al., 2005). The yeast model shows a high
level of analogies with mammalian systems (Steinmetz
et al., 2002) allowing a genetic evidence of CoQ participation in plasma membrane redox activities that it is more
difficult to assess in mammal cells. The COQ3 gene of S.
cerevisiae encodes for a methyl transferase in CoQ biosynthesis pathway, and yeasts harboring a COQ3 gene deletion
(coq3D) do not synthesize CoQ (Clarke et al., 1991). Yeast
mutants coq3D displayed a significant decrease of NADHascorbate free radical reductase activity at the plasma
membrane, and its full restoration was achieved when
mutant cells were cultured either in presence of exogenous
CoQ, or when transformed with a plasmid harboring the
wild-type COQ3 gene (Santos-Ocaña et al., 1998).
Based on these results it is possible to scheme a plasma
membrane containing a trans-membrane electron transport
system (Fig. 1) that drives electrons either from NADHascorbate free radical reductase, NQO1 or both to CoQ,
which follows a cycle to CoQH2 through the semiquinone
radical. This compound is then able to recycle other antioxidants such as ascorbate and a-tocopherol. Both CoQH2
and a-tocopherol also prevent lipid peroxidation chain
reaction.
brane resulting in enhanced trans-membrane redox activity
(Gómez-Dı́az et al., 1997). Trans-plasma membrane redox
system is then increased to reoxidize cytosolic NADH and
to export reducing equivalents to external acceptors, maintaining the NAD+/NADH ratio (Martinus et al., 1993),
which is important to guarantee the genome stabilization
through sirtuins (Sauve et al., 2006). This adaptation could
be thus considered as a general response of eukaryotic cells
to impaired mitochondrial function in order to regulate
cytosolic NAD+/NADH levels (Larm et al., 1994). A similar interpretation would be considered for the improvement of both plasma membrane antioxidant system (De
Cabo et al., 2004; Hyun et al., 2006a) and mitochondria
efficiency (Lopez-Lluch et al., 2006) induced by caloric
restriction, a nutritional model that extends life span by
inducing sirtuins (Cohen et al., 2004).
CoQH2 protects membrane lipids from peroxidation
either directly or through the regeneration of a-tocopherol
and ascorbate. However, CoQ is synthesized in all animal
species and it is possible to postulate a regulatory pathway
for CoQH2 in order to provide an antioxidant protection
of the cell. The oxidative stress induced by camptothecin in
mammal cells increase CoQ biosynthesis to prevent cell
death (Brea-Calvo et al., 2006), as it was observed under several kinds of oxidative stress (Turunen et al., 2004), suggesting that it represents an adaptation rather than the cause of
the stress. According to this idea, enhanced biosynthesis of
CoQ and/or CoQ-reductases could be responses evoked by
cells for protection against oxidative stress.
Mammals can not synthesize a-tocopherol (vitamin E)
and require Se. A severe chronic oxidative stress can be
provoked by feeding rats with diets deficient in both nutrients (Hafeman and Hoekstra, 1977). After 3 weeks of deficient diet consumption, animals show markedly reduced
levels of a-tocopherol in tissues, and display a dramatically
increased Ca2+-independent phospholipase A2 activity
(PLA2), which may play a protective role in cells leading
to increased metabolism of fatty acid hydroperoxides
(Kuo et al., 1995).
2.2. Oxidative stress modulates the CoQ-dependent
antioxidant system of plasma membrane
The transfer of CoQ to the plasma membrane is an
active process that depends on the endomembrane system
after its biosynthesis in mitochondria (Fernandez-Ayala
et al., 2005). It is interesting then to explore the mechanisms involved in the incorporation of CoQ in the plasma
membrane.
The impairment of mitochondrial function with ethidium bromide, which causes mitochondria-deficient q
cells, induces an increase of CoQ levels at the plasma mem-
Fig. 1. An scheme of the plasma membrane redox system. It involves an antioxidant system and its role on the sphingomyelinase regulation.
Abbreviations: n-SMase, neutral-sphingomyelinase; NQO1, NAD(P)H:quinone reductase 1.
97
Using this approach, an increase in both CoQ9 and
CoQ10 in liver plasma membranes was observed when atocopherol and selenium had reached minimum levels
(Navarro et al., 1998, 1999). CoQ increase at the plasma
membrane may be the result of enhanced biosynthesis
and/or translocation from intracellular reservoirs such as
the endoplasmic reticulum and mitochondria. These results
would be supported because lower levels of total CoQ have
been found in heart mitochondria isolated from vitamin Edeficient and vitamin E and Se-deficient rats (Scholz et al.,
1997). An increase of CoQ biosynthesis under vitamin E
and Se deficiency might be not enough to compensate for
its accelerated consumption by oxidative degradation in
the heart, an organ with high demand for CoQ utilization
in oxidative metabolism. A transitional effect was observed
when rats were submitted only to vitamin E deficiency,
showing a milder adaptation to oxidative stress where antioxidants were induced earlier than the phospholipases (De
Cabo et al., 2006).
Consistent with higher CoQ levels, deficiency was
accompanied by a twofold increase in redox activities associated with trans-plasma membrane electron transport such
as NQO1 and ascorbate free radical-reductase (De Cabo
et al., 2006; Navarro et al., 1998). NQO1 was also
increased in liver of rats fed with a diet deficient in selenium
(Olsson et al., 1993), and it has been also shown that the
expression of the NQO1 gene was induced in rat liver after
7 weeks of consuming a vitamin E and selenium-deficient
diet (Fischer et al., 2001). However, the increase of CoQ
and NADH-cytochrome b5 reductase was earlier than
NQO1 translocation to the plasma membrane indicating
a timing of events leading to protect cells from oxidative
stress (De Cabo et al., 2006). This is apparently a general
aspect of response to endogenous oxidative stress (Bello
et al., 2005b). Although the mechanisms involved in regulating the changes of CoQ concentration in the plasma
membrane, and also the accumulation of its reductases
are still elusive, it is postulated that the activation of
stress-dependent signaling pathways such as mitochondrial
retrograde signals would be involved.
S37
of docosahexaenoic acid to arachidonic acid are accompanied by a decrease in fluidity of the plasma membrane in aged
rats (Hashimoto et al., 2001). These findings support the
hypothesis that alteration of membranes by oxidative damage to their structural basic molecules, lipids and proteins,
can be involved in the basic biology of aging.
Rats fed with a diet enriched with polyunsaturated fatty
acids (PUFAn-6) and supplemented with CoQ10 show an
increased life-span compared to those fed without the supplementation (Quiles et al., 2004). In these conditions,
CoQ10 was increased in plasma membrane at every time
point compared to control rats fed on a PUFAn-6-alone
diet. Also, ratios of CoQ9 to CoQ10 were significantly lower
in liver plasma membranes of CoQ10-supplemented animals (Bello et al., 2005a). These results clearly support
the role of both CoQ and its content in plasma membrane
in the regulation of aging process.
Data from our laboratories and others, provide support
that the plasma membrane redox system is, at least in part,
responsible of the maintenance of the antioxidant capacity
during oxidative stress challenges induced by the diet and
aging. The up-regulation of the plasma membrane redox
system that occurs during CR decreases the levels of oxidative stress in aged membranes (De Cabo et al., 2004; Hyun
et al., 2006b; López-Lluch et al., 2005). CR is the only reliable experimental model to extend life span in several
mammalian models (Heilbronn and Ravussin, 2003;
Ingram et al., 2006). CR extends life span of yeasts by
decreasing NADH levels (Lin et al., 2004), which would
connect this intervention to plasma membrane NADHdependent dehydrogenases. CR modifies composition of
fatty acid in the plasma membrane, resulting in decreased
oxidative damage including lipid peroxidation (Yu, 2005;
Zheng et al., 2005). More importantly, plasma membrane
redox activities and also the content of CoQ, which decline
with age, are enhanced by CR providing protection to
phospholipids and preventing the lipid peroxidation reaction progression (De Cabo et al., 2004; Hyun et al.,
2006b; López-Lluch et al., 2005).
3. CoQ participates in the regulation of apoptosis
2.3. The antioxidant system of plasma membrane is
associated to aging process
3.1. CoQ of the plasma membrane prevent stress-induced
apoptosis
There are a number of the key players on the plasma membrane that are affected by aging and age-associated diseases.
The levels of antioxidants a-tocopherol and CoQ are
decreased with age and elderly non-insulin-dependent diabetes mellitus (NIDDM) patients, suggesting that the pathogenesis of NIDDM could be associated with the
impairment of an electron transfer mechanism by the plasma
membrane redox system (Yanagawa et al., 2001). Oxidative
damage to plasma membrane phospholipids in rat hepatocytes and brain increases with age and is retarded by caloric
restriction (CR) (De Cabo et al., 2004; Hayashi and Miyazawa, 1998; Hyun et al., 2006b; López-Lluch et al., 2005).
Increased levels of lipid peroxidation and decreased ratio
The supplementation of mammal cells cultures with CoQ
increases its concentration at the plasma membrane (Fernandez-Ayala et al., 2005), and also enhances cell growth
(Crane et al., 1995). Also, molecular mechanisms that
increase cell growth also increase trans-plasma membrane
reductases (Crowe et al., 1993), most of them depending on
the CoQ concentration in this membrane, as explained
above.
Since the maintenance of cell population depends on the
equilibrium among proliferation and cell death, it is important to understand the mechanisms that regulate cell survival. Hormones and growth factors are required to
98
S38
prevent apoptosis that occurs with a mild oxidative stress
(Ishizaki et al., 1995; Slater et al., 1995), and an increase
of peroxidation levels in membranes (Barroso et al.,
1997a; Ishizaki et al., 1995; Raff, 1992). As expected, the
supplementation of cell cultures with various antioxidants
in the absence of serum results in the protection against cell
death (Barroso et al., 1997a,b). Steady-state levels of intracellular reactive oxygen species are significantly elevated in
cells with low CoQ levels, particularly under serum-free
conditions. These effects can be ameliorated by restoration
with exogenous CoQ, indicating the major role of CoQ in
the control of oxidative stress in animal cells (GonzalezAragon et al., 2005).
Plasma membrane can be also a source of reactive oxygen species through the transport of electrons in the transmembrane system (Hekimi and Guarente, 2003), which can
be increased by antagonists of CoQ such as short-chain
ubiquinone analogues and capsaicin that trigger apoptotic
program starting at the plasma membrane (Macho et al.,
1999; Wolvetang et al., 1996). This activity is different from
the plasma membrane NAD(P)H oxidase of some cells
such as neutrophils because it is currently accepted that this
enzyme does not produce oxygen free radicals. The oxidase
pumps electrons into the phagocytic vacuole, thereby
inducing a charge across the membrane that must be compensated. The movement of compensating ions produces
conditions in the vacuole conducive to microbial killing
(Segal, 2005). CoQ is involved not only in the prevention
of lipid peroxidation progression but also in recycling other
antioxidants as indicated above. However, cells showing a
higher concentration of CoQ in the plasma membrane
(Gómez-Dı́az et al., 1997) were more resistant to serumremoval oxidative stress-mediated apoptosis and accumulated lower levels of ceramide (Barroso et al., 1997b; Navas
et al., 2002). We proceed then to analyze the role of CoQ of
the plasma membrane in the ceramide signaling pathway.
in the regulation of the n-SMase in vivo. The inhibition of
n-SMase in the plasma membrane is carried out more efficiently by CoQH2, and also depends on the length of the
isoprenoid side chain (Martin et al., 2002) If the inhibition
of plasma membrane n-SMase by ubiquinol has physiological significance, then endogenous levels of ubiquinol
should also exert this regulatory action. Moreover, since
endogenous CoQ can be reduced in plasma membrane by
the intrinsic trans-membrane redox system, the activity of
plasma membrane NAD(P)H-dependent dehydrogenases
should also modulate the activity of n-SMase. This function of CoQ occurs at the initiation phase of apoptosis
by preventing the activation of the n-SMase in the plasma
membrane through the direct inhibition of this enzyme
and, as a consequence, the prevention of caspase activation
(Navas et al., 2002). Fig. 1 shows not only the antioxidant
function of CoQ and its reductases in the plasma membrane but also indicates the role of CoQ/CoQH2, and
probably lipid peroxides, in regulating the neutral
sphingomyelinase.
Interestingly, different experimental studies have indicated that the exogenous treatment with CoQ stimulates
the immune response (Bentinger et al., 2003). This latter
effect and the inhibition of n-SMase by CoQ are factors
to be considered that could be related to its beneficial
effects on cells and organisms, beyond its participation in
mitochondrial energy production or as antioxidant.
4. Conclusions and future directions
The plasma membrane redox system is important in cellular life because it prevents membrane damage but also regulates the apoptosis signaling that starts at this membrane.
It is currently known that this system responds to different
type of stress increasing the concentration in the plasma
membrane by new biosynthesis or translocation from the
cytosol. More precisely, the study of biosynthesis regulation
of both cytochrome b5 reductase and NQO1, and its location to the plasma membrane is very important because is
an essential enzyme not only for mammals but also to all
eukaryotes. It is then important to analyze the signaling
pathways responsible in the regulation of the plasma membrane redox system, and particularly its connection to mitochondria, where coenzyme Q is particularly involved.
3.2. CoQ inhibits neutral sphingomyelinase of the plasma
membrane
The activation of a Mg2+-dependent neutral-sphingomyelinase (n-SMase) located at the plasma membrane has
been recognized as one of the initial signaling events that
take place during apoptosis induced by growth factorswithdrawal (Jayadev et al., 1995; Liu and Anderson,
1995). Serum deprivation induces a progressive increase
of ceramide levels, which is then able to induce cell death
after its intracellular accumulation (Barroso et al., 1997b;
Jayadev et al., 1995; Obeid et al., 1993). These compounds
then activate caspases, the general executioners of apoptosis (Navas et al., 2002; Wolf and Green, 1999).
Mg2+-dependent n-SMase was purified from plasma
membrane showing that is highly inhibited by CoQ0, an
isoprenoid-free ubiquinone. This enzyme was also observed
to be inhibited by CoQ10 in plasma membrane from pig
liver through a non-competitive mechanism (Martin
et al., 2001). These results suggest that CoQ may play a role
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101
102
 Health Trust Alliance, Inc. 2000
Asendin, Elavil, Etrafon, Norpramin, Pamelor,
Sinequan, Tofranil
Tricyclic Antidepressants:
Navane, Mellaril, Prolixin, Thorazine
Lipitor
L-Dopa
Lovastatin
Major Tranquilizers:
Lescol, Mevacor, Pravachol, Zocor
Cholesterol Lowering Drugs:
Diazoxide, Propranolol, Metoprolol,
Hydrochlorothiazide, Hydralazine, Clonidine
Blood Pressure Medications:
Inderal, Lopressor, Tenormin, Visken
Beta Blockers:
Diabeta, Glynase, Tolinase, Micronase, Dymmelor
Adriamycin
Anti-Diabetic Drugs:
For more information on CoQ10, go to www.life-span.com
Alzheimer's disease
Asthma
Candidiasis
Chronic fatigue syndrome
Congestive heart failure/dilated cardiomyopathy
• Angina pectoris (chest pain due to heart disease)
• Atherosclerosis
• Coronary bypass surgery/heart surgery
• Mitral valve prolapse
Elevated total & LDL cholesterol
Heart disease
High blood pressure
HIV/AIDS
Hormone-dependent cancers (breast cancer, e.g.)
Insulin resistance, which is often associated with:
• adult-onset diabetes/elevated fasting blood sugar
• abdominal/central obesity
• high blood pressure
• elevated serum cholesterol and triglycerides
• heart disease
• sleep apnea
• polycystic ovary disease
• certain hormone-dependent cancers
Kearns-Sayre syndrome (a chronic progressive ophthalmoplegia
beginning in childhood, associated with short stature, hearing
loss, and heart conduction defects)
Leukemia (animal studies)
Male Infertility
Mitochondrial encephalomyopathy
Multiple sclerosis
Muscular dystrophy
Ophthalmoplegia (paralysis of some or all eye muscles)
Parkinson's disease
Periodontal disease
• Gingivitis
• Periodontitis
• Tooth loss
• Gum and tooth pain
• Tooth abscess
Aging
B12, C, &/or selenium deficiency, e.g.)
Bleeding of the gums with light brushing or probing.
Chronic gum disease (gingivitis, periodontitis)
Chronic intense exercise
Congestive heart failure
Coronary artery disease
Elevated cholesterol
Heart disease & heart surgery
High animal protein diet
High blood pressure (essential, systolic &/or
diastolic)
HIV/AIDS
Hormone dependent cancers (breast cancer, e.g.)
Low dietary intake of vegetables
Nutrient deficient diet (B2, B3, B5, B6, folic acid,
Poor or slow healing of diseased gums.
Swollen &/or infected gums.
Type 2 diabetes, insulin resistance
Use of anti-hypertensive medications (see list below)
Prescription Medications That May Increase
Risk of CoQ10 Deficiency
Medical Conditions Associated with
Low Serum or Tissue Levels of CoQ10
Major Risk Factors Associated
with CoQ10 Deficiency
Diets high in animal protein, low in vegetables
Diets deficient in riboflavin (vitamin B2), niacin (B3),
pantothenic acid (B5) pyridoxine (B6), folic acid, B12,
vitamin C &/or trace minerals such as selenium.
Diets That Increase Risk of CoQ10 Deficiency
Angina (severe chest pain, crushing chest pressure, e.g.)
Chronic coughing, wheezing, chest tightness
Chronic fatigue, lack of energy and vitality
Elevated blood sugar & insulin levels (insulin resistance,
type 2 diabetes--often associated with high blood
pressure, elevated cholesterol & triglycerides,
sleep apnea, & obesity)
Elevated cholesterol
Heart disease, scheduled for heart surgery
High blood pressure, systolic &/or diastolic
HIV infection/AIDS
Muscle weakness
Periodontal Disease:
• Gingivitis: Bleeding gums, gums that bleed with
light brushing or probing, swollen gums, reddened
gums
• Periodontitis: Bleeding and pus with probing at the
gum-tooth margins, chronic inflammation of gums,
infection, often with abscess formation, premature
loss of permanent teeth
• Diseased gums slow to heal
• Chronic dental and gum pain
Poor muscle work tolerance (early muscle exhaustion
with heavier or more intense workloads)
Progressive muscle weakness with seizures
Selenium deficiency
Shortness of breath, difficulty breathing at rest
Vitamin deficiencies (C, B2, B3, B5, B6, folic acid &or
B12
CoQ10 Deficiency
Warning Signs & Symptoms
“…topical application of CoQ10 improves adult periodontitis not only as a sole treatment but also in combination with traditional nonsurgical periodontal therapy.”36
“Treatment of periodontitis with CoEnyme Q10 [was so ‘extraordinarily effective’ that it] should be considered as adjunctive treatment with current dental practice.”35
COENZYME Q10 (COQ10) DEFICIENCY & RISK FACTORS
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Baggio E, et al., Italian multicenter study on the safety and efficacy of coenzyme Q-10 as
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Med 15, (Suppl.), S287-S294, 1994.
Hamada M, Kazatani Y, Ochi T, et al., Correlation between serum CoQ-10 level and
myocardial contractility in hypertensive patients. In: Biomedical and Clinical Aspects of
Coenzyme Q, Vol. 4. Folkers K and Yamamura Y (eds.). Elsevier Science Publ.,
Amsterdam, 1984, pp. 263-270.
Morita K, et al.,Journal of Thoracic and Cardiovascular Surgery, 1995;110:1221-7.
Digiesi V, et al., Coenzyme Q-10 in essential hypertension. Mol Aspects Med 15, (Suppl.),
S257-S263, 1994.
Langsjoen PH, Vadhanavikit S, and Folkers K, Response of patients in classes III and IV of
cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q-10. Proc Natl
Acad Sci 82, 4240, 1985.
Mayell M, How to Use Herbs and Nutrients to Stay Well, 43.
Lockwood K, Moesgaard S, and Folkers K, Partial and complete regression of breast cancer
in patients in relation to dosage of coenzyme Q-10. Biochem Biophys Res Comm 199,
1504-1508, 1994.
Balch J and Balch P, Prescription for Nutritional Healing, 10.
Balch J and Balch P, Prescription for Nutritional Healing, 10.
Vanfraechem JHP and Folkers K, Coenzyme Q-10 and physical performance. In: Biomedical
and Clinical Aspects of Coenzyme Q-10, Vol. 3. Folkers K and Yamamura Y (eds.)
Elsevier/ North-Holland Biomedical Press, Amsterdam, 1981, 235-241.
Balch J and Balch P, Prescription for Nutritional Healing.
Folkers K Institute for Biomedical Research, University of Texas at Austin 78712, USA.
Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a
rationale for the molecular causes of cancer and a therapy. Biochem Biophys Res
Commun, 1996 Jul, 224:2, 358-61
Vadhanavikit S; Ganther HE Department of Preventive Medicine and Community Health,
University of Texas Medical Branch, Galveston 77555, USA. Selenium deficiency and
decreased coenzyme Q levels. Mol Aspects Med, 1994, 15 Suppl:, s103-7
Kishi H; Kishi T; Folkers K Bioenergetics in clinical medicine. III. Inhibition of coenzyme Q10enzymes by clinically used anti-hypertensive drugs. Res Commun Chem Pathol
Pharmacol, 1975 Nov, 12:3, 533-40
Bertazzoli C; Sala L; Ballerini L; Watanabe T; Folkers K Effect of adriamycin on the activity of
the succinate dehydrogenase-coenzyme Q10 reductase of the rabbit myocardium. Res
Commun Chem Pathol Pharmacol, 1976 Dec, 15:4, 797-800
Folkers K; Langsjoen P; Willis R; Richardson P; Xia LJ; Ye CQ; Tamagawa H University of
Texas, Austin 78712. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad
Sci , 1990 Nov, 87:22, 8931-4
Mortensen SA Department of Cardiology and Internal Medicine, Rigshospitalet B 2142, State
University Hospital, Copenhagen. erspectives on therapy of cardiovascular diseases with
coenzyme Q10 (ubiquinone). Clin Investig, 1993, 71:8 Suppl, S116-23
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 Health Trust Alliance, Inc. 2000
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18.
17.
16.
15.
14.
12.
13.
9.
10.
11.
7.
8.
6.
4.
5.
3.
2.
1.
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during heart surgery. Clin Investig, 1993, 71:8 Suppl, S155-61
21. Folkers K; Drzewoski J; Richardson PC; Ellis J; Shizukuishi S; Baker L
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24. Götz ME; Gerstner A; Harth R; Dirr A; Janetzky B; Kuhn W; Riederer P; Gerlach M Clinical
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25. Bonetti A; Solito F; Carmosino G; Bargossi AM; Fiorella PL Chair of Sport Medicine,
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Q10 deficiency. J Neurol Sci, 1998, 156:1, 41-6
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Institute for Biomedical Research, University of Texas, Austin 78712. Biochemical
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Biophys Res Commun, 1988 Jun, 153:2, 888-96
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COENZYME Q10 (COQ10) DEFICIENCY & RISK FACTORS
SCIENTIFIC REFERENCES
NUTRITION – SANT�E
� re
� bral
Vitamine A et vieillissement ce
V�eronique PALLET
�rie ENDERLIN
Vale
UMR 1286, Nutrition and Integrative
Neurobiology, Inra-Universit�e de
Bordeaux F-33076 France
<[email protected]>
Abstract: To date, convergent data on the role of retinoic acid in the mature brain have
established that this molecule, which acts as a hormone, helps to preserve cerebral
plasticity by controlling dendritic spine density as well as hippocampal neurogenesis.
Deterioration in cerebral plasticity seems to be at the base of the cognitive decline
disease. Furthermore, the transcription of several genes, known as muted, in Alzheimer’s
patients and whose transcripts are involved in the formation of senile plaques, are
controlled by retinoic acid. As seen in other nutrients, aging leads to a lower production
of retinoic acid; a phenomenon probably accentuated by the fact that Western
populations consume an insufficient amount of vitamin A (60 % of the population has a
consumption lower than the recommendations). These two phenomena (i.e. level of
consumption, the lack of activation of vitamin A) accompanied by important individual
differences, would help to explain why some patients have an almost normal aging
process, whereas others gradually develop cognitive disorders and then, the disease. A
better understanding of the role of a collapse of the retinoid status in the genesis of
Alzheimer lesions could, beyond the definition of a preventive nutritional strategy, open
therapeutic perspectives, through the use of molecules targeting the nuclear receptors.
Key words: aging, brain, memory, Retinoic acid nuclear receptors (RAR, RXR), Alzheimer’s disease
La vitamine A est une vitamine liposo�sente des ro
^ les importants
luble qui pre
�rents tissus de l’organisme.
dans diffe
�e dans la vision, dans le
Elle est implique
�grite
� des surfaces
maintien de l’inte
�pithe
�liales, dans l’immunite
�, la reproe
duction ou encore dans la croissance et
�veloppement (Blomhoff et
le de
^ le
Blomhoff, 2006). En dehors de son ro
dans la vision, la vitamine A agit
�diaire de
principalement par l’interme
�tabolite l’acide re
�tinoı̈que (AR)
son me
�cepteurs
qui, en se liant �
a des re
�aires, r�
�nes
nucle
egule l’expression de ge
dans les tissus cibles.
� tabolisme
Me
et transport
de la vitamine A
�rieurs la vitaPour les mammif�
eres supe
mine A provient exclusivement de l’alimentation : soit sous forme de vitamine
�forme
�e (dans sa forme majoritaire il
pre
� par des acides
s’agit de r�
etinol est�
erifie
gras �
a longues chaı̂nes comme le palmi�tinyle par exemple) dans les
tate de re
produits animaux, ou bien sous forme de
�noı̈des provitaminiques tels que le
carote
�ne, a-carote
�ne, b-cryptoxanb-carote
�sents dans les aliments d’orithine, pre
�ge
�tale (figure 1). On recomgine ve
mande actuellement que 60 % de
l’apport en vitamine A soit sous la forme
�noı̈des (sources v�
�tales) et
de carote
ege
�tinol (sources
40 % sous forme de re
animales) (Cordain et al., 2005). L’ester
�tinol (RE) doit e
^tre hydrolyse
� avant
de re
^tre absorbe
� au niveau intestinal.
d’e
� d’absorption est meilleure
L’efficacite
�form�
pour la vitamine A pre
ee (80 �
a
�noı̈des (5090 %) que pour les carote
�ne est converti en r�
60 %). Le carote
etinol
au niveau de la muqueuse intestinale. Le
� dans les
re�tinol est ensuite est�
erifie
cellules de la muqueuse par la LRAT
(Lecithin : retinol acyltransf�erase), le RE
�sultant de cette catalyse est incorpore
�
re
� via le
dans les chylomicrons et absorbe
�me lymphatique (Harrison, 2005).
syste
Dans des conditions nutritionnelles normales, la plupart de la vitamine A de
�e dans le foie
l’organisme est stocke
�tinyl
(essentiellement sous forme de re
ester : RE) pour une part dans les
�patocytes et pour la majorite
� sous
he
forme de gouttelettes lipidiques dans les
�toile
�es du foie (encore appele
�es
cellules e
�r�ebral. OCL 2011 ; 18(2) : 68-75. doi : 10.1684/ocl.2011.0375
Pour citer cet article : Pallet V, Enderlin V. Vitamine A et vieillissement ce
68
OCL VOL. 18 N8 2 MARS-AVRIL 2011
104
doi: 10.1684/ocl.2011.0375
�tinoı̈des, et en
Il est bien connu que les re
^ le capital
particulier l’AR, jouent un ro
�veloppement du syste
�me
dans le de
nerveux central, mais ce n’est que r�
ecemment que son action dans le cerveau
adulte a retenu l’attention des scientifi�es actuellement disponiques. Les donne
�rent qu’une
bles sur ce sujet sugge
�gulation tre
�s fine de l’expression des
re
�nes cibles de l’AR est fondamentale
ge
�re
�brales optimales,
pour des fonctions ce
� synaptique,
telles que la plasticite
�moire. Plus
l’apprentissage et la me
�cemment encore, des donne
�es prore
�tudes mettent en
venant de plusieurs e
�vidence l’implication de la voie de
e
�tinoı̈des dans l’�
signalisation des re
etiologie de la maladie d’Alzheimer (MA).
Aliments d’origine animale
Fruits et légumes
RE
Ester de
rétinol (RE)
muqueuse intestinale
Retinol
CRBP-II
Provitamine A
Caroténoïdes
entérocyte Chylomicrons
APOE
sang
Ester de rétinol Chylomicrons
Rétinol-CRBP2
APOE
Rétinol-CRBP2
RBP
RétinolRBPTTR
TTR
RBP4
Hépatocyte
Ester de rétinol
Rétinol-RBP4-TTR
Cellule étoilée
Foie
Rétinol-APOD
Ester de rétinol-APOE
Rétinol
Rétinal
Acide rétinoïc
CRBP-I
CRABP
RA
RAR RXR
HRE
noyau
Cellule
cérébrale
Figure 1. M�etabolisme et action cellulaire de la vitamine A.
�, en fonction des
cellules de Ito). De la
besoins de l’organisme, elle sera
�e vers les tissus cibles
mobilise
(Bellovino et al., 2003). Pour ce faire, le
� et le r�
RE est hydrolyse
etinol libre est
� �
ensuite complexe
a la retinol binding
protein (RBP4). Approximativement
95 % de la RBP circule dans le plasma
sous forme d’un complexe avec la
�ine de transport de la thyroxine :
prote
la transthyretin ou pr�
ealbumine (TTR). Le
�tinol constitue le re
�tinoı̈de le plus
re
abondant dans le sang (95 % du r�
etinol
�ines vectrices permetsont li�
es aux prote
tant leur transport). Le flux de r�
etinol
� r�
�gule
�
libe
e par le foie est tr�
es finement re
�re �
de manie
a maintenir une concentra�tinol dans le plasma
tion constante de re
(2 mmol/L). Au-del�
a des besoins
�diats, la vitamine A alimentaire sert
imme
�
�serves he
�patiques
a constituer des re
�es au cours
qui seront ensuite utilise
�riodes d’apports insuffisants
des pe
(Theodosiou et al., 2010). Au niveau de
la cellule cible, il semble que la RBP soit
�cepteur trans-memreconnue par un re
branaire nomm�
e STRA6, qui prendrait en
charge le re�tinol en le faisant entrer dans
�
la cellule (Kawaguchi et al., 2007). A
�tinol peut alors
l’int�
erieur de celle-ci, le re
�tabolisme non oxydatif,
subir un me
�tinyl esters, re
�tinylproduisant des re
phosphate, 3-d�
ehydror�
etinol, ainsi
�tabolisme oxydatif donnant
qu’un me
�tinal (aussi appele
� re
�tinald�
du re
ehyde)
�tabolite actif de la
puis de l’AR, me
�tinol en
vitamine A. L’oxydation du re
AR est un processus enzymatique, qui se
�roule en deux e
�tapes, et dont le re
�tinal
de
�tabolite interm�
est le me
ediaire. La pre-
�re oxydation est re
�versible, tandis
mie
�me est irre
�versible. Notons
que la deuxie
que des voies cytosoliques et microsomales dans les processus d’oxydation
�crites. La
du r�
etinol en AR ont �
et�
e de
� interm�ediaire, le
formation du compose
�tinal, peut e
^tre catalys�
re
ee par des
enzymes cytosoliques ou microsomales
�es re
�tinol de
�shydroge
�nases (RDH)
appele
(Gottesman et al., 2001 ; Pares et al.,
2008). Ces RDH peuvent ainsi appartenir
�
�shydrog�
a la famille des alcool de
enases
(ADH), enzymes cytosoliques, ou �
a la
�nases/re
�ductases
famille des d�
eshydroge
�
a chaı̂nes courtes (SDR), enzymes micro�tinal
somales (Pares et al., 2008). Le re
^tre converti de manie
�re
peut ensuite e
�versible en AR par des ald�
irre
ehydes
�shydroge
�nases (ALDH) cytosoliques
de
(Chen et al., 1994). Par ailleurs, il a
�galement �
�, in vitro, qu’une
e
et�
e montre
vari�
et�
e de cytochromes P450 (CYP)
�taient implique
�s dans l’oxydation
e
�tinal en AR (Zhang
microsomale du re
et al., 2000). Enfin, signalons que la
�gradation et
CYP26 permet la de
�limination de l’AR tout-trans spe
�cifil’e
^ le
quement, et contribue ainsi au contro
�tinoı̈de (Petkovich, 2001).
du signal re
� cepteurs nucle
� aires
Les re
� tinoı̈que
de l’acide re
Le fait que l’AR active des facteurs de
�aire a e
�te
� de
�couvert
transcription nucle
�cepen 1987. Il existe deux types de re
teurs de l’AR (Mangelsdorf, 1994). Le
�cepteurs
premier type comprend les re
RAR (retinoic acid receptor) qui peuvent
lier l’AR tout-trans et l’AR 9-cis. Le
�me type comprend les RXR (retideuxie
�couverts par
noid X receptor) de
�
Mangelsdorf et al. (1990), dont l’affinite
�leve
�e pour l’AR 9-cis, mais plus faible
est e
pour l’AR tout-trans (Levin et al., 1992)
�cemment, il a
(Chambon, 1996). Plus re
�te
� de
�montr�
e
e que certains acides gras,
�noı̈que
dont le DHA (acide docosahexae
�galement des ligands
C22 : 6 n-3) sont e
�
du RXR, qu’ils lient avec une affinite
�tinoı̈que luicomparable �
a l’acide re
m^
eme (de Urquiza et al., 2000). Pour
�cepteurs (RAR et
chacun de ces deux re
�ines, code
�es par
RXR), trois types de prote
�rents, ont e
�te
� isol�
trois g�
enes diffe
ees :
RARa, b, g et RXR a, b, g (Chambon,
1996).
�cepteurs appartiennent �
Ces re
a une
�cepteurs nucle
�aires
superfamille de re
�ines transre
�gulatrices
qui sont des prote
capables de se fixer principalement sous
105
69
�res de RXR, ou
forme d’homodime
�res RAR-RXR au niveau
d’h�
et�
erodime
�cifiques de l’ADN, appele
�s
de site spe
�el�ements de r�e ponse (RXRE et RARE)
�s en amont du ge
�ne cible
et situe
(occasionnellement dans les introns)
(Mangelsdorf et Evans, 1995). Il existe
une forte homologie de structure entre
�cepteurs
les membres de la famille des re
�aires, qui comprend les re
�cepteurs
nucle
de diff�
erents ligands hydrophobes tels
�roı̈des, les hormoque les hormones ste
�rive
�s hydrones thyroı̈diennes, les de
�s de la vitamine D, l’acide re
�tinoı̈que
xyle
ou encore les acides gras et eicosanoı̈des
(Huang et al., 2010). Cependant, cer�cepteurs n’ont pas encore �
tains re
a ce
jour de ligands connus, ce sont les
�cepteurs dits orphelins. En pre
�sence
re
de leur ligand et en association avec des
co-activateurs ou co-represseurs, ces
�cepteurs re
�gulent positivement ou
re
�gativement l’expression de leurs
ne
�nes cibles. RAR se lie principalement
ge
�re avec le
au RARE sous forme de dime
�pendamment de
RXR qui lui agit inde
son ligand. Il semble que le dim�
ere RAR/
�gule environ 500 ge
�nes
RXR re
(Blomhoff et Blomhoff, 2006).
^ le central dans
Notons que RXR joue un ro
�gulation ge
�nique puisqu’il est
la re
�re
� comme le partenaire commun
conside
�risation d’autres membres de la
de dime
�cepteurs
superfamille, dont les PPAR (re
des acides gras) (Germain et al., 2006).
�te
�rodime
�risation du RXR avec
Ainsi, l’he
les diff�
erents membres de la superfamille
implique une interaction, voire une
�tition, entre les diffe
�rentes voies
compe
�aires.
de signalisation nucle
� que l’AR
Certains auteurs ont montre
�galement agir selon une voie non
peut e
�nomique. Cette action ultra-rapide
ge
participerait �
a la modulation de la
�tine,
formation des spinules dans la re
�
�gulation des GAP jonctions et
a la re
�pines dendritiaurait des effets sur les e
ques dans l’hippocampe.
La vitamine A et le
cerveau adulte
La voie de signalisation de
l’acide r�etinoı̈que dans le cerveau
�veloppement, la vitamine
Au cours du de
�ment l’acide r�
A et plus pr�
ecise
etinoı̈que
^ le cle
� dans la structuration
joue un ro
�re
�brale, la neurogene
�se, l’adressage
ce
�e des neurites. Des
neuronal, la pousse
70
�tudes re
�centes rapportent que les re
�tie
�galement un ro
^ le impornoı̈des jouent e
�me nerveux central
tant dans le syste
adulte (Lane et Bailey, 2005 ; Bremner et
McCaffery, 2007 ; Tafti et Ghyselinck,
�
2007) en particulier dans des r�
egions ou
� neuronale est tre
�s imporla plasticite
tante, i.e. l’hippocampe, le cortex pr�
e�dian ainsi que les re
�gions
frontal me
�trosple
�niales. Un ensemble de donne
�es
re
montre �
egalement l’importance de l’acide
�tinoı̈que dans le fonctionnement du
re
striatum et du noyau accubems. D’autres
travaux ont montr�
e que le striatum
�tise l’acide re
�tinoı̈que et contient
synthe
�culaire associe
�e �
toute la machinerie mole
a
�tabolisme et �
�.
son me
a son activite
Transport vers le cerveau
� ce jour, quelques donne
�es sont disA
ponibles sur le mode de passage du
�tinol �
�re he
�matore
a travers la barrie
enc�
ephalique (BHE). Yamagata et al.
�tudie
� le transport jusqu’au
(1993) ont e
� dans la cavite
�
cerveau d’AR injecte
�ritone
�ale. D’autres re
�sultats, obtenus
pe
dans des conditions d’apports suffisants
� que
en vitamine A chez le rat, ont montre
90 % de l’AR total du cerveau n’est pas
� localement mais provient du
synth�
etise
pool circulant dans le plasma
(Kurlandsky et al., 1995). Par la suite, il
�te
� montre
� que l’isome
�re tout-trans de
ae
l’AR est la forme la plus largement
transport�
ee du sang au cerveau par
rapport aux deux autres isoformes, l’AR
13-cis et l’AR 9-cis (Le Doze et al., 2000).
Par ailleurs, la pr�
esence d’AR a �
et�
e mise en
�vidence au niveau c�
e
er�
ebral, chez des
�s en vitamine A traite
�s avec
rats carence
de l’AR, l’hippocampe et le cortex
contenant les proportions les plus importantes (Werner et Deluca, 2002). L’origine de l’AR dans le cerveau semble donc
�ne dans des situations
largement exoge
d’apports suffisants en vitamine A.
Me�tabolisme ce�re�bral
Bien que l’apport en AR au niveau
� re
�bral soit majoritairement d’origine
ce
exog�
ene, le cerveau adulte poss�
ede
toute la machinerie n�
ecessaire �
a la
�se de l’AR, �
synthe
a son transport et �
a
�aire (Lane et Bailey,
son action nucle
2005).
�ines de liaison
L’identification de prote
�tinoı̈des et des enzymes impliqudes re
�es dans la biosynthe
�se de l’AR dans le
e
cerveau adulte plaide en faveur d’un
� re
�bral du re
�tinol. En
m�
etabolisme ce
�sence des prote
�ines de
effet, la pre
transport CRBP (cellular retinol binding
106
protein) et CRABP (cellular retinoic acid
binding protein) (Zetterstrom et al.,
1994) (Zetterstrom et al., 1999), des
enzymes de conversion ADH1, ADH4
(Martinez et al., 2001) et RALDH
� te
�
(McCaffery et Drager, 1994) a e
�ve
�le
�e dans certaines structures du
re
cerveau adulte telles que l’hippocampe
et le striatum, structures particu�rement implique
�es dans les processus
lie
�siques.
mne
�vidence des enzymes
Outre la mise en e
intervenant dans le me�tabolisme de la
vitamine A, le cerveau adulte est capable
�tiser l’AR de novo et ce de façon
de synthe
efficace (Dev et al., 1993). La synth�
ese
� te
� mise en �
d’AR a en effet e
evidence
dans le cerveau de souris adulte et plus
�
particuli�
erement dans le striatum, ou
�se serait plus importante
cette synthe
que dans l’hippocampe (McCaffery and
�quipe de
Drager, 1994). De plus, l’e
� que l’AR est
Sakai et al. (2004) a montre
�tise
� par la RALDH2 au niveau des
synthe
m�
eninges adjacentes �
a l’hippocampe.
�sence de re
�tinol et surtout
Enfin, la pre
�tinyl esters a pu ^
des re
etre mise en
�vidence dans l’hippocampe de cerveau
e
humain mature (Connor et Sidell,
1997).
Modulation de la plasticite� ce�re�brale
�nes dont l’expresParmi les nombreux ge
�gule
�e par l’AR dans le cerveau
sion est re
adulte, il ya ceux codant pour ses propres
�cepteurs, et ceux codant pour des
re
�ines spe
�cifiques des neurones impliprote
�es dans beaucoup de fonctions du
que
� titre d’exemples on
cerveau mature. A
peut citer : la synaptophysine, le NGF, les
�cepteurs au N-methyl-D-aspartate
re
�cepteur 2 a� la dopamine,
(NMDA), le re
la choline acetyltransferase, la neurogranie ou encore la neuromoduline. Enfin,
�tinoı̈que et ses re
�cepteurs
l’acide re
�gulent aussi un certain nombre de
re
�nes codant pour des prote
�ines implige
�es dans les processus neurode
�g�
que
e�ratifs telles que l’APP (amyloid protein
ne
�ine tau.
precursor) ou en encore la prote
Il est actuellement admis que l’AR joue un
^ le dominant dans la pr�
ro
eservation des
�re
�brales. Ainsi, l’e
�tude des
fonctions ce
effets du statut en vitamine A, ou en acide
�tinoı̈que, dans le cerveau adulte est de
re
la plus grande importance, et en particulier au cours du vieillissement. En effet,
�es re
�centes ont montre
� que
des donne
�tinoı̈des
des modifications du statut en re
�rations
induisent la mise en place d’alte
�ines neurodans l’expression des prote
nales cibles et en cons�
equence, affectent
le maintien des processus physiologiques
dans le cerveau adulte (Malik et al.,
�rations de la
2000). Ainsi, des alte
�re
�brale et des de
�ficits de
plasticit�
e ce
�te
� de
�crits chez l’animal
m�
emoire ont e
�te
�
carenc�
e en vitamine A. Il a aussi e
�montre
� que les souris Knockout pour
de
les r�
ecepteurs RARb et RXRb-RXRg
�sentaient une alte
�ration de la LTP
pre
(potentialisation �
a long terme, une forme
� synaptique) ainsi que des
de plasticite
�ficits substantiels des performances
de
�siques, mis en e
�vidence dans un test
mne
�moire spatiale de
�pendante de
de me
l’hippocampe (Chiang et al., 1998 ;
Mingaud et al., 2008). La mutation du
RARb avec, soit celle du RXRb, soit celle
�ficits de locodu RXRg, entraı̂ne des de
�ristiques d’une fonction
motion caracte
anormale du striatum et probablement
li�
es �
a une diminution de l’expression des
�cepteurs �
re
a la dopamine dans les
neurones striataux (Krezel et al., 1998 ;
Alfos et al., 2001).
�tinoı̈que re
�gule aussi l’expresL’acide re
�nes codant pour des prote
�ines
sion de ge
�es dans les processus de neuroimplique
gen�
ese, telles que les neurotrophines
�cepteurs resNGF et BDNF, et leurs re
pectifs TrkA et TrkB (Scheibe et Wagner,
�cemment, quelques e
�tudes se
1992). Re
�resse
�es aux effets d’une hyposont inte
� de la voie des re
�tinoı̈des sur les
activite
�se chez l’adulte,
processus de neurogene
en utilisant la carence nutritionnelle en
�le d’e
�tude.
vitamine A comme mode
�raAinsi, une augmentation de la prolife
�renciation et une diminution de la diffe
�te
� observe
�es dans le bulbe
tion ont e
�ficients (Assonolfactif des animaux de
Batres et al., 2003). Une diminution de la
�renciation neuronale a
survie et de la diffe
�te
� mise en �
e
evidence dans l’hippocampe,
�s en vitamine A.
d’animaux carence
�gime enrichi en vitaCependant, un re
�tablir le
mine A ne permettait pas de re
�se chez les souris
niveau de neurogene
carenc�
ees (Jacobs et al., 2006). Enfin, des
�cents ont mis en �
travaux re
evidence que
la carence en vitamine A induit une
�ration de la neurogene
�se hippocamalte
�ration
pique (diminution de la prolife
�renciacellulaire, survie cellulaire et diffe
�lement �
tion neuronale) paralle
a une
�taient
diminution de TrkA. Ces effets e
�verse
�s par l’administration d’AR toutre
trans (Bonnet et al., 2008).
Modulation des capacite�s mn�
e siques
La carence vitaminique A, induisant un
� de la voie des re
�tinoı̈des,
hypoactivite
entraı̂ne chez la souris adulte des d�
eficits
�ve
�le
�s dans un test de me
�moire
cognitifs re
relationnelle (Etchamendy et al., 2003).
De plus, l’administration d’AR �
a des rats
carenc�
es en vitamine A permet de corri�ficits de me
�moire spatiale de
ger les de
�fe
�rence mesur�
re
es dans le labyrinthe
aquatique de Morris (Bonnet et al.,
�tudes confortent la
2008). D’autres e
� de la
relation entre le niveau d’activite
voie de signalisation des r�
etinoı̈des et les
�te
�
processus cognitifs. Pour exemple, il a e
�montre
� qu’une carence vitaminique A
de
induisait des de�ficits d’apprentissage et
de m�
emoire spatiale dans un test de
�menlabyrinthe radial, et qu’une supple
tation en vitamine A permettait de
�ficits observ�
corriger les de
es (Cocco
et al., 2002). En revanche, d’autres
�re
travaux mettant en oeuvre l’isome
�cule utilis�
13-cis de l’AR, mole
ee sous la
�nomination Accutane dans le traitede
�e, ont montre
� des effets
ment de l’acne
�fastes de cette mole
�cule dans un test
ne
�moire hippocampo-d�
de me
ependante
chez la souris jeune (Crandall et al.,
�sultat est �
2004). Ce re
a ce jour con� par l’e
�tude de Ferguson et Berry
troverse
�montre, au contraire, que
(2007) qui de
le traitement par la forme 13-cis de l’AR
est sans effet sur l’apprentissage et la
m�
emoire spatiale chez le rat.
�es montre que
L’ensemble de ces donne
les situations nutritionnelles ou physio�ficit
logiques conduisant �
a un de
d’activit�
e de la voie de signalisation des
�tinoı̈des, et en particulier �
re
a des modi�cepteurs
fications de l’expression des re
�aires ou de leurs ge
�nes cibles dans le
nucle
�rables
cerveau, conduisent �
a de conside
dommages neurobiologiques et �
a des
�rations des performances mn�
alte
esiques.
Vitamine A et vieillissement
c�e r�e bral
�tabolisme
Une forte perturbation du me
de la vitamine A apparaı̂t au cours du
vieillissement. Elle peut conduire �
a des
concentrations �
elev�
ees de cette vitamine
dans le foie (van der Loo et al., 2004) alors
^me temps la capacite
� de
que dans le me
�serves
l’organisme �
a mobiliser les re
�tinol et �
h�
epatiques de re
a les utiliser
efficacement semble fortement affect�
ee
� (Azais-Braesco et al.,
chez l’homme ^
age
�sulte une diminution de la
1995). Il en re
� cellulaire en acide
biodisponibilite
�tinoı̈que qui se traduit chez l’animal
re
^
�, dans plusieurs tissus cibles (foie,
age
� de la
cerveau) par une baisse d’activite
�tinoı̈des
voie de signalisation des re
(Enderlin et al., 1997 ; Pallet et al.,
� des
1997). Cette baisse d’activite
�tinoı̈des, dans les tissus cibles, a
re
�galement e
�te
� mise en e
�vidence chez
e
� (Feart et al., 2005).
l’homme ^
age
Il est maintenant admis que la baisse
d’activit�
e cellulaire de la vitamine A joue
^ le cle
� dans l’e
�tiologie de d�
un ro
eficits
�siques sp�
�s au vieilmne
ecifiques associe
lissement et qu’un traitement par l’acide
�tinoı̈que (AR), est �
^me de restaurer
re
a me
�s mne
�siques des animaux
les capacite
^
�s. Enfin, plus r�
�monage
ecemment, la de
�menstration de l’efficacit�
e d’une supple
tation nutritionnelle en vitamine A chez
les animaux adultes, permettant �
a la fois
le maintien de l’activit�
e de la voie de
�vention de l’apparisignalisation et la pre
�siques spe
�cifiques
tion de troubles mne
li�
es au vieillissement, a �
et�
e faite (Mingaud
et al., 2008). Il est donc aujourd’hui bien
�troite
admis qu’il existe une relation e
� ce
�re
�brale de la
entre le niveau d’activite
�tinoı̈des, l’expression
voie d’action des re
�nes cibles codant pour des prode ge
�ines neuronales implique
�es dans certe
tains processus de plasticit�
e (Husson
�siet al., 2004), et les performances mne
ques au cours du vieillissement (Mingaud
et al., 2008).
�es sugge
�rent
�gulation pre
�cise de l’expression
qu’une re
�nes contro
^ le
�s par les re
�tinoı̈des est
des ge
fondamentalement importante pour le
fonctionnement optimal du cerveau et
pour le maintien des performances de
m�
emoire.
Vitamine A et maladie
d’Alzheimer
La maladie d’Alzheimer (MA) est la
�mence la plus re
�pandue chez les sujets
de
^
�s. C’est une maladie chronique de
�g�
age
e�rative caracte
�rise
�e par la de
�te
�rioration
ne
progressive des fonctions cognitives
incluant la m�
emoire, le jugement, la
prise de d�
ecision, le langage, l’orientation, etc. Les symptomes cliniques
�
incluent les alt�
erations de plasticite
neuronale (e.g. la perte selective des
neurones et des synapses) et la formation
de plaques s�
eniles extracellulaires consti�es de peptides b-amyloı̈des (Ab) ainsi
tue
^trements neurofibrillaires
que d’encheve
intracellulaires.
�cemment, des donne
�es issues de
Re
�tudes se
�pare
�es apportent
plusieurs e
^ le de
des arguments en faveur d’un ro
la voie de signalisation de l’acide
�tinoı̈que dans l’�
re
etiologie de la maladie
107
71
lipocaline, apolipoprot�
eine D, un autre
�tinol dans le syste
�me
transporteur du re
�s dans
nerveux central sont augmente
les neurones de patients atteints de la
�gulation positive de son
MA. Une re
� te
� observe
�e in
expression par l’AR a e
vitro.
� re
�gulation de ge
�nes codant
ou �
a la de
�ines du me
�tabolisme des
pour des prote
�tinoı̈des et entraı̂nant des alte
�rations
re
�nes cibles de
dans l’expression de ge
ceux-ci, pourrait alors ^
etre fortement
�tiologie de la forme
impliqu�
ee dans l’e
tardive (ou sporadique) de la MA
(Goodman et Pardee 2003 ; Goodman,
2006).
d’Alzheimer. Tout d’abord, Goodman a
�montre
� les liens g�
�tiques entre
de
ene
cette voie de signalisation et la MA, en
�vidence que les loci les plus
mettant en e
�quemment trouve
�s modifi�
fre
es chez les
sujets atteints de la maladie �
etait
�matiquement situe
�s sur des clusters
syste
�s proches de ge
�nes codant pour des
tre
�ines ayant un ro
^ le majeur dans le
prote
m�
etabolisme et la signalisation des
�tinoı̈des, �
re
a savoir : CYP26, RARa,
RXRbg, RXRb, CRABP-II et RBP par
exemple. CYP26 est un cytochrome
P450 impliqu�
e dans le catabolisme de
^ le
l’AR et participant de ce fait au contro
du niveau d‘AR dans les tissus. Une
diminution de la concentration de
�tinol se
�rique a, par ailleurs, e
� te
�
re
�ve
�le
�e chez les patients Alzheimer,
re
ainsi qu’une diminution de l’expression
�hyde
et de l’activit�
e de la retinalde
�sydroge
�nase, enzyme implique
�e dans
de
la production de l’AR. Une diminution
�e �
de la biodisponibilit�
e de l’AR lie
a l’^
age
Vitamine A et encheve�trements
neurofibrillaires :
�nes potentiellement re
�gule
�s
Parmi les ge
�ne codant pour
par l’AR, on trouve un ge
�ine tau encore appele
�e MAPT
la prote
pour microtubules-associated-protein tau,
�ine pre
�ponde
�rante dans
et qui est la prote
^trements neula formation des encheve
rofibrillaires.
Les transporteurs de la vitamine A et la
MA
�ine E (ApoE), apolipoL’apolipoprote
�ine majeure du liquide cere
�brospiprote
�ment de RBP
nal, participerait en comple
�tinol et des re
�tinyl
au transport du re
�le e4 de son
esters dans le cerveau. L’alle
�ne a e
� te
� identifie
� comme un facteur
ge
de risque de la MA ; il semble favoriser
l’agr�
egation des peptides Ab. En revan�le e2 de
che, un effet protecteur de l’alle
�tant le meilleur
l’ApoE, connu comme e
� te
� trouve
�
transporteur des r�
etinoı̈des, a e
dans plusieurs �
etudes. Les niveaux de
Compartiment extracellulaire
Vitamine A et b-amyloı̈des (Ab)
�se des
La voie biochimique de synthe
peptides Ab, peptides constituants de la
�nile, est une voie pathologique
plaque se
�e voie amyloı̈dog�
appele
e nique (figure 2).
�quences de clivaElle comporte deux se
�olytiques successifs de la
ges endoprote
Membrane
Cytoplasme
COOH
APPαCTF
APPsα
Voie physiologique
α –secrétase
(ADAM10)(clivage)
AR
NH2
AR
Voie amyloïdogènique,
(pathologique)
β β’
APP695
γ
COOH
β –secrétase
(BACE)(clivage)
+
APPsβ
APP-β CTF
APP-β’CTF
γ –secrétase
complexe Preseniline
(PS1,PS2)(clivage)
AR
+ APP-γ CTF
APOE
APOD
Aβ40/Aβ 42
AR
AR
IDE
Régulation négative par l’AR
Régulation positive par l’AR
Figure 2. Acide r�e tinoı̈que et processus de d�
e gradation de la prot�e ine pr�ecurseur du peptide Ab.
72
108
�ine APP (Ab precursor protein)
prote
�es par deux prote
�ases distinctes
catalyse
�tases. La b-secre
�tase ou
les b- et g-secre
b-site cleaving enzyme (BACE) est hau�e dans le cerveau des
tement exprime
�e sur les sites de
patients et est localise
production du peptide Ab. Le clivage de
�tase gene
�re des
l’APP par la b-secre
fragments APPb dans l’espace extracel�tase intervient ensuite
lulaire. La g-secre
�dent
pour cliver la partie, issue du pr�
ece
�e dans la
clivage qui est demeure
�tape promembrane. Cette deuxi�
eme e
�olytique produit le petide Ab, le
te
composant central des plaques s�
eniles.
En condition physiologique, l’APP peut
^tre prote
�olyse
�e par une voie non
aussi e
amyloı̈dog�
enique. Cette autre voie de
�gradation de l’APP comporte une
de
�tape prote
�olytique par une ae
�tase, dans la se
�quence Ab, emp^
secre
e�finitivement la production
chant ainsi de
� adu peptide Ab. Cette activite
�tase est attribue
�e aux metallosecre
�ases ADAM9 et ADAM10.
prote
�te
� montre
� que l’hypoactivite
� de la
Il a e
�tinoı̈des
voie de signalisation des re
entraı̂ne la formation anormale et le
�po
^ t des petides Ab (Corcoran et al.,
de
�te
� montre
�
2004). Ceci a en particulier e
chez des rats carenc�
es en vitamine A.
�s consommation pendant 1 an
Apre
�pourd’une alimentation totalement de
vue de cette vitamine, les animaux pr�
esentaient une hypoactivation de la voie de
signalisation de la vitamine A, et avaient
�velopp�
de
e des d�
epots b-amyloı̈des dans
�menleur cerveau. Des donn�
ees supple
�ve
�le
� que la carence en
taires ont re
�ne
�ratrice d’une diminuvitamine A, ge
� de l’AR, induit
tion de la biodisponibilite
�nique
une activation de la voie amyloı̈doge
dans le cortex des rats, structure connue
�re
�e par la
comme �
etant la premi�
ere alte
maladie (Husson et al., 2006).
�rive
�s, par l’interLa vitamine A ou ses de
�cepteurs, sont e
�galement
m�
ediaire des re
�
a m^
eme d’inhiber ou destabiliser les
�gats Ab pre
�form�
�venant ainsi la
agre
es, pre
formation des plaques (Ono et al., 2004)
(Sahin et al., 2005). Il y a de nombreuses
�es biochimiques qui vont dans le
donne
sens de l’implication de la voie de
signalisation de la vitamine A dans la
formation de Ab. En effet, comme on le
�tapes cle
�s du
voit sur la figure 2, les e
processus de formation des peptides
^ le de
amyloı̈des sont sous le contro
�ines dont l’expresssion a e
�te
�
prote
�e in vitro, comme e
�tant r�
montre
egul�
ee
par l’AR. Ceci comprend : APP, la b�tase, les presenilines 1 et 2 (PS1 et
secre
�ines du complexe gPS2), deux prote
�re
secr�
etase ainsi que ADAM10. De manie
�ressante, une e
�tude in vitro montre
inte
qu’un traitement par l’AR augmente
l’expression de ADAM10 au niveau
�ique, sugge
�rant ainsi que l’AR
prote
�grainduit un basculement dans la de
dation de l’APP, en faveur de la voie asecr�
etase ou voie dites physiologique.
L’insulin d�egrading enzyme (IDE), une
�ase responsable de la
mettaloprote
�gradation de l’insuline a e
�te
� montr�
de
ee
^ le capital dans la
comme jouant un ro
�gradation du peptide Ab �
de
a la fois in
�te
� mis en e
�vidence
vitro et in vivo. IDE a e
�re
�brospinal. Son niveau
dans le liquide ce
� de ses prote
�ine ou
d’activit�
e, la quantite
�s, sont diminue
�s dans le
ARNm exprime
�s �
cerveau des malades et sont associe
a
� de d�
^ ts
une diminution de la quantite
epo
�re que l’augmentation de
Ab. Ceci sugge
l’activit�
e IDE pourrait induire une diminution du risque de d�
evelopper la MA.
�ne codant pour
Or, le promoteur du ge
�ment de re
�ponse aux
IDE pr�
esente un e�le
�f�
RAR (RARE), zone pre
erentielle de fixation des r�
ecepteurs de l’AR, et la trans�gule
�e positivement
cription de IDE est re
par l’AR.
�cents laissent supEnfin, des travaux re
^tre conside
�re
�
poser que l’AR pourrait e
�rapeutique potencomme un agent the
tiel pour le traitement de la MA. L’admi�niques
nistration d’AR �
a des souris transge
�veloppant les le
�sions de types Alzheide
mer induit, en effet, une importante
�pots amyloı̈des et des
diminution des de
^trements neurofibrillaires (Ding
encheve
et al., 2008).
Conclusion
�es sugge
�re
�gulation tre
�s pre
�cise de
qu’une re
�nes m�
�e par les
l’expression des ge
edie
�tinoı̈des est cruciale pour un fonctionre
� re
�bral optimal, et apporte des
nement ce
^ le imporarguments en faveur d’un ro
�cepteurs
tant de la vitamine A, via ses re
�aires dans les multiples processus
nucle
impliqu�
es dans la formation des plaques
�niles.
se
�vention
Dans une perspective de pre
nutritionnelle de la maladie d’Alzhei�cessaire de mieux commer, il sera ne
�
prendre l’implication de l’hypoactivite
�tinoı̈des
de la voie de signalisation des re
se mettant en place naturellement au
cours du vieillissement, dans la gen�
ese
�sions pathologiques.
des le
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Feuillet_Anti Age.indd

Transcription

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