Antioxidantes e Envelhecimento da Pele

Prévia do material em texto

Correspondence: Aleksandar Godic, MD, PhD, Faculty of Medicine, Vrazov trg 2, 1000 Ljubljana, Slovenia. Tel: � 386-51-415-678. E-mail: aleksandar.
godic@gmail.com 
 (Received 2 September 2012 ; accepted 3 December 2012 ) 
 Introduction 
 More than 50.000 papers appear in Medline when a 
keyword “ oxidative stress ” is typed, but not all are 
related to the skin. Skin aging is a consequence of 
two overlapping mechanisms, intrinsic and extrinsic 
(UV-exposure, smoking) (1,2). It seems that oxida-
tive damage is the major cause and single most 
important contributor of skin aging. Not only that 
the free radical production increases with age but the 
ability of human skin cells to repair DNA damage 
steadily reduces with years and the antioxidative 
defense becomes less effective (Figure 1). 
 The skin contains a pool of protective antioxi-
dants. It includes enzymatic antioxidants such as 
glutathione peroxidase, superoxide dismutase and 
catalase, and nonenzymatic low-molecular-weight 
antioxidants such as vitamin E isoforms, vitamin C, 
glutathione (GSH), uric acid, and ubiquinol (3). 
Other potent antioxidants, which are in the skin, are 
ascorbate, uric acid, carotenoids and sulphydrils. 
Water-soluble antioxidants in plasma are glucose, 
pyruvate, uric acid, ascorbic acid, bilirubin and 
 glutathione, and lipid-soluble are alpha-tocopherol, 
ubiquinol-10, lycopene, ß -carotene, lutein, zeaxan-
thin and alpha-carotene (4). In general, surface of 
the skin, the epidermis, contains higher concentra-
tions of antioxidants than the dermis (5). Alpha- 
tocopherol is the most prominent antioxidant in the 
lipophilic compartments while vitamin C and GSH 
have the highest abundance in the cytosol. Hydrophilic 
non-enzymatic antioxidants, including L- ascorbic 
acid, GSH and uric acid are predominant antioxi-
dants in the human skin compared on an equivalent 
molar basis (6). Their overall dermal and epidermal 
concentration is more than 10- to 100-fold greater 
than those found for vitamin E or ubi quinol. Kera-
tinocytes and skin fi broblasts contain milimolar levels 
of GSH, α -tocopherol, ascorbate, and DNA repair 
enzymes. The stratum corneum (SC) was found to 
contain both hydrophilic and lipophilic antioxidants. 
Vitamins C and E (both α γ and α -tocopherol) as well 
as GSH and uric acid were found to be present in 
the SC (7,8). Surprisingly, they were not distributed 
evenly, but in gradient fashion, with low concentra-
tions in the outer layers, which increase toward the 
deeper layers of the SC. 
Journal of Cosmetic and Laser Therapy, 2013; 15: 107–113
ISSN 1476-4172 print/ISSN 1476-4180 online © 2013 Informa UK, Ltd.
DOI: 10.3109/14764172.2012.758380
 REVIEWS OF TREATMENT STUDIES 
 Skin and antioxidants 
 BORUT POLJSAK 1 , RAJA DAHMANE 1 & ALEKSANDAR GODIC 2 
 1 University of Ljubljana, Faculty of Health Studies, Zdravstvena pot 5, 1000 Ljubljana, 
Slovenia, and 2 University of Ljubljana, Faculty of Medicine, Vrazov trg 2, 1000 Ljubljana, Slovenia 
 Abstract 
 It is estimated that total sun exposure occurs non-intentionally in three quarters of our lifetimes. Our skin is exposed to 
majority of UV radiation during outdoor activities, e.g. walking, practicing sports, running, hiking, etc. and not when we 
are intentionally exposed to the sun on the beach. We rarely use sunscreens during those activities, or at least not as much 
and as regular as we should and are commonly prone to acute and chronic sun damage of the skin. The only protection 
of our skin is endogenous (synthesis of melanin and enzymatic antioxidants) and exogenous (antioxidants, which we con-
sume from the food, like vitamins A, C, E, etc.). UV-induced photoaging of the skin becomes clinically evident with age, 
when endogenous antioxidative mechanisms and repair processes are not effective any more and actinic damage to the skin 
prevails. At this point it would be reasonable to ingest additional antioxidants and/or to apply them on the skin in topical 
preparations. We review endogenous and exogenous skin protection with antioxidants. 
 Key Words: aging , antioxidants , photoaging , skin 
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108 B. Poljsak et al. 
 Exogenous antioxidants – compounds 
derived from the diet 
 Most important preventive mechanisms against ROS-
induced damage are antioxidative enzymes, non-en-
zymatic compounds, and repair processes, but they 
are less effective with aging. It would be rational at 
this point to ingest additional antioxidants or to apply 
them on the skin in topical preparations. The identi-
fi cation of free radical reactions as promoters of the 
aging process implies that interventions, which limit 
their production or inhibit their interactions, reduce 
the disease pathogenesis and consequently rate of 
aging. Dietary antioxidants play a major role in main-
taining the homeostasis of the oxidative balance. Vita-
min C (ascorbic acid), vitamin E (tocopherol), 
beta-carotene and other micronutrients such as caro-
tenoids, polyphenols and selenium have been evalu-
ated as antioxidant constituents in the human diet. It 
is important to obtain many different water and lipid 
soluble antioxidants by intake of different kinds of 
fruits and vegetables since all antioxidants work in 
synergy. Thiols, which are associated with membrane 
proteins, may also be important antioxidants. Tocoph-
erols and tocotrienols (vitamin E) and ascorbic acid 
(vitamin C) as well as the carotenoids exhibit their 
antioxidative properties through reacting with free 
radicals, notably peroxyl radicals, and with singlet 
molecular oxygen (1O2). RRR-alpha-tocopherol is 
the major peroxyl radical scavenger in biological lipid 
phases such as membranes or low-density lipopro-
teins (LDL). L-Ascorbate is present in aqueous com-
partments (e.g. cytosol, plasma, and other body 
fl uids) and can reduce the tocopheroxyl radical; it is 
also important cofactor in hydroxylations. Carote-
noids, notably beta-carotene and lycopene as well as 
oxycarotenoids (e.g. zeaxanthin and lutein), exert 
antioxidative functions in lipid phases by free-radical 
or 1O2 quenching (9). 
 Many studies on usage of different antioxidants 
or combinations of them with phytochemicals were 
performed in order to fi nd evidence against ROS-
induced skin damage (10). 
 Recommended daily intake 
 The Dietary Reference Intake (DRI) is a system of 
nutrition recommendations from the Institute 
of Medicine (IOM) of the U.S. National Academy of 
Sciences. The DRI system is used by both the United 
States and Canada and is intended for the general 
public and health professionals. The Reference Daily 
Intake or Recommended Daily Intake (RDI) is the 
daily intake level of a nutrient that is considered to 
be suffi cient to meet the requirements of 97 – 98% of 
healthy individuals in every demographic in the 
United States (where it was developed, but has since 
been adopted in other countries). The DRI values 
are not currently used in nutrition labeling, where 
the older Reference Daily Intakes (RDAs) are still 
used. The reference values, collectively called the 
Dietary Reference Intakes (DRIs), include the Rec-
ommended Dietary Allowance (RDA), the Adequate 
Intake (AI), the Tolerable Upper Intake Level (UL), 
and the Estimated Average Requirement (EAR). A 
requirement is defi ned as the lowest continuing 
intake level of a nutrient that, for a specifi ed indica-
tor of adequacy, will maintain a defi ned level of 
nutriture in an individual (11) (Table I). 
 Tolerable upper intake levels (UL) were devel-
oped to caution against excessive intake of nutrients 
(like vitamin A) that can be harmful in largeamounts. 
The exaggerated intake of antioxidant(s) could cause 
antioxidative stress (12) and alter the complex sys-
tem of endogenous antioxidative defense of cells or 
alter the necrosis or apoptosis pathways. UL is the 
highest level of consumption that is considered safe 
according to current data. It is recommended that 
intake of certain nutrients should be from food 
source only to prevent adverse effects. 
 Topical application and safety risk assessment 
of vitamins A, C, and E 
 Vitamins A, C and E are most frequently used anti-
oxidants in skin-care products and authors of the 
paper decided to present the summary of their risk 
Consequence: Cause: 
Premature skin aging
Clinical signs of the aging skin 
Increased oxidative stress 
Inflammatory reactions 
Immunosupression 
Depleated cutaneous antioxidants 
Oxidised proteins, DNA and lipids 
Premalignant and malignant skin lesion 
Intrinsic free radical formation 
Oxidative 
stress 
Skin aging 
Extrinsic free radical formation 
Figure 1. Causes and consequences of skin aging.
J 
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 Skin and antioxidants 109
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110 B. Poljsak et al. 
assessment, what might be of special interest for der-
matologists and other medical professionals. From the 
Elmore ’ s Final report (13) of the safety assessment of 
L-Ascorbic Acid, Calcium Ascorbate, Magnesium 
Ascorbate, Magnesium Ascorbyl Phosphate, Sodium 
Ascorbate, and Sodium Ascorbyl Phosphate as used 
in cosmetics it can be concluded that they function 
in cosmetic formulations primarily as antioxidants. 
Ascorbic Acid is used as an antioxidant and pH 
adjuster in a large variety of cosmetic formulations, 
over 3/4 of which were hair dyes and colors at con-
centrations between 0.3 and 0.6%. For other uses, the 
reported concentrations were either very low ( � 0.01%) 
or in the 5 – 10% range. Ascorbic Acid is generally rec-
ognized as safe (GRAS) substance for use as a chem-
ical preservative in foods and as a nutrient and/or 
dietary supplement. Ascorbic Acid was a photopro-
tectant in clinical human UV studies at doses well 
above the minimal erythema dose (MED). One prob-
lem of vitamin C is in its instability in various topical 
products, as vitamin C is prone to oxidation, and may 
lose its effi cacy this way. For effective topical applica-
tion, vitamin C has to be non-esterifi ed, acidic and 
optimally at 20% concentration (14). 
 Safety and risk assessment of tocopherol and its 
compounds were published in Int J Toxicol by Zondlo 
in 2002. Tocopheryl Acetate, Tocopherol, and 
Tocopheryl Linoleate are used in 2673 formulations, 
generally at concentrations of up to 36%, 5%, and 
2%, respectively, although Tocopheryl Acetate is 
100% of vitamin E oil (15). Tocopherol, Tocopheryl 
Acetate, Tocopheryl Linoleate, and Tocopheryl Suc-
cinate were all absorbed in human skin. Tocopherol 
is a natural component of cell membranes thought 
to protect against oxidative damage. Tocopherol, 
Tocopheryl Acetate, and Tocopheryl Succinate each 
were reported to protect against ultraviolet radiation-
induced skin damage. These ingredients are generally 
not toxic in animal feeding studies, although very 
high doses ( � 2 g/kg/day) have hemorrhagic activity. 
These ingredients are generally not irritating or sen-
sitizing to skin or irritating to eyes, although a 
Tocopheryl Acetate did produce sensitization in one 
animal test, and Tocophersolan was a slight eye irri-
tant in an animal test (15). According to Burke (14), 
for effective topical application, vitamin E must 
be the non-esterifi ed isomer d-alpha-tocopherol at 
2 – 5% concentration. Skin penetration experiments 
showed that 55% of the topically applied α - tocopherol 
accumulated in full thickness of the skin after 24 
hours (16). Tocopherol acetate is very often used 
antioxidant in sunscreen products. 
 Vitamin A derivatives are used as anti-aging ingre-
dients in cosmetics. Vitamin A is absorbed through 
the skin, increases the rate of epidermal keratinocytes 
turnover and collagen production, and consequently 
leads to more youthful appearanceof the skin (17). 
Topical retinoids remain the mainstay therapy of the 
photoaged skin, and their effi cacy can be noticed T
ab
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 Skin and antioxidants 111
clinically, evaluated histologically, and measured 
biochemically. Their regular use might also prevent 
photoaging (18). Available topical retinoids include 
tretinoin (Retin-A ® ), adapalene (Differen ® ), and 
tazarotene (Tazorac ® ) and over-the-counter Retinol ® 
and Retinol-A ® . These drugs are derivatives of vitamin 
A which might have anti-aging properties (19). 
 Discussion 
 It is important to pretreat the skin with antioxidants 
before sun exposure. Human studies have convinc-
ingly demonstrated pronounced photoprotective 
effects of ‘ natural ’ and synthetic antioxidants when 
applied topically before UVR exposure. No signifi cant 
protective effect of melatonin and antioxidants (vita-
mins E and C), when applied either alone or in com-
bination, were observed when antioxidants were 
applied after UVR exposure even after multiple 
attempts. UVR-induced skin damage starts rapidly, 
and antioxidants effectively prevent such damage only 
when present in relevant concentrations, at the site of 
damage, and during the oxidative stress (20). Treat-
ment of the skin with antioxidants after the UVR dam-
age might cause additional harmful effects on cell 
cycle control and apoptosis process. The photoprotec-
tive effects of antioxidants are signifi cant when applied 
in distinct mixtures and in appropriate vehicles. Usage 
of topically applied creams/ointments with such com-
binations may improve antioxidative capacity of the 
skin due to sustained antioxidative synergism. UVA-
induced skin alterations are believed to be largely 
determined by oxidative processes, and topical admin-
istration of antioxidants might be particularly promis-
ing (21). However, delivery of topically applied 
antioxidants through the skin is hard since they must 
penetrate through the epidermal barrier to reach its 
site of action and they are very unstable, what makes 
them diffi cult to formulate. Antioxidants like tocoph-
erols, vitamin C, and fl avonoids are now being added 
as protective agents to the skin creams. However, their 
ability to penetrate deep into the skin is limited, and 
their amount in the dermis might be raised by 
 consuming them with the diet. 
 Usage of topical antioxidants is favored among 
dermatologists because of their broad biologic activ-
ity. Many are not only antioxidants but also possess 
anti-infl ammatory and anti-carcinogenic activities, 
and thus have many potential benefi ts. In general, 
topical antioxidants exert their effects by down- 
regulating free-radicals-mediated pathways that 
damage skin (22). 
 Endogenous oxidative stress could be infl uenced 
in two ways: by preventing ROS formation or by 
quenching ROS with antioxidants. Results of epide-
miological studies on healthy volunteers, who were 
treated with oral antioxidants, are inconclusive and 
even contradictory: from no effect to proven either 
benefi cial or harmful effect of oral antioxidant 
supplements. None of the major clinical studies, 
which used mortality or morbidity as an end point, 
proved positive effects of supplementation with oral 
antioxidants such as vitamin C, vitamin E or β - 
carotene. Some recent studies showed that therapy 
with antioxidants has no effect and can even increases 
mortality (23 – 33). The intake of only one antioxidant 
could alter the complex system of endogenous anti-
oxidative defence of cells or necrosis or apoptosis 
pathways. It is wrong to search the » redox magic bul-
let « among different compounds with increased redox 
potential. Better approach is to focus on detailed 
understanding of the complex redox system of human 
cells and to investigate the synergistic effects of dif-
ferent antioxidants on total oxidative stress. There are 
other methods to decrease oxidative stress, e.g. pre-
vention of free radical formation at fi rst instance 
(10). We have to realize that usage of synthetic vita-
min supplements is not an alternative to regular con-
sumption of fruits and vegetables. It is quite possible 
that many antioxidants are still undiscovered; fur-
thermore the combination of antioxidants in fruits 
and vegetables cause their reciprocal regeneration 
and consecutively intensifi es their defense from free 
radicals. However, defi ciency of vitamins B-12, folic 
acid, B-6, C or E, or iron or zinc appears to mimic 
radiation damage of DNA by causing single- and 
double-strand breaks, oxidative lesions or both. Evi-
dence is accumulating that a multivitamin/mineral 
supplement could improve the health of specifi c 
populations, e.g. poor, young, obese, elderly and 
people exposed to increased ROS from the environ-
ment, but the lack of suffi cient double-blind, multi-
centric studies does not permitrecommendations on 
systemic usage of antioxidants. Nevertheless, antiox-
idant-rich diets with fruits and vegetables can be 
recommended without any risk. It is important to 
mention that antioxidants as dietary supplements 
can protect in conditions of elevated oxidative stress 
and that they could be therapeutically effective in 
those individuals. On the other hand, presented evi-
dences show that synthetic antioxidant supplements 
cannot protect appropriately or entirely against oxi-
dative stress in situations where it is not increased 
and that their usage to prevent diseases or slow aging 
is controversial. 
 Conclusions 
 A wide variety of antioxidants or other phytochemi-
cals, such as licopene, coenzyme Q, glutathione, car-
nosine, selenium, zinc, biofl avonoids, green tea 
polyphenols, grape seed proanthocyanidins, resvera-
trol, silymarin, genistein, and others have been 
reported to possess substantial protective effects on 
UV-induced skin infl ammation, oxidative stress and 
DNA damage. 
 In order to determine oxidative stress in individu-
als, both, the ROS potential as well as the antioxidative 
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112 B. Poljsak et al. 
defense potential should be measured in blood or 
cytosol. Numerous in vitro antioxidational potential 
determinations exist that are easy to perform and 
largely used in screening. It is important to recognize 
oxidative imbalance in individuals early in order to 
prevent the long term oxidative and antioxidative 
stresses (12). These requirements should be consid-
ered when determining individuals ’ oxidative status 
before begining or ending the therapy with antioxi-
dants. Even better approach would be to monitor in 
vivo the oxidative stress in skin cells. Several tech-
niques exist to assess oxidative stress in the skin and 
many methods are currently under development, e.g. 
electron spin resonance, fl uorescence probes, cyclic 
voltammetry, but they are not routinely used (10). 
From the consumers point of view, they would be 
interested in the information regarding antioxidative 
potential of skin products. 
 There is no widely accepted and standardized 
method to evaluate antioxidative capacity of skin-
care products, like SPF rating system in sunscreens. 
ORAC (Oxygen Radical Absorbance Capacity) and 
ABEL-RAC (Analysis By Emitted Light-Relative 
Antioxidant Capacity) are both accepted worldwide 
as a standard measure of the antioxidative capacity 
of foods, and a similar rating system could be devel-
oped for the antioxidative capacity of skin-care prod-
ucts (34). Although many methods already exist for 
evaluation of skin-care cosmetic antioxidative capac-
ity, e.g. indirect spectorphotometric determination of 
a free radical DPPH or ABTS (34 – 36), they are not 
commercially available for skin-care products found 
on the market. The standardization and evaluation of 
antioxidative potential of skin-care products could 
help consumers to choose products with effective 
antioxidative properties. 
 Disclosures of interest: Authors have no fi nancial and 
confl ict of interests to disclose. The authors alone are 
responsible for the content and writing of the paper. 
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