ISRN DermatologyVolume 2013 (2013), Article ID 930164, 11 pageshttp://dx.doi.org/10.1155/2013/930164

Review Article

Skin Photoaging and the Role of Antioxidants in Its Prevention

Ruža Pandel,¹ Borut Poljšak,¹ Aleksandar Godic,2,3 and Raja Dahmane¹

¹Faculty of Health Studies, University of Ljubljana, Zdravstvena pot 5, 1000 Ljubljana, Slovenia²Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia³Department of Dermatology, Cambridge University Hospitals, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK

Received 9 July 2013; Accepted 7 August 2013

Academic Editors: E. Alpsoy, C.-C. Lan, and J. F. Val-Bernal

Copyright © 2013 Ruža Pandel et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Photoaging of the skin depends primarily on the degree of ultraviolet radiation (UVR) and on an amount of melanin in the skin (skin phototype). In addition to direct or indirect DNA damage, UVR activates cell surface receptors of keratinocytes and fibroblasts in the skin, which leads to a breakdown of collagen in the extracellular matrix and a shutdown of new collagen synthesis. It is hypothesized that dermal collagen breakdown is followed by imperfect repair that yields a deficit in the structural integrity of the skin, formation of a solar scar, and ultimately clinically visible skin atrophy and wrinkles. Many studies confirmed that acute exposure of human skin to UVR leads to oxidation of cellular biomolecules that could be prevented by prior antioxidant treatment and to depletion of endogenous antioxidants. Skin has a network of all major endogenous enzymatic and nonenzymatic protective antioxidants, but their role in protecting cells against oxidative damage generated by UV radiation has not been elucidated. It seems that skin’s antioxidative defence is also influenced by vitamins and nutritive factors and that combination of different antioxidants simultaneously provides synergistic effect.

1. Introduction

Unlike chronological aging, which is predetermined by individual’s physiological predisposition, photoaging depends primarily on the degree of sun exposure and on an amount of melanin in the skin. Individuals who have a history of intensive sun exposure, live in sunny geographical areas, and have fair skin will experience the greatest amount of ultraviolet radiation (UVR) skin load and consequently severe photoaging [1, 2]. Clinical signs of photoaging include wrinkles, mottled pigmentation (hypo- or hyperpigmentation), rough skin, loss of the skin tone, dryness, sallowness, deep furrows, severe atrophy, telangiectasias, laxity, leathery appearance, solar elastosis, actinic purpura, precancerous lesions, skin cancer, and melanoma [3, 4]. Sun-exposed areas of the skin, such as the face, neck, upper chest, hands, and forearms, are the sites where these changes occur most often [5]. Chronological skin aging, on the other hand, is characterized by laxity and fine wrinkles, as well as development of benign growths such as seborrheic keratoses and angiomas, but it is not associated with increased/decreased pigmentation or with deep wrinkles that are characteristic for photoaging [6]. Seborrheic keratoses are regarded as best biomarker of intrinsic skin aging since thier appearance is independent on sun exposure. While intrinsically aged skin does not show vascular damage, photodamaged skin does. Studies in humans and in the albino and hairless mice showed that acute and chronic UVB irradiation greatly increases skin vascularization and angiogenesis [7, 8]. The sun is the main source of UVR and the main contributor to the photoaging. UVC radiation (100 to 290 nm) is almost completely absorbed by the ozone layer and does not affect the skin. UVB (290 to 320 nm) affects the superficial layer of the skin (epidermis) and causes sunburns. It is the most intense between 10 am and 2 pm, during summer months, does not penetrate through the glass, and accounts for 70% of a person’s yearly average cumulative UVB dose. UVA (320 to 400 nm) was believed to have a minor effect on the skin, but studies showed that they penetrate deeper in the skin (e.g., about 20% at 365 nm), are more abundant in sunlight (95% of UVA and 5% of UVB), and therefore exhibit more severe damage [9, 10]. Significantly more photons in the UVA are needed to cause the same degree of damage compared to UVB since they are less energetic, but they are present in much higher quantities in sunlight and are more penetrant than in UVB [9]. Until recently, it has become evident that also infrared radiation (IR) could induce skin damage and contribute to the skin photoaging. While proton energy of IR is low, total amount of IR which reaches humans’ skin accounts approximately for 54% (compared to 5–7% of UV rays). Most of the IR lies within the IR-A band ( to 1440 nm), which represents approximately 30% of total solar energy, and penetrates human skin deeply compared to IR-B and IR-C, which only penetrate the upper skin layers. In comparison, IR-A penetrates the skin deeper than UV, and approximately 50% of it reaches the dermis. Molecular mechanisms of damaging effect of IR-A on the skin are attributed to induction of matrix mtalloproteinase-1, as well as to generation of reactive oxygen species (ROS). The exposure of human to environmental and artificial UVR has increased significantly in the last 50 years. This is due to an increased solar UVR as a consequence of the stratospheric ozone depletion, use of sunscreens, false believe of being well protected while exposed to sun for longer time, outdoor leisure activities, and prolonged life expectancy in industrialized countries [11].

2. Effects of UVR on Cells and Tissues

Studies in hairless mice demonstrated the carcinogenicity of UVR, with UVB being the most effective, followed by UVC and UVA [12]. UVB radiation is three to four orders of magnitude more effective than UVA. In none of the experiments it was possible to exclude completely a contribution of UVC, but the size of the effects observed indicate that they cannot be due to UVB alone [13]. People with a poor ability to tan, who burn easily, and have light eye and hair colour are at a higher risk of developing melanoma, basal-cell, and squamous-cell carcinomas. UVB most commonly causes cyclobutane pyrimidine dimmers. UVA, on the other hand, primarily causes DNA damage indirectly by the production of short-lived reactive oxygen species (ROS) such as singlet oxygen, superoxide, and H₂O₂ via endogenous photosensitizers. UVA radiation generates more phosphodiester bond breaks in DNA than would be expected by the total amount of energy directly absorbed by the DNA; therefore, it most likely causes indirect damage to DNA, which is caused by endogenous photosensitizers such as riboflavin, nicotinamide coenzymes, and rarely RNA bases [9]. Damage of the skin cells’ DNA is repaired by two different mechanisms: nucleotide excision repair (NER) and base excision repair (BER). The ROS-induced DNA damage is primarily repaired by the BER system and damage caused by direct influence of UVR on DNA by the NER system. DNA damage that can be induced by UVA radiation includes pyrimidine dimmers, single-strand breaks (both are critical in UVA radiation-induced cellular lethality), and perhaps more importantly DNA protein cross-links [14–17]. On the other hand, ROS can oxidize guanine in DNA to form 8-hydroxy-7,8-dihydroguanine (8-OHdG). The frequency of this characteristic mutation in human skin increases with cumulative sun exposure and could be used as an internal marker of cumulative sun exposure [18]. OH• can be added to guanine at positions 4, 5, and 8 (causing 8-OHdG) or undergoes opening of the imidazole ring, followed by one-electron reduction and protonation, to give 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPyG) [19]. Photoexcitation of cytosine and guanine may lead to the formation of relatively rare 6-hydroxy-5,6-dihydrocytosine and 8-oxo-7,8-dihydroguanine.

A second mechanism, which requires participation of endogenous photosensitizers and oxygen, causes most of the DNA damage generated by the UVA and visible light. Singlet oxygen is likely to be mostly involved in the formation of 8-oxo-7,8-dihydroguanine that was observed within both isolated and cellular DNA. It may be expected that oxidized purine together with DNA strand breaks and pyrimidine base oxidation products is also generated with a lower efficiency through Fenton type reactions [20]. The number of different DNA modifications that are capable of producing OH• appears to be over 100 [21].

Solar UVR induces a variety of photoproducts in DNA, including cyclobutane-type pyrimidine dimers, pyrimidine-pyrimidone (6-4) photoproducts, thymine glycols, cytosine damage, purine damage, DNA strand breaks, and DNA-protein cross links [22]. Substantial information on biological consequences is available only for the first two classes. Both are potentially cytotoxic and can lead to mutations in cultured cells, and there is evidence that cyclobutane-type pyrimidine dimers may be precarcinogenic lesions [13].

UVR also directly or indirectly initiates and activates a complex cascade of biochemical reactions in the human skin. Besides, the UV light-induced ROS interfere with signalling pathways. On a molecular level, UVR activates cell surface receptors of keratinocytes and fibroblasts in the skin, which initiates signal transduction cascades. This, in turn, leads to a variety of molecular changes, which causes a breakdown of collagen in the extracellular matrix and a shutdown of new collagen synthesis [23]. UV-induced liberation of ROS in human skin is responsible for stimulation of numerous signal transduction pathways via activation of cell surface cytokine and growth factor receptors. UVA or UVB induce activation (sometimes via peroxides or singlet O₂ as signalling molecules) of a wide range of transcription factors in skin cells, including factor activator protein-1 (AP-1) [10]. This can increase production of matrix metalloproteinases that can degrade collagen and other connective tissue components. For example, the UV light-induced ROS induce the transcription of AP-1. AP-1 induces upregulation of matrix metalloproteinases (MMPs) like collagenase-1 (MMP-1), stromelysin-1 (MMP-3), and gelatinase A (MMP-2), which specifically degrade connective tissue such as collagen and elastin and indirectly inhibit the collagen synthesis in the skin [24]. As indicated by their name, these zinc-dependent endopeptidases show proteolytic activity in their ability to degrade matrix proteins such as collagen and elastin [25]. Destruction of collagen is a hallmark of photoaging. The major enzyme responsible for collagen 1 digestion is matrix metalloproteinase-1 (MMP-1) [26]. Skin fibroblasts produce MMP-1 in response to UVB irradiation, and keratinocytes play a major role through an indirect paracrine mechanism involving the release of epidermal cytokine after UVB irradiation [27]. MMPs are produced in response to UVB irradiation in vivo and are considered to be involved in the changes in connective tissue that occur in photoaging [28]. They are associated with a variety of normal and pathological conditions that involve degradation and remodelling of the matrix [29–32]. UV rays and aging lead to excess proteolytic activity that disturbs the skin’s three-dimensional integrity [33]. These proteinases are important for breaking down the extracellular matrix during chronic wound repair, in which there is reepithelialization by keratinocyte migration. Thus, MMPs are continuously involved in the remodelling of the skin after chronic damage. Photodamage also results in the accumulation of abnormal elastin in the superficial dermis, and several MMPs have been implicated in this process [33]. ROS activate cytoplasmic signal transduction pathways in resident fibroblasts that are related to growth, differentiation, senescence, and connective tissue degradation [34]. ROS activate cytoplasmic signal transduction pathways that are related to growth differentiation, senescence, transformation and tissue degradation and cause permanent genetic changes in protooncogenes and tumour suppressor genes [35]. The study of Kang et al. [36] revealed that UVA/UVB irradiation of the skin causes generation of H₂O₂ within 15 minutes. AP-1, which leads to increased collagen breakdown, becomes elevated and remains elevated within 24 hours following UV irradiation [37]. Decreased procollagen synthesis within eight hours of UV irradiation was demonstrated [38]. Consequently, increased collagen breakdown was demonstrated [39]. It is hypothesized that dermal breakdown is followed by repair that, like all wound repair, is imperfect. Imperfect repair yields a deficit in the structural integrity of the dermis, a solar scar. Dermal degradation followed by imperfect repair is repeated with each intermittent exposure to ultraviolet irradiation, leading to accumulation of solar scarring and ultimately visible photoaging [40]. While it may seem that the signs of photoaging appear overnight, they actually lie invisible beneath the surface of the skin for years (Figure 1). UV exposure of the skin causes oxidative stress, leading to inflammatory reactions, such as acute erythema and chronic damage. Most problematic consequences of chronic damage include premature skin aging and skin cancer [41].

Figure 1: DermaView skin analyser accentuates areas of sun-damaged skin of the face.

3. Skin Antioxidants Protect against UVR

UVR exposure affects the skin antioxidants. Ascorbate, glutathione (GSH), superoxide dismutase (SOD), catalase, and ubiquinol are depleted in all layers of the UVB-exposed skin. Studies of cultured skin cells and murine skin in vivo have indicated that UVR-induced damage involves the generation of ROS and depletion of endogenous antioxidants [42]. In the study by Shindo et al. [43], enzymatic and nonenzymatic antioxidants in the epidermis and dermis and their responses to ultraviolet light of hairless mice were compared. Mice were exposed to solar light and subsequently examined for UV-induced damage of their skin. After irradiation, epidermal and dermal catalase and SOD activities were greatly decreased. Alpha-tocopherol, ubiquinol 9, ubiquinone 9, ascorbic acid, dehydroascorbic acid, and reduced GSH decreased in both epidermis and dermis by 26% to 93%. Oxidized GSH showed a slight nonsignificant increase. Because the reduction in total ascorbate and catalase was much more prominent in epidermis than dermis, the authors concluded that UV light is more damaging to the antioxidant defences in the epidermis than in the dermis. Many other studies confirmed that acute exposure of human skin to UVR in vivo leads to oxidation of cellular biomolecules that could be prevented by prior antioxidant treatment. There have been many studies performed where different antioxidants or combinations of antioxidants and different phytochemicals were tested in order to find evidence against ROS-induced damage. Some of them are presented in Tables 1 and 2.

Table 1: Exogenous antioxidants with photoprotective or damage protective effects.

Antioxidants
Outcome of the study
Study

Ascorbic acid
Topical vitamin C 5% cream applied for six months led to clinical improvement in the appearance of photoaged skin

Topical vitamin C stimulates the collagen-producing activity of the dermis

Magnesium ascorbyl phosphate administration immediately after exposure in hairless mice significantly delayed skin tumor formation and hyperplasia induced by chronic exposure to UV radiation
Elmore, 2005 [51]

Ascorbic acid was a photoprotectant when applied to mice and pig skin before exposure to ultraviolet (UV) radiation
Elmore, 2005 [51]

Vitamin E
UV-induced vitamin E depletion
Packer and Valacchi, 2002 [52]

The interaction of vitamin E with the eicosanoid system may result in an anti-inflammatory effect and thereby complement the photoprotective effects of other antioxidants in the skin
Boelsma et al., 2001 [53]

Vitamin E has skin barrier-stabilizing properties
Packer et al., 2001 [54]

Lycopene
UV light decreased skin lycopene concentrations more so than skin -carotene concentrations
Ribaya-Mercadoet al., 1995 [55]

Lycopene protects against UV-induced erythema in humans

Carotenoids (carotene, -carotene, and carotenoid mix)
Carotenoids are efficient in photoprotection, scavenging singlet oxygen, and peroxyl radicals. Supplements or a carotenoid-rich diet decreased sensitivity against UV-induced erythema
Sies and Stahl, 2004 [56]

Supplementation with carotenoids contributes to basal protection of the skin but is not sufficient to obtain complete protection against severe UV irradiation
Stahl and Krutmann, 2006 [57]

Dietary beta-carotene has effect on wrinkles and elasticity, procollagen gene expression, and ultraviolet (UV)-induced DNA damage in human skin
Cho et al., 2010 [58]

Erythema-protective effect of a carotenoid mix inhibited serum lipid peroxidation
Heinrich et al., 1998 [59]Heinrich et al., 2003 [60]Lee et al., 2000 [61]

Presupplementation with -carotene before and during sunlight exposure provides protection against sunburn
Gollnick et al., 1996 [62]

Inhibition of UV-induced epidermal damage and tumor formation in mouse models
Mathews-Roth and Krinsky, 1987 [63]

Tretinoin
Topical tretinoin ameliorates the clinical signs of photoaging
Cordero, 1983 [64]Kligman et al., 1986 [65]

The treatment of photodamaged skin with tretinoin increased collagen I formation.
Griffiths et al., 1993 [66]

Topical tretinoin is safe and effective in the treatment of photodamage
Gilchrest, 1997 [67]

Improvement in photodamaged skin
Weinstein et al., 1991 [68]

Topical tretinoin reduced the effects of photoaging
Voorhees, 1990 [69]

Topical tretinoin in combination with sun protection as a useful approach to the treatment of sun-damaged skin
Leyden, 1998 [70]

Coenzyme Q10 (CoQ10)
Topical application of CoQ10 has the beneficial effect of preventing photoaging
Hoppe et al., 1999 [71]

Coenzyme Q10 protects against oxidative stress-induced cell death and enhances the synthesis of basement membrane components in dermal and epidermal cells
Muta-Takada et al., 2009 [72]

CoQ10 was shown to reduce UVA-induced MMPs in cultured human dermal fibroblasts
Inui et al., 2008 [73]

Glutathione
Glutathione is a photoprotective agent in skin cells
Connor and Wheeler, 1987 [74]

Zinc
Zn-treated fibroblasts were more resistant to UVR than cells grown in normal medium
Richard et al., 1993 [75]

Zn can positively influence the effects of oxidative stress on cultured human retinal pigment epithelial (RPE) cells
Tate et al., 1999 [76]

Resveratrol
Application of resveratrol to the skin of hairless mice effectively prevented the UVB-induced increase in skin thickness and the development of the skin edema
Afaq and Mukhtar, 2002 [77]

Green tea
Green tea polyphenols were shown to reduce UV light-induced oxidative stress and immunosuppression
Katiyar et al., 2000 [78]

Topical treatment or oral consumption of green tea polyphenols (GTP) inhibits chemical carcinogen- or UV radiation-induced skin carcinogenesis in different laboratory animal models
Katiyar, 2003 [79]

Green tea or caffeine
Oral administration of green tea or caffeine in amounts equivalent to three or five cups of coffee per day to UVB-exposed mice increased levels of p53, slowed cell cycling, and increased apoptotic sun burn cells in the epidermis
Lu et al., 2008 [80]

Sylimarin
Silymarin strongly prevents both photocarcinogenesis and skin tumor promotion in mice
Singh and Agarwal, 2002 [81]

Skin cancer chemopreventive effects
Ahmad et al., 1998 [82]

Genistein
Antioxidant and anticarcinogenic effects on skin
Wei et al., 1995 [83]

Cocoa
Dietary flavanols from cocoa contribute to endogenous photoprotection, improve dermal blood circulation, and affect cosmetically relevant skin surface and hydration variables
Heinrich et al., 2006 [84]

Photoprotection against UV-induced erythema
Heinrich et al., 2006 [84]

Table 2: Exogenous antioxidant’s mixtures with photoprotective or damage protective effects.

Antioxidant mixtures
Outcome of the study
Study

Oral vitamin E and beta-carotene supplementation
Ultraviolet radiation-induced oxidative stress in human skin
McArdle et al., 2004 [85]

Carotenoids and tocopherols
Scavenging reactive oxygen species generated during photooxidative stress
Stahl et al., 2000 [86]

Beta-carotene, lutein, and lycopene
UV irradiation induced intensity of erythema was diminished
Albanes et al., 1996 [87]

Tomato extract and a drink containing solubilized Lyc-o-Mato
Reduction in erythema formation following UV irradiation
Aust et al., 2005 [88]

Quercetin, hesperetin and naringenin
Protective agents in certain skin diseases caused, initiated, or exacerbated by sunlight irradiation
Bonina et al., 1996 [89]

-Tocopherol and ascorbate
MEDs increased markedly after intake of the combination of -tocopherol and ascorbate
Fuchs and Kern, 1998 [45]

Combination of vitamins C and E
Mean MEDs increased in group receiving vitamins compared with baseline
Eberlein-Konig et al., 1998 [90]

Vitamin C, vitamin E, lycopene, beta-carotene, the rosemary polyphenol, and carnosic acid
Vitamin C, vitamin E, and carnosic acid showed photoprotective potential human dermal fibroblasts exposed to ultraviolet-A (UVA)
Offord et al., 2002 [91]

Lycopene, beta-carotene, alpha-tocopherol, and selenium
Many parameters of the epidermal defense against UV-induced damage were significantly improved
Csarini et al., 2003 [92]

-Carotene, lycopene, tocopherol, and ascorbic acid
Significant increase of melanin concentrations in skin was found
Postaire et al., 1997 [93]

Carotenoids (beta-carotene and lycopene), vitamins C and E, selenium, and proanthocyanidins
A selective protection of the skin against irradiation was confirmed
Greul et al., 2002 [94]

4. Endogenous Skin Antioxidants

Skin has a network of protective antioxidants. They include endogenous enzymatic antioxidants such as GSH peroxidase (GPx), SOD, and catalase and nonenzymatic low-molecular-weight antioxidants such as vitamin E isoforms, vitamin C, GSH, uric acid, and ubiquinol [43]. All the major antioxidant enzymes are present in the skin, but their roles in protecting cells against oxidative damage generated by UV radiation have not been elucidated. In response to the attack of ROS, the skin has developed a complex antioxidant defence system including, among others, the manganese-superoxide dismutase (MnSOD). MnSOD is the mitochondrial enzyme that disposes of superoxide generated by respiratory chain activity. Of all electrons passing down the mitochondrial respiratory chain, it is estimated that 1% to 2% are diverted to form superoxide (although recent studies claim that this amount is even less); thus, production of hydrogen peroxide occurs at a constant rate due to MnSOD activity. MnSOD dismutates the superoxide anion () derived from the reduction of molecular oxygen to hydrogen peroxide (H₂O₂), which is detoxified by GSH peroxidase to water and molecular oxygen. The study of Poswig et al. [44] revealed that adaptive antioxidant response of MnSOD following repetitive UVA irradiation can be induced. The authors provide evidence for the increasing induction of MnSOD upon repetitive UVA irradiation that may contribute to the effective adaptive UVA response of the skin during light hardening in phototherapy. The study of Fuchs and Kern showed that acute UV exposures lead also to changes in GSH reductase and catalase activity in mouse skin but insignificant changes in SOD and GSH peroxidase [45]. The study of Sander et al. [46] confirmed that chronic and acute photodamage is mediated by depleted antioxidant enzyme expression and increased oxidative protein modifications. Biopsies from patients with histologically confirmed solar elastosis, from non-ultraviolet-exposed sites of age-matched controls, and from young subjects were analysed. The antioxidant enzymes catalase, copper-zinc superoxide dismutase, MnSOD, and protein carbonyls were investigated. Whereas overall expression of antioxidant enzymes was very high in the epidermis, low baseline levels were found in the dermis. In photoaged skin, a significant depletion of antioxidant enzyme expression was observed within the stratum corneum and in the epidermis. Importantly, an accumulation of oxidatively modified proteins was found specifically within the upper dermis of photoaged skin. Upon acute ultraviolet exposure of healthy subjects, depleted catalase expression and increased protein oxidation were detected. Exposures of keratinocytes and fibroblasts to UVB, UVA, and H₂O₂ led to dose-dependent protein oxidation confirming in vivo results.

Not all skin cells are exposed to the same level of oxidative stress. It was found that keratinocytes utilize as much oxygen as fibroblasts, even though maximal activities of the respiratory chain complexes are two- to five-fold lower, whereas expression of respiratory chain proteins is similar. Superoxide anion levels are much higher in keratinocytes, and keratinocytes display much higher lipid peroxidation level and a lower reduced glutathione/oxidized glutathione ratio [47].

It can be concluded that oxidative stress is a problem of skin cells and that endogenous as well as exogenous antioxidants could play an important role in decreasing it.

5. Compounds Derived from the Diet with Photoaging/Damage Protective Effects

Natural antioxidants are generally considered to be beneficial fruit and vegetable components. It seems that skin’s antioxidative defence is also influenced by nutritive factors. Besides vitamins A, C, and E, η-3 fatty acids certain nonvitamin plant-derived ingredients might have beneficial effect on skin aging, skin sun protection, or skin cancer. The laboratory studies conducted in animal models suggest that many plant compounds have the ability to protect the skin from the adverse effects of UVR. The proliferation of products, however, can cause confusion among consumers, who often ask their dermatologists for advice as to which antiaging products they should choose. Ideally, the antiaging claims of cosmeceutical formulations and their components should be demonstrated in controlled clinical trials [48], but there is a lack of such studies due to their high costs. Since cosmeceutical products are claiming that they therapeutically affect the structure and function of the skin, it is rational and necessary to hold them to specified scientific standards that substantiate efficacy claims [49].

Many studies have found that vitamin C can increase collagen production, protect against damage from UVA and UVB rays, correct pigmentation problems, and improve inflammatory skin conditions [50] (Table 1).

Topical retinoids remain the mainstay for treating photoaging given their proven efficacy in both clinical and histological outcomes. The application of retinoids might not only clinically and biochemically repair photoaged skin, but their use might also prevent photoaging [102]. Retinoid-mediated improvement of photoaging is associated with increased collagen I synthesis [103], reorganization of packed collagen fibres [104], and increased number of type VII anchoring fibrils [105]. However, up to 92% of subjects who used tretinoin in various clinical studies have reported “retinoid dermatitis,” that is, erythema and scaling at the site of application [106, 107]. Irritation can be minimized by reducing dose and frequency of treatments.

It seems that the biochemistry of CoQ10 may inhibit the production of IL-6, which stimulates fibroblasts in dermis by paracrine manner to upregulate MMPs production, and contribute to protecting dermal fibrous components from degradation, leading to rejuvenation of wrinkled skin [108]. It was reported that CoQ10 strongly inhibits oxidative stress in the skin induced by UVB via increasing SOD2 and GPx [109]. It was reported that it is considered that CoQ10 appears to have also a cutaneous healing effect in vivo [110].

Green tea polyphenols have received attention as protective agents against UV-induced skin damage. Analysis of published studies demonstrates that green tea polyphenols have anti-inflammatory and anticarcinogenic as well as anti-aging properties. These effects appear to correlate with antioxidant properties of green tea polyphenols, which could be used as new photoprotection agents (Table 1).

A number of experimental studies indicate protective effects of beta-carotene against acute and chronic manifestations of skin photodamage. However, most clinical studies have failed to convincingly demonstrate its beneficial effects so far. Studies on skin cells in culture have revealed that beta-carotene acts not only as an antioxidant but also has unexpected prooxidant properties [111]. For this reason, further studies with focus on in vivo β-carotene-induced prooxidative properties and its relevance on human health are needed. Another problem represents the dosage. Although studies convincingly showed that vitamin supplementation effectively protects the skin against sunburn, the doses of vitamins used were generally much higher than amounts generally ingested from habitual diets [112]. Additionally, it was shown that the combination of different antioxidants applied simultaneously can provide a synergistic effect [50]. Antioxidants are most effective when used in combination (Table 2). Vitamin C regenerates vitamin E, and selenium and niacin are required to keep glutathione in its active form. It has been demonstrated that vitamin C can regenerate α-tocopherol from its chromanoxyl radical [113] and that the vitamin C radical may be recycled by GSH nonenzymatically under slightly acidic conditions [114] that are present in the stratum corneum [115]. Werninghaus et al. [116] reported that vitamin E given orally at 400 IU/day for a period of six months affords no significant increase in UV protection. Similarly, in a study with 12 volunteers, vitamin C given at 500 mg/day over eight weeks had no effect on the UV-induced erythemal response [85], indicating again the importance of antioxidants to be supplemented together to obtain the synergistic effect.

6. Conclusion

Studies (usually performed on skin cells in vitro or on animal models) suggest that oral uptake of selected micronutrients and phytochemicals can provide photoprotection of human skin [117]. Nevertheless, photoprotection can only be achieved if an optimal pharmacological dose range is reached in the human skin due to well-known prooxidative reactions of antioxidants, for example, in the case of excessive carotenoid concentrations (Table 3). Nevertheless, research is continuously demonstrating that various phytopharmaceuticals offer significant protection against different diseases and skin aging. The primary treatment of photoaging is photoprotection, but secondary treatment could be achieved with the use of antioxidants and some novel compounds such as polyphenols. Exogenous antioxidants like vitamin C, E, and many others cannot be synthesized by the human body and must be taken up by the diet.

Table 3: Exogenous antioxidants with no protective/beneficial effects.

Antioxidant
Outcome of the study (nonbeneficial results)
Study

Lycopene
Lycopene enhances UVA-induced oxidative stress in C3H cells
Yeh et al., 2005 [95]

Carotenoids
Carotenoids were not protective against DNA lesions repairable by excision repair
Wolf et al., 1988 [96]

No significant change in the intensity of erythema; no effects of supplementation
Garmyn et al., 1995 [97]

No significant difference between the beta-carotene and placebo groups in incidence of cancer
Green et al., 1999 [98]

No significant effect of -carotene on either number or time of occurrence of new nonmelanoma skin cancer
Greenberg et al., 1990 [99]

An average of 12 years of supplementation with beta-carotene does not affect the development of a first NMSC
Frieling et al., 2000 [100]

Supplementation with -carotene produced no reduction of the incidence of malignant neoplasms
Hennekens et al., 1996 [101]

References

G. J. Fisher, S. Kang, J. Varani et al., “Mechanisms of photoaging and chronological skin aging,” Archives of Dermatology, vol. 138, no. 11, pp. 1462–1470, 2002.

L. H. Kligman and A. M. Kligman, “The nature of photoaging: its prevention and repair,” Photodermatology, vol. 3, no. 4, pp. 215–227, 1986.

M. Yaar, M. S. Eller, and B. A. Gilchrest, “Fifty years of skin aging,” Journal of Investigative Dermatology Symposium Proceedings, vol. 7, no. 1, pp. 51–58, 2002.

B. A. Gilchrest, “Skin aging and photoaging,” Dermatology Nursing, vol. 2, no. 2, pp. 79–82, 1990.

Y. R. Helfrich, D. L. Sachs, and J. J. Voorhees, “Overview of skin aging and photoaging,” Dermatology Nursing, vol. 20, no. 3, pp. 177–184, 2008.

M. Yaar, M. S. Lee, T. M. Rünger, M. S. Eller, and B. Gilchrest, “Telomere mimetic oligonucleotides protect skin cells from oxidative damage,” Annales de Dermatologie et de Vénéréologie, vol. 129, pp. 1–18, 2002.

D. R. Bielenberg, C. D. Bucana, R. Sanchez, C. K. Donawho, M. L. Kripke, and I. J. Fidler, “Molecular regulation of UVB-induced cutaneous angiogenesis,” Journal of Investigative Dermatology, vol. 111, no. 5, pp. 864–872, 1998.

K. Yano, H. Oura, and M. Detmar, “Targeted overexpression of the angiogenesis inhibitor thrombospondin-1 in the epidermis of transgenic mice prevents ultraviolet-B-induced angiogenesis and cutaneous photo-damage,” Journal of Investigative Dermatology, vol. 118, no. 5, pp. 800–805, 2002.

L. E. Laurent-Applegate and S. Schwarzkopf, “Photooxidative stress in skin and regulation of gene expression,” in Environmental Stressors in Health and Disease, J. Fuchs and L. Packer, Eds., Marcel Dekker, New York, NY, USA, 2001.

B. Halliwell and J. Gutteridge, Free Radicals in Biology and Medicine, Oxford University Press, New York, NY, USA, 4th edition, 2007.

S. Grether-Beck, M. Wlaschek, J. Krutmann, and K. Scharffetter-Kochanek, “Photodamage and photoaging—prevention and treatment,” Journal der Deutschen Dermatologischen Gesellschaft, vol. 3, no. 2, pp. S19–S25, 2005.

W. A. Bruls, H. Slaper, J. C. van der Leun, and L. Berrens, “Transmission of human epidermis and stratum corneum as a function of thickness in the ultraviolet and visible wavelengths,” Photochemistry and Photobiology, vol. 40, no. 4, pp. 485–494, 1984.

International Agency for Research on Cancer (IARC), “Summaries & Evaluations, Solar and ultraviolet radiation,” vol. 55, 1992, http://monographs.iarc.fr/ENG/Monographs/vol55/volume55.pdf

M. J. Peak, J. G. Peak, and C. A. Jones, “Different (direct and indirect) mechanisms for the induction of DNA-protein crosslinks in human cells by far- and near-ultraviolet radiations (290 and 405 nm),” Photochemistry and Photobiology, vol. 42, no. 2, pp. 141–146, 1985.

M. J. Peak, J. G. Peak, and B. A. Carnes, “Induction of direct and indirect single-strand breaks in human cell DNA by far- and near-ultraviolet radiations: action spectrum and mechanisms,” Photochemistry and Photobiology, vol. 45, no. 3, pp. 381–387, 1987.

J. G. Peak, M. J. Peak, R. S. Sikorski, and C. A. Jones, “Induction of DNA-protein crosslinks in human cells by ultraviolet and visible radiations: action spectrum,” Photochemistry and Photobiology, vol. 41, no. 3, pp. 295–302, 1985.

B. S. Rosenstein and J. M. Ducore, “Induction of DNA strand breaks in normal human fibroblasts exposed to monochromatic ultraviolet and visible wavelengths in the 240–546 nm range,” Photochemistry and Photobiology, vol. 38, no. 1, pp. 51–55, 1983.

D. B. Yarosh, “DNA damage and repair in skin aging,” in Textbook of Aging Skin, M. A. Farage, K. W. Miller, and H. I. Maibach, Eds., Springer, Berlin, Germany, 2010.

B. Halliwell and J. Gutteridge, Free Radicals in Biology and Medicine, Clarendon Press, Oxford, UK, 3rd edition, 1999.

J. Cadet, M. Berger, T. Douki et al., “Effects of UV and visible radiation on DNA—final base damage,” Biological Chemistry, vol. 378, no. 11, pp. 1275–1286, 1997.

F. Hutchinson, “Chemical changes induced in DNA by ionizing radiation,” Progress in Nucleic Acid Research and Molecular Biology, vol. 32, no. C, pp. 115–154, 1985.

H. Patrick and R. O. Rahn, “Photochemistry of DNA and polynucleotides: photoproducts,” in Photochemistry and Photobiology of Nucleic Acids, S. Y. Wang, Ed., vol. 2, pp. 35–95, Academic Press, New York, NY, USA, 1976.

G. J. Fisher, “The pathophysiology of photoaging of the skin,” Cutis, vol. 75, no. 2, pp. 5–9, 2005.

C. Rasche and P. Elsner, “Skin aging: a brief summary of characteristic changes,” in Textbook of Aging Skin, M. A. Ferage, K. W. Miller, and H. I. Maibach, Eds., Springer, Berlin, Germany, 2010.

J. Krutman and B. A. Gilchrest, “Photoaging of skin,” in Skin Aging, B. Gilchrest and J. Krutmann, Eds., Springer, Berlin, Germany, 2006.

K. K. Dong, N. Damaghi, S. D. Picart et al., “UV-induced DNA damage initiates release of MMP-1 in human skin,” Experimental Dermatology, vol. 17, no. 12, pp. 1037–1044, 2008.

D. Fagot, D. Asselineau, and F. Bernerd, “Direct role of human dermal fibroblasts and indirect participation of epidermal keratinocytes in MMP-1 production after UV-B irradiation,” Archives of Dermatological Research, vol. 293, no. 11, pp. 576–583, 2002.

J. Brinckmann, Y. Acil, H. H. Wolff, and P. K. Muller, “Collagen synthesis in (sun-)aged human skin and in fibroblasts derived from sun-exposed and sun-protected body sites,” Journal of Photochemistry and Photobiology B, vol. 27, no. 1, pp. 33–38, 1995.

R. A. Greenwald, S. Zucker, and L. M. Golub, Inhibition of Matrix Metalloproteinases: Therapeutic Applications, New York Academy of Sciences, New York, NY, USA, 1999.

L. J. McCawley and L. M. Matrisian, “Matrix metalloproteinases: multifunctional contributors to tumor progression,” Molecular Medicine Today, vol. 6, no. 4, pp. 149–156, 2000.

L. J. McCawley and L. M. Matrisian, “Matrix metalloproteinases: they're not just for matrix anymore!,” Current Opinion in Cell Biology, vol. 13, no. 5, pp. 534–540, 2001.

G. Smutzer and P. Billings, “Molecular demolition,” The Scientist, vol. 16, no. 4, pp. 34–36, 2002.

C. Rocquet and F. Bonté, “Molecular aspects of skin ageing: recent data,” Acta Dermatovenerologica Alpina, Pannonica et Adriatica, vol. 11, no. 3, pp. 71–94, 2002.

K. Scharffetter-Kochanek, P. Brenneisen, J. Wenk et al., “Photoaging of the skin from phenotype to mechanisms,” Experimental Gerontology, vol. 35, no. 3, pp. 307–316, 2000.

K. Scharffetter-Kochanek, M. Wlaschek, P. Brenneisen, M. Schauen, R. Blaudschun, and J. Wenk, “UV-induced reactive oxygen species in photocarcinogenesis and photoaging,” Biological Chemistry, vol. 378, no. 11, pp. 1247–1257, 1997.

S. Kang, J. H. Chung, J. H. Lee et al., “Topical n-acetyl cysteine and genistein prevent ultraviolet-light-induced signaling that leads to photoaging in human skin in vivo,” Journal of Investigative Dermatology, vol. 120, no. 5, pp. 835–841, 2003.

G. J. Fisher, S. C. Datta, H. S. Talwar et al., “Molecular basis of sun-induced premature skin ageing and retinoid antagonism,” Nature, vol. 379, no. 6563, pp. 335–339, 1996.

T. Quan, T. He, S. Kang, J. J. Voorhees, and G. J. Fisher, “Ultraviolet irradiation alters transforming growth factor β/Smad pathway in human skin in vivo,” Journal of Investigative Dermatology, vol. 119, no. 2, pp. 499–506, 2002.

G. J. Fisher, Z. Wang, S. C. Datta, J. Varani, S. Kang, and J. J. Voorhees, “Pathophysiology of premature skin aging induced by ultraviolet light,” The New England Journal of Medicine, vol. 337, no. 20, pp. 1419–1428, 1997.

G. J. Fisher and J. J. Voorhees, “Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo,” Journal of Investigative Dermatology Symposium Proceedings, vol. 3, no. 1, pp. 61–68, 1998.

C. Oresajo, M. Yatskayer, A. Galdi, P. Foltis, and S. Pillai, “Complementary effects of antioxidants and sunscreens in reducing UV-induced skin damage as demonstrated by skin biomarker expression,” Journal of Cosmetic and Laser Therapy, vol. 12, no. 3, pp. 157–162, 2010.

F. McArdle, L. E. Rhodes, R. Parslew, C. I. A. Jack, P. S. Friedmann, and M. J. Jackson, “UVR-induced oxidative stress in human skin in vivo: effects of oral vitamin C supplementation,” Free Radical Biology and Medicine, vol. 33, no. 10, pp. 1355–1362, 2002.

Y. Shindo, E. Witt, and L. Packer, “Antioxidant defense mechanisms in murine epidermis and dermis and their responses to ultraviolet light,” Journal of Investigative Dermatology, vol. 100, no. 3, pp. 260–265, 1993.

A. Poswig, J. Wenk, P. Brenneisen et al., “Adaptive antioxidant response of manganese-superoxide dismutase following repetitive UVA irradiation,” Journal of Investigative Dermatology, vol. 112, no. 1, pp. 13–18, 1999.

J. Fuchs and H. Kern, “Modulation of UV-light-induced skin inflammation by D-alpha-tocopherol and L-ascorbic acid: a clinical study using solar simulated radiation,” Free Radical Biology and Medicine, vol. 25, no. 9, pp. 1006–1012, 1998.

C. S. Sander, H. Chang, S. Salzmann et al., “Photoaging is associated with protein oxidation in human skin in vivo,” Journal of Investigative Dermatology, vol. 118, no. 4, pp. 618–625, 2002.

T. Blatt, H. Wenck, and K. P. Wittern, “Alterations of energy metabolism in cutaneous aging,” in Textbook of Aging Skin, M. A. Farage, K. W. Miller, and H. I. Maibach, Eds., Springer, Berlin, Germany, 2010.

S. Bruce, “Cosmeceuticals for the attenuation of extrinsic and intrinsic dermal aging,” Journal of Drugs in Dermatology, vol. 7, no. 2, supplement, pp. s17–s22, 2008.

J. Levin, J. Q. del Rosso, and S. B. Momin, “How much do we really know about our favorite cosmeceutical ingredients?” Journal of Clinical and Aesthetic Dermatology, vol. 3, no. 2, pp. 22–41, 2010.

B. Poljsak, Skin Aging, Antioxidants and Free Radicals, Nova Science, New York, NY, USA, 2012.

A. R. Elmore, “Final report 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,” International Journal of Toxicology, vol. 24, no. 2, pp. 51–111, 2005.

L. Packer and G. Valacchi, “Antioxidants and the response of skin to oxidative stress: vitamin E as a key indicator,” Skin Pharmacology and Applied Skin Physiology, vol. 15, no. 5, pp. 282–290, 2002.

E. Boelsma, H. F. J. Hendriks, and L. Roza, “Nutritional skin care: health effects of micronutrients and fatty acids,” American Journal of Clinical Nutrition, vol. 73, no. 5, pp. 853–864, 2001.

L. Packer, S. U. Weber, and G. Rimbach, “Molecular aspects of α-tocotrienol antioxidant action and cell signalling,” Journal of Nutrition, vol. 131, no. 2, pp. 369S–373S, 2001.

J. D. Ribaya-Mercado, M. Garmyn, B. A. Gilchrest, and R. M. Russell, “Skin lycopene is destroyed preferentially over β-carotene during ultraviolet irradiation in humans,” Journal of Nutrition, vol. 125, no. 7, pp. 1854–1859, 1995.

H. Sies and W. Stahl, “Carotenoids and UV protection,” Photochemical and Photobiological Sciences, vol. 3, no. 8, pp. 749–752, 2004.

W. Stahl and J. Krutmann, “Systemic photoprotection through carotenoids,” Hautarzt, vol. 57, no. 4, pp. 281–285, 2006.

S. Cho, D. H. Lee, C.-H. Won et al., “Differential effects of low-dose and high-dose beta-carotene supplementation on the signs of photoaging and type I procollagen gene expression in human skin in vivo,” Dermatology, vol. 221, no. 2, pp. 160–171, 2010.

U. Heinrich, M. Wiebusch, and H. Tronnier, “Photoprotection from ingested carotenoids,” Cosmetics & Toiletries, vol. 113, pp. 61–70, 1998.

U. Heinrich, C. Gärtner, M. Wiebusch et al., “Supplementation with β-carotene or a similar amount of mixed carotenoids protects humans from UV-induced erythema,” Journal of Nutrition, vol. 133, no. 1, pp. 98–101, 2003.

J. Lee, S. Jiang, N. Levine, and R. R. Watson, “Carotenoid supplementation reduces erythema in human skin after simulated solar radiation exposure,” Proceedings of the Society for Experimental Biology and Medicine, vol. 223, no. 2, pp. 170–174, 2000.

H. P. M. Gollnick, W. Hopfenmüller, C. Hemmes et al., “Systemic beta carotene plus topical UV-sunscreen are an optimal protection against harmful effects of natural UV-sunlight: results of the Berlin-Eilath study,” European Journal of Dermatology, vol. 6, no. 3, pp. 200–205, 1996.

M. M. Mathews-Roth and N. I. Krinsky, “Carotenoids affect development of UV-B induced skin cancer,” Photochemistry and Photobiology, vol. 46, no. 4, pp. 507–509, 1987.

A. Cordero Jr., “La vitamina a acida en la piel senile,” Actualizaciones Ter Dermatologica, vol. 6, pp. 49–54, 1983.

A. M. Kligman, G. L. Grove, R. Hirose, and J. J. Leyden, “Topical tretinoin for photoaged skin,” Journal of the American Academy of Dermatology, vol. 15, no. 4, pp. 836–859, 1986.

C. E. M. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” The New England Journal of Medicine, vol. 329, no. 8, pp. 530–535, 1993.

B. A. Gilchrest, “Treatment of photodamage with topical tretinoin: an overview,” Journal of the American Academy of Dermatology, vol. 36, no. 3, part 2, pp. S27–S36, 1997.

G. D. Weinstein, T. P. Nigra, P. E. Pochi et al., “Topical tretinoin for treatment of photodamaged skin: a multicenter study,” Archives of Dermatology, vol. 127, no. 5, pp. 659–665, 1991.

J. J. Voorhees, “Clinical effects of long-term therapy with topical tretinoin and cellular mode of action,” Journal of International Medical Research, vol. 18, no. 3, pp. 26C–28C, 1990.

J. J. Leyden, D. F. Heffel, and T. A. Miller, “Treatment of photodamaged skin with topical tretinoin: an update,” Plastic and Reconstructive Surgery, vol. 102, no. 5, pp. 1672–1675, 1998.

U. Hoppe, J. Bergemann, W. Diembeck et al., “Coenzyme Q₁₀, a cutaneous antioxidant and energizer,” BioFactors, vol. 9, no. 2-4, pp. 371–378, 1999.

K. Muta-Takada, T. Terada, H. Yamanishi et al., “Coenzyme Q₁₀ protects against oxidative stress-induced cell death and enhances the synthesis of basement membrane components in dermal and epidermal cells,” BioFactors, vol. 35, no. 5, pp. 435–441, 2009.

M. Inui, M. Ooe, K. Fujii, H. Matsunaka, M. Yoshida, and M. Ichihashi, “Mechanisms of inhibitory effects of CoQ₁₀ on UVB-induced wrinkle formation in vitro and in vivo,” BioFactors, vol. 32, no. 1-4, pp. 237–243, 2008.

M. J. Connor and L. A. Wheeler, “Depletion of cutaneous glutathione by ultraviolet radiation,” Photochemistry and Photobiology, vol. 46, no. 2, pp. 239–245, 1987.

M.-J. Richard, P. Guiraud, M.-T. Leccia, J.-C. Beani, and A. Favier, “Effect of zinc supplementation on resistance of cultured human skin fibroblasts toward oxidant stress,” Biological Trace Element Research, vol. 37, no. 2-3, pp. 187–199, 1993.

D. J. Tate Jr., M. V. Miceli, and D. A. Newsome, “Zinc protects against oxidative damage in cultured human retinal pigment epithelial cells,” Free Radical Biology and Medicine, vol. 26, no. 5-6, pp. 704–713, 1999.

F. Afaq and H. Mukhtar, “Photochemoprevention by botanical antioxidants,” Skin Pharmacology and Applied Skin Physiology, vol. 15, no. 5, pp. 297–306, 2002.

S. K. Katiyar, N. Ahmad, and H. Mukhtar, “Green tea and skin,” Archives of Dermatology, vol. 136, no. 8, pp. 989–994, 2000.

S. K. Katiyar, “Skin photoprotection by green tea: antioxidant and immunomodulatory effects,” Current drug targets. Immune, endocrine and metabolic disorders, vol. 3, no. 3, pp. 234–242, 2003.

Y.-P. Lu, Y.-R. Lou, Q.-Y. Peng, J.-G. Xie, P. Nghiem, and A. H. Conney, “Effect of caffeine on the ATR/Chk1 pathway in the epidermis of UVB-irradiated mice,” Cancer Research, vol. 68, no. 7, pp. 2523–2529, 2008.

R. P. Singh and R. Agarwal, “Flavonoid antioxidant silymarin and skin cancer,” Antioxidants and Redox Signaling, vol. 4, no. 4, pp. 655–663, 2002.

N. Ahmad, H. Gali, S. Javed, and R. Agarwal, “Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression,” Biochemical and Biophysical Research Communications, vol. 247, no. 2, pp. 294–301, 1998.

H. Wei, R. Bowen, Q. Cai, S. Barnes, and Y. Wang, “Antioxidant and antipromotional effects of the soybean isoflavone genistein,” Proceedings of the Society for Experimental Biology and Medicine, vol. 208, no. 1, pp. 124–130, 1995.

U. Heinrich, K. Neukam, H. Tronnier, H. Sies, and W. Stahl, “Long-term ingestion of high flavanol cocoa provides photoprotection against UV-induced erythema and improves skin condition in women,” Journal of Nutrition, vol. 136, no. 6, pp. 1565–1569, 2006.

F. McArdle, L. E. Rhodes, R. A. G. Parslew et al., “Effects of oral vitamin E and β-carotene supplementation on ultraviolet radiation-induced oxidative stress in human skin,” American Journal of Clinical Nutrition, vol. 80, no. 5, pp. 1270–1275, 2004.

W. Stahl, U. Heinrich, H. Jungmann, H. Sies, and H. Tronnier, “Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in humans,” American Journal of Clinical Nutrition, vol. 71, no. 3, pp. 795–798, 2000.

D. Albanes, O. P. Heinonen, P. R. Taylor et al., “α-tocopherol and β-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base- line characteristics and study compliance,” Journal of the National Cancer Institute, vol. 88, no. 21, pp. 1560–1570, 1996.

O. Aust, W. Stahl, H. Sies, H. Tronnier, and U. Heinrich, “Supplementation with tomato-based products increases lycopene, phytofluene, and phytoene levels in human serum and protects against UV-light-induced erythema,” International Journal for Vitamin and Nutrition Research, vol. 75, no. 1, pp. 54–60, 2005.

F. Bonina, M. Lanza, L. Montenegro et al., “Flavonoids as potential protective agents against photo-oxidative skin damage,” International Journal of Pharmaceutics, vol. 145, no. 1-2, pp. 87–94, 1996.

B. Eberlein-Konig, M. Placzek, and B. Przybilla, “Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-α-tocopherol (vitamin E),” Journal of the American Academy of Dermatology, vol. 38, no. 1, pp. 45–48, 1998.

E. A. Offord, J.-C. Gautier, O. Avanti et al., “Photoprotective potential of lycopene, β-carotene, vitamin E, vitamin C and carnosic acid in UVA-irradiated human skin fibroblasts,” Free Radical Biology and Medicine, vol. 32, no. 12, pp. 1293–1303, 2002.

J. P. Césarini, L. Michel, J. M. Maurette, H. Adhoute, and M. Béjot, “Immediate effects of UV radiation on the skin: modification by an antioxidant complex containing carotenoids,” Photodermatology Photoimmunology and Photomedicine, vol. 19, no. 4, pp. 182–189, 2003.

E. Postaire, H. Jungmann, M. Bejot, U. Heinrich, and H. Tronnier, “Evidence for antioxidant nutrients-induced pigmentation in skin: results of a clinical trial,” Biochemistry and Molecular Biology International, vol. 42, no. 5, pp. 1023–1033, 1997.

A.-K. Greul, J.-U. Grundmann, F. Heinrich et al., “Photoprotection of UV-irradiated human skin: an antioxidative combination of vitamins E and C, carotenoids, selenium and proanthocyanidins,” Skin Pharmacology and Applied Skin Physiology, vol. 15, no. 5, pp. 307–315, 2002.

S.-L. Yeh, C.-S. Huang, and M.-L. Hu, “Lycopene enhances UVA-induced DNA damage and expression of heme oxygenase-1 in cultured mouse embryo fibroblasts,” European Journal of Nutrition, vol. 44, no. 6, pp. 365–370, 2005.

C. Wolf, A. Steiner, and H. Honingsmann, “Do oral carotenoids protect human skin against ultraviolet erythema, psoralen phototoxicity, and ultraviolet-induced DNA damage?” Journal of Investigative Dermatology, vol. 90, no. 1, pp. 55–57, 1988.

M. Garmyn, J. D. Ribaya-Mercado, R. M. Russel, J. Bhawan, and B. A. Gilchrest, “Effect of beta-carotene supplementation on the human sunburn reaction,” Experimental Dermatology, vol. 4, no. 2, pp. 104–111, 1995.

A. Green, G. Williams, R. Neale et al., “Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squamous-cell carcinomas of the skin: a randomised controlled trial,” Lancet, vol. 354, no. 9180, pp. 723–729, 1999.

E. R. Greenberg, J. A. Baron, T. A. Stukel et al., “A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin,” The New England Journal of Medicine, vol. 323, no. 12, pp. 789–795, 1990.

U. M. Frieling, D. A. Schaumberg, T. S. Kupper, J. Muntwyler, and C. H. Hennekens, “A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physicians' health study,” Archives of Dermatology, vol. 136, no. 2, pp. 179–184, 2000.

C. H. Hennekens, J. E. Buring, J. E. Manson et al., “Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease,” The New England Journal of Medicine, vol. 334, no. 18, pp. 1145–1149, 1996.

R. Serri and M. Iorizzo, “Cosmeceuticals: focus on topical retinoids in photoaging,” Clinics in Dermatology, vol. 26, no. 6, pp. 633–635, 2008.

C. E. M. Griffiths, A. N. Russman, G. Majmudar, R. S. Singer, T. A. Hamilton, and J. J. Voorhees, “Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid),” The New England Journal of Medicine, vol. 329, no. 8, pp. 530–535, 1993.

O. Yamamoto, J. Bhawan, G. Solares, A. W. Tsay, and B. A. Gilchrest, “Ultrastructural effects of topical tretinoin on dermo-epidermal junction and papillary dermis in photodamaged skin. A controlled study,” Experimental Dermatology, vol. 4, no. 3, pp. 146–154, 1995.

M. Chen, S. Goyal, X. Cai, E. A. O'Toole, and D. T. Woodley, “Modulation of type VII collagen (anchoring fibril) expression by retinoids in human skin cells,” Biochimica et Biophysica Acta, vol. 1351, no. 3, pp. 333–340, 1997.

J. S. Weiss, C. N. Ellis, J. T. Headington, and J. J. Voorhees, “Topical tretinoin in the treatment of aging skin,” Journal of the American Academy of Dermatology, vol. 19, no. 1, pp. 169–175, 1988.

L. Rittie, G. J. Fisher, and J. Voorhees, “Retinoid therapy for photoaging,” in Skin Aging, B. Gilchrest and J. Krutmann, Eds., Springer, Berlin, Germany, 2006.

M. Inui, M. Ooe, K. Fujii, H. Matsunaka, M. Yoshida, and M. Ichihashi, “Mechanisms of inhibitory effects of CoQ₁₀ on UVB-induced wrinkle formation in vitro and in vivo,” BioFactors, vol. 32, no. 1–4, pp. 237–243, 2008.

D.-W. Kim, I. K. Hwang, D. W. Kim et al., “Coenzyme Q₁₀ effects on manganese superoxide dismutase and glutathione peroxidase in the hairless mouse skin induced by ultraviolet B irradiation,” BioFactors, vol. 30, no. 3, pp. 139–147, 2007.

B. S. Choi, H. S. Song, H. R. Kim et al., “Effect of coenzyme Q₁₀ on cutaneous healing in skin-incised mice,” Archives of Pharmacal Research, vol. 32, no. 6, pp. 907–913, 2009.

H. K. Biesalski and U. C. Obermueller-Jevic, “UV light, beta-carotene and human skin—beneficial and potentially harmful effects,” Archives of Biochemistry and Biophysics, vol. 389, no. 1, pp. 1–6, 2001.

E. Boelsma, H. F. J. Hendriks, and L. Roza, “Nutritional skin care: health effects of micronutrients and fatty acids,” American Journal of Clinical Nutrition, vol. 73, no. 5, pp. 853–864, 2001.

J. E. Packer, T. F. Slater, and R. L. Willson, “Direct observation of a free radical interaction between vitamin E and vitamin C,” Nature, vol. 278, no. 5706, pp. 737–738, 1979.

R. Stocker, M. J. Weidemann, and N. H. Hunt, “Possible mechanisms responsible for the increased ascorbic acid content of Plasmodium vinckei-infected mouse erythrocytes,” Biochimica et Biophysica Acta, vol. 881, no. 3, pp. 391–397, 1986.

H. Ohman and A. Vahlquist, “in vivo studies concerning a pH gradient in human stratum corneum and upper epidermis,” Acta Dermato-Venereologica, vol. 74, no. 5, pp. 375–379, 1994.

K. Werninghaus, M. Meydani, J. Bhawan, R. Margolis, J. B. Blumberg, and B. A. Gilchrest, “Evaluation of the photoprotective effect of oral vitamin E supplementation,” Archives of Dermatology, vol. 130, no. 10, pp. 1257–1261, 1994.

B. Poljsak, R. Dahmane, and A. Godic, “Skin and antioxidants,” Journal of Cosmetic and Laser Therapy, vol. 15, no. 2, pp. 107–113, 2013.