Resveratrol: Apromising Antiaging Agent for Cosmetic Skin Treatments

Abstract

Nowadays, resveratrol, a polyphenolic phytoalexin is increasingly included in the formulas of cosmetic products and dermatology as an active ingredient, as a consequence of the well-known health beneficial properties, namely antioxidant, anti-inflammatory, anti-viral and anti-bacterial effects. This important compound can be biosynthesized naturally by plants or by industrial synthetic processes. Apart from its anti-inflammatory and antioxidant effects, a broad spectrum of effects has been attributed to the use of this compound such as anti-aging, skin-whitening, anti-angiogenic, collagen I and III stimulation (in fibroblasts) and estrogen-like effects, as well as the ability to protect cells against hydrogen peroxide-induced oxidative stress and UV-irradiation-mediated cell death. In cosmetology and dermatology has been popular because of its ability to penetrate the skin barrier and its anti-aging activity. In fact, resveratrol as an important impact on the regulation of inflammation and, as consequence, repair-related processes in skin. Furthermore, when administered either topically or orally has been proven to be safe and also to overcome the skin barrier. This review will focus in its potential application on melasma treatment and in photo-aging. Resveratrol chemistry, pharmacology, mechanism of action and evidence of its efficacy as photo skin aging protector and its potential use in melasma is discussed.

1. Introduction

1.1 Chemistry and biological properties

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a naturally occurring compound, belongs to the stilbenoid group of polyphenols, which is synthesized by plants (e.g., red grapes and berries). It can also be obtained by chemical synthesis, biotechnological synthesis or by plant extraction [1]. As observed in Figure 1, resveratrol consists in two phenol rings linked by an ethylene bridge, giving rise to two geometric isomers, is the biologically active trans-isomer and an inactive cis-isomer [2]. The trans-resveratrol can undergo photoisomerization (exposed to sun light or to artificial or natural UV radiation) to be converted into its biologically inactive cis-isomer [3, 4, 5].

Figure 1.

Chemical structures of resveratrol and its two isomers, trans- and cis-resveratrol. Highlighted in red circles the hydroxyl groups of the phenolic moieties of resveratrol. Highlighted in a brown squared the biologically active trans-isomer.

Resveratrol is a compound that presents several important biological properties, Figure 2.

Figure 2.

Biological properties from resveratrol.

The aim of this study is to show the efficacy and tolerability of resveratrol, that can have a topical application to the face and to determine whether this topical treatment with resveratrol can reduce anti-aging effects by improving skin barrier, and elasticity. In fact, Andrzej et al., 2022 [6] concluded that “resveratrol shows an excellent biocompatibility” representing an interesting and promissing novel therapeutical compound for the cosmetic industry.

2. Pharmacology, toxicity and skin permeation

Orally, and considering its structure, resveratrol is rapidly absorbed from the gastrointestinal tract, but with a low bioavailability because is rapidly metabolized in the liver [2]. In human, its plasma half-life has been reported to be 9.2 ± 0.6 hours [7], resulting not carcinogenic in mouse, without developmental and reproductive toxicity [8]. Another important characteristic from this compound, is that, as already proved, it is non-irritating to skin and eyes and non-sensitizing. In vitro and in vivo resveratrol demonstrated to be nontoxic, safe for oral and dermal application, as well as being well tolerated [9, 10, 11]. Resveratrol also showed high permeability in the skin, overcoming the skin barrier in its neutral (non-ionized) form, showing that it is readily available in the stratum corneum (SC) in animal and human studies [12, 13]. This is of high importance, once the most exposure to reactive oxygen species (ROS) takes place in the SC, supporting the use of resveratrol in cosmeceuticals [14, 15].

2.1 Possible skin application in melasma and it use in skin photoaging

2.1.1 Antioxidant activity

Skin care formulations are usually based on exogenous antioxidants that cannot be synthesized by our body, like vitamins or phenolic compounds. Some studies referred in Literature, report that resveratrol is able to inhibit UV-induced lipid peroxidation. UV irradiation (UV A and B) and blue light are known to induce the formation of free radicals, reactive oxygen species (ROS; e.g., peroxides, superoxide, hydroxyl radical) in vivo [16, 17, 18], and these reactive oxygen species may be toxic and mutagenic. They can also negatively influence some immunological processes and aging, as well as pathophysiological mechanisms leading to skin inflammatory disorders [19]. Melasma was associated with the increased ROS levels which will lead to the oxidation of proteins and lipids, and causing oxidative damage to the cells [20, 21, 22, 23]. Skin photoaging is also associated with ROS due to the exposure of the skin to sun light [24]. Recent studies also suggested melasma as a photoaging skin disorder [25]. Resveratrol is active in neutralizing, and inhibiting, the formation of ROS, but it also is effective in neutralizing synthetic DPPH and AAPH radicals in vitro [26]. Resveratrol was also proven to have radical scavenging properties owing most of it by the para/hydroxyl group of its structure [25, 27]. In a different study was observed to be a better antioxidant than many flavonoids [28]. For example, the antiradical activity of resveratrol relative to peroxide radicals was higher than catechins, gallic acid, and elagic acid (resveratrol> catechin> epicatechin = gallocatechin> gallic acid = ellagic acid.

In an in vitro study in human keratinocyte cells (HaCaT cells) after UV A radiation, considered by some authors as the major actor for the photoaging process [29], resveratrol is able to decrease oxidative by-products (e.g., maleic dialdehyde) and to increase antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPX) [30]. Manganese superoxide dismutase (MnSOD), a very important antioxidant enzyme, was also increased in the presence of resveratrol [31]. Compared to Vitamins A and C, it was proved to be even more effective against lipid peroxidation and protein oxidation in vitro [32, 33, 34], but also in an in vivo study in hairless mice [35]. Furthermore, DNA damage caused by peroxidyl radicals in human lymphocytes was reduced by resveratrol treatment after UV B induced H₂O₂ production [36]. Another key molecule in oxidation is the transcription factor nuclear factor-E2-related factor-2 (Nrf2) which regulates genes that help synthesize more antioxidants and remove ROS. Resveratrol upregulates Nrf2 which increase the levels of antioxidants such as GPX, SOD, catalase, and hemoxygenase [31, 37, 38]. In addition, Resveratrol activates a NAD⁺-dependent protein deacetylase, SIRT-1, a protein which is involved in cell survival against oxidative stress by decreasing the ROS levels [39]. In different in vivo studies was also observed an increase in SIRT-1 following resveratrol treatment of 0.02% in the diet for 4 weeks in wild-type mice Figure 3 [40].

Figure 3.

Association of Resveratrol in the different biological processes triggered by UV radiation in the skin.

2.1.2 Skin-whitening activity and photoaging protection

One the common clinical characteristic of melasma is the appearance of skin hyperpigmentation mainly in the face [22, 23]. In photoaging hyperpigmentation also occurs by cumulative sun exposure [41]. Resveratrol has the ability to modulate the tyrosinase activity by the inhibition of this enzyme and by acting as a competitive substrate, and thus blocking melanogenesis [42, 43, 44]. This compound also inhibits hyperpigmentation by other different mechanisms of action. According to Newton R. A. et al., 2007 [45], at a transcriptional level, resveratrol inhibits the mRNA expression of tyrosinase, tyrosinase-related proteins (Tyrp1 and Tyrp2), microphthalmia-associated transcription factor (MITF), a major regulator of melanogenesis, and DOPAchrome tautomerase (DCT) in human melanocytes in vitro study. On the other hand, it decreases the levels of melanin and in in vivo studies were observed by topically administration of resveratrol in guinea pig [46]. Resveratrol was also found effective in the inhibition of melanogenesis, Figure 3.

2.1.3 Anti-inflammatory activity and collagen synthesis stimulation

Both, in melasma and skin aging, a decrease in the quantity of collagen I, III, IV-VII (decrease in collagen I, IV in melasma, and all of them in skin aging) in the dermis and basal membrane has been described. In keratinocytes UV A radiation, ROS can upregulate the AP-1 (activator protein 1) and NF-kB (nuclear factor kappa beta) transcription factors [47, 48]. Their upregulation results in the induction of matrix metalloproteinase activity leading to the interference with intracellular signaling pathways responsible to the expression of genes regulating the process of collagen type I and III, resulting in hypertrophy and degradation of elastin and hyaluronic acid [45, 48, 50]. Resveratrol was found to reduce the expression of AP-1 and NF-kB transcription factors, limiting the degradation process of collagen and elastin in the skin, but also skin inflammation [48, 49, 51, 52]. In addition, resveratrol has been to act as an NF-kB inhibitor [53] which can be activated by ROS playing and important role in the inflammatory response [54, 55].

3. Wound healing potential of resveratrol

Another interesting potential property of this substance is their application to the wound healing process. Wound healing is a natural biological mechanism of repairing tissues after suffering from an injury. After tissue damage Nrf-2 and NF-kB play a crucial role in both inflammation and oxidation processes during wound healing process [56]. On the other hand, it is suggested that ROS in not excessive, low, levels are necessary for the wound healing process to fight against pathogens invading the organism, but not good when are produced in high levels in the tissue [57]. So, a control of the ROS produced by compounds such as Resveratrol knowing its proven anti-oxidant capacity is of interest to reduce the excess of tissue damage [58]. In addition, in a work from 2006 [59] was observed the association of an increase in the expression of the VEFG (Vascular Endotelian Growth Factor) in vitro and in vivo (mice) with the increase in agiogenesis which favored an improvement of the wound healing process. Evidence which demonstrates the potential of resveratrol on treating wound healing has been published [60, 61]. In this works was demonstrated the antioxidant, anti-inflammatory properties as well as the upregulation of Sirt-1 and VEFG expressions to play an important role in the ability of the resveratrol to improve wound healing in tissues such as the skin.

To sum up, if we take into account the related inhibition of the pro-inflammatory mediators’ expression, the ROS reduction ability, the scavenging properties, the increasing in angiogenesis via increasing VEFG and Sirtuins (Sirt-1), resveratrol seems to be a valuable candidate in order to both regulate and improve the wound healing process after skin damage.

4. Clinical evidence of resveratrol uses in cosmetics

The use of resveratrol in cosmetic formulas has increased in the last 15 years because of its potential biological activities described above. The use of this substance in cosmetic formulas such as a cream containing this active ingredient was studied in the work from Igielska-Kalwat [62]. In this study 20 volunteers were administrated topically on the face a cream composed by 0.007% resveratrol and with placebo (no resveratrol cream). Results after 6 weeks showed that treated patients increased skin hydration and firmness, concluding that resveratrol has moisturizing and tightening effects in skin but also safety without any sign of skin irritation. In a different work from Ferzli G. [63], a resveratrol enriched formulation which combined resveratrol with green tea polyphenols and caffeine, reduced facial redness in 13 of the 16 subjects from this study after 12 weeks study period. The other 3 subjects left were seen only to improve skin quality at the end of this study. In 2014, Farris P. [52] demonstrated also the efficacy of another resveratrol enhanced formulation (1% resveratrol, 0 1% Vitamin E and 0.5% baicalin) in the treatment of photodamaged skin. After a 12 weeks period an improvement in fine lines and wrinkles derived from photo aging processes were observed. In a similar work from 2013 [64] the efficacy on protecting the skin after UV aggression on 15 healthy volunteers was performed. In this study after repetitive UV radiation 1% resveratrol treatment after UV damage showed better protective effect even than other antioxidants alone, and logically better than placebo treated subjects.

In a different study form Moyano J.R. [65] a W/O (water in oil) cream was prepared to optimize the permeability and stability of the trans isomer of the resveratrol and study the elasticity, hydration and luminosity capacity of the formulas in 8 women ranging from 45 to 70 years old during a 30 days trial. Results suggested the efficacy of the resveratrol emulsion produced in all patients tested. The increase in all parameters studied was 20.53%, 49.70% and 6.17% for hydration, elasticity and colorimetry respectively.

5. Conclusions

As conclusion, resveratrol could be potentially effective in the treatment of several skin disorders, including diseases or signs of aging, for example. Several studies have shown important biological activity of resveratrol, especially in reconstituted skin models, skin cell cultures, or in animal models. The high activity, and efficacy, of resveratrol as both an antioxidant and a melanin synthesis inhibitor make this compound as a promising candidate for the treatment and prevention of skin aging. Despite this beneficial influence on the skin aging effects and dermal diseases, resveratrol is also effective in healing of wounds and burns. Exist similarities between melasma and skin aging (and photoaging) in terms of the hyperpigmentation, the basement membrane disruption of the skin, as well as the association with ROS owing to the UV exposure. These similarities would make resveratrol as a promising contributor for their treatment and prevention of melasma. Because the vast majority of the literature refers to the activity of resveratrol to in vitro studies and in vivo in animal models, it would be desirable more clinical evidences of its efficacy in human skin treatment.

In our opinion, resveratrol may be able to induce collagen synthesis in vivo, although the molecular mechanism is not clearly established. We pretend to proceed our study of this molecule, to give an added value to the potential opportunities of this compound.

Acknowledgments

The authors thanks to Dr. José Rocha from Mesosystem for the development of the pictures.