Polyphenols against Skin Aging

C H A P T E R

63 Polyphenols against Skin Aging Farid Menaa*, Abder Menaa† and Jacques Tre´ton‡ †

*Fluorotronics, Inc., Department of Oncology, Regenerative Medicine and Nanomedicine, San Diego, CA, USA Centre Me´dical des Guittie`res, Department of Nutrition, Dermato-Esthetics and Anti-Aging Medicine, Saint-Philbert de Grand Lieu, France ‡Universite´ Paris V-Rene´ Descartes, Department of Geriatry and Gerontology, Centre de Recherches des Cordeliers, Paris, France

1. INTRODUCTION Aging is associated with a gradual decline of physiological and cognitive functions.1 Over the past two decades, significant progress has been made in elucidating the molecular mechanisms of aging,2,3 an active but still challenging area. Hundreds of genetic factors, called longevity-related genes, have been identified to modulate lifespan and healthspan in model organisms ranging from yeast (e.g., Sacharromyces cerevisiae), worms (e.g., Caenorhabditis elegans), flies (e.g., Drosophila melanogaster), and rodents (e.g., Mus musculus, Rattus norvegicus). Among them, a large number of the longevity-related genes fall into three conserved nutrient sensing pathways: target-of-rapamycin (TOR), insulin/IGF-1-like signaling (IIS), and sirtuin pathways.4,5 The recent studies have shed light on some of the mechanisms involved in aging processes, and provide valuable guidance for developing and promoting effective healthy skin aging interventions.6 Skin aging is a complex, progressive and inevitable biological process. Although it is primarily a physiological process (i.e., the so-called chronologic aging) involving our own genetic background, it may also become a pathological process (i.e., the so-called premature aging). Premature skin aging is manifested by accelerated induction of wrinkling, scaling, roughness, dryness, laxity, as well as mottled pigment abnormalities including hypo-pigmentation and hyperpigmentation, and can be caused by the detrimental effects of xenobiotics agents or environmental (e.g., chronic exposure to solar ultraviolet radiation-induced oxidative stress aka hotoaging, pollution, cigarette smoke, extreme temperature change).7,8

Polyphenols in Human Health and Disease. DOI: http://dx.doi.org/10.1016/B978-0-12-398456-2.00063-3

One of the major features of aging skin is the progressive proteolytic degradation of cutaneous elastic fibers that cannot be adequately replaced or repaired by adult dermal fibroblasts.9 In fact, the impact of both chronological aging and photoaging on the skin appears particularly concerning when enhanced oxidative stress is involved. Interestingly, a recent study showed quantitative and qualitative differences in the oxidative stress generated either by chronological aging or by hotoaging in the skin of hairless mice.10 Indeed, while the lipid peroxides level was increased in both skin types, and so would represent a good parameter to determine the oxidative stress, a difference in the decay capacity of lipid membrane turnover was noticed between chronological and hotoaging skin.10 Importantly, neither superoxide dismutase (SOD), which remained unchanged, nor catalase, which increased with chronologic aging and decreased in irradiated mice, could have been considered as good biomarkers of oxidative stress.10 Plants are the source of important products with nutritional and therapeutic value. There is emerging evidence that topical application or oral intake of some polyphenol-rich plant extracts can reduce a number of degenerative diseases and skin conditions such as skin aging.11,12 Polyphenols represent a superfamily of diverse naturally occurring plant chemicals, and are abundant micronutrients in our diet (e.g., vegetables, fruits, flowers, nuts, seeds).13,14 The protective health effects exerted by polyphenols as neutraceuticals depend not only on the dietary intake but also on their systemic bioavailability.13,14 Indeed, the most abundant polyphenols in our diet are not necessarily those that have the best bioavailability profile.13 The

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© 2014 Elsevier Inc. All rights reserved.

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bioavailability and sources of polyphenols and polyphenol-containing foods has been previously reviewed,13,14 showing that it mainly depends on: (1) their intestinal absorption during which the microflora of each given individual plays an important role in the catabolism of polyphenols and the production of some active metabolites, (2) their chemical structure (e.g., glycosylation, esterification, and polymerization), (3) their inclusion in the food matrix, and (4) their excretion back into the intestinal lumen. Globally, there are three main types of polyphenols: the flavonoids, the stilbenes, and the lignans, which are classified by the number of phenol rings they contain as well as the binding properties of the ring structures.11
14 The phenol rings are comprised of phenyl and hydroxyl group structures that possess diverse biological activities such as anti-inflammatory, immune-modulatory and antioxidant properties.11,12,15 Further, each class of these phytochemicals can be subclassified in accordance to the interactions of their respective phenyl rings to carbon, oxygen, and organic acid molecules.13,14 Thereby, flavonoids represent a large class of edible polyphenols, and are divided into six main sub-classes: (1) flavonols (highly concentrated in onions, apples, red wine, tea, broccoli and Ginkgo biloba), (2) flavones (a good amount in the herb chamomile), (3) isoflavones (predominant in soy), (4) flavanones (largely present in citrus fruits), (5) anthocyanidins (abundant in berries and cherries), and (6) flavanols (i.e., catechins, mainly found in red wine, tea and apples), among which the most abundant is (2)epigallocatechin-3-gallate (EGCG), extensively studied because of its potent therapeutic effects in skin.16,17 Stilbenes (aka stilbenic phytoalexins) are found in low quantities in the human diet, and are mainly represented by resveratrol that exist in both cis and trans isomeric forms, mostly glycosylated. Resveratrol has been detected in more than 70 plant species (e.g., red grapes, particularly in the fresh skin, berries, peanuts, red wine, grape juice), and presents potential benefit against premature skin aging.13,14,18,19 Most lignans are naturally present in the free form, while their glycoside derivatives represent a minor form. They are also found in low quantities in the human diet (e.g., mainly present in linseed, nuts, and whole grain cereals).13,14 Being widely abundant and relatively inexpensive, the use of polyphenols is highly attractive to researchers as a cost-effective alternative or as a strategy to supplement current skin pharmacologic therapeutics,20 skin protection agents (e.g., sunscreens)21
24 and cosmeticesthetic techniques (e.g., microdermabrasion).25 Since the structure, metabolism, pharmacokinetics, pharmacodynamics, sources and amounts of relevant polyphenols have been extensively reviewed,13,14 our manuscript aims to provide an update about the

studies of polyphenols (e.g., purified polyphenols, polyphenol-rich plant extracts) that claim potential benefits (i.e., biologic and clinical effects) against skin aging, being aware that further clinical studies are still required to uneqivocally prove their efficacy and safety.26,27

2. POLYPHENOLS BENEFITS ON SKIN AGING: AN OVERVIEW Skin, the largest organ of the body, is the organ in which changes associated with aging are most visible. The skin is made up of three main layers: the hypodermis, the dermis, and the epidermis.28 The hypodermis is the deepest section of skin, and is primarily a place of connection and fat storage.28 The epidermis is made up mostly of keratinocytes, is rich in reactive oxygen species (ROS), detoxifying enzymes and in low molecular weight antioxidant molecules, and also contains melanocytes, Merkel cells, and Langerhans cells.28 The primary function of the epidermis is to provide a weather- and water-proof layer to protect the body.28 The dermis contains most of the connective tissues of the skin, as well as nerve endings, sweat glands, and hair follicles.28 Similar to the entire organism, skin is subject to an unpreventable intrinsic aging process (e.g., respirationinduced oxidative stress). Intrinsic skin aging is characterized by atrophy of the skin with loss of elasticity and slowed metabolic activity.29,30 Additionally, skin aging is influenced by exogenous/extrinsic factors (e.g., sunlight/UV radiation (UVR) and other atmospheric conditions) that can lead to premature skin aging,31
33 resulting in hypertrophic repair response with thickened epidermis and increased melanogenesis, as well as even more striking changes in the dermis (i.e., massive elastosis, collagen degeneration, twisted and dilated microvasculature).29,30 In normal/unstressed cells, there is a constant production of ROS from the mitochondria, which is balanced by the production of antioxidant enzymes in the cell, such as SOD, catalase, and glutathione (GSH) peroxidase.34 When a cell comes under stress, this balance is interrupted, and the ROS can overwhelm the cells and lead to a change in normal cellular behaviors.35,36 Therefore, despite their morphological and pathophysiological differences, intrinsic and extrinsic aging (i.e., chronologic skin aging and skin hotoaging, respectively) share several molecular similarities. In summary, the central aspects of the skin aging are reflected by the intracellular and extracellular oxidative stress initiated by two main events: (1) the formation of ROS, and (2) the induction of matrix metalloproteinases (MMPs).

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ROS (e.g., singlet oxygen, superoxide, peroxyl radicals, hydroxyl radicals, and peroxynitrite),37 overbalances the antioxidant defense system potential of the skin structure (i.e., horny layer, epidermis and dermis).38,39 ROS react with nucleic acids, proteins, glucids and fatty acids, causing oxidative damage (i.e., lipid peroxidation),40 and contribute to chronologic skin aging,37,40,41 pathogenesis of inflammatory processes and allergic responses in the skin,29 as well as to skin hotoaging and skin cancer development (e.g., photocarcinogenesis).40 The roles and mechanisms of ROS metabolism (i.e., generation and elimination) in the body, as well as the effects of ROS generated in the skin (e.g., free radical damage, cell-mediated responses associated with the mitogen-activated protein kinase (MAPK) activity), have been previously reviewed.37,38 The induction of MMPs, which leads to the accumulation of fragmented collagen fibrils, which prevents neocollagenesis and accounts for the further degradation of the extracellular matrix (ECM) by means of positive feedback regulation.41 For instance, it is known that after UVR-induced ROS, MMP-1 (aka collagenase-I), -3, -9 levels are increased, causing collagen and elastin degradation before forming coarse wrinkles and sagging skin.42 In recent years, epidemiological and biochemical studies have shown that the occurrence of various diseases (e.g., cancer, degenerative and cardiovascular pathologies, premature skin aging) has been reduced, notably because of the antioxidative effects of polyphenols. Indeed, antioxidants such as flavonoids and phenolic acids play a main role in fighting ROS, and the inhibiting mechanisms of photoaging by polyphenols (e.g., inhibition of MMP-1, elastase and hyaluronidase) are being unraveled in order to develop agents able to slow down the aging process.42,43 In this regard, the evaluation of local polyphenolbased anti-aging therapy (e.g., polyphenol-rich sunscreens and skin care products),21,23
25,39,40,42 as well as the potential benefit of dietary polyphenol,16
19,22,43 remains an active but challenging field of research. Briefly, it is now well-accepted that topical polyphenol-rich products (i.e., cosmeceutics) can partially “reverse” the clinical and histologic changes in the epidermis and dermis induced by the combination of sunlight exposure and chronologic aging (e.g., repair of keratinocyte ultrastructural damage, distribution of melanin, deposition of new papillary dermal collagen, improvements in vasculature, normalization of hyperkeratinization, increased epidermal thickness and dermal glycosaminoglycan (GAG) such as hyaluronic acid).23 Thus, the topical use of such agents may favorably supplement sunscreens providing additional anti-aging (and anticarcinogenic) skin benefits.24,44 Besides, the protective effects on skin aging exerted by polyphenol-rich food products (i.e.,

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neutraceuticals) depend not only on the dietary intake, the source plant, the polyphenolic content and nature in the food matrix, but also on the polyphenols systemic bioavailability.13,14 Some herbs such as green tea (EGCGrich plant),16,17 or some fruits such as grapes (resveratrol-rich plant),18,19 have been shown as promising edible products against skin aging. Further, polyphenol-rich agents should strengthen the use of some esthetic techniques, supporting the role of topical antioxidants as antiaging factors. For instance, a recent study using adult female volunteers (n 5 10), reported that the addition of skin polyphenolic antioxidant-based serum enhanced the dermatologic changes (i.e., increased epidermal and papillary dermal thickness, enhanced fibroblast density, increased hyalinization of the papillary dermis with newly deposited collagen fibers). This was seen following facial treatments using microdermabrasion, a reliable, non-invasive tool for facial rejuvenation.25 Nevertheless, one should also keep in mind that some polyphenols could be a double-edged sword for the human skin, exerting both protective (i.e., as antioxidants) and damaging actions (i.e., allergic reactions, contact dermatitis, phytodermatoses, photo-phytodermatoses, and enhanced UV-induced apoptosis).36,37,45 Anyhow, we believe that skin, as the largest exposed organ, needs aggressive research as well as new, multidisciplinary approaches for its management.

3. POLYPHENOLS WITH POTENTIAL BENEFITS IN ANTI-AGING PROCESS Although there is a paucity of clinical studies concerning the efficacy of polyphenols as topical anti-aging agents, most relevant studies highlighting the biological effects of active polyphenols (e.g., resveratrol, EGCG, genistein) for their possible development and use as anti-aging cosmeceutics (i.e., polyphenolrich topical agents), adjuvant therapeutics or even neutraceutics are reviewed in this chapter. As previously evoked, some pharmacologically active polyphenols are capable of preventing the occurrence of skin aging (chronologic and/or photo-induced or photoindependent premature skin aging as seen in some inherited disorders such as Costello or Werner syndromes) and skin diseases (e.g., skin cancers), as well as reducing the severity of UV-induced skin damage.21,23
25,39,40,42,46,47

3.1 Resveratrol Resveratrol (3,5,40 -trihydroxy-trans-stilbene), is a phytoalexin antioxidant derived from natural products such as the skin of red grapes, peanuts, blueberries

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and cranberries.13,14 Resveratrol has received extensive attention through the link with the “French paradox,” and later with its chemopreventive activity demonstrated in vitro and in animal cancer models.18,48
51 A plethora of laboratory investigations has provided evidence for the multi-faceted properties of resveratrol, and suggests that resveratrol may target aging by regulating inflammation and oxidative stress.18 Thereby, resveratrol displayed a protective action on skin aging and various disorders associated with aging.18,19,52
54 A recent study found that resveratrol, used as a radioligand (i.e., 3H resveratrol), exert anti-apoptotic effects by acting on specific plasma membrane polyphenol binding sites in the human skin (especially in the epidermis) exposed to nitric oxide (NO) free radical donor sodium nitroprusside (SNP).55 In another ex vivo study, resveratrol treatment blocked UVB-mediated activation of the nuclear factor-kappa B (NF-κB) pathway in the normal human epidermal keratinocytes (NHEK), in a dose- and time-dependent fashion.52 Further, it was shown that resveratrol protects human keratinocytes (HaCaT) from UVAinduced oxidative stress damage by downregulating Kelch-like ECH-associated protein 1 (Keap1) expression.56 However, there are still a few roadblocks in the way of this promising agent regarding its translation from the bench to the bedside. For instance, an independent and contradictory study showed that resveratrol sensitizes human keratinocytes to UVA-induced apoptosis by a mechanism that involves a decrease of the mitochondrial membrane potential, resulting in opening of the mitochondrial permeability transition pores.46 Further, data reporting the effects of resveratrol consumption in a capsule versus food form are conflicting, providing uncertainties on long-term dosing.18 Besides, based on a few in vivo studies, it appears that the prospects are very bright for the possible use of resveratrol in skin aging and diseases. For instance, studies53,57
59 have shown that a topical application of resveratrol to SKH-1 hairless mice skin results in significant inhibitions of UVB-mediated effects such as decreases in: (1) skin edema and hyperplasia, (2) inflammation, (3) infiltration of leukocytes into the epidermis and dermis, (4) cyclooxygenase-2 (COX-2) level, (5) ornithine decarboxylase (ODC), (6) hydrogen peroxide (H2O2), (7) lipid peroxidation, (8) proliferating-cell nuclear antigen (PCNA) protein level in the epidermis, (9) cellular proliferations (Ki-67 immuno-staining), (10) established markers of tumor promotion, (11) surviving activity and expression levels, and (12) MAPK-1/2 and MAPK kinase (MEK-1). Conversely, increases in p53 and p53-downstream WAF1/p21 protein levels were noticed, significantly reversing the UVB-mediated responses in these proteins.58

Topical application of resveratrol to the skin appears to be a better option in mammals than oral or systemic administration because of its rapid metabolism into glucuronides and sulfonates by the intestine and liver (i.e., within 30
60 minutes after administration), which leads to a poor plasmatic bioavailability.59 Possible scenarios for improving the bioavailability and efficacy of resveratrol have been suggested,60,61 and include: (1) combination of resveratrol with agents that can inhibit the in vivo metabolism of resveratrol, (2) use of nano-formulations (nanoparticle-, hydrogel-, nanosuspension-mediated delivery systems), (3) synthesis and/or evaluation of analogs of resveratrol with improved bioavailability, (4) careful evaluation of conjugated metabolites of resveratrol, which may be deconjugated at the target organ to elicit a biological response. Nowadays, a number of resveratrol-supplemented skin care products and cosmetics are available in the market. However, it is worth noting that these products have not been rigorously tested for their claims.

3.2 (2)-Epigallocatechin-3-Gallate (2)-Epigallocatechin-3-gallate is a green-tea derived catechin polyphenol (i.e., flavanol). Several studies reported on the potential benefits of topical applications of EGCG for preventing or treating skin conditions. Indeed, EGCG displays a number of features such as anti-inflammatory, antioxidant and DNA repair activities.11 A recent ex-vivo study showed that EGCG was able to reduce the cell death caused by exposure of human HaCaT cells to SNP, although this effect was much lower than that observed with resveratrol.55 Also, EGCG treatment of human fibroblasts in culture blocked UV-induced collagen secretion and collagenase transcriptional levels, and inhibited the binding activities of the UV-induced nuclear transcription factors NF-κB and activated protein (AP-1).62 Treatment of normal human epidermal keratinocytes with EGCG could inhibit UVB-induced intracellular release of H2O2 concomitantly with the inhibition of UVBinduced oxidative stress-mediated phosphorylation of epidermal growth factor receptor (EGF-R) and MAPKs signaling pathways.63 Besides, topical treatment of SKH-1 hairless mouse skin with EGCG in a hydrophilic ointment significantly inhibited UVB-induced skin tumor development.64 In another study,65 topical treatment of human skin with EGCG prior to UVB exposure significantly reduced the: (1) UVB-induced infiltration of inflammatory leukocytes, (2) UVB-induced NO and H2O2 production, which was in accordance

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with the effect of (1) above, (3) UVB-induced production of prostaglandin (PG) metabolites, including PGE2, PGF2α, and PGD2, which play a critical role in inflammatory disorders and in proliferative skin diseases. In separate experiments, it has been shown that topical treatment with EGCG in the skin of mice significantly inhibits acute or chronic UV irradiationinduced protein oxidation.66 Independent studies observed an exceptionally high photo-protective effect of EGCG against UV radiation-induced oxidative stress (e.g., lipid peroxidation, H2O2 production) and depletion of antioxidant defense enzymes (e.g., catalase, GSH, and SOD levels).64,67 Further, a study in mouse skin evaluating DNA repair mechanisms suggested that the rapid repair of UV-induced cyclobutane pyrimidine dimers (CPDs) by topically applied EGCG is mediated through stimulation of the cytokine interleukin-12 (IL-12).68 Taken together, these studies suggested that EGCG might prevent skin aging and related diseases (e.g., photo-induced skin cancers) in humans. Topical application of EGCG to the skin is preferred to oral administration, owing to the consideration that this large molecular weight polyphenol is poorly absorbed through the gut barrier (i.e., in the gut mucosa and inner tissues).69 Topical cream-based formulations of EGCG for human use have been developed, and their photo-protective effects have been evaluated using animal models.

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An in vivo study showed that pretreatment of human skin with genistein inhibited UV-induced EGFR tyrosine kinase activity as well as both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK) activities.73 In this same study, genistein did not protect against UV-induced erythema, suggesting that it is unlikely to act as a sunscreen.73 Interestingly, a recent double-blind, randomized, placebo-controlled trial, indicated that oral intake of 40 mg genistein per day safely improves the aged skin of middle-aged women (n 5 26).74 Further, a most recent study conducted in aged rats demonstrated the potential benefit of relatively longterm systemic treatment with genistein to “revert” some molecular, histological and functional changes of the skin associated with ovariectomy (e.g., decrease in transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor (VEGF), MMP-2, MMP-9, tissue inhibitor of MMP (TIMP)-1 and TIMP-2).75 This in vivo study meantime suggested that genistein might be an effective alternative therapy for the management of age-related skin changes in postmenopausal women.75

4. OTHER POLYPHENOLS WITH POTENTIAL ANTI-AGING CAPACITY: EMERGING STUDIES 4.1 Tannic and Ellagic Acids

3.3 Genistein The soybean isoflavone genistein (aglycone) is a potent antioxidant, a specific inhibitor of protein tyrosine kinase, and a phytoestrogen.70 In the past decade, a series of studies and reports demonstrated that genistein (as topical, oral or systemic agent) has significant anti-photocarcinogenic and anti-hotoaging effects, suggesting considerable promise as an effective agent against the aging process in humans.70
75 Indeed, a study showed that genistein was able to greatly decrease the H2O2 increment in human keratinocytes caused by UVB radiation.70,71 Also, in a recent study using dermal fibroblasts, it was demonstrated that genistein protects UVB-induced senescence-like characteristics (e.g., senescence-associated beta-galactosidase (SA-β-gal), apoptosis) via maintenance of antioxidant enzyme activities and modulation of mitochondrial oxidative stress (i.e., inhibition of the forkhead protein FKHRL1 expression, induction of SOD and malondialdehyde (MDA) levels) through downregulation of the 66-kilodalton isoform of the growth factor adapter Shc (p66Shc)-dependent signaling pathway.72

Ellagic acid (EA) and tannic acid (TA) are phenolic acids found in a wide variety of fruits and nuts such as raspberries, strawberries, pomegranate, walnuts, grapes, and blackcurrants.76,77 These molecules are receiving attention as agents that may have potential bioactivities preventing chronic diseases and skin aging. Indeed, they possess potent ability to scavenge ROS and reactive nitrogen species (RNS).77 Further, EA was shown to decrease the expression of proMMP-2 and pro-MMP-9, precursors of two elastolytic enzymes.78 Besides, TA was shown to bind to insoluble bovine and porcine elastin, and inhibit their degradation by porcine pancreatic elastase.79 More recently, data have indicated that treatment of cultured human dermal fibroblasts and organ cultures of human skin biopsies with lipophilic EA and/or hydrophilic TA significantly (and synergistically) enhances their net deposition of elastic fibers (i.e., elastogenesis), by a mechanism that, once the elastogenic compounds are bound to purified elastin, premature proteolytic degradation of both tropoelastin and fully polymerized elastin (major component of mature elastic fibers) are prevented from elastolytic enzymes (e.g., serine proteinases, cysteine proteinases, and MMPs).9 This finding

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has particular implications for the treatment of pediatric patients with inherited skin aging (i.e., Werner’s syndrome, Costello’s syndrome or Cutis Laxa), who generally present impaired primary deposition of elastic fibers and subsequent wrinkles and deep dermal creases.9 Concordingly, a recent study examining the photoprotective effects of EA on collagen breakdown and inflammatory responses in UVB-irradiated human skin cells (HaCaT keratinocytes, human dermal fibroblasts) and hairless mice (SKH-1), showed that EA prevents collagen destruction and inflammatory responses caused by UVB.80 Indeed, in this study, EA: (1) markedly prevented collagen degradation by blocking matrix MMP production in UVB-exposed fibroblasts, (2) attenuated UVB-triggered skin wrinkle formation and epidermal thickening in hairless mice, (3) diminished the production of pro-inflammatory cytokines IL-1β and IL-6 and blocked infiltration of inflammatory macrophages in the integuments, when topically applied to hairless mice chronically exposed to UVB, and (4) mitigated inflammatory intracellular cell adhesion molecule-1 (ICAM-1) expression in UVB-irradiated keratinocytes and hotoaged mouse epidermis. Eventually, these studies showed that topical application of TA and/or EA may represent promising treatment strategies interrupting skin wrinkle and inflammation associated with skin aging.

4.2 Quercetin, Dihydroquercetin and Quercitrin Quercetin, dihydroquercetin and quercitrin are flavonoids (flavonols) found in various vegetarian foods including onions.13,14 Research studies suggest that quercetin may act to prevent the development of cancers81,82 and skin aging.83 Interestingly, a study showed that quercetin, alone or in cooperation with ascorbic acid (vitamin C), is able to protect neurovasculature structures in skin from injury induced by oxidative stress, and thus may be of therapeutic benefit against skin aging.83 Indeed, quercetin (EC50: 30
40 μM) protected cutaneous tissue-associated cell types (i.e., human skin fibroblasts, keratinocytes, and endothelial cells) from injury (i.e., cell death) induced by intracellular peroxides generated by buthionine sulfoximine (BSO), an irreversible inhibitor of glutathione (GSH) synthesis.83 Dihydroquercetin (taxifolin) is a potent flavonoid that can also be found in the market in its semisynthetic form under the trade name of Venorutons.84 The therapeutic promise of dihydroquercetin in major inflammatory disease states such as cancer was recently reviewed.84 In particular, it was reported that dihydroquercetin can act as a scavenger of

myeloperoxidase (MPO)-derived RNS.84 Interestingly, and although the efficacy was lower than that observed with quercetin, dihydroquercetin was able to decrease BSO-induced injury to dermal fibroblasts.83 Further, a most recent controlled study, showed that dihydroquercetin was able to downregulate the collagenase I (MMP-1) in UVB-treated skin cells.85 Although there is still a paucity of reports associating quercitrin with skin aging, a promising recent study revealed a cytoprotective effect of this compound on UVB-induced cell injury in human keratinocytes (HaCaT).86 As a result, it was showed that the intracellular ROS and cell death generated by the exposure of HaCaT cells to UVB radiation were significantly decreased after treatment with quercitrin.86 Overall data therefore suggest that the three flavonols: quercetin, dihydroquercetin and quercitrin, may present benefits to delay skin aging in humans.

4.3 Equol S-Equol, a non-steroidal estrogen (17β estradiol), is a soy-derived isoflavonoid molecule produced by the metabolism of the isoflavone daidzein by intestinal flora.87 To date, the evidenced primary mechanism of action of this antioxidant is to activate estrogen receptor-β (ER-β), which in turn enhances the expression of antioxidant enzymes and inhibits the expression of snail, a transcription factor that regulates keratinocyte cell proliferation and migration.88 A recent study showed that equol can influence expression of skin genes and proteins (i.e., increased collagen I and III, elastin, and TIMPs levels; decreased MMPs gene expression) using human monolayer fibroblast and three-dimensional organotypic cultures.89 Altogether, the current findings suggest that equol: (1) is a scavenger of free radicals to prevent skin damage and skin aging, (2) has the potential to be used topically for the treatment and prevention of skin aging, by enhancing ECM components in human skin, and (3) could be a safer ER-β agent than typical estrogen chemotherapy.

5. POLYPHENOLS EXTRACTS: MAY THE RINGS MAKE THE DIFFERENCE TO FIGHT AGING? Relevant studies associating polyphenol-rich plant extracts (i.e., neutraceutics or cosmeceutics) such as herbs (e.g., tea), fruits (e.g., grapes, pomegranate), vegetables (e.g., soy), cereals (e.g., sorghum) or nuts (e.g., almonds) with skin aging are reviewed. Currently, only products such as green and black tea, soy,

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pomegranates, and dates have had clinical trials published for the treatment of extrinsic aging.90 Increasing evidence has shown that regular and acceptable consumption or application of these products can delay the process of skin aging and related skin diseases.

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of their overall alkaloids; in particular, their polyphenolic fraction.95 Indeed, when aqueous extracts (i.e., gels) of black and green tea were tested in vivo in the forearms of a few subjects (n 5 6) using an artificial UV (200
400 nm) source, peaks were found for catechins (e.g., EGCG) and polyphenols with dimeric and polymeric structures (e.g., theaflavins and thearubigins).95

5.2 Coffee

Herbs have been used in medicines and cosmetics for centuries. Indeed, herbal preparations, such as green tea extracts, have gained popularity as ingredients in topical skin care (i.e., in the improvement of skin appearance, treatment of different skin diseases, skin rejuvenation, and prevention of photo-damage).91 Although isolated plant compounds have shown a high potential for protecting the skin, whole herb extracts, such as green tea (Camellia sinensis), generally showed better potential due to their complex composition.92 Green tea polyphenolic (GTP) compounds (e.g., EGCG, cf. Section 3.2) display significant antioxidant and anti-inflammatory activities. Studies in humans and animal models suggest that GTP extracts can prevent cutaneous adverse effects of UVR (e.g., premature skin aging, skin cancers, erythema) or improve hotoaging skin.68,93
95 Thereby, a study led in SKH-1 hairless mice and in human skin fibroblast HS68 cells, strongly suggested that oral GTP (i.e., as dietary supplement) could be useful to attenuate solar UVB light-induced premature skin aging (i.e., oxidative damage such as protein oxidation and induction of MMPs such as MMP-2, -3, -7 and -9).68 Interestingly, a randomized study involving women with moderate hotoaging (n 5 40) has evaluated the effects of a combination regimen of topical (i.e., green tea cream) and oral green tea supplementation on the clinical and histologic characteristics of hotoaging. While no significant differences in clinical grading were found between the green tea-treated and placebo groups, histologic grading of skin biopsies did show significant improvement in the elastic tissue content of treated specimens.93 Further, a recent doubleblind, placebo-controlled trial of adult women (n 5 56) that aimed to evaluate the long-term effects of oral GTPs on the clinical and histologic characteristics of hotoaging skin, revealed that GTPs contribute to significant improvement in overall solar damage, at least during the 24 months of use.94 Most recently, an independent in vivo study reported that green tea and black tea extracts incorporated in dermal gels were able to confer protection against the harmful effects of UVR.95 This effect of strong UV absorbance elicited by these herbs was explained by the possible cooperative action

Coffee berry (Coffea arabica L.) is a natural ingredient that has promising efficacy in the topical treatment of oxidative stress-induced pathologies (e.g., premature skin aging, dermatoses), and its seed oil is widely used in cosmetic formulations.42,96
98 Indeed, it was recently shown that Coffea arabica leaf extract, naturally rich in polyphenols, can prevent photo-damage in skin through: (1) stimulation of type I pro-collagen, (2) inhibition of MMP expression (i.e., MMP-1, -3, -9), and (3) inhibition of MAPK pathway (i.e., phosphorylation of JNK, ERK and p38 MAPK).42 Further, an in vitro study showed protective effects of green Coffea arabica oil (GCO) in human skin cells and explants.97 Indeed, in human skin fibroblasts, GCO produced a dosedependent stimulation in the synthesis of collagen, elastin, and GAGs, in addition to increasing the release of TGF-β1 and granulocyte-macrophage colonystimulating factor (GM-CSF).97 Also, in cultured keratinocytes and human skin explants, GCO induced a significant transcriptional expression of the waterchannel aquaglycerolporins-3 (AQP-3).97 Interestingly, in a recent double-blinded, randomized, controlled clinical usage study led with Caucasian female participants (n 5 40), a novel topical, highly antioxidant polyphenolic skin care system containing Coffea arabica produced statistically significant improvements in the appearance of photo-damaged/hotoaged skin (e.g., reduced wrinkles, hypo-pigmentation, decreased blotchy redness and tactile roughness), and demonstrated that the antioxidant skin care system was well tolerated, with no adverse events reported by the participants during the course of the study.98

5.3 Grapes Grape seeds are waste products of the wine and grape juice industry. However, these seeds contain lipids, proteins, carbohydrates, and 5
8% polyphenols (mainly flavonoids such as proanthocyanidins) depending on the variety of grape.99 Grape seed extract exerts a powerful antioxidant effect to bond with collagen, and has been shown to notably protect the body from premature (skin) aging.99 Also, grape wine extracts exert protective effects against aging in

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general, notably because of the presence of the antioxidant polyphenol resveratrol.13—14,99 Thereby, in an in vitro study using a three-dimensional tissue culture model of human epidermis, a grape wine extract was able to prevent skin oxidative damage induced by UVB exposure (e.g., reduction of GSH and inflammatory molecules such as IL-1 and PGE).100

5.4 Pomegranate Pomegranate (Punica granatum L.) is a kind of fruit consumed fresh or in beverage, and has been widely used in traditional medicine in various parts of the world because of its strong antioxidant and antiinflammatory properties.101 The polyphenol content of this fruit (i.e., catechin, quercetin, kaempferol, and equol) is known to prevent adverse cutaneous effects of UV irradiation.101,102 Indeed, an extract of the Korean red P. granatum was able to protect cultured human skin fibroblasts against UVB-induced damage.101 Thereby, the P. granatum extract, especially the one prepared from rind, collagen synthesis was increased and MMP-1 expression was decreased.101 Concordantly, another study showed that pretreatment of human immortalized HaCaT keratinocytes with a polyphenolrich pomegranate fruit extract inhibited UVB-induced oxidative stress and hotoaging,102 in the following ways: (1) upregulation of MMP-1, -2, -7 and -9 protein levels, (2) decrease in TIMP-1 protein level, (3) phosphorylation of MAPKs, and (4) phosphorylation of c-Jun but not c-fos. These results suggest that POMx protects HaCaT cells against UVB-induced oxidative stress and markers of hotoaging and could be a useful supplement in skin care products.102 Essentially, these few studies suggest that dietary consumption of this fruit and its use as a supplement in skin care products can be valuable against skin aging.

5.5 Soybean Soybeans are known to contain isoflavones (e.g., genistein and daidzein) with beneficial biological activity in the skin (e.g., reduction of ROS and skin hyper-pigmentation; stimulation of collagen synthesis, cellular GSH content and glutathione S-transferase (GST) activity; prevention of ODC; increased moisture and GAGs such as hyaluronic acid (HA)).71,103,104 It is still unclear whether soy isoflavones act as antioxidants themselves or affect cell signaling processes that increase the skin’s own antioxidant capabilities.71 Nonetheless, studies showed that the soybean isoflavones, genistein and daidzein, were able to greatly decrease the H2O2 increment in human keratinocytes caused by UVB radiation,71,72 suggesting that topical

soybean extracts may be capable of preventing the biochemical alteration associated with aging.105 Interestingly, and albeit weaker activity than estradiol, genistein and daidzein are considered as potent phytoestrogens which can bind to α- and β-estrogen receptors of the skin to retard skin thinning and collagen loss associated with postmenopause.24,106
108 Interestingly, a double blind, vehicle-controlled clinical study involving women (n 5 65) with moderate facial photo-damage, demonstrated the efficacy and safety of a novel soy moisturizer in skin aging (i.e., improvements in mottled pigmentation, blotchiness, dullness, fine lines, overall texture, overall skin tone, and overall appearance).106 Recently, an in vitro and in vivo study, that aimed to evaluate the effects and possible mechanisms of an isoflavone extract from soybean cake against UVB-induced skin damage,109 revealed the following: (1) reduced cell death and decreased phosphorylation of p38 MAPK, JNK, and ERK1/2 in UVB-treated HaCaT cells, (2) and decreased epidermal thickness and the expressions of COX-2 and PCNA as well as increased of catalase in ICR-Foxn/(nu) mice treated with topical application of isoflavone extract before UVB. Overall, these data show that soy extracts can contribute to the prevention of skin aging, notably through inhibition of ROS, UVB-induced apoptosis and inflammation.

6. OTHER POLYPHENOL EXTRACTS WITH POTENTIAL ANTI-AGING CAPACITY: EMERGING STUDIES 6.1 Cacao Cacao (aka cocoa) bean is a popular edible plant that contains polyphenols and xanthine derivatives. Interestingly, an in vivo study showed that topical application of cacao bean extracts to the dorsal skin of hairless mice exposed to solar UV-like radiation suppressed photo-damage such wrinkle formation, dermal connective alteration, and collagen accumulation.110 Cacao bean extract also possesses protective effects against UVinduced erythema when taken orally, and an H2O2-scavenging effect.110

6.2 Apples Apples (sp. Malus domestica) contain nutrients and other compounds of interest, including high levels of polyphenols (e.g., triterpenoids in peel, anthocyanins in red apples).111
114 Oligomeric proanthocyanidins give the largest contribution to the antioxidant activity of apple extracts.112 While numerous studies

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undertaken in recent years have shown that apples and their derivatives may have a wide range of biological activities and benefits in several diseases (e.g., cancers, cardiovascular diseases), studies evaluating beneficial effects of apple extracts on aging in mammalian skin are lacking. Instead, yeast has appeared as a valuable model organism to study aging.115 Thereby, a recent and interesting study in yeast strains (e.g., Saccharomyces cerevisiae) showed that apple extracts are able to increase lifespan of mutants (e.g., Kllsm4Δ) that shows premature aging and cell death.116 The best result was obtained with the whole fruit, indicating a cooperative role of all apple components116

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(e.g., mix of vitamins such as C and E, pigments such as carotenoids) or polyphenol-rich blends (e.g., sea buckthorn (Hippophae rhamnoides L.) fruit blend) might be more beneficial to treat skin conditions (e.g., skin aging) than the pure, selected polyphenols. However, highly purified polyphenols are important for the study of biological effects and in unraveling mechanisms of action. Essentially, clinical studies combining pure polyphenols, polyphenol extracts or polyphenolbased nano-formulations with other modalities (e.g., chemotherapeutics, sunscreens, techniques used in esthetics) in order to increase their respective efficacy, are lacking.

6.3 Sorghum brans Sorghum varieties deserve consideration as possible nutraceutical and cosmeceutical ingredients for functional skin care, foods, and beverages. Indeed, while black sorghum cultivar lacks condensed tannins (proanthocyanidins), it has abundant anthocyanins and other polyphenols.43 A relatively recent study revealed the ability of ethanolic extracts of bran from six cultivated varieties of sorghum bicolor to inhibit hyaluronidase activity in vitro, when compared to extracts of wheat and rice bran.43 Thereby, black sorghum exhibited more potency to inhibit hyaluronidase than white sorghum, and sorghum varieties displayed more potency than wheat and rice bran. Hyaluronidase inhibition correlated positively with total phenolic content and ferric reducing antioxidant power values for each bran extract. This finding is quite interesting because the balance between HA and hyaluronidase activity (i.e., GAGs hydrolysis) in ECM influences tissue repair, tissue remodeling and maintenance of skin hydration,43,117 and so plays a role in preserving the skin against aging.

7. CONCLUSIONS The traditional use of plants in medication (e.g., skin anti-aging and associated diseases) or beautification (e.g., cosmetics) is the basis for active but challenging research, and should make new trends in cosmetics and medical therapy. Polyphenols are believed to have photo-protective anti-aging effects through decreasing inflammation and acting as a scavenger of free radicals. For many compounds, a large number of well-conducted clinical studies are required to prove their safety and efficacy before they are used as anti-aging cosmeceutics, anti-aging neutraceutics, or as adjuvant therapeutics. Besides, the complexity of polyphenol-rich extracts of the whole food product

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6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS