L'environnement marin représente une ressource sous‐exploitée pour la découverte de nouveaux produits, malgré son niveau élevé de diversité biologique et chimique. Avec la prise de conscience croissante des effets néfastes de l'exposition chronique aux ultraviolets et un désir universel d'améliorer l'apparence, le marché des nouveaux ingrédients cosmétiques est en croissance et les tendances actuelles ont généré une plus grande demande pour les produits issus de l'environnement. Un nombre croissant de nouvelles molécules issues de la flore et de la faune marines présentent des activités dermatologiques efficaces et performantes. Les métabolites secondaires isolés des macroalgues, y compris les caroténoïdes et les polyphénols, ont démontré des activités antioxydantes, anti‐vieillissement et anti‐inflammatoires. De plus, il a été démontré récemment que les bactéries extrêmophiles marines produisent des molécules exopolymériques bioactives, dont certaines ont été commercialisées. Les données disponibles sur leurs activités montrent des activités antioxydantes, hydratantes et anti‐ages significatives, mais une investigation plus ciblée de leurs mécanismes et applications est requise. Cette revue étudie les activités biologiques rapportées d'une gamme émergente et croissante de molécules marines prometteuses, dans le traitement des problèmes de peau cosmétiques, y compris les dommages causés par les ultraviolets, le vieillissement et la sécheresse cutanée.

The marine environment represents an underexploited resource for the discovery of novel products, despite its high level of biological and chemical diversity. With increasing awareness of the harmful effects of chronic ultraviolet exposure, and a universal desire to improve cosmetic appearance, the market for new cosmetic ingredients is growing, and current trends have generated a greater demand for products sourced from the environment. A growing number of novel molecules from marine flora and fauna exhibit potent and effective dermatological activities. Secondary metabolites isolated from macroalgae, including carotenoids and polyphenols, have demonstrated antioxidant, anti‐ageing and anti‐inflammatory activities. In addition, marine extremophilic bacteria have recently been shown to produce bioactive exopolymeric molecules, some of which have been commercialized. Available data on their activities show significant antioxidant, moisturizing and anti‐ageing activities, but a more focussed investigation into their mechanisms and applications is required. This review surveys the reported biological activities of an emerging and growing portfolio of marine molecules that show promise in the treatment of cosmetic skin problems including ultraviolet damage, ageing and cutaneous dryness.

Introduction Increasing antibiotic resistance and incidence of infectious disease is a serious and growing concern 1-4. Crucially, the skin offers a primary barrier to infection 5 by providing a semi‐permeable surface allowing the passage of materials into and out of the body. The skin also provides a barrier to excessive water loss 6-8, which is important in maintaining tissue hydration as well as cutaneous health. Should this primary barrier become compromised, the body may be more susceptible to infection; therefore, preserving the health, integrity and function of the skin is vital. However, maintaining healthy skin is problematic due to several damaging factors, which can lead to cosmetic issues that affect the overall complexion of the skin. Wrinkles, skin laxity, abnormal pigmentation and skin dryness can be artefacts of harmful oxidative molecules that originate internally and externally, and may become more apparent with age. In youthful skin, dryness is generally caused by low humidity, leading to failure of normal desquamation and disrupted production of the natural moisturizing factor of the stratum corneum 9, whereas an ageing‐related reduction in integral dermal skin matrix molecules further contributes to laxity and dryness 10, 11. Thus, there is a growing and unmet need for new cosmetic active ingredients that can alleviate these problems. Increasingly, the analysis and characterization of active substances from biologically derived materials, in particular plant‐derived substances, are being reported 12-15. The marine environment is also being recognized as a promising source of cosmetic ingredients, due to its unrivalled biological and chemical diversity 16-18. Several bioactive molecules from marine organisms have been shown to enhance the cosmetic appearance of skin through antioxidative, moisturizing and anti‐ageing actions. This review discusses the current applications and prospects for marine‐derived molecules in cosmetic applications.

Photoprotective molecules Increased awareness of the harmful effects of ultraviolet radiation (UVR) has generated a greater demand for photoprotective products. Chronic exposure to UVR is known to cause skin cancer, photo‐ageing and sunburn 19-23. UVA and UVB can damage skin cell DNA 24, 25, increasing the risk of skin cancers via gene mutations 20, 26 and immunosuppression 21, 27. Although the best way of avoiding UV damage is to avoid sunlight, this is not always feasible. Frequent use of antioxidant UV protectants is essential to lessen skin damage; otherwise, treatments exist to combat the resulting skin problems associated with excessive UV exposure. The term ‘antioxidant’ encompasses a broad range of molecules with several activities, including photoprotection, and scavenging/immobilizing of reactive oxygen species (ROS), thus preventing oxidative damage to cell components. As the body ages, its ability to regulate ROS decreases, whereas the production of mitochondrial ROS increases 28, meaning tissues are more susceptible to oxidative stress with age. Several antioxidants exist in the pharmaceutical, cosmetic and food industries, including the marine exopolysaccharide (EPS) deepsane. Deepsane was isolated from the deep‐sea marine bacterium Alteromonas macleodii, from a hydrothermal vent polychaete Alvinella pompejana, close to the East Pacific rise at 2600 m 29. Two oligosaccharides within the EPS were found to protect epidermal keratinocytes and Langerhans cells from inflammatory mediators, including UVR 30. Deepsane has been marketed as Abyssine® by Lucas Meyers as the first commercialized marine EPS 12, 31. The chemical structure of this unusual polysaccharide has also been reported 32. It contains, for example, an unusual trisubstituted galacturonic acid and represents one of the most complex carbohydrate structures so far reported. It was found to contain seven types of monosaccharides, with considerable variability of the repeating unit 32. Progress towards its full chemical structure determination and analysis of its constituent oligosaccharide components will add in developing a mechanistic understanding of its cosmetic activities. This exciting discovery highlights the great chemical complexity that exists in the marine environment, with extremophilic bacteria offering a platform for the future discovery of new cosmetic molecules with novel structures and functions. Several other marine molecules (summarized in Table 1.) including mycosporine‐like amino acids 33-36, carotenoids 37-39 and polyphenols 40-46 have also shown antioxidant activity. Table 1. The marine molecules, their sources, actions and limitations explored in this review Molecule class Bioactive molecule(s) Source(s) Action(s) Type of data presented Limitation(s) References Ultraviolet damage Mycosporine‐like amino acids Mycosporine‐glycine:valine Palythoa tuberculosa, Porphyra tenera, Lissoclinum patella Antioxidant: lipid peroxidation, radical scavenging, antibacterial In vitro High reactivity, instability 62 33, 36, 34, 35 Porphyra‐334, shionine, palythine Porphyra umbilicalis Antioxidant: photoprotection, antiaging Commercialised (Helionori®, Helioguard 365®) N/A 57, 64 13‐O‐(β‐galactosyl)‐porphyra‐334 Nostoc sphaericum Antioxidant: radical scavenging, UV protective In vitro Preliminary data 36 Carotenoids Astaxanthin, zeaxanthin, lutein/lutein B, Tunaxanthin, Halocynthiaxanthin, fucoxanthin, β‐carotene Agrobacterium auranitiacum, Haematococcus pluvalis, Pneuoatophorus japonicas, Oncorhynchus mykiss, Sehola quinqueradiata, Undaria pinnatifida Antioxidant: radical scavenging In vitro, some in vivo Mostly in vitro data, low bioavailability 66 in vivo trials 39 37-39 Polyphenols compounds Unspecified flavonoids/tannins Lithrum salicaria, Frankenia pulverulenta, Pistacia lentiscus, F. laevis Antioxidant: radical scavenging, metal chelation In vitro Potential cytotoxicity 71 69 Phlorotannins: diphlorethol, triphloroethol, trifuhalol and tetrafuhalol, phloroglucinol, eckol, eckstolonol Halidrys siliquosa, Ecklonia cava, Ascoseira mirabilis, Cystosphaera jacquinotii, Ishige okamurae Antioxidant: UV protective, radical scavenging In vitro, some in vivo Mostly in vitro studies, in vivo study conducted on zebrafish 45 42-46, 79 Hyperpigmentation Polyphenols compounds Unspecified flavonoids and tannins, phlorotannins: phloroglucinol, eckstolonol, eckol, phlorofucofuroeckol, dieckol Sargassum polycystum, Ecklonia stolonifera, E. cava, S. silquastrum Tyrosinase inhibition, anti‐melanogenesis In vitro, some in vivo Cytotoxicity 97 in vivo study conducted on zebrafish 45 97-99 Unspecified flavonoids and tannins Pistacia lentiscus Tyrosinase inhibition In vitro Preliminary data, yet to be confirmed in vivo 69 Sulphated flavonoid: luteolin 7‐sulphate Phyllospadix iwatensis Preliminary data 101 Polysaccharides Sulphated polysaccharide: fucoidan Fucus vesiculosus Indirect anti‐melanogenesis In vitro Trials on non‐human cells 103, 104 Aging Proteins and peptides Marine collagen Fish skin/bone, echinoderm tests, cnidarians, cephalopods Alternative to terrestrial collagen N/A Not hailed as antiaging remedy, terrestrial collagen unclear antiaging mechanism 127-135 Unspecified serine endo‐protease, oleic acid, linoleic acid Salmo salar Wrinkle reduction, anti‐erythema, pigment correction, skin hydration Commercialised: Zonase enzyme N/A 141 Tripeptide containing arginine‐glycine‐aspartic acid Ulva lactuca Induced collagen 1 synthesis via TGF‐p pathway In vitro Lack of recent literature 151 Unspecified peptide extracts Chlorella vulgaris, Ulva pertusa Reduced expression of MfvlP‐1, induced collagen I synthesis In vitro Lack of recent literature 145, 146 Polysaccharides Sulphated polysaccharide: fucoidan Undaria pinnatifida, Fucus vesiculosus Collagenase and elastase inhibition, SIRT1 upregulation Few in vitro and in vivo trials In vivo trials less significant 139, 140 Carotenoids Astaxanthin Haematococcus pluvialis, Euphausia superba Decreased TEWL, wrinkle reduction, improved elasticity, skin hydration, improved age spots, murine MMP‐13 suppression Clinical trials, in vivo (murine) Majority of literature from one research group, mechanism of action not clear in human trials 147-153 Dry skin Fatty acids Omega‐3 and ‐6 oils, EPA, DHA Several species of marine and freshwater fish, Loligo loligo Reduced irritation and TEWL, skin hydration In vivo (murine) Not trialled as topical treatment 164-167, 173 Fish oil wax ester containing fatty alcohols/acids Hoplostethus atlanticus Skin hydration Clinical H. atlanticus vulnerable to exploitation 172 170 Proteins Marine collagen Nemopilema nomurai, Chondrosia reniformis Moisturising, increased skin lipid content In vitro Preliminary data, prospective outcomes, insolubility 116 121, 182 Polysaccharides Bacterial EPS Polaribacter sp. SM1127, Phyllobacterium sp. Water absorption, humectant N/A No in vivo or in vitro data available 195, 196 Vibrio diabolicus Stimulated HA synthesis and fibroblast proliferation, skin hydration, neuronal exocytosis inhibition In vitro Only patent literature available 197 Unspecified marine bacteria Antiaging, moisturising Commercialised: (Hyanify™, Hyadisine®) No supporting literature 198, 199 Mycosporine‐like amino acids Mycosporine‐like amino acids (MAAs) are protective secondary metabolites commonly produced by marine organisms under high UV stress, including cyanobacteria, macro‐ and microalgae 47, 48. These compounds absorb UVR of 310‐360 nm 49 and avoid the production of ROS by dissipating the absorbed energy as heat 49-51. Karentz et al. 52 hypothesized that Antarctic organisms produce biological sunscreens due to ozone‐related increases in UVR levels 53-55. Fifty‐seven species were collected, including fish, algae and invertebrates, 90% of which contained MAAs. It was highlighted that whereas plants are known to synthesize MAAs, marine animals bioaccumulate MAAs from their diet; therefore, their exploration as UV protectants may be better focussed on marine algae, where high MAA content has been frequently reported in the Rhodophyta 56-59. In particular, MAAs containing mycosporine‐glycine: valine have shown most promise as antioxidants as they can scavenge superoxide anions 33, 36 and impede lipid peroxidation 34, 35, which otherwise promotes membrane lipid damage 60, 61. Despite these potent activities, few MAAs have reached the cosmetic market, due to high reactivity and instability 62. Cosmetic formulations containing MAAs (porphyra‐334, shinorine and palythine), isolated from the rhodophyte Porphyra umbilicalis, have reached the cosmetics market under the trade names Helionori® and Helioguard 365® 63. Some peer‐reviewed data have been published on their actions, suggesting photoprotective and anti‐ageing properties 64, and some commercial literature has also been reported. However, more robust biochemical data are needed to understand the underlying mechanisms of action. Carotenoids The inhibition of lipid peroxidation is also a function of carotenoids. Shimidzu et al. 37 isolated several carotenoids from various marine organisms which exhibited 40‐600 times greater antioxidant activity against the superoxide anion producer 1,4‐dimethylnaphthalene, than the commercially available antioxidant α‐tocopherol. Similarly, the carotenoid fucoxanthin, extracted from the phaeophyte Undaria pinnatifida, has shown 13 times greater scavenging ability of hydroxyl radicals (HO•) than α‐tocopherol 38. In addition, marine‐derived carotenoids astaxanthin, zeaxanthin, fucoxanthin, β‐carotene and lutein, have exhibited potent ROS scavenging activity in vivo 39, greater than that of known antioxidants. Astaxanthin was 94 times more effective at scavenging hypochlorous acid (HOCl) than both α‐tocopherol. Zeaxanthin and lutein were also highly effective at scavenging HOCl which act in accord with ROS to cause oxidative stress to cell components 65. Despite these data suggesting that several marine carotenoids are efficient antioxidants, few are present in topical cosmetics or sunscreens, due to a lack of promising data from in vivo trials. Oral supplements containing marine antioxidants to improve skin health have scarcely reached the cosmetic market due to their low bioavailability 66. The absorption efficiency and biocompatibility of marine carotenoids on the skin are yet to be determined and will be crucial in understanding their true potential as antioxidant sunscreen ingredients. Polyphenolic compounds It has been recognized for several decades that polyphenols from terrestrial plants have antioxidant properties 67. More recently, marine plants have been highlighted as a viable source of unique polyphenolic antioxidants, due to their easy production and maintenance 68. Polyphenols are aromatic secondary metabolites derived from plants with benzene ring structures attached to at least one polyphenolic hydroxyl group (Fig. 1) and encompass flavonoids and tannins 41. Polyphenolic extracts containing flavonoids and tannins from the halophytes Lithrum salicaria, Frankenia pulverulenta, Pistacia lentiscus and F. laevis, are suggested to have significant antioxidant activities 69. During in vitro radical scavenging and metal chelation assays, these polyphenolic extracts were effective at low concentrations allowing 50% of maximal oxidative inhibition (ranging from 0.03 to 0.50 mg mL−1), in free radical solutions 69. Ferrous iron (Fe2+) is able to transfer single electrons to hydrogen peroxide to form HO• 40, 70; therefore, its chelation is considered a promising route in the inhibition of free radical activity 71. It has, however, been reported that some metal chelators show cytotoxicity 71, and several plant‐derived antioxidants have been shown to cause allergic reactions 72, 73; thus, the safety profile of these extracts would need to be determined in vivo to determine their commercial viability. Figure 1 Open in figure viewer PowerPoint Chemical structures of a simple phenol and polyphenol phlorotannins. Phlorethols: diphlorethol and triphloroethol, eckol: dieckol, and fuhalols: trifuhalol and tetrafuhalol. The fuhalol structures shown here are the A isomers. Marine algae have been shown to produce polyphenolic compounds collectively known as phlorotannins, which have unique chemical structures (Fig. 1) due to the extreme environments in which they are found 74-76. These compounds are thought to make efficient antioxidants due to the large number of hydroxyl groups present in their structures (Fig. 1), capable of donating protons 77, 78. Recently, novel extracts from the phaeophyte Halidrys siliquosa containing phlorotannins diphlorethol, triphloroethol, trifuhalol and tetrafuhalol, showed their radical/superoxide scavenging ability was positively correlated with the total phenolic content of the extract 44. Other phaeophyte phlorotannins have been reported to show UV screening 43, 79, cellular damage reduction 80, ROS scavenging 42, 43 and antioxidative effects 45, 46, with most cosmetic interest from Ecklonia cava phlorotannins. Overall, it can be concluded that marine antioxidants show promise in the prevention of UV‐related skin damage. Nevertheless, there is a surprising lack of their incorporation into skin products. This may be due to greater interest in marine antioxidants as anti‐cancer molecules 67 than for UV protection, as this is considered a more crucial avenue of antioxidant research. Several of the explored antioxidants have dual cosmetic function, such as polyphenolic compounds which have exhibited antioxidant, anti‐bacterial, anti‐pigmentation and anti‐ageing activities 44, 81, 82; therefore, the current knowledge is essential to progress to in vivo trialling and for the development of these compounds as new cosmetic ingredients.

Anti‐pigmentation molecules Hyperpigmentation is a common symptom of ageing and chronic ultraviolet (UV) exposure, often appearing as abnormal brown patches of skin, particularly in areas frequently exposed to the sun 83, 84. The production of melanin occurs in the melanocytes of the epidermis via a series of oxidation reactions, catalysed by metalloenzyme oxidase: tyrosinase. Tyrosinase catalyses the conversion of L‐tyrosine to dihydroxyphenylalanine (DOPA) and the conversion of DOPA to quinone 85, 86 – two important steps in melanin synthesis that limit the rate of production. As the body ages, the distribution of DOPA‐positive melanocytes becomes less even as their frequency decreases 83, 87, meaning remaining areas of high melanocyte density are likely sites of discoloured skin. Consequently, a common route of hyperpigmentation treatment is via the inhibition of tyrosinase 88. Current topical inhibitors: hydroquinone (HQ) – a phenol – and kojic acid (KA) 89 have been reported to cause irritation, erythema and contact dermatitis 90-94; therefore, alternative tyrosinase inhibitors are being explored 95, with the skin‐whitening industry predicted to be worth USD 23 billion by 2020 96. Polyphenolic tyrosinase inhibitors derived from marine plants and algae have shown moderate success 95. Phlorotannins from the phaeophyte Sargassum polycystum have shown potent anti‐melanogenesis/skin‐whitening effects in both cell‐free mushroom and cellular tyrosinase assays 97. Tyrosinase activity and melanogenesis were inhibited in murine B16F10 melanoma cells, comparable to KA, and the extract displayed cytotoxicity at doses greater than 100 μg mL−1, although this may not represent its cytotoxicity profile in human cells. This is consistent with similar studies on the activities of polyphenolic extracts from other phaeophytes: Ecklonia stolonifera, E. cava and S. silquastrum 98, 99. Phlorotannin dieckol, extracted from E. stolonifera, has shown anti‐tyrosinase activity three times that of KA 95. It is thought that cellular tyrosinase assays produce more reliable results than cell‐free tyrosinase assays, due to differences in the origins of plant and animal cell tyrosinases 97. Therefore, results obtained from mushroom tyrosinase assays 98, 99 may not be analogous to human cell equivalents and should be cautiously interpreted. Recently, other marine plants and their polyphenolic compounds have been identified as potential tyrosinase inhibitors, in assays using human cell lines. Lopes et al. 69 demonstrated the inhibition of tyrosinase on both human and murine cells, using phenolic extracts containing flavonoids and tannins from the halophyte Pistacia lentiscus. It was thought that the high concentrations of flavonoids within its leaves are responsible for its anti‐tyrosinase action 100, showing potential in the treatment of pigment‐related issues; however, this is yet to be confirmed in vivo. Similarly, phenolic extracts from 50 marine algae have been shown to inhibit tyrosinase activity of human epidermal melanocytes 101. The most effective tyrosinase inhibitor was the sulphated flavonoid luteolin 7‐sulphate (Fig. 2), isolated from the seagrass Phyllospadix iwatensis, which showed up to 100% greater inhibition than commercial inhibitor arbutin, in addition to low cytotoxicity. It is reported that compounds which possess a 4‐substituted resorcinol skeleton (highlighted in Fig. 2) exhibit great tyrosinase inhibition as this region competes for DL‐DOPA inhibition 102, leading to decreased melanin production. This highlights a promising foundation of anti‐melanogenesis research, where several polyphenols and flavonoids are emerging as novel cosmetic and pharmaceutical ingredients, but mainly as antioxidants and photoprotectants 83, 84. Figure 2 Open in figure viewer PowerPoint Chemical structure of the sulphated flavonoid, luteolin 7‐sulphate. The active 4‐substituted resorcinol region is highlighted. Fucoidan, also a phaeophyte secondary metabolite, has been documented as a potential anti‐pigment treatment, with evidence for its mechanism of indirect melanogenesis inhibition 103, 104, but has not yet been pursued as a cosmetic ingredient. Song et al. 103 reported that this sulphated polysaccharide from phaeophyte Fucus vesiculosus downregulated melanin synthesis via the activation of the extracellular signal‐related kinase (ERK) pathway, which has been shown to cause the degradation of microphthalmia‐associated transcription factor 105 – which is involved in melanin production 106. This was shown using Mel‐Ab cells – a murine melanocyte cell line which is particularly efficient in producing melanin 107. The addition of potent ERK inhibitor PD98059 caused the resumption of melanin production, illuminating the anti‐melanogenesis mechanism of fucoidan. Like the previous studies 97-99, in vitro assays were conducted on non‐human cells; thus, the effect of fucoidan as an anti‐pigment treatment is yet to be determined in human trials. Although the cosmetic treatment of hyperpigmentation using marine molecules has been explored, the data are preliminary. Other cosmetic and ageing‐related issues, such as wrinkles, loss of elasticity and dry skin, are considered to have a broader impact; for example, two‐thirds of cosmetic sales were attributed to anti‐ageing and moisturizing products in 2012 108.

Anti‐ageing molecules With ever‐increasing life expectancies in several countries around the world, the physical appearance of ageing is becoming an increasingly common cosmetic issue 109. Ageing is generally associated with the formation of wrinkles, skin laxity, and hyperpigmentation 110-112 and can commonly be classed as long‐term damage from various stressors. Damage to dermal cellular proteins, responsible for the synthesis of structural components, can lead to the propagation of these characteristics associated with ageing 113, 114. Whereas the aforementioned antioxidants may delay the appearance of ageing, other treatments exist to lessen the symptoms of aged skin (Table 1.), for example wrinkle reduction, increased cutaneous hydration and collagen replenishment, where chronological ageing may be caused by the slowing of cellular processes 113, 115 and the resulting progressive loss of key dermal skin matrix molecules such as collagen and hyaluronic acid 10, 11, 116. Collagen Despite the crucial role of collagen as a structural skin protein, its efficiency as an active ingredient in topical moisturizers is not well supported. Terrestrial collagen and its derivatives have been shown to induce keratinocyte proliferation in vitro 117, 118, and reduce UVB photo‐ageing 119, increase dermal fibroblast density and improve collagen fibril structure 120 as oral supplements in vivo. Interestingly, the use of collagen from marine sources in cosmetic products is increasing 12, 121-126. Large quantities of collagen have been extracted from marine biomass (Fig. 3) 127-135. In addition, biocompatibility studies have shown that marine collagen exhibits lower cytotoxicity and greater cell viability than bovine collagen in tissue engineering assays 126. Although not directly linked to cosmetic applications, this demonstrated biocompatibility suggests that the cosmetic applications of marine collagen are likely to grow in the future. Figure 3 Open in figure viewer PowerPoint 127-130 134, 135 131 132, 133 Approximate dry mass yields of collagen from different marine sources; fish skin and bone, cephalopods, echinoderm testsand cnidarians Available scientific data on topical collagen anti‐ageing effects are negligible, which is surprising considering its widespread application in several products 136. Therefore, the aim of future cosmetic collagen research should be based upon understanding its mechanisms as an anti‐ageing ingredient, where the available data on marine collagen extraction provide good preliminary data on potential collagen sources. Alternatively, the inhibition of the degradative enzymes, collagenase and elastase, can counteract the process of ageing. This has been demonstrated successfully using several terrestrial plant extracts 137, 138, but marine sources have received less attention. Recently, sulphated polysaccharide fucoidan was obtained from the phaeophyte Undaria pinnatifida and was shown to inhibit bacterial collagenase and human neutrophil elastase in vitro 139. Additionally, a polyphenolic extract, containing fucoidan from the phaeophyte Fucus vesiculosus, showed significant inhibition of elastase in vitro 140. Further in vitro assays showed that both extracts upregulated the SIRT1 protein, which causes the skin to appear more youthful by catalysing the breakdown of sugars and lipids 140. Despite this success, it was noted that these results may not represent the true effects achieved in clinical trials, of which initial results were less significant in vivo. Enzymes and peptides A novel enzyme isolated from the eggs of Atlantic salmon, Salmo salar has been explored as a skin rejuvenation/anti‐ageing ingredient 141. The serine endoprotease (named Zonase) is used to break down the eggshell during hatching, leaving the embryo intact. It is also shown to be capable of enzymatic exfoliation of dead keratinocytes whilst stimulating new skin cells to grow. Lønne et al. 141 demonstrated that topical application of S. salar egg extract promoted wrinkle reduction, anti‐erythema, even pigmentation and improved cutaneous hydration, without any adverse side effects. The extract contained unsaturated fatty acids, proteins, DNA, RNA, vitamins and minerals. It was speculated that the fatty acids (e.g. oleic acid and linoleic acid) increased transdermal absorption, allowing active ingredients to penetrate the dermis. The anti‐wrinkle activity was the most potent effect observed and was hypothesized to be an effect of vitamin A, amino acids, zinc and copper, which aid in maintaining skin elasticity and structure of the extracellular matrix 142, 143, subsequently reducing wrinkle formation and laxity. Zonase enzyme from S. salar egg extract is available in several cosmetic products due to its effective anti‐ageing mechanisms and simple recovery as a waste product from the salmon egg processing industry. Macroalgae are also a rich and sustainable source of amino acids and peptides, of which some chlorophyte peptides have been shown to protect collagen stores and enhance collagen synthesis. A tripeptide containing an arginine–glycine–aspartic acid sequence, from the chlorophyte Ulva lactuca, has been reported to stimulate collagen synthesis in human fibroblasts 144. In addition, peptides from Chlorella vulgaris have been shown to reduce matrix metalloproteinase‐1 (MMP‐1) expression in human skin cell fibroblasts 145, responsible for the breakdown of collagen. Similarly, hydrolysed U. pertusa has also been reported to stimulate type I collagen synthesis in human fibroblast cells via MMP‐1 inhibition 146. Chlorophytes may therefore represent a novel source of proteinaceous compounds with potential as anti‐ageing effects, although it should be noted that these data are preliminary. Astaxanthin Other algal molecules have received attention as potential anti‐ageing active ingredients. Astaxanthin (ASX), for example, belongs to a class of carotenoids present in some species of microalgae and is present in some oral supplements as an antioxidant. In addition to its antioxidant activities, it has been reported to have anti‐ageing actions in both oral and topical administrations 147-153. However, this has not been substantially investigated thus far and the majority of available literature is confined to one research group 147, 149-152. Dietary ASX from the marine microalga Haematococcus pluvialis has been shown to penetrate both the dermis and epidermis in murine trials, leading to a decrease in transepidermal water loss and a visual improvement in the appearance of wrinkles, comparable to untreated controls 153. Orally and topically administered ASX has shown significant visual improvements in the appearance of skin wrinkles, elasticity, age spots and increased cutaneous hydration in clinical trials 150. Although the mechanism of action has not been clarified in human applications, it is suggested that the suppression of MMP‐13 in mice causes the inhibition of anti‐ageing features 153, where MMP‐13 in mice is analogous to MMP‐1 in humans 154. Observed increases in water content of the skin suggest ASX may have applications in dry skin moisturizers as well as anti‐ageing formulae.

Moisturizing molecules Dry skin may be caused by an imbalance or reduction in the natural moisturizing factor (NMF) of the stratum corneum (SC), and a disruption to the usual process of desquamation 9, 155, and is also a symptom of ageing. The NMF is mainly comprised of amino acids, which act to maintain cutaneous hydration, thus allowing for normal desquamation and healthy skin 156, 157. Common treatments of dry skin are topical moisturizers, which contain ingredients to mimic those comprising the NMF 158, or are formulated to encourage the occlusion or attraction of water into the epidermis. Linoleic acid (an omega‐6 fatty acid) acts as a precursor for ceramide lipid molecules, which comprise half of the extracellular lipid matrix 159, an important factor of the SC permeability barrier (SCPB). The SCPB reduces both transepidermal water loss (TEWL) and pathogenic invasion 160-162; therefore, loss of lipid components may cause skin dryness 9, 155, 163. Marine‐derived lipids can aid in preserving skin hydration by maintaining the lipid matrix of the SC 163, 164. Omega‐3 oils, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can be easily extracted from several marine and freshwater fish 165-167, which are naturally enriched in EPA and DHA. Barcelos et al. 164 administered daily omega‐3 fish oils (FOs) to rats and observed the changes in dermal response to skin irritation after 30, 60 and 60 days of supplementation. After 60 days of supplementation, both irritation and TEWL were significantly reduced in response to acetone exposure. After 90 days, TEWL had reduced by 50% compared to the control group without FO. Cutaneous hydration significantly increased by 30% after 60 days of FO treatment which was maintained after 90 days, compared to controls. This supports previous claims that dietary fatty acids are transported to the SC 168, 169 and are able to improve cutaneous health through oral administration; however, this study did not assess the potential of FOs in topical moisturizers. Similarly, the oil of the deep‐sea perch, Hoplostethus atlanticus, has been reported to exhibit moisturizing and emollient abilities comparable to that of petroleum‐based products like Vaseline® 170. The oil produced is a wax ester composed mainly of fatty alcohols and fatty acids 171, and has been reported to improve skin dryness up to 70% as efficiently as petrolatum products 170. However, H. atlanticus is reported as vulnerable to exploitation due to its late maturity, slow growth and low fecundity 172, therefore has not been considered as a sustainable source for skin moisturizing products, despite its significant moisturizing ability. This raises an important issue in recognizing the marine environment as a finite source of new cosmetic discovery, where the sustainability of target organisms should always be considered. Similarly, the oil of squid (Loligo loligo) has been reported as a new source of omega‐3 and omega‐6 oils, where 13% of the wet weight of an adult squid equates to oil, with a high percentage of linoleic acid, EPA and DHA 173. The culturing of squids is yet to be explored; however, Octopus vulgaris aquaculture is currently being developed and has shown some early success 174. Cephalopods are considered good candidates for successful aquaculture, due to their short life spans, early maturity and easy adaptation 175, 176; therefore, this route of production of omega‐3 and omega‐6 oils merits further investigation. Lipids act to retain water by the process of occlusion, whereas humectants such as collagen and its derivatives act differently by attracting water into the epidermis 120, 135, 177. Collagen and collagen hydrolysate are common moisturizing active ingredients 135 with little supporting scientific evidence of their hydrating benefits. Bovine collagen sources are scrutinized due to hygiene concerns, but collagen can be derived from several marine fish 126-129, as well as organisms belonging to the Porifera 120, 178, Echinodermata 130, Cnidaria 179, 180 and Mollusca 133, 134, offering alternative sources 125, where some marine collagen has shown better biocompatibility. It should however be considered that marine collagen also has weaknesses such as a lower degradation temperature 181 and therefore more limited application than bovine sources. Jellyfish collagen is currently being used for wound dressing and scaffolding applications 182. Recently, collagen extracted from the jellyfish Nemopilema nomurai has been proposed to have a significant moisturizing effect, but the data are preliminary 183. Swatschek et al. 120 demonstrated the successful extraction of collagen from the marine sponge Chondrosia reniformis. Thirty per cent yield of freeze‐dried collagen was obtained, and two cosmetic formulae were trialled on human skin. There was no significant difference in skin hydration between the sponge collagen treatments and the existing collagen product control; however, there was a significant increase in skin lipid content of 140–180 μg cm−2, one hour after treatment. Despite these similarities in the efficacies of terrestrial and marine collagen as moisturizers, these preliminary data have highlighted the potential of marine collagen as an additional source of collagen. Skin dryness is also a symptom of ageing, caused by a loss of the glycosaminoglycan (GAG) hyaluronic acid (HA), a major constituent of the dermal skin matrix found in every tissue and body fluid 183. Hyaluronic acid is responsible for water retention, tissue regeneration and protection from ultraviolet radiation (UVR) 184-187, and its epidermal content decreases as the body ages 188, slowing moisture replenishment and tissue repair 10, 11. This reduction also causes loss of skin elasticity, due to the decline in integral linkages between collagen and elastin that are facilitated by HA 189. As a result, there has been an increase in moisturizers containing HA, yet only a few studies support their action of reducing wrinkles and maintaining skin moisture in topical treatment 188, 190; therefore, there is a growing interest in discovering replacement molecules 191. In recent years, alternative water‐absorbing molecules have been investigated from marine sources. Polysaccharides, derived from the Crustacea, Phaeophyta and Rhodophyta, have been shown to possess several desirable cosmetic qualities, such as water retention, anti‐inflammatory, non‐toxic and broad antimicrobial action 192, 193. Conversely, the cosmetic potential of marine bacterial exopolysaccharides (EPS) may rival that of their plant and animal counterparts due to their ease of supply, and biochemical diversity 194 – a result of the extreme environments that they inhabit. Recently, two EPS were isolated from marine bacteria, Polaribacter sp. SM1127 195 and Phyllobacterium sp. 921F 196, which displayed significant water‐absorbing properties that exceeded those shown by common cosmetic humectants, including HA. Furthermore, it has been reported that an EPS produced by Vibrio diabolicus stimulates the production of HA and keratinocytes, increasing the moisture content of the skin, in addition to inhibiting neuronal exocytosis, a process which promotes wrinkle formation and deepening 197. Few examples of marine bacterial EPS have found their way into products, including Hyadisine® and Hyanify™, which are reported to stimulate the production of HA, giving rise to anti‐ageing and moisturizing effects 198, 199, but their underlying mechanisms are not widely reported. With few examples of commercialized bacterial EPS, the scope for discovery of novel extremophile EPS is great, due to their relatively unexplored biochemical diversity. This may offer a promising route to new bioactive molecules with moisturizing or anti‐ageing actions.

Conclusions With the cosmetics market forecasted to be worth USD 430 billion by 2022 200, the need for the discovery and production of new cosmetic molecules is growing. The key active molecules are set to be skincare and antioxidant compounds. There is also growing evidence that the marine environment may serve as a rich source of these substances. A great variety of molecules from marine macroalgae, including carotenoids and polyphenolic extracts, have generated attention due to several cosmetic actions. Their antioxidant, anti‐melanogenic and anti‐ageing properties may find application in a variety of cosmetic and pharmaceutical products. This, coupled with easy production and maintenance of macroalgae, presents an exciting and viable source of cosmetic discovery. Marine fish have received less attention as a source of cosmetic ingredients, but are also producing molecules showing promise for applications such as antioxidants, moisturizing and anti‐ageing compounds. Several fish species have exhibited high content of essential fatty acids which have shown potential as moisturizing ingredients. In addition, high collagen extraction yields from marine fish and other marine organisms have provided a platform for the easy production and application of marine‐derived collagen. Other marine products include the anti‐ageing enzyme Zonase from salmon eggs and extremophile bacterial EPS compounds which have moisturizing and anti‐ageing properties that rival not only current moisturizing ingredients, but also molecules produced by the skin to maintain hydration. Similarly, halophytes which inhabit extreme saline environments have recently been recognized as a source of tyrosinase inhibitors and antioxidant molecules. Organisms from extreme environments offer access to a unique chemical diversity and therefore may provide an untapped resource for new bioactive molecules with applications in cosmetics. Despite these promising discoveries, the exploitation of the marine environment should be approached with caution, where the sustainability of all potential marine resources being considered. The variety of molecules and compounds described in this review highlight the marine environment as an underexploited resource for cosmetic innovation and discovery and the data presented are crucial in shortening the pipeline to the commercialization of new and effective cosmetic products. Accessing marine chemical diversity is therefore needed to address the large and unmet need for a pipeline of new cosmetically active molecules.

Acknowledgements The authors would like to thank Dr Sara Marsham for the critical appraisal of the manuscript and support throughout.