Abstract
Nutrition is one of the most important parameters involved in modulating skin health and condition. In this regard, the demand for natural compounds capable of promoting skin health and beauty has been attracting the attention of researchers and companies around the world. An interesting option to meet this demand is the use of Spirulina microalga, which has biotechnological potential, including several functional and nutritional applications. Although this microalga has been used in human nutrition since ancient times, it now has new applications and is being studied as a promising ingredient for nutricosmetics. The present review article summarizes Spirulina's most relevant activities, mainly its biologically active metabolites, which are interesting ingredients for nutricosmetic formulations and an important advance for skin care.
Introduction
An increase of life expectancy, which has been observed since the beginning of the 21st century, has emerged as a new preoccupation for industrialized countries and for nutritional science because it is one of the challenges in offering new strategies to improve the quality of human life. The aging population has also increased interest in products that prolong health and beauty. 1 To benefit facial appearance and improve skin health, ingestion of nutritional supplements has been gaining attention. 2 In the last 15 years, researchers and companies around the world have been investing in scientific research seeking solutions for well-being and skin health. 3 Advances in research and development of new products have identified microalgae as a means to improve skin health and protection. 4
Microalgae are a diversified group of prokaryotic and eukaryotic photosynthetic microorganisms. Prokaryotic microalgae are called cyanobacteria. Spirulina is a photosynthetic, multicellular, filamentous and spiral cyanobacterium (Fig. 1) produced on a large scale. This microalga stands out for its high protein content and the presence of essential fatty acids, vitamins, and minerals. The diversity and versatility of Spirulina promotes its application in a wide range of industrial products, from lower-value biofuels to high-value food supplements and cosmetics. 4–5 The present review article summarizes Spirulina's most relevant activities, mainly its biologically active metabolites, which are interesting ingredients for nutricosmetic formulations and an important advance for skin care.

Spirulina sp. LEB 18 from LEB/FURG strain bank. Image magnification 400 ×.
Human Skin and Aging
Human skin is composed of two layers, the epidermis and dermis, and each one displays distinct structural and physiological functions. 6 The epidermis is the most exposed part of the skin to the external environment. Its main function is to protect the skin from potentially dangerous environmental threats and to provide biochemical, chemical, physical, and immunologic barriers. Below the epidermis is the dermis, which is a layer of connective tissue, that provide mechanical, compact and flexible support function to the skin. 7
Tissues gradually change over time. These alterations are easily recognized in human skin. 8 The skin aging process occurs through two biologically divergent mechanisms: chronological aging and photoaging. 9 Chronological aging is an irreversible phenomenon that includes several factors such as genetics and hormonal and metabolic processes, when the repair machinery may become dissatisfactory. The repair process plays an important role in the prevention of aging. When damaged skin cells are not repaired, mutations may occur, which results in premature aging. 10
Unlike chronological aging, photoaging is an avoidable phenomenon. 11 It is caused by environmental exposure, mainly by long-term, inadequate protection from solar ultraviolet radiation (UVR) or UV light from artificial tanning sources. 12 Skin effects promoted by UVR are cumulative and depend on duration, frequency and intensity of exposure along with the natural protection of the skin. 13 Photoaging is responsible for 80 to 90% of skin aging and is a consequence of the deleterious effects of the sun. 14
UVR induces matrix metalloproteinases (MMPs), which are responsible for degradation of collagenous in the extracellular matrix (ECM). On the molecular level, UVR attacks keratinocytes and fibroblasts, which results in activation of the cell surface receptors that initiate signal transduction cascades. This, in turn, leads to a variety of molecular changes and causes the breakdown of collagen and a decrease of collagen synthesis. 15 It is assumed that dermal collagen breakdown is followed by imperfect repair and yields a deficit in structural skin integrity, the formation of a solar scar, and ultimately, atrophy of clinically visible skin with formation of deep furrows and wrinkles. 13 Other clinical signs of photoaging include atypical pigmentation, loss of elasticity, leathery appearance, laxity, dryness, loss of the skin tone, and rough-textured appearance. 6,16 Sun-exposed skin areas, including the forearms, hands, neck, upper chest, and face are the places where these changes occur most often. 16 Another process of UV-induced skin damage is photocarcinogenesis. 17 UVR induces (direct or indirectly) a variety of DNA damage, including cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). 18–19 Others damages, such as DNA-protein cross-links, DNA strand breaks, 8-oxo-7,8-dihydroguanine (8-oxo-dG), oxidized pyrimidine bases, thymine glycols, purine damage, and cytosine damage can also be generated. 20 –23
These damages occur, in large part, by the generation of free radicals, especially reactive oxygen species (ROS). ROS production, due to intracellular and extracellular oxidative stress, is considered the main cause of aging. 24 In the skin, from 1.5 to 5% of the consumed oxygen is converted into ROS by intrinsic processes. 25 ROS are constantly generated in keratinocytes and fibroblasts and are rapidly removed by non-enzymatic and enzymic antioxidant substances to prevent the living system from the harmful effects of free radicals. 26 However, when produced in excess, they can damage all cellular components. 27 ROS can also induce signaling pathway activation related to cell (or tissue) growth, differentiation, senescence, and connective tissue alterations. 28
Nutricosmetics
Nutricosmetics may be defined as nutritional supplements. They are concentrated sources of nutrients or other substances used to improve skin health and facial appearance. 29 This concept was formed by the intersection of the terms nutraceuticals and cosmeceuticals. 3 According to DeFelice, a nutraceutical is “any substance that is a food or part of a food that provides medical or health benefits, including the prevention and/or treatment of diseases”, 30 whereas a cosmeceutical is a cosmetic product formulated with bioactive ingredients that promotes benefits beyond traditional cosmetic cream. 31 Although the term nutricosmetic is used extensively in the personal care segment, this term together with “nutraceutical” and “cosmeceutical” is not recognized under any categories of food, drugs and cosmetics by the Food and Drug Administration (FDA). 32,33
Despite being relatively new, nutricosmetics are a market trend with exponential annual growth. 34 This reflects that people are becoming aware of nutritional products that not only contribute to general health and disease prevention but also to skin health. 3 It is well known that skin functions and healthy appearance depend on a sufficient supply of essential nutrients, and diet strategies are more effective when used against skin aging caused by environmental factors. 35,36 The understanding of bioactive molecule effects in skin functions have stimulated interest in developing nutritional supplements and functional foods aiming to benefit human skin. Nutricosmetics may act on skin (pigmentation, whitening, prevention, and repair), nails (strengthening), and hair (restoration, growth, and nourishment). Ingredients used in nutricosmetics should be safe, and in general, they mostly have antioxidant and anti-inflammatory functions. 37
Some of the most popular ingredients applied in nutricosmetic formulations (Table 1) 40 –56 involve combinations of micronutrients, vitamins, polyunsaturated fatty acids (including linoleic and γ-linolenic), amino acids, carotenoids, and polyphenols, 38 all of which can be found in varying amounts in Spirulina, with the exception of Vitamin D. Effective forms for oral delivery of Spirulina biomass or extracts are those common for other nutricosmetics, including market products or do-it-yourself recipes such as soups, yogurts, jams, chocolate, cereal bars, and beverages, capsules or tablets. 37,39
Compounds Naturally Present in Spirulina Microalga (Exception—Vitamin D) with Nutricosmetic Functions
Spirulina Microalga
Spirulina has been used as a source of several nutrients since ancient times. This microalga is known as a superfood due to the diversity and the concentration of its nutrient content. It is easily digested and absorbed in the human body because its cell membrane does not contain cellulose. On dry weight basis, its biomass is composed of more than 60% protein, the rest being composed of carbohydrates and fats. Spirulina also has relatively low nucleic acids content even though it is rich in pigments, vitamins, and minerals. 57
The increasing scientific and clinical evidence for Spirulina's nutritional and potential health benefits has been attracting its use in several food applications, such as pasta, instant soup, food bars, cereals, crackers, corn chips, popcorn, snack foods, frozen desserts, muffins, donuts, salad dressing, confectionary, juice smoothies, and even specialty beer. 5 This microalga has been granted Generally Recognized as Safe (GRAS) status by the FDA. 58 This status allows Spirulina to be legally marketed as a food supplement or as a bioactive ingredient in functional foods and beverages. 59 Other applications of Spirulina biomass or its bioactive metabolites include animal feed, coloring for food and cosmetics, and purified biomolecules. 4
Several companies have produced and commercialized Spirulina for human nutrition. The world's largest producers are located in United States and Asia. In United States, large scale-production began about 40 years ago by Earthrise (Irvine, CA) and Cyanotech Corporation (Kailua-Kona, Hawaii).
5
Years later, other countries initiated Spirulina production, in particular, India.
4
Indian producers include Parry Nutraceuticals (Tamil Nadu,
Spirulina presents a wide range of interesting bioactive compounds (Table 2). 5,39,57,60,61 C-phycocyanin (CPC) is the most abundant accessory light-harvesting pigmented protein found in cyanobacteria. It contains an open tetrapyrrole chromophore and phycocyanobilin, which is covalently linked to apoprotein. Allophycocyanin is also an important phycobiliprotein because it transfers energy to chlorophyll molecules. 62 The promising beneficial properties of Spirulina may be due to its CPC content. 63 In addition, although β-carotene is best known, Spirulina contains an antioxidant rich complex of at least ten carotenoids. The daily intake of 2.5 g of Spirulina would be sufficient to provide a remarkable 5,750 IU (3.5 mg) of β-carotene, corresponding to 115% of the daily recommendation of vitamin A. 57 Carotenoids are often applied in the food and pharmaceutical industries because of its pigmentation ability and antioxidant properties. 60
Bioactive Compounds from the Spirulina Genus
Numerous investigations have shown that Spirulina plays an important role in biological activities, including antioxidant, immunomodulatory, anti-inflammatory, anticancer, antibacterial, and antiviral activities. This microalga also presents positive effects against obesity, malnutrition, diabetes, hyperlipidemia, anemia, and heavy metal chemical-induced toxicity. 5,57,64
What is the Evidence of Spirulina's Role on Skin Aging?
Antioxidant, Anti-Inflammatory, Immunomodulatory and Photoprotective Properties
A balanced diet provides all required nutrients for the proper function of organ or tissue. This is also the case for the maintenance of healthy skin. 65 This can be observed by the development of skin disorders as a response to nutritional deficiencies. Oral supplementation of antioxidants can be a strategy to improve skin conditions in these cases. 66
Due to its bioactivities, Spirulina has been recognized as potential raw materials for making food products for skin care, as observed in clinical studies. 67,68 In previous work of our research team, in a double-blind randomized controlled trial, 45 women aged 40–60 years ingested 2.8g/day of Spirulina. A significant improvement in skin, hair and nails after 90 days of treatment was observed. 68
Bioactive compounds from Spirulina, such as CPC and β-carotene, show promising antioxidant, anti-inflammatory, immunomodulatory, and photoprotective properties. It has been demonstrated in vitro that CPC scavenges peroxyl, hydroxyl, and alkoxyl radicals; inhibits lipid peroxidation; 69 –71 decreases nitric oxide (NO); and suppresses inducible nitric oxide synthase (iNOS). 72 Other investigations have reported that CPC exerts inhibitory effects on tumor necrosis factor-α (TNF-α) and on nitrite levels in serum of mice, 73 and represses pro-inflammatory cytokine expression and secretion (TNF-α, interleukin-1β (IL-1β), and IL-6) in macrophages and splenocytes via inhibition of nuclear factor-κB (NF-κB) pathway. 74
CPC has also been studied as a potential inhibitor of gene expression that regulate factors involved in skin tumorigenesis. Gupta and Gupta have demonstrated that CPC can inhibit cyclooxygenase-2 (COX-2), IL-6, signal transducer and activator of transcription-3 (STAT3) protein, and ornithine decarboxylase expressions after topically administration of CPC in skin mouse. 75 The CPC doses applied ranging from 50 to 400 μg in 200 μL of 50% dimethyl sulfoxide immediately after the application of a potent tumor promoting agent (12-O-tetradecanoyl-phorbol-13-acetate (TPA)). Thus, CPC, a compound with strong anti-inflammatory activity, can act as chemopreventive agent as well. 75 However, it should be noted that gene-expression data from skin models used in drug development may provide indirect evidence of applicability in skin care through nutricosmetics.
Skin cancer is considered a complex and multistep process. 76,77 The study of early alterations in the skin and of the mechanisms involved, as well as the development of novel therapeutic strategies, are of interest for both scientific research and clinical practice. 78 For this reason, the ingestion of bioactive compounds as a nutritional strategy to prevent skin cancer has been studied. 79,80 However, Spirulina has not been extensively studied in relation to its inhibitory effects on UVB-induced skin inflammatory responses and carcinogenesis. 81
A study conducted by Yogianti et al. 81 demonstrated that oral administration of 10% Spirulina can inhibit the development and induction of UVB-induced skin tumors in mice. These suppressive effects on acute response mediated by UVB exposure were confirmed immunohistochemically along with a significant decrease in the pro-inflammatory cytokine expressions, such as IL-1β and chemokine (C-X-C motif) ligand 1 (CXCL-1). Spirulina has also reduced the epidermal 8-oxo-dG formation, indicating that it has exerted a suppressive effect on ROS production caused by UVB in the skin. In addition, this microalga can suppress the phosphorylation of p38 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and extracellular signal-regulated kinase (ERK), demonstrating that it possesses various effective sites for the inhibition of skin tumor development upon UVB exposure. In summary, it is assumed that the combined antioxidant and anti-inflammatory properties of Spirulina exerts antitumor effects against UVB irradiation in the skin and in this way play a role important in prevention of skin cancer. 81 These data support a chemopreventive role of Spirulina with promising potential for broad use in the chemoadjuvant treatment of skin cancer.
Additionally, β-carotene provides protection against singlet oxygen-mediated lipid peroxidation and it has been considered an efficient in vitro membrane antioxidant. 82 Studies also report that β-carotene can downregulate pro-inflammatory markers in response to environmental sources in murine skin; 83 inhibit the nitric oxide as well as prostaglandin E(2) production; and suppress the IL-1β, TNF-α, iNOS, and COX-2 expression in cells and primary macrophages. 84 It is believed that the suppression of these inflammatory mediators promoted by β-carotene is due to inhibition of NF-κB activation by blocking nuclear translocation of NF-κB p65. 84
Antityrosinase Activity
Melanin, which is a major constituent of skin color, is synthesized by a process that involves several chemical and enzymatic reactions called melanogenesis. 85 In this process, tyrosinase is considered the key and rate-limiting enzymatic step of melanogenesis. 86
The accumulation of an abnormal amount of melanin in several parts of the skin results in the development of pigmented patches that might be viewed as an aesthetic problem. The overproduction of melanin and abnormal hyperpigmentation from exposure to UVR may cause increased ROS production, which can lead to various injuries, including inflammation, freckles, melasma, and age spots. 87 This drives research with the goal of identifying effective and safe skin-whitening ingredients.
CPC has been reported as a potential melanin biosynthesis inhibitor. Wu et al. suggested that CPC inhibits melanogenesis by two mechanisms: (1) the suppressed activation of cAMP response element-binding protein (CREB) through the down-regulation of the p38 MAPK pathway and (2) promoted degradation of microphthalmia-associated transcription factor (MITF) via up-regulation of the MAPK/ERK signaling pathway. 88 According to Wu et al., CPC can supply a cellular abundance of cyclic adenosine monophosphate (cAMP), which activates the down-stream MAPK/ERK pathway; as a result, there is a decrease of the MITF. 89 Activation of ERK1/2 results in the phosphorylation of MITF at S73, which induces the subsequent ubiquitin-dependent proteasomal degradation of MITF. Nevertheless, CPC may also exert its negative impact on p38 phosphorylation to restrict the activation of CREB, which results in restricted MITF gene expression. 89
Anti-Collagenase and Anti-Elastase Activities
Fibroblasts are responsible for the production of elastin and collagen, which are indispensable for various protective roles in human skin. Elastin provides elasticity to connective tissues. However, it may be degraded by elastase, a metalloproteinase enzyme. 90 Despite its strong resistance to proteolytic degradation, continuous exposure to elastases causes damage to the elastic fibers and contributes to wrinkle formation. A significant increase of elastase activity has been described with age, and therefore, there has been an increased interest in natural compounds to reduce skin aging and wrinkles. 91 Collagen is the most important ECM component and is responsible for flexibility, elasticity, and skin resistance. Its degradation may be induced by UVR. In the aging process, collagen and elastin levels decrease, resulting in the loss of strength and flexibility and subsequently the formation of wrinkles. 92
MMPs are members of the zinc-endopeptidases family. In normal cells, the expression of MMPs is low, and these low levels allow the remodeling and maintenance of healthy connective tissue. However, in pathological conditions, the level of MMP' expression considerably increases. The result is the degradation of all components of the ECM and the basement membrane. 15,92
MMP-1 is the main metalloproteinase that degrades collagen. Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors whose function is to control undesired expression of MMPs and further protect ECM. ROS generated due to overexposure to UVR stimulates mitogen-activated protein kinases that also stimulate the activator protein factor 1 (AP-1) and leads to the uncontrolled expression of MMPs. In this context, studies have been conducted to find natural inhibitors of AP-1 to inhibit the expression of MMPs. Despite the fact that there are no available reports on the anti-elastase and anti-collagenase activities of Spirulina and its metabolites, evidence of these activities has been found in marine algae 93 and plant extracts. 94 These studies offer an insight and require further investigation on Spirulina microalga to confirm its potential anti-elastase and anti-collagenase activities.
Commercially Available Products with Spirulina-Based Ingredients
Research has been motivated for the development of innovative food and cosmetics that supply protection and improvement of skin health (Table 3). 95,96 The addition of Spirulina in topically applied cosmetic formulations has shown efficacy in young and mature skin care. 95,96 Additionally, Spirulina-based ingredients have the potential for applications in nutricosmetics since this microalga is already legally authorized as a food supplement. 58,59 This market, which is expanding, will likely attract thousands of consumers in the coming years because bioactive compounds used in nutricosmetic formulations may modulate multiple biological functions in the organism.
Example Products with Spirulina-Based Ingredients Showing Different Skin Benefits and Ingestible Product Presentations
Conclusions and Future Perspectives
In conclusion, ingredients with bioactive functionalities play a fundamental role in skin health and protection with the goal of minimizing multiple damages that occur during the process of human aging. Ingestion of nutricosmetics containing Spirulina or its constituents, especially C-phycocyanin and carotenoids, may configure an attenuation therapy of these damages. Several activities of Spirulina, including antioxidant, anti-inflammatory, and immunomodulatory activities, have been well investigated in recent years. However, there is still a lack of research regarding elastase, collagenase and tyrosinase inhibition. The currently observed beneficial effects make Spirulina and its metabolites promising ingredients for nutricosmetics formulations and may provide protection and skin health benefits.
Footnotes
Acknowledgments
The authors would like to thank the Coordination for the Improvement of Higher Education Personnel (CAPES) and the MCTIC (Ministry of Science Technology, Innovation and Communications).
Author Disclosure Statement
No competing financial interests exist.
