Elaine Cristina Faria Abrahão Machado1, Letícia Ambrosano1, Renan Lage1, Beatrice Martinez Zugaib Abdalla2 and Adilson Costa1, 1Catholic University of Campinas, Campinas, SP, Brazil, 2ABC School of Medicine, Santo Andre, SP, Brazil
Dermatologists are increasingly seeking the best way to prevent or reverse symptoms and signs of skin aging. Aside from classical dermatological procedures such as peels, aesthetic surgery, lasers, fillers, and the use of botulinum toxin, among others, oral supplements that could enhance beauty—what are now known as nutraceuticals—have been used the most. From the basic, preliminary concept of vitamin C as the most important factor involved in collagenesis up to the use of omega fatty-based compounds, patients have been prescribed with an interesting and clinically active arsenal of nutraceuticals not only to prevent the effects of aging but also to work as adjuvants toward that end. From the past shadow of criticism to the days of methodologically well-designed studies, such systemic “beauty” compounds have garnered a spotlight among all cosmetic prescriptions. This chapter will comprehensively approach the use and clinical indications for several prescribed nutraceuticals in dermatological clinical practices in the hope of helping physicians in their clinical routines provide a better look at patients’ skin.
Aging skin; photodamage; nutraceuticals; polyphenols; vitamin C; probiotics; Polypodium leucotomos
Skin aging is a multifactorial process related to the continuous reduction of size and the number and physiological functions of cells at the molecular level (Ramos-e-Silva and Carneiro, 2001). This process involves intrinsic (genetic and hormonal) and environmental factors (e.g., exposure to sunlight and pollution) as well as lifestyle factors (Rexbye et al., 2006).
A nutraceutical is a food or part thereof that provides health benefits, including prevention and treatment of diseases. Nutraceuticals can be isolated nutrients, dietary supplements, herbal products, or processed foods such as cereals, soups, and beverages, or even capsules, tablets, and powders (Kwak and Jukes, 2001). A related category, nutricosmetics, has products that meet the concepts of nutrition, health, and beauty. The active form of a nutraceutical is administered orally (Tabor and Blair, 2009).
Skin cells are constantly exposed to harmful processes that are mediated by reactive oxygen species (ROS) and oxidative stress, inflammation, and photodamage (Indo et al., 2015).
Oxidative stress is damage caused by reduction–oxidation products and an increase in the number of free radicals—molecules with unpaired electrons—that associated with a reduction in the number of antioxidants (Powers and Jackson, 2008). The most important types of free radicals are the ROS, such as peroxide, superoxide anions, radical oxygen, and singlets (Wu and Cederbaum, 2003).
Lipid oxidation by ROS may damage cell structures and result in premature cell death because mitochondria are the main source of ROS in the cells; this process can be prevented by antioxidant action (Anderson et al., 2014). Over time, levels of antioxidants naturally decrease, which may lead to accumulated oxidative damage, which manifests as aging that affects different tissues (Kruk and Duchnik, 2014).
The exact role of ROS and mitochondrial dysfunction in the aging process remains unknown, but oxidative stress is evident in various diseases, including dermatological, neurological, and cardiovascular conditions (Adly, 2010).
Due to the exacerbation of such external stressors as ultraviolet radiation (UVR), pollution, and lifestyles, people began to supplement their diets with exogenous antioxidants. However, their misuse can alter the balance between the process of oxidation and natural oxidation, and thus should be prescribed cautiously based on knowledge of their actions (Cornelli, 2009).
Antioxidants are classified according to their functions (Cornelli, 2009):
Membrane or lipophilic antioxidants are active primarily in collagen fibers, elastin, and cellular structures. Examples include vitamins A and E, and beta-carotene.
Circulating or hydrophilic antioxidants are present at the microcirculatory level and in the extracellular matrix. Examples include vitamin C, polyphenols, flavonoids, and amino acids.
Intracytoplasmic or cytosolic antioxidants are mainly active in the cytoplasm of epidermal cells. Examples include coenzyme Q10, lipoic acid, and squalene.
System antioxidants act in the epidermis and in the elastic and collagen fibers of the dermis, at the microcirculatory level, and in the cells of the epidermis and dermis. Examples include zinc, selenium, and some amino acids (Costa, 2012).
In this chapter, the main nutraceuticals used in dermatology will be addressed. These have the potential to prevent and treat diseases related to intrinsic and extrinsic aging and inflammation and aid in the treatment of some cancers.
Beta-carotene, the most abundant and efficient precursor of vitamin A, is a liposoluble antioxidant whose main activity occurs in collagen and elastin fibers (Wertz et al., 2005). It is a carotenoid derived from natural food sources such as carrots, tomatoes, spinach, sweet potato, other yellow and green vegetables, fruits, and seaweeds (Bayerl, 2008). It is a sunscreen agent and inhibits the peroxidation of lipids induced by free radicals. However, in those who smoke tobacco, it can increase the risk of lung cancer (Evans and Johnson, 2010).
Beta-carotene is used for the prevention of sunburns and photodamage, erythropoietic protoporphyria, psoriasis, vitiligo, and hairy leukoplakia in doses of 6–15 mg per day in adults. Separate dosages are used in erythropoietic protoporphyria—150–180 mg per day—and prevention of sunburns: 25 mg per day (Costa, 2012).
Biotin is a hydrophilic vitamin that is also known as vitamin B7 or vitamin H. Found in yeast, brown rice, fruits, nuts, eggs, meat, and milk, it is a coenzyme in carboxylation reactions, where it acts as a carrier of activated carbon dioxide. It is a cofactor in the metabolism of fatty acids, amino acids, and gluconeogenesis (Fiume, 2001).
Biotin is indicated in cases of androgenetic alopecia, alopecia areata, poliosis, onychorexis, onycholysis, palmoplantar pustulosis, atopic dermatitis, seborrheic dermatitis, palmoplantar keratodermia, and chronic cutaneous lupus erythematosus (Costa, 2012). The suitable dose for adults is 30 mcg, but for most of the diseases and nails doses of 2500–3000 mg per day are used (Fiume, 2001).
Coenzyme Q10 is present in all living cells of the body where it acts as an important antioxidant and is also active in the mitochondrial respiratory chain. However, the endogenous production of coenzyme Q10 decreases after age 20 and is reduced in myocardial cells (Sanoobar et al., 2014).
Coenzyme Q10 acts on oxidative stress and is indicated for prevention and treatment of fine lines and wrinkles, but it also aids in the treatment of heart failure and fibromyalgia (De Luca et al., 2016).
There is an important interrelationship between selenium and coenzyme Q10 because selenium is required to process the active form of coenzyme Q10 (Xia et al., 2003).
The oral absorption is limited due to its high molecular weight and because it is fat-soluble, the recommendation is to ingest it with food at a dose of 30–200 mg per day (Costa, 2012).
Citrulline–arginine is a component of marine biomass originating from a red algae, Chondrus crispus, which is found along the shores of the northern Atlantic Ocean. It is a stable dipeptide that improves the bioavailability of the arginine by increasing skin energy levels, encouraging cell growth and metabolism, and protecting the skin. In addition, it releases arginine and citrulline, amino acids that are important sources of nitrogen and essential for protein and collagen synthesis (Bidri and Choay, 2003).
Citrulline-arginine is indicated for the prevention and improvement of skin aging. It acts as a skin protector in extreme conditions such as cold and dry climates, pollution, and air conditioning. It also aids wound healing. The recommended dose is 100–1000 mg per day (Zhu et al., 2008).
The best-known isoflavones are genistein, glycitein, and daidzein. They inhibit carcinogenesis and photocarcinogenesis through their antioxidant and antiproliferative effects and have also proven effective in reducing the formation of erythema induced by UVR (Wright et al., 2006). They unite and activate the alpha and beta estrogen receptors. They are widely used as preventive supplements for some types of cancer such as breast cancer and are also indicated for the prevention of osteoporosis (Pop et al., 2008). According to the North American Menopause Society, the doses range from 25 to 100 mg per day (Wright et al., 2006).
L-carnosine is a dipeptide composed of two amino acids—β-alanine and L-histidine—and is naturally found in muscle and heart tissues, the brain, and the liver. It has a powerful antioxidant function and protects and stabilizes cell membranes by preventing oxidative stress caused by free radicals. It also acts as a metal chelator and has a buffer effect on lactic acid in the muscle, including cases of intensive exercise (Prokopieva et al., 2016). The recommended dose is 500–2000 mg per day (Eades, 1994).
Lycopene is a liposoluble carotenoid and a powerful antioxidant found in some red foods such as tomatoes and their products, guava, watermelon, papaya, and cherry (Krinsky, 2001). It has a strong ability to attach to singlet oxygen, being suggested for the prevention of carcinogenesis and atherogenesis and to protect molecules such as lipids, low-density lipoproteins (LDLs), proteins, and DNA (Agarwal and Rao, 2000). Oxidation of lipids by reactive oxygen species can damage cell structures, and their high levels contribute to aging and carcinogenisis. Oxidative stress induced by ROS can be prevented by lycopene’s antioxidant action (Kandola et al., 2015). It also has protective properties against erythema induced by UVR and photoaging mediated by oxidative stress (Rizwan et al., 2011). The average daily recommended intake of lycopene is about 35 mg (Agarwal and Rao, 2000).
Lutein belongs to the group of carotenoids along with beta-carotene and lycopene. While the beta-carotene accumulates in the skin to provide a golden-yellow color, lutein accumulates preferentially in the macula lutea, protecting the retina from oxidative damage from UVR (Scarmo et al., 2010). It has antioxidant, anti-inflammatory, photoprotection, and anticarcinogenic properties and also acts to improve skin elasticity (Woodside et al., 2015).
The main natural sources of lutein are vegetables and green vegetables such as kale, spinach, chicory, celery, lettuce, fresh herbs, and egg yolk (Nachtigall et al., 2007). The oral and topical administration of lutein associated with zeaxanthin provided greater antioxidant functions and better hydration for severe skin compared to isolated treatments (Anunciato and Filho, 2012).
Melatonin is a hormone released by the pineal gland and an important regulator of the circadian cycle with rhythmic production during both night and day but peak production at night (Hardeland, 2013). It also acts as an immunomodulator, modifies endocrine activity, and protects against UVR-induced damage (Fischer et al., 2008). An interrupted circadian clock can be an initial factor for the development of cutaneous diseases associated with oxidative stress. Melatonin and its metabolites act as local antioxidants, reducing mitochondrial damage and protecting skin from free radicals and thus act against skin aging (Kleszczynski and Fischer, 2012).
Melatonin is used for patients with insomnia, photoaging, protection against UVR-induced skin damage, and skin cancer and aids in the treatment of neurodegenerative diseases such as Alzheimer’s (Ndiaye et al., 2014). The indicated initial dose is similar to physiological production of 0.3 mg per day and 1–3 mg per day is recommended for insomnia (Desotelle et al., 2012).
Omega-3 is a long-chain polyunsaturated fatty acid found mainly in fish such as salmon, tuna, cod, and dogfish (Raatz et al., 2013). It acts on cycloxygenase and lipoxygenase and in leukotrienes having a positive effect on blood flow (Alestas et al., 2006) and anti-inflammatory and antioxidant properties (Humbert et al., 2011). It also acts as a regulator of physiological functions of the skin such as inflammatory responses, platelet aggregation, vasodilation, and cell proliferation (Jung et al., 2014). It has been used in conventional treatments of various diseases such as cardiovascular disease, hypertriglyceridemia, atopic dermatitis, psoriasis, and acne vulgaris (Jeengar et al., 2015). The recommended daily dose is from 1.0 to 5.0 g (Koch et al., 2008).
Polyphenols are plant-derived micronutrients from diet that are important in preventing and improving the outcome of diseases. Since bioavailability differs greatly from one to another polyphenol, not necessarily the most abundant polyphenol in our diet has one the highest concentration of active metabolites in target tissues (Manach et al., 2005).
Polyphenols must go through two important phases to be absorbed and utilized systemically. The first phase is oxidation, reduction, and hydrolysis of polyphenol to increase its affinity for water. When added or exposed to a functional group with hydroxyl it transitions to phase two. During the second phase, new combinations occur to the polyphenols to make them more soluble in water and polarized, facilitating their transport and eventual elimination from the body (Scheepens et al., 2010).
There are several known groups of polyphenols. In this chapter, we will address those most closely related to the pathology of the skin and appendages.
The polyphenols of green tea are largely monomeric catechins, which include catechin, gallocatechin, epicatechin, epigallocatechin, gallate epicatechin, and epigallocatechin-3-gallate, the last being the most abundant and accounting for about 60% of catechins (Chow et al., 2001). They act as antioxidants, capturing ROS by transferring electrons to them so that are stable by becoming free radicals with one flavinic radical (Senger et al., 2011).
Epigallocatechin-3-gallate has potent antioxidant, antiinflammatory, and anticarcinogenic properties. It acts on matrix metalloproteinases, which are responsible for remodeling the extracellular matrix, and contributes to the structural integrity of tissue (Philips et al., 2007). It also prevents immunosuppression induction of interleukin-12 (IL-12). It also promotes the seizure and apoptosis of melanoma cells (Katiyar et al., 2007). It is also indicated for the prevention and treatment of photodamage and some types of cancer, including melanoma and squamous cell carcinoma. The recommended dosage is 200–800 mg per day fasting because it has low bioavailability (Costa, 2012).
Pycnogenol is a hydrosoluble flavinoid extracted from the bark of French Pinus pinaster. It is a potent antioxidant, recycles vitamin C, and regenerates vitamin E (Pinto et al., 2015). It inhibits gene expression of proinflammatory cytokines IL-1 and IL-2 and also inhibits matrix metalloproteinases and nitric oxide (Cho et al., 2001). It is indicated for the treatment of melasma and postinflammatory hyperpigmentation, traveler thrombosis, and chronic venous insufficiency, among others (Rohdewald, 2002). The recommended dose is 60–300 mg per day (Pinto et al., 2015).
Resveratrol is a natural polyphenol found in more than 70 species of plants such as grapes (Vitis vinifera), cranberry (Vaccinium macrocarpon), and peanut (Arachis hypogaea). It acts by decreasing the vasoactive peptides, inhibits the oxidation of LDLs and the neurotoxicity of beta-amyloid. It increases the expression of glutathione peroxidase, which has a protective effect against oxidative stress (Perez and Gomez, 2015).
Resveratrol is suitable for preventing and improving skin aging and prevents photodamage. It also helps prevent some cancers such as breast, prostate, and colorectal cancer (Kennedy et al., 2010). There is no recommended daily dose but is safely used with dose of between 500 and 2000 mg per day. They should not be prescribed to women with a history of estrogen-dependent cancer. It can change the bioavailability of some drugs since it interacts with the cytochrome P450 (Perez and Gomez, 2015).
Polypodium leucotomos is derived from a native tropical fern from Central and South America. It possesses beneficial properties attributed to the presence of numerous compounds with photoprotective and antioxidant properties (Nestor et al., 2014). It is able to eliminate free radicals and ROS, prevents the depletion of Langerhans cells, and inhibits mast cells in the skin (Nestor et al., 2014). Treatment use is indicated in photosensitivity, systemic lupus erythematosus, psoriasis, and vitiligo at a dose of 240 mg per day (Schalka et al., 2014).
Prebiotics are nondigestible oligosaccharides, however fermentable, with the function of changing the activity and composition of the intestinal microbiota. They stimulate the growth of endogenous microbial populations (Blaut, 2002). They modulate key physiological functions such as absorption of calcium, lipid metabolism, modulation of intestinal microbiota, and reduced risk for colon carcinoma (Roberfroid, 2002). The indications are similar to those of probiotics as well as the doses.
Probiotics are live microorganisms, mostly bacteria, that can be added to diets and confer a health benefit to the host when consumed in adequate amounts. They improve immunity and prevent some cancers such as colorectal and myeloid leukemia (Saad, 2006). The oral administration may regulate proinflammatory skin cytokines with specific decrease in IL-1α. They are indicated in the treatment of acne, seborrheic dermatitis, atopic dermatitis, and urticaria. The indicated doses are 5–10 million colony-forming units (CFUs) in children and 10–20 million CFUs in adults (Folster-Holst, 2010).
Selenium is an essential micronutrient related to the action of glutathione peroxidase and thioredoxin reductase, enzymes involved in defending against oxidative stress (Schrauzer, 2000). It acts as an endogenous antioxidant in tissue oxygenation and protects against lipid peroxidation and neutrophils’ phagocytic activity and is active in the regulation of thyroid hormones, DNA synthesis, and cell proliferation (Heyland et al., 2005). The indications are still controversial but suggested as a sunscreen because it protects against cytotoxicity induced by ultraviolet B radiation and wound healing (Bronsnick et al., 2014). The recommended daily dose for adults is 55 μg and is believed to contribute to the reduction of circulating antibodies in Hashimoto’s thyroiditis when used at a dose of 200 mg (Costa, 2012).
The largest source of silicon is foods with a high concentration of fiber such as vegetables and whole grains. It plays a vital role in human health by regulating the metabolism of various tissues, such as bone, cartilage, and connective tissue. One main function is the synthesis of collagen type I and its performance in the activity of prolyl hydroxylase enzyme (Reffit et al., 2003).
The skin plays an important structural role by connecting with glycosaminoglycans. In association with vitamin C, silicon stimulates the synthesis of hyaluronic acid and proteoglycan, increasing the affinity of water with glycosaminoglycans and reducing the destruction process of the dermal matrix produced by matrix metalloproteinases. It has also an active role in neutralizing free radicals (Calomme and Vanden-Berghe, 1997).
Silicon absorption in the gastrointestinal tract is inversely proportional to age, decreasing by the rate of 0.1 mg for every year of life. With aging, the amount of water in the dermis tends to decrease, and the presence of silicon in optimal quantities allows the connection of this water to dermal structures. It is used to prevent and improve skin aging and to improve the healing of wounds, burns, acne, eczema, psoriasis, and osteoporosis. The recommended dosage is 2–5 mg per day (Jugdaohsingh et al., 2004).
Vitamin C is a hydrophilic vitamin that is commonly consumed in large doses through its addition to many food products with the purpose of inhibiting the formation of carcinogenic nitrous metabolites (Bianchi and Antunes, 1999). It acts as an antioxidant, neutralizing ROS that are produced by cells of the dermis and epidermis, protecting the intracellular structures from oxidative stress (Manach et al., 2005).
It is also a cofactor for the production of collagen fibers and participates in the inhibition of the biosynthesis of elastin in fibroblasts, preventing its accumulation, highly present in photodamaged skin (Costa, 2012). When used with vitamin E, it acts synergistically working with its mechanism of transformation. (Eberlein-Koning et al., 1998).
It is indicated in the prevention and treatment of photodamage. For women, the recommended dose is 75 mg per day for men and 90 mg per day, and smokers should increase to 35 mg intake for those suffering increased oxidative stress. The maximum intake limit is 2000 mg per day, and it may cause side effects such as diarrhea (Amaya et al., 2001).
Vitamin E is the main lipophilic antioxidant and is found in the form of tocopherols. It is an important binder of paroxil radicals, preventing lipid peroxidation of polyunsaturated fatty acids. It is secreted by sebaceous glands, and the highest concentration of vitamin E is where fat production is greatest (Shils et al., 1999). It is indicated for preventing photodamage, sunburn, chronic cutaneous lupus erythematosus, granuloma annular, and atopic dermatitis (Costa, 2012). The recommended dose is 400–1000 mg per day for men and women. The maximum tolerated dose without adverse effects is 1000 mg per day (Eberlein-Koning et al., 1998) and should be used for at least 2–3 weeks to achieve its protective effect. Since it inhibits platelet aggregation, its use should be discontinued before any surgical procedure (Costa, 2012).
Zinc is an essential element of the human body, and the skin is rich in zinc (Reeve et al., 1999). It serves as a catalyst for the enzymes responsible for DNA replication, gene transcription, and protein synthesis to neutralize free radicals (Vallee and Falchuk, 1993). Similar to selenium, it participates in the endogenous antioxidant system and plays an important physiological role in the immune response and wound healing. In studies with human fibroblasts, zinc performed its protective function against the cytotoxicity induced by UVR and lipid peroxidation (Leccia et al., 1999). It is indicated for treatment of acne, telogen effluvium, and periodontitis and for its photoprotective effects on topical use (Pinnell, 2003). The recommended daily dose is 8 mg but varies according to specific diseases (Kurmis et al., 2013).
Today’s growing market for healthy lifestyles in which people are more observant of their health and seek to improve it by consuming food and other natural sources that contribute to their well-being and reduce the damage caused by intrinsic and extrinsic factors. Healthy aging may be strongly associated with a balanced diet, healthy lifestyle, and proper supplementation of nutraceuticals. Oxidative stress can lead to damage to biological structures and contribute to the aging process, inflammation, and some cancers.
Because the effectiveness of nutraceuticals is already known and demonstrated in a growing number of studies, antioxidants, vitamins, minerals, fatty acids, and other dietary nutrients are indispensable for maintaining the health of skin and other tissues throughout the body.