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The Role of Functional Foods in Cutaneous Anti-aging

Oral supplementation of micronutrients, or functional foods, to prevent aging has gained much attention and popularity as society ages and becomes more affluent, and as science reveals the pathological mechanisms of aging. Aging of the skin combines biologic aging and extrinsic aging caused predominantly by sunlight and other environmental toxins. Anti-aging functional foods exert their influence mostly through their anti-oxidant and anti-inflammatory effects, thereby abrogating collagen degradation and/or increasing procollagen synthesis. Clinical evidence supporting a role in preventing cutaneous aging is available for oral supplements such as carotenoids, polyphenols, chlorophyll, aloe vera, vitamins C and E, red ginseng, squalene, and omega-3 fatty acids. Collagen peptides and proteoglycans are claimed to provide building blocks of the dermal matrix. This review summarizes the current study findings of these functional foods.


INTRODUCTION
Cutaneous aging is the composite sum of biologic aging and extrinsic aging due to environmental factors including sunlight, smoking, pollution, and inflammation. Regardless of etiology, the aging process essentially involves the generation of reactive oxygen species (ROS) with subsequent signal transduction and activation of transcription factors activator protein 1 (AP-1) and nuclear factor κB (NF-κ B). AP-1 increases the secretion of matrix-degrading enzymes called matrix metalloproteinases (MMPs), which results in the degradation of the dermal matrix, including collagen [1]. Functional foods and 'nutraceuticals' include all kinds of food with health or medical effects. According to an international survey, about 69% of adults worldwide take vitamins, minerals, or food supplement products daily [2].
There is an ever increasing interest in anti-aging substances derived from food, and since the aging process inevitably involves the generation of reactive oxygen species, oral supplements with antioxidant properties are the most popular.
These include botanicals with carotenoids or polyphenols, isoflavones, vitamins, coenzyme Q10, phytoestrogens, probiotics, and omega-3 fatty acids. In addition, collagen peptides and hyaluronic acid, which provide building blocks of the skin, are on the market.
Although nutritional antioxidants are all mainly free radical scavengers, they act through different mechanisms and in different compartments: 1) they directly neutralize free radicals, 2) they reduce peroxide concentrations and repair  Resveratrol is a small polyphenol compound found in red grape skin, nuts, fruits, and red wine. Many studies have suggested that this compound has anti-carcinogenic effects that can be attributed to its free radical-scavenging ability [9] and anti-inflammatory effects [10]. It has been shown to protect against depletion of endogenous antioxidant defense enzymes, suppress H2O2 and NO production as well as lipid and protein oxidation, inhibit activation of mitogen-activated protein kinase (MAPK) and NF-κB, and inhibit apoptosis through activation of p53 activity [11]. It has poor bioavailability, and up to 5 g of resveratrol intake

POLYPHENOLS AND ISOFLAVONES
has been described as safe [12]; however, in a recent pilot study with 10 healthy volunteers, resveratrol was shown to possess cytokine-potentiating, pro-inflammatory properties with a significant increase in TNF-α and activation of alternative NF-κB signaling, suggesting enhanced immune surveillance as the mechanism behind its anti-carcinogenic effects [13].
Green tea polyphenols have been shown to prevent UVB-induced protein oxidation and MMP expression in mouse skin [14]. Epigallocatechin gallate (EGCG) comprises 59% of total catechins and is responsible for most of the biological activity of tea, and oral EGCG supplementation has been shown to increase MED, skin barrier function, and to reduce UVB-induced skin damage in rats [15]. However, similar studies in human beings have not demonstrated such effects [16,17], presumably because the human dermis forms a stronger barrier to absorption from the vasculature [18], warranting further clinical studies with high methodological quality.
Soybean isoflavone, a well-known anti-aging agent, is also referred to as a phytoestrogen because it has a chemical structure similar to estrogen [19]. In hairless mouse models, dietary soy isoflavones cause less skin wrinkling in UV-irradiated skin than in controls, with a concomitant increase in collagen deposition, which is partly due to the inhibitory effects on UV-induced MMP expression and subsequent colla-gen degradation [20]. In human subjects, facial fine wrinkles are decreased after 12 weeks of isoflavone aglycone supplementation [21]; however, more robust clinical studies are necessary to substantiate these initial findings.

OTHER BOTANICALS
We reported that chlorophyll improves facial wrinkles and elasticity in female volunteers over the age of 45 who received two different doses of chlorophyll extract supplement for 90 days. Compared to baseline, type I procollagen synthesis was increased, with a substantial reduction in UV-induced thymine dimer staining and UV-induced apoptosis of keratinocytes in a dose-dependent manner [22]. has been found in the tested doses. The known therapeutic effect of aloe vera is due to its immunostimulatory properties attributed to the presence of polysaccharides; the polysaccharides have no significant anti-oxidant activity [24].
An acetylated glucomannan, acemannan, is the biologically active, dominant polysaccharide that has been shown to increase collagen biosynthesis, probably through macrophage immunostimulation [25].

VITAMINS C AND E
Vitamin C (ascorbic acid) is the major water-soluble endogenous antioxidant; it is a powerful inhibitor of lipid peroxidation, regenerates vitamin E in lipoproteins and mem- branes, and is essential for the production of collagen. It has been shown to provide a wide variety of benefits including lowering blood pressure and decreasing infectious episodes in daily doses of 500 mg to 6 g [26]; however, no benefit has been reported regarding skin aging. Vitamin E (α-tocopherol) is a lipid-soluble anti-oxidant vitamin found in cell membranes and circulating lipoproteins. Vitamin E can also enhance immune function, reducing infection rates in elderly subjects [27]. For a systemic photoprotective effect, several hundred mg/d is required, and doses up to 800 mg/d have been taken for years without harm. Vitamin C and vitamin E act synergistically [28]. Simultaneous oral intake of these two vitamins has been shown to reduce UV-induced skin inflammation, in contrast to either vitamin alone, which has shown no protective effects [29]. Several controlled clinical studies have demonstrated that the two vitamins act synergistically to reduce sunburn reaction and increase MED [30]. Unfortunately, oral supplementation of vitamin C and E has proven insufficient in preventing skin aging owing to their poor solubility, inefficient skin permeability, or instability during storage [31]. Chemical modification of the molecules or new delivery systems would make optimized delivery of these molecules to the skin possible in the future. On the other hand, there are some promising reports regarding mixtures of antioxidants: an antioxidant combination containing vitamins C and E, carotenoids, selenium, and proanthocyanidins decrease MMP-1 compared to placebo in humans [32], and a combination of vitamins C and E, pycnogenol, and evening primrose oil also decrease wrinkles and MMP while increasing collagen synthesis in hairless mice [33]. Both studies imply that antioxidants are effective when they work together.

RED GINSENG
The roots of Panax ginseng have been used as a general tonic in Oriental medicine for several thousand years. Red ginseng is prepared by steaming and air-drying P. ginseng, and reportedly has more bioactivity than white ginseng, which is the peeled and air-dried form [34]. Red ginseng contains various ginsenosides that have antioxidant, immunostimulatory, and anti-aging activity. Our group performed the first controlled human study on 82 female volunteers to assess red ginseng's effects on photoaged skin.
Compared to placebo, the group that took 3 g/d of a red ginseng extract-containing herbal mixture for 24 weeks had decreased facial wrinkles with concomitant increases in type I procollagen synthesis (Fig. 3) and fibrillin-1 fiber length (Fig. 4). Therefore, objective evidence of a reduction in facial wrinkles by long-term ingestion of red ginseng was provided for the first time; the clinical improvement was substantiated by biochemical and histological evidence of increased collagen and elastic fiber synthesis in the dermis [35]. The clinical improvement may be due to the activation  of COL1A2 promoter and Smad signaling [36], through ginseng's estrogen-like activity [37], and/or additionally through increased hyaluronan levels by a metabolite of ginsenosides [38].

SQUALENE AND OTHER LIPIDS
Squalene is a polyunsaturated aliphatic hydrocarbon that is abundant in shark liver oil. Our group previously reported that 27 g/day (high dose) oral squalene supplementation for 90 days decreased facial wrinkles, while 13.5 g/day (low dose) increased type I procollagen mRNA levels and MED  [42,43].

COLLAGEN PEPTIDES
In a study by Proksch et al., oral supplementation of collagen hydrolysate composed of specific collagen peptides (2.5 g/d or 5.0 g/d for 8 weeks) increased skin elasticity in middle-aged women after 4 weeks of supplementation, and a skin moisturizing effect was observed in women over 50 years of age. The supplement had a long-lasting effect, especially in women over 50 years of age [44]. Prior studies have demonstrated that collagen hydrolysate is absorbed in the digestive tract, appears in human blood partly in a small peptide form, and is deposited in the skin for up to 96 hrs [45]. Food-derived collagen peptides in human blood are chemotactic for dermal fibroblasts [46], and they increase the migration and growth of mouse skin fibroblasts [47].
One controlled study found that type I and IV collagen increases while MMP-2 decreases, implying that the effect of collagen is protein-specific [48], and providing evidence for the improved cutaneous elasticity. In animal studies, oral administration of collagen peptide induced an increase in fibroblast density and formation of dermal collagen fibrils in piglet skin [49], and suppressed UVB-induced decreases in skin hydration, epidermal hypertrophy, and soluble type I collagen in mouse skin [50].

PROTEOGLYCANS
Proteoglycans (PG) are a family of complex macromolecules consisting of a core protein with covalently attached glycosaminoglycan chains. In hairless mice, oral administration of high molecular weight PG from salmon nasal cartilage inhibited UVB-induced skin aging, i.e., increased erythema and transepidermal water loss, and decreased hydration, in a molecular weight-dependent manner [51].
From decreased serum and dorsal skin inflammatory cytokine levels, it is speculated that PG acts on gut immunity and improves skin condition by inhibiting surplus inflammatory cytokine production induced by UVB irradiation.
Aggrecan, the most abundant PG in cartilage, was shown to bind to hyaluronic acid in vivo [52]; in contrast, chondroitin sulfate, a degradation product of salmon nasal cartilage PG, did not show any beneficial anti-photoaging effects [53]. Therefore, the cutaneous anti-aging effects of PG are molecular weight-dependent [51].