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Of particular concern to the anti-aging physician are related issues such as carcinogenesis, immune suppression, cutaneous infrastructure destruction, hyperkeratosis, and psychological stress. Fortunately, recent developments now make it "...possible to remarkably correct the various deteriorations of the photo damaged face..."1 and other sun-exposed skin.
Skin exposed to ultraviolet radiation (UVR) initially experiences a "...state of chronic inflammation and repeated exposure to proteolytic enzymes released by inflammatory cells [that are] postulated to disrupt the dermal matrix."2 These processes have the following short- and long-term effects.
There are two primary mechanisms of action by which UVR is thought to cause neoplasms. One is by the effect of a direct hit by an ultraviolet photon on DNA itself. The damage to the DNA, if unrepaired and if affecting particular gene(s), can result in skin cancer.8 Alternately, if UVR hits other molecules within the cell or tissue matrix, the resulting free radicals can themselves damage the DNA, leading ultimately to skin cancer.9
Cellular: Uneven pigmentation, roughness, hyperkeratinosis, are the direct consequences of disruption of the cellular replication and immunological processes. As discussed above, these are brought about by DNA damage and oxidative stress resulting from absorption of UVR photons. Collagen: Other long-term consequences of photoaging, such as the dramatic loss of skin elasticity and thinning of the skin, are largely the result of the effects of UVR on the collagen matrix. The collagen matrix of the dermis is the 'scaffolding' that gives firmness and directional strength to the skin. The spaces within the 'scaffolding' are filled in large part by glycosaminoglycans, forming a water-saturated gel that provides the hydration and plumpness of healthy skin. Both collagen and glycosaminoglycans (GAG) are produced by fibroblasts within the dermis. The fibroblasts also product collegenase, a metalloproteinase which participates in the normal restructuring of skin by dismantling existing collagen, ideally at a similar rate as de novo collagen production. A feature of intrinsic aging is that fibroblasts become less responsive to stimulating cellular messengers such as growth factors, resulting in lessened production of both collagen and GAG. At the same time, fibroblasts stimulated by the singlet oxygen created by UVR, even in sub-erythemal doses, respond by increasing production of collagenase, leading to accelerated breakdown of the collagen matrix.15,16
A range of effective tools has been developed over recent years that enable one not only to largely halt further sun damage but to also repair and minimize past damage. Following is a brief discussion of some of the most innovative and effective of these. Antioxidants: Much work has been focused on oral supplementation of antioxidant nutrients. More recently, there has been a growing interest in the function of antioxidants on and in the skin and on topical application of antioxidant nutrients.
Study results strongly suggest that the most effective antioxidant protection
against photodamage is found with a combination of multiple, complementary
antixodiants, which appear to produce synergistic effects.17
Vitamin E is comprised of eight different tocol compounds, four of which are tocopherols (alpha, beta, gamma and delta) and four of which are tocotrienols. The two types differ in that the phytyl side chain of the tocotrienols are triple-unsaturated and the tocopherols are fully saturated. In contrast to tocopherols, tocotrienols have as much as 40-60 times greater antioxidant activity and remarkable anti-tumorgenic effects.22,23 In addition, tocotrienols appear to have a high degree of specificity to skin, being up to 15 times more likely to be directed to the skin than are tocopherols.24,25 It is known that UV-irradiation of the skin destroys its antioxidants. The topical application of tocotrienol rich fraction (TRF) of palm oil prior to UV exposure results in preservation of tocopherol forms of vitamin E.26 Topical application of TRF application was also shown to prevent significant ozone oxidative damage to skin.27 Alpha tocopherol is often used in cosmetics in its ester form on the assumption that enzymatic hydrolysis in the skin will restore it to an active form. Unfortunately, in the stratum corneum, where vitamin E's antioxidant defenses are most needed, the enzymatic activity necessary to hydrolyze the ester is very limited. The result is that many 'vitamin E' products remain largely inactive. Ubiquinone: Coenzyme Q10, or ubiquinone, in addition to being a critical participant in mitochondrial energy management, also functions as an antioxidant. Of particular interest to this discussion is its ability to significantly inhibit the expression of collagenase following UVR exposure.28 Melatonin: While best known as a hormone associated with the pineal gland and the diurnal cycle, melatonin is a very potent antioxidant. Topical application of melatonin has been demonstrated to inhibit UV-induced erythema on a distinct, dose-dependent relationship.29 Procyanadins
& Catechins: Polyphenolic compounds are found in a variety
of plants and have beneficial activities in humans. In particular, procyanadins
and catechins, found in grape seeds, green tea, green apples and other
sources, have substantial anti-tumor-promoting activity attributed to
their strong antioxidant effects.30 Polyphenol fractions from unripe
green apples have been demonstrated to have, among other activities,
antimutagenicity, inhibition of histamine release,31 antioxidation and
UV-B absorption/screening activity.32 Colostrum: Unlike any other species, the cow is a "universal donor," producing colostrum which is accepted by virtually all other mammals, including humans.33 Not only are the immune and growth factors in bovine colostrum identical in molecular structure to those of humans34 but bovine colostrum contains up to 40 times the levels of IgG as are found in human colostrum. Among the immune factors transferred in bovine colostrum are epithelial growth factor, lactoferrin, interleukin-10, immunoglobulins, and lysozyme. These factors variously inhibit viruses, inactivate bacteria, reduce inflammation, induce apoptosis of cancerous cells, modulate allergic response, and activate macrophage activity.35 Mushroom Extracts: Recent studies have demonstrated that polysaccharide extracts of Ganoderma lucidum protect DNA from strand breakage caused by UVR and have "antitumor and immune enhancing properties, along with no cytotoxicity."36 Other studies show that Ganoderm lucidum extract boosts production of cytokines and killer T-cells,37 and is an effective, non-toxic antiherpetic agent.38 Collagen repair: Vitamin C has been used effectively to stimulate collagen repair, thus diminishing some of the effects of photoaging on skin. However, Vitamin C is easily degraded by heat and light, which along with its high acidity, presents certain challenges for use in a multi-purpose skin care formulation. A recently introduced synthetic collagen fraction offers greater stability and compatibility, along with improved efficacy. Microcollagen Pentapeptides: Fibroblast collagen production has been reported to be stimulated by a pentapeptide fragment of the collagen molecule.39 Application of this pentapeptide (characeterized by Katayama and colleagues as lys-Thr-Thr-Lys-Ser) demonstrated an increase in production of soluble collagen IV by as much as 427% by fibroblasts in a biopsy sample from a 63 year old female donor. Glycosaminoglycan production in the same sample was increased by 367% above control. Ex vivo testing of the pentapeptide (3% concentration) on a panel of 35 subjects for a period of six months demonstrated significant to highly significant changes (percent wrinkle with an area >200ɠm, wrinkle density, roughness, volume of main wrinkle, mean depth of main wrinkle) over a placebo cream as well as a commercial 5% vitamin C product.40 Exfoliants: In the superficial layer of aging skin (stratum corneum), cells characteristically develop increased cohesion - leading to decreased desquamation. The result is hyperkeratinization, a thickened layer of dead cells, which contributes to a generalized dryness and the development of fine wrinkles. Organic acids: Alpha hydroxy acids (AHAs) and beta hydroxy acids (BHAs) are organic acids that have been found to reduce corneocyte adhesion. AHAs have been studied in strengths ranging as high as 70% (applied in-office), but show appreciable activity in wrinkle-reduction and improved roughness, sallowness and mottled hyperpigmentation at concentrations as low as 5-8%.41,42 However, as concentrations increase much above those levels side effects of erythema and irritation increase. Evidence also suggests that AHA's stimulate an increase in the amounts of glycosaminoglycans (GAG) present in the interstices of the collagen matrix,43 thus boosting the amount of moisture in the skin as well as minimizing the fine wrinkles. There are also data suggesting that AHAs (glycolic acid) have a synergistic effect on the antioxidant activity of vitamin E and melatonin, increasing protection up to 250% and 80%, respectively.44
The compounds reviewed in this monograph belong to a new category of skin care ingredients, dubbed 'cosmeceuticals,' due to the fact that these substances exert pharmacological effects on the structure and function of the skin. However, products containing these compounds are generally regarded by the U.S. Food and Drug Administration (FDA) as cosmetics ?regardless of whether they are distributed by healthcare professionals or via other modes of distribution. This engenders two difficulties for the physician wishing to evaluate or recommend skin protective products to patients. First, manufacturers of cosmetics may not make any claims ?whether true or not ?regarding a product or ingredient's ability to make permanent structural changes to the skin, or to provide protection against disease processes. This strictly limits the ability of the manufacturer to provide even independent, referenced material regarding the actions of components of the product. Secondly, labeling requirements for cosmetics do not compel the manufacturer to disclose the amounts or percentages of ingredients, although all ingredients must be listed on the label. In a highly competitive and proprietary marketplace, manufacturers are understandably reluctant to reveal the details of their formulations. As a result, it can be difficult to distinguish between a product containing an ingredient in meaningful quantities (e.g., those supported by scientific research) and a product that includes only a "whiff" of a high-profile ingredient, in order to maximize marketability while minimizing cost. Barring the creation of a new category of skincare product, perhaps parallel to the nutritional supplement, which might alter regulatory issues, the clinician is forced to rely upon independent review of scientific literature, such as that summarized in this paper, as well as the reputation of manufacturers or independent evaluation of individual products. While burdensome, the effort involved in this research allows the health care professional to offer patients effective, new solutions to the widely-experienced damage of photoaging. Given the wide range of pathologies associated with photodamage, appropriate skin care and skin nutrition has moved beyond the exclusive domain of the dermatologist or esthetician, becoming relevant to any clinician aiming to promote the overall health and well-being of patients.
1. Kligman AM, Koblenzer C. Demographics and psychological implications for the aging population. Dermatol Clin 1997;15(4):549-53. 2. Gilchrest BA. A review of skin aging and its medical therapy. Br J Derm 1996;135:867-875. 3. Olsen R. Ultraviolet light induced individual cell keratinization. J Clin Pathol 1974;1:120-121 4. Charif M, Geller AC, Koh HK. Photodamage 1995; Blackwell Science, Inc. 5. Weinstock MA. Epidemiology of nonmelanoma skin cancer: clinical issues, definitions, and classification. J Invest Dermatol 1994;102(6):4S-5S. 6. Longstreth J. Cutaneous malignant melanoma and ultraviolet radiation: A review. Cancer and Metastasis Reviews 1988;7:321-333 7. Langley RG, Sober AJ. A clinical review of the evidence for the role of ultraviolet radiation in the etiology of cutaneous melanoma. Cancer Invest 1997;15(6):561-7. 8. Ananthaswamy HN, Pierceall WE. Molecular mechanisms of ultraviolet radiation carcinogenesis. Photechem Photobiol 1990;52:1119-1136. 9. Steenvoorden DP, van Henegouwen GM. The use of endogenous antioxidants to improve photoprotection. J Photochem Photobiol 1997;41(1-2):1-10. 10. DiSalvo, RM Cosmeceuticals, in The Chemistry and Manufacture of Cosmetics 2000, 183-253. 11. Goettsch W, Garssen J, et al. UV-B and the immune system. Thymus 1993;21:93-114 12. Denkins Y, Fidler I, Kripke M. Exposure of mice to UV-B radiation suppresses delayed hypersensitivity to Candida albicans. Photochem Photobiol 1989;49(5):615-619. 13. Goettsch W. Ibid 14. Gilchrest BA. Ibid 15. Wlaschek M, Wenk J, et al. Singlet oxygen is an early intermediate in cytokine-dependent ultraviolet-A induction of interstitial collagenase in human dermal fibroblasts in vitro. FEBS Letters 1997; 413:239-42. 16. Scharffetter-Kochanek K, Wlaschek M, Briviba K, Sies H. Singlet oxygen induces collagenase expression in human skin fibroblasts. FEBS Lett. 1993;331(3):304-6 17. Steenvoorden DP. Ibid 18. Chen W, Barthelman M, et al. Inhibition of cyclobutane pyrimidine dimer formation in epidermal p53 gene of UV-irradiated mice by alpha-tocopherol. Nutr Cancer 1997;29(3):205-211. 19. Steenvoorden DP, Beijersbergen van Henegouwen G. Protection against UV-induced systemic immunosuppression in mice by a single topical application of the antioxidant vitamins C and E. Int J Radiat Biol 1999;75(6):747-755. 20. Fuchs J. Ibid 21. Ricciarelli R, Maroni P, et al. Age-dependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition. Free Radic Biol Med 1999;27(7-8):729-737. 22. Elson CE, Yu SG. The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J. Nutr 1994; 124:167-614. 23. For a more complete discussion, see Tocotrienols and Modification of Coronary Heart Disease Risk Factors, Randall Wilkinson, MD, available upon request from Aspen Benefits Group, 1-800-539-5195. 24. Podda M, Weber C, Traber MG, Packer L. Simultaneous determination of tissue tocopherols, tocotrienols, ubiquinols, and ubiquinones. J Lipid Res 1996;37(4):893-901. 25. Ikeda S, Niwa T, Yamashita K. Selective uptake of dietary tocotrienols into rat skin. J Nutr Sci Vitaminol 2000;46(3):141-143. 26. Weber C, Podda M, Rallis M, Thiele JJ, Traber MG, Packer L. Efficacy of topically applied tocopherols and tocotrienols in protection of murine skin from oxidative damage induced by UV-irradiation. Free Radic Biol Med 1997;22(5):761-769. 27. Thiele JJ, Traber MG, Podda M, Tsang K, Cross CE, Packer L. Ozone depletes tocopherols and tocotrienols topically applied to murine skin. FEBS Lett 1997;401(2-3):167-170. 28. Hoppe U, Bergemann J, Diembeck W, et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 1999;9(2-4):371-378. 29. Bangha E, Elsner P, Kistler GS Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study. Archives of Dermatological Research (Germany) 1996;288/9:522-526. 30. Zhao J, Wang J, Chen Y, Agarwal R. Anti-tumor-promoting activity of a polyphenolic fraction isolated from grape seeds in the mouse skin two-stage initiation-promotion protocol and identification of procyanidin B5-3'-gallate as the most effective antioxidant constituent. Carcinogenesis 1999;20(9):1737-1745. 31. Kanda T, Akiyama H et al. Inhibitory effects of apple polyphenol on induced histamin release from RBL-2H3 Cells and Rat Mast Cells. Biosci Biotehnol Biochem 1998;62(7):1284-1289. 32. Tomen, Inc. Unpublished data. 1994 -1999 33. DiSalvo RM, 235. 34. Frances. Purification and partial sequence analysis of insulin-like growth factor 1 of bovine colostrum. Biochemical Journal 1986;233(1):207-213.
35. DiSalvo RM, 235-236. 36. Kim KC, Kim IG. Ganoderma lucidum extract protects DNA from strand breakage caused by hydroxyl radical and UV irradiation. Int J Mol Med 1999;4(3):273-277. 37. Haak-Fredscho M. et al. Ling Ahi-8: A novel T cell mitogen induces cytokine production and upregulation of ICAM-1 expression. Cellular Immunology 1993;150:101-113. 38. Eo SK, Kim YS, Lee CK, Han SS. Antiherpetic activities of various protein bound polysaccharides isolated from Ganoderma lucidum. J Ethnopharmacol 1999;68(1-3):175-181. 39. Katayama K, Armendariz-Borunda J, Raghow R, Kang AH, Seyer JM. A pentapeptide from type I procollagen promotes extracellular matrix production. J Biol Chem 1993;268(14):9941-9944. 40. Sederma, Inc. Unpublished data. 41. Van Scott EJ, Yu RJ. Hyperkeratinization, corneocyte cohesion, and alpha hydroxy acids. J Am Acad Derm 1984;5(11)867-879. 42. Stiller MJ, Bartolone J, et al. Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin. Arch Dermatol 1996;132(6):631-636. 43. Van Scott EJ, Yu RJ. Alpha Hydroxy Acids: Procedures for use in Clinical Practice. Cutis 1989;43:222-228. 44. Morreale M, Livrea MA. Synergistic effect of glycolic acid on the antioxidant acitivy of alpha-tocopherol and melatonin in lipid bilayers and in huma skin homogenates. Biochem Mol Biol Int (Australia) 1997;42(6):1093-1102. |