Photoaging

"The Role of UV Radiation in Premature Skin Aging
and a Review of Effective Defense Strategies"
Research By Randall M Wilkinson, MD

Introduction

If any doubt exists as to the primary role played by UV radiation in skin aging, one need only consider the radical difference in appearance of the skin of the face and hands and the skin of typically unexposed areas such as the buttocks. Despite popularly-held ideas, the majority of the observable changes in aging skin are driven not by advancing time (intrinsic aging), but by photoaging ‚ that is, the damaging effects of ultraviolet radiation (UVR).

Although many of its effects are cosmetic in nature, it is crucial to understand that photoaging is a pathological process. Of particular concern to the physician are issues such as carcinogenesis, immune suppression, cutaneous infrastructure destruction, hyperkeratosis, and resultant psychological stress. Fortunately, it is now "...possible to remarkably correct the various deteriorations of the photo damaged face..."1 and other sun-exposed skin.

This monograph will present an overview of the pathology associated with ultraviolet exposure and of factors known to have a mitigating effect on such exposures. With the tools described, the physician can do more than simply warn against the dangers of sun exposure; s/he now has effective remedial therapies to offer the patient with photodamaged skin.

Ultraviolet Radiation

Ultraviolet radiation is a portion of the light spectrum generated by our sun. UV wavelengths range from 200 to 400 nanometers, just shorter than visible light, and can have significant effects on biological systems when their photons are absorbed.

The UV spectrum is divided into three bands, each of which has unique biological effects. UV-C (200-290 nm) is the most potentially damaging, but is largely blocked from reaching the earth's surface by the ozone layer. Most of the UV-B band (290-320 nm) does reach the earth's surface and is believed to be the most damaging to skin, even though its penetration of skin is limited to the epidermis. UV-A (320‚400 nm) penetrates deeper into the dermis, but possesses less damaging power.

When a UV photon impacts the skin, the energy is absorbed by molecules with a particular affinity for that photon. These molecules are known as chromophores and the most important chromophore for the UV-B range is DNA.2 Other chromophores absorb wavelengths in the UV-B as well as UV-A range.

Upon absorption of the UVR, a recipient molecule undergoes physical change and enters an 'excited state', frequently leading to a series of damaging chemical reactions. In the case of DNA, the effect is the creation of photolesions within the DNA strand itself. In the presence of a vigorous DNA repair capability, the long-term effects of such photolesions may be minimized, but if capacity for DNA repair is limited for any reason, the effects of those DNA lesions can be far-reaching.

When other cellular or matrix chromophores absorb the energy of the UVR photon, the typical result is production of a free radical. The resulting oxidative damage can impact a wide range of cellular functions. Over time, the cumulative effects of UVR have a profound effect on the exposed skin, resulting in a characteristic set of findings.

The Effects of Ultraviolet Radiation

For most people, exposure to sunlight is a routine and often sought-after occurrence. The cumulative effects of those exposures, however, lead to highly undesirable, long-term consequences. Skin explosed to 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."3 These processes have the following short- and long-term effects.

Sunburn:

Excessive UVR exposure, especially in the UV-B band, results in sunburn. The level which constitutes 'excessive' varies between individuals based on race/pigmentation and other intrinsic factors. Sunburn pathology typically includes vasodilation, pain, and development of characteristic 'sunburn cells' (seen on biopsy).4 Evidence is growing that even a single acute sunburn episode can induce permanent 'skin memory', resulting in such conditions as: solar urticaria, melanotic nevi (moles), radiation recall, xeroderma pigmentosum and malignant melanoma.5

Increased Cancer Risk:

Nonmelanoma skin cancers (NMSCs), which include squamous cell carcinoma and basal cell carcinoma, together comprise the most common form of human cancer.6 The incidence of NMSC in the USA has been rising steadily for decades and, in 1994, was reported at 1,200,000 annual new cases.7,8 The association between UVR and skin cancer has been well-documented. Incidence rates for basal cell cancer around the globe follow a pattern that reflects sunlight exposure: Hawaii > Australia > New Zealand > Minnesota >> Iceland.9 The relative risk for a person with an outdoor job in Alexandria, Eygypt, of developing NMSC is 7.7 times higher than a control subject with an indoor job.10

The case for UVR causation of malignant melanoma is not as definitive as for NMSCs. However, the data strongly implicate UVR as a major factor in the increasing rates (particularly since the mid-1970's) of melanoma.11,12 Increased melanoma risk is associated with childhood sunburn, although the association may reflect only the individual's pigmentary characteristics relating to poor sun tolerance.13

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.14 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.15

Suppressed Immune Function:

A primary function of the skin is to form a barrier against threats including fungi, bacteria, viruses, parasites, toxins, and other pathogens. As our first and largest interface with the world around us, the skin "is the body's most important primary defense system, both as a physical barrier and as a metabolic and immunological biochemical-response system."16 The detrimental effects of UVR exposure on the skin's immune function are both immediate and long-term.

An immediate effect of UVR exposure is to suppress cellular-mediated immune function. Most clinicians ‚ and even the general public ‚ are aware of activation of Herpes Simplex "cold sores" in susceptible individuals following suberythemal doses of UVR.17 However, fewer are aware of such effects as the suppression of delayed hypersensitivity to candida albicans18 or suppression of resistance to syngeneic melanoma cells injected into UV-B irradiated ear skin as compared to non-irradiated ear skin.19

Effects on Appearance:

Photoaging causes characteristic effects on the appearance of the skin, including laxity, roughness, sallowness, irregular hyperpicmentation, and telangiectasia. These represent the various effects of vascular, cellular, and metabolic damage.

• Vascular: An immediate effect, within 2 to 6 hours of acute UVR exposure, is the development of erythema. The long-term vascular effects of UVR are also seen in the microcirculation, with telangiectasia resulting from dilated and twisted blood vessels, which ultimately become very sparse, with thinned walls.20

• 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.21, 22

The result of collagen degeneration is a general thinning of the skin and the presence of wrinkles and furrows as it folds in on itself.

Psychology of Aging

Premature aging of the skin also can negatively affect a patient's attitudes and health habits. An individual with a self-perception as 'younger than my age' typically exhibits behavior congruent with that perception. An irony inherent in accelerated photoaging is that it is frequently those individuals most concerned with their appearance who seek out sun exposure in order to tan the skin, resulting in a more rapid deterioration of their appearance. Indeed, unattractive aged persons tend to have low self-esteem and are less healthy than those who have aged well.23,24

The damage of sun exposure is cumulative over a lifetime. Typically, much of an individual's unprotected exposure to UVR (whether incidental or intentional) occurs years or even decades before the price is paid in the form of prematurely aged skin and its associated pathologies.

A challenge is to educate young people about the long-term dangers of sun exposure in a way that will effectively motivate them to take protective action. To the extent that these efforts may not be entirely successful, and for patients for whom such warnings come after a great deal of damage has already occurred, the physician is still in need of techniques that can ameliorate the effects of photoaging.

Fortunately, 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.

A complete list of available skin care ingredients is beyond the scope of this paper. Instead, we have attempted to include substances that may be unfamiliar to the clinician because of their recent introduction, and/or those that may offer better alternatives to more well-known compounds for reason of greater potency, efficacy or chemical stability, or reduced adverse effects.

New Tools for Remediation and Prevention:

The damage of sun exposure is cumulative over a lifetime. Typically, much of an individual's unprotected exposure to UVR (whether incidental or intentional) occurs years or even decades before the price is paid in the form of prematurely aged skin and its associated pathologies.

A challenge is to educate young people about the long-term dangers of sun exposure in a way that will effectively motivate them to take protective action. To the extent that these efforts may not be entirely successful, and for patients for whom such warnings come after a great deal of damage has already occurred, the physician is still in need of techniques that can ameliorate the effects of photoaging.

Fortunately, 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.

A complete list of available skin care ingredients is beyond the scope of this paper. Instead, we have attempted to include substances that may be unfamiliar to the clinician because of their recent introduction, and/or those that may offer better alternatives to more well-known compounds for reason of greater potency, efficacy or chemical stability, or reduced adverse effects.

Sunscreens:

The effectiveness of sunscreen tools is measured in terms of their 'sun protection factor' (SPF). An SPF of 15 signifies that skin protected by that agent would be exposed to sun for 15 hours before it received the same dose of UVR as unprotected skin did in one hour. The SPF rating for a particular sunscreen product is determined by testing on humans according to FDA guidelines.

Fabric can be an effective physical sunscreen. Typical T-shirt material has an SPF of approximately 15. Cultures in some areas of the world have developed very effective styles of clothing for use as sunscreens.

Other effective physical sunscreens include inorganic mineral-based compounds like zinc oxide and titanium dioxide. While useful, these have substantial limitations as ingredients in skin care products. Inorganic sunscreens tend to leave a visible, silvery film on the skin and lend a sticky or gritty feel to the carrier lotion or cream.

Chemical sunscreens (known as 'organic' sunscreens) have become the ingredient of choice in recent years. They deposit a thin, transparent film on the surface of the skin that acts as a filter of various UVR frequencies.

For years, PABA (para-aminobenzoic acid) was the most frequently used chemical sunscreen but has become much less popular, in large part due to the frequency of allergic reaction, staining of clothing, and its ability to filter only UV-B radiation.

The greatest breadth of protection from UVR is achieved by combining several compounds which filter complimentary bands of ultraviolet wavelengths.25 A popular triad of sunscreen agents is octyl-methoxycinnamate (UV-B), avobenzone (UV-A) and oxybenzone (UV-A), which between them screen the wavelengths reaching earth. They are observed to be well-tolerated by the majority of individuals, with a low occurrence of allergy or irritation, and are easily combined with other skin care ingredients.

The SPF rating used to measure protection against erythema and other sequelae of UVR exposure does not, unfortunately, directly correlate with protection of immune function. PABA has no impact on immune protection, giving it an IPF ('immune protection factor') of 1.0. In contrast, sunscreens methoxycinnamate and titanium dioxide have IPF values of 1.127 and vitamin E had an IPF of 1.2.26

Antioxidants:

Within the last decade, a new school of thought has emerged, which regards aging as a disease process, driven largely by the process of unchecked oxidation within the organism. This has led to an increased appreciation of the importance of antioxidants as protection against the broadly-damaging effects of free radical species.

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.27

Much of the work to this point 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.

One apparent mechanism of action leading to tumorgenesis in the skin layers is through the oxidizing effect of free radicals,28 suggesting a valuable role for topical antioxidants in preventing skin cancer. And, while sunburn represents a more acute process than skin cancers, antioxidants can be also protective.29

In addition, certain antioxidants, discussed below, have been shown to inhibit UVR-stimulated production of collagenase, thereby bolstering the collagen matrix and diminishing the wrinkling and loss of elasticity typical of photodamaged skin.

As with oral supplementation, a complementary approach utilizing a variety of different antioxidants is likely to yield the best results.

Enzymatic and non-enzymatic (nutritive) antioxidants are two broad categories of antioxidant nutrients. Non-enzymatic antioxidants include vitamin E, vitamin C, melatonin, ubiquinone (Coenzyme Q10), and procyanadins. Enzymatic antioxidants include superoxide dismutase (SOD), peroxidase, and catalase.

These differing types exert their antioxidant effects through different pathways. One distinction is that levels of the non-enzymatic antioxidants are depleted by free-radical scavenging activity and must be replenished, especially where the free radical burden is high. By contrast, enzymatic antioxidants will remain active as long as a substrate is present.

Non-Enzymatic Antioxidants:

• Tocotrienol & Tocopherol Forms of Vitamin E - Vitamin E enjoys a wide-spread reputation and application as a skin protective ingredient. This is well-supported by the scientific literature:

Vitamin E "acts as an effective sunscreen in vivo, preventing the formation of premutagenic DNA lesions in a gene known to be important in skin carcinogenesis."30

With regard to immune suppression, a single, topical application of Vitamin E prevented UV-induced suppression of the contact hypersensitivity response.31

Vitamins E and C suppress the skin's sunburn reaction in a synergistic fashion.32

Vitamin E was an effective inhibitor of collagenase expression.33

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. This structural difference results in dramatic functional differences between the two. In contrast to tocopherols, tocotrienols have a.) as much as 40-60 times greater antioxidant activity,34 b.) cholesterol-lowering effects via modulation of the HMG-CoA reductase pathway,35 c.) anti-thromboxane A2 activity similar to aspirin36 and d.) remarkable anti-tumorgenic effects.37,38

In addition to these systemic effects, tocotrienols appear to have a high degree of specificity to skin. As nutrients are distributed around mice body systems, tocotrienols are 15 times more likely to be directed to the skin than are tocopherols.39, 40

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.41

Topical application of TRF application was also shown to prevent significant ozone oxidative damage to skin.42

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.

The ideal form of topical vitamin E is a natural blend of the tocotrienols and tocopherols. When applied topically, both tocotrienols and tocopherols are by far the most concentrated in the superficial stratum corneum layer of the skin ‚ where the UV threat is the greatest ‚ and they penetrate rapidly into the skin in both forms.43

• 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.44

• 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.45

• 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.46

Polyphenol fractions from unripe green apples have been demonstrated to have, among other activities, antimutagenicity, inhibition of histamine release,47 antioxidation and UV-B absorption/screening activity.48

Immune Function Modulators

As appreciation has grown for the damaging effects of UVR on immunological function, there has been a growing interest in the use of known immune modulating compounds as topical agents to enhance the immunological function of the skin.

• Colostrum - Unlike any other species, the cow is a "universal donor," producing colostrum which is accepted by virtually all other mammals, including humans.49

Not only are the immune and growth factors in bovine colostrum identical in molecular structure to those of humans50 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.51

• Mushroom Extracts - Mushrooms have been an essential element of medical treatments used in the Orient for centuries, though no laboratory analysis of potential modes of action had been undertaken until quite recently. 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."52

Other studies show that Ganoderm lucidum extract boosts production of cytokines and killer T-cells,53 and is an effective, non-toxic antiherpetic agent.54

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 - While fibroblasts in aged tissue produce less collagen than those in younger skin, they have not lost the capability. In fact, when isolated from tissue and stimulated by endogenous growth factors, they are able to again produce significant quantities of collagen.55

Fibroblast collagen production has been reported to be stimulated by a pentapeptide fragment of the collagen molecule.56

At the carboxyl-terminal end of the collagen molecule is a fragment that has been identified as a participant in the regulation of its own synthesis. Katayama and colleagues have characterized that fragment as a five amino acid stretch: Lys-Thr-Thr-Lys-Ser. This pentapeptide is a potent stimulator of collagen and fibronectin synthesis ‚ both important components of the interstitial matrix.57

A synthesized version of this naturally occurring pentapeptide 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 >200µm, 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.58

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.

• Retinoic Acids - It was long known that hypovitaminosis A resulted in increased corneocyte cohesion, resulting in a thickened stratum corneum layer of the skin. In 1969, Kligman published documentation that treatment topically with trans-retinoic acid of vitamin A resulted in much the opposite effect of low vitamin A, in that it stimulated detachment of corneocytes59

Since that time, various retinoids have been used effectively in topical form for acne and wrinkled skin. While there is some animal-model evidence for carcinogenicity of tretinoin,60 some reviewers question a relationship to human risk. A risk of fetal malformations does exist with oral isotretinoin, but does not appear to be associated with topical tretinoin.61

Topical use of retinoids can result in both inter- and intracellular edema, thinning of the granular layer along with thickening of the germinative layer of the epidermis, and increased cell proliferation. Repeated use can result in severe inflammation, a loosely attached stratum corneum,62 followed by diminished epidermal permeability barrier function.63

Retinoids are thus available only by prescription and are generally reserved for more advanced skin conditions.

• Organic acids - Alpha hydroxy acids (AHAs) and beta hydroxy acids (BHAs) are organic acids that have been found to reduce corneocyte adhesion. While AHAs have similar effects on skin as retinoids, offering enhanced exfoliation and improvement in appearance of aging skin, the mechanisms of action differ. While not without adverse effects in some users, AHAs are generally considered to be less irritating than retinoids, although similarly effective when used at appropriate concentrations.

Retinoids are hydrophobic, while AHAs and other acids are hydrophylic. "As hydrophiles, acids freely diffuse throughout the intercellular watery phase, which activity is thought in part to contribute to the somewhat milder secondary effects exhibited by AHAs as compared to the usually more harsh reactions which may be exhibited by topical use of retinoids."64

AHAs include ascorbic acid, citric acid, gluconic acid, glycolic acid, lactic acid, malic acid, and tartaric acid, and are derived from a wide range of sources, including milk, apples, citrus fruits, grapes and maple trees.

These acids 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%.65, 66

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,67 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.68

Use of AHAs can increase the sensitivity of the skin to UVR. Recent FDA guidelines recommend that consumer products containing AHAs should either contain sunscreen ingredients or warn the user to apply an additional sunscreen-containing product when using AHAs. The FDA further recommends that concentrations not exceed 10% and that the finished product have a pH of at least 3.0 to minimize irritation.

Liposomal Delivery Systems

Liposomes are a useful technology for delivery of nutrients and other components to the skin. Because the skin is designed to be a very effective barrier, steps must be taken to ensure efficient absorption of active compounds through the skin. This is particularly true of antioxidants. Some have demonstrated very good absorption qualities, but others much less.

Liposomes are small vesicles approximately 300 times smaller than the human cell, with lecithin-based lipid membrane surrounding the designed contents. When applied to the skin, the structural similarity of the liposome to the cells, as well as its small size, allow it to penetrate readily into the various levels of the skin.

When it encounters a target cell, the membrane of the liposome fuses into the cell membrane, discharging its payload into the cytoplasm over the course of 6-8 hours. Use of liposomal systems can dramatically increase the effectiveness of an active ingredient, providing up to 10 times the effectiveness of the same material used neat. 69

Evaluating Skin Care Formulations

In recent years, a growing body of knowledge regarding nutritional biochemistry and the benefits of appropriate nutritional supplementation to support and complement the body's functions, has led many physicians to prescribe or recommend oral nutrient therapies for their patients. It is now clear that topical application of nutrients to the skin to support and complement its functions, is a logical and necessary extension of this practice. However, the general physician may feel reluctant to recommend specific skin care products without a means to evaluate their effectiveness.

Many of 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 ãregardless of whether they are distributed by healthcare professionals or via other modes of distribution. (Any product making sun protection claims or carrying an SPF rating is considered by the FDA to be an over-the-counter drug as is regulated as such.)

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 ãwhether true or not ãregarding 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, labelling 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. This practice is regrettably common, even among more expensive, higher-end products.

Labelling regulations stipulate that ingredients be listed in descending order, from the greatest to the least, for those ingredients constituting 1% or more of the total weight. Ingredients making up less than 1% of the total may be listed in any order. The label, therefore, is of limited usefulness in determining the concentration of ingredients that may be highly effective at low concentrations. A product containing 1% of melatonin, for example, would be indistinguishable from a product containing .001%.

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. Manufacturers may also provide documentation of the product's effect on the appearance of the skin (e.g., photo studies, etc.) because these do not overtly claim to represent structural changes. Obviously, dramatic changes in the skin suggest more than just temporary cosmetic effects. Effects which become more noticeable with longer-term usage also suggest improvements in the underlying structure and function of the skin.

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. Guercio-Hauer C, Macfarlane DF, Deleo VA. Photodamage, Photoaging and Photoprotection of the Skin. American Family Physician 1994;50(2):327-332.

3. Gilchrest BA. A review of skin aging and its medical therapy. Br J Derm 1996;135:867-875.

4. Olsen R. Ultraviolet light induced individual cell keratinization. J Clin Pathol 1974;1:120-121

5. Charif M, Geller AC, Koh HK. Photodamage 1995; Blackwell Science, Inc.

6. Weinstock MA. Epidemiology of nonmelanoma skin cancer: clinical issues, definitions, and classification. J Invest Dermatol 1994;102(6):4S-5S.

7. Miller DL, Weinstock MA. Nonmelanoma skin cancer in the united States: incidence. J Am Acad Dermatol 1994; 30(5 Pr 1):774-778.

8. Corona R. Epidemiology of nonmelanoma skin cancer: a review. Ann Ist Super Sanita 1996;32(1):37-42.

9. Chuang TY, Popescu A, Su WP, et al. Basal cell carcinoma. A population-based incidence study in Rochester, Minnesota. J Am Acad Dermatol 1990;22:413-417.

10. el Khwsky F, Dedwani R, D'Avanzo B, et al. Risk factors for nonmelanomatous skin cancer in Alexandria, Egypt. Int J Cancer 1994;56(3):375-378.

11. Longstreth J. Cutaneous malignant melanoma and ultraviolet radiation: A review. Cancer and Metastasis Reviews 1988;7:321-333

12. 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.

13. Green A, Siskind V, Bain C, Alexander J. Sunburn and malignant melanoma. Br. J Cancer 1985;51:393-397.

14. Ananthaswamy HN, Pierceall WE. Molecular mechanisms of ultraviolet radiation carcinogenesis. Photechem Photobiol 1990;52:1119-1136.

15. Steenvoorden DP, van Henegouwen GM. The use of endogenous antioxidants to improve photoprotection. J Photochem Photobiol 1997;41(1-2):1-10.

16. DiSalvo, RM Cosmeceuticals, in The Chemistry and Manufacture of Cosmetics 2000, 183-253.

17. Goettsch W, Garssen J, et al. UV-B and the immune system. Thymus 1993;21:93-114

18. 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.

19. Goettsch W. Ibid

20. Gilchrest BA. Ibid

21. 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.

22. 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

23. Taylor CR, Stern RS, Leyden JJ, Gilchrest BA. Photoaging/photodamage and photoprotection. J Am Acad Derm 1990;22(1):1-15.

34. Kligman AM 1997 Ibid

35. Luftman DB, Lowe NJ, Moy RL. Sunscreens: Update and Review. J Dermatol Surg Oncol. 1991;17:744-746.

26. Halliday GM, Yuen KS, Bestak R, Barnetson RS. Sunscreens and vitamin E provide some protection to the skin immune system from solar-simulated UV radiation. Australas J Dermatol 1998;39(2):71-75.

27. Steenvoorden DP. Ibid

28. Vural P, Canbaz M, Selcuki D. Plasma antioxidant defense in actinic keratosis and basal cell carcinoma. J Eur Acad Dermatol Venereol 1999;113(2):96-101

29. Fuchs J, Kern H. Modulation of UV-light-induced skin inflammation by D-alpha-tocopherol and L-ascorbic acid: a clinical study using solar simulated radiation. Free Radic Biol Med 1998;25(9):1006-1012.

30. 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.

31. 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.

32. Fuchs J. Ibid

33. 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.

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69. Personal correspondence with Ron DiSalvo, PhD, Cchem FRSC