Vitamin A and Skin Antiaging

• The Antiaging Series:
  This series is undertaken as a public service to our readers as a systematic and comprehensive review of the topic of antiaging agents and their use both in personal care products and as prescription items if so available. We review the latest evidence concerning the most effective agents and products, provide guidance on their optimal use and proper application, and discuss any warnings or cautions that may be relevant. In this newsletter issue we discuss the world of Vitamin A and its derivatives (retinoids), both natural and synthetic. Subsequent articles in this series review alpha hydroxy acid (AHA) and related agents, antioxidants (including vitamins), moisturizers, and several other recently introduced agents.
  
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• Wrinkles and the Photoaged Skin:
  Vitamin A is now widely recognized as an important agent (actually, a family of agents) for skin health, and has achieved considerable use in both medical dermatology and in the personal care arena. Topical products may contain natural forms of vitamin A (retinol, retinaldehyde) or retinoids (tretinoin (also known as retinoic acid), isotretinoin, tazarotene, and adapalene), which are vitamin A derivatives. These agents have been shown to be beneficial on photoaged skin (skin damaged by the sun) and also by natural aging.
  
  We now know that most of the visible signs of aging skin ("photodamage") - progressive wrinkling, decreased clarity, hyperpigmentation, roughness and tone loss - are mainly due to the effects of long-term UV exposure; tretinoin is known to protect the skin against damage from UVA and UVB rays (see the recent review of Stern in NEJM: Treatment of Photoaging). In this connection, the retinoids have been clinically proven to reduce some of the stigmata (so-called age or liver spots and related discoloration, technically known as lentigines) of such photodamaged skin and to reverse much of the photodamage / photoaging process. At present, both tretinoin (commercially known as Retin-A) and, more recently, tazarotene, are FDA approved topical agents for treating photoaging. See also in Skin and Aging: Treating Extrinsically Aged Skin, in pdf format)
  
  

• Tretinoin (Retina):
  Tretinoin and a closely related compound isotretinoin have been confirmed in several well-designed clinical trials to reduce both fine and coarse wrinkles and hyperpigmentation (when mild to moderate), liver/age spots (lentigines) and photoaged-induced blemishes and related discoloration, in addition to increasing the thickness of the epidermis (skin's outer layer), with sustained improvement using prolonged topical tretinoin for photodamaged skin demonstrated for up to 22 - 48 months of continuous treatment. These agents help to normalize hyperkeratinization (scarring) and demonstrate significant anti-inflammatory activity. Retinoid-based topical agents like tretinoin can provide comparable, and possibly superior, results even when compared to superficial chemical peels. (See the review by Rolewski in Medscape: Clinical Review: Topical Retinoids.)
  
  

• Retinol:
  Retinol is a natural form of vitamin A, but until recently was not used in skin products because of its instability, and how easily it could be broken down by UV radiation. However, new formulations have overcome this problem, and stable preparations are now available over the counter. The evidence now indicates that in the proper concentrations (.075% - 1%) retinol may be as effective as tretinoin, typically with fewer side effect, and that retinol actually may prevent sun damage to the skin. Furthermore, adding antioxidant creams (such as those containing vitamins C or E) appears to offer added protection against degradation of retinol. (See See the discussion in Medscape of Chiu and Kimball's: Topical Vitamins, Minerals and Botanical Ingredients As Modulators of Environmental and Chronological Skin Damage.)
  
  

• Tazarotene:
  Tazarotene has also demonstrated impressive results as an anti-photoaging agent. A tazarotene 0.1% cream significantly reduced signs of photodamage to the skin: it reduced fine and coarse wrinkling, mottled hyperpigmentation and irregular depigmentation, roughness, with no systemic accumulation of drug. At high doses, tazarotene can cause very severe irritation; it is possible that some of the associated redness and peeling may be reduced by first administering tretinoin as a "primer", to get the skin acclimated.
  

• The Importance of the Right Regimen:
  It's important to note that the right application regimen is critical: Dr. Elise Olsen and associates found that reducing the frequency of a 05% tretinoin cream from one application daily to a three times per week regimen maintained the reduction of photodamage (in some cases, possibly enhancing it). However, it was observed that cessation of a 48 weeks tretinoin therapy for just 6 months was enough to reverse some of the benefits. We may conclude, based in part of a recent study by Baumann in 2003 (as cited in the Medscape review by Rolewski: Clinical Review: Topical Retinoids) that continuous / indefinite use is required to maintain the anti-photoaging efficacy of tretinoin. Recent studies have found that low tretinoin concentrations (as low as .02%) may produce significant improvements in treating photodamaged skin (wrinkles and skin color, in particular), but with less irritation than the higher doses.
  
  The user should be aware that noticeable improvement from the antiaging benefits of retinoids typically takes from two to six months, so patience is required to see the course through.
  
  

• How Best to Apply:
  Tretinoin may be applied to face, neck, chest, hands, and forearm, preferably on an three times a week regimen. Although the official package inserts typically suggest using a pea-sized amount, Sheri Rowelski at the Department of Dermatology, Cosmetic Surgery & Skin Health Center at the University of Pittsburgh recommends applying 1 inch of the retinoid to the entire face, reasoning that by treating the entire face, efficacy can be enhanced, for the active ingredient works at the point of placement (see the review by Rolewski in Medscape: Clinical Review: Topical Retinoids) . She cautions that spot treatment should be avoided, as this may decrease efficacy and can lead to a blotchy appearance of the skin. Application at nighttime is best given the ability of retinoids to make a person's affected skin more sensitive to the sun (see below).
  
  

• Caution:
  Since all retinoids may increase sensitivity to the sun, administration at bedtime is advised, and a sunblock should be worn during the day, avoiding overexposure to the sun (best would be an aqueous-based sunscreen with SPF > 15). Many users will experience some "retinoid dermatitis": some degree of redness (erythemia), scaling, burning, and itching (pruritis) after the first two or three days of application, and in some cases this may last up to three months. It is best to wash at least 30 minutes before applying at bedtime: this ensures that the skin is dry, as it is known that irritation can result if applied on still moist skin. If such irritation is experienced, a daytime moisturizer (do not use at nighttime as it can dilute the concentration of the retinoid), or low-dose over-the-counter corticosteroid cream or gel, such as 1% hydrocortisone, can be used, again only at daytime. And as cited above, a three times per week regimen appears optimal and helps avoid the excess irritation of daily application. It is also important to avoid the use of astringents and other harsh skin care products
  
  Warning: Any vitamin A derivative should be avoided by pregnant women or those who may become pregnant. It is known that oral tretinoin can cause birth defects, and women are advised to avoid even topical tretinoin when pregnant or trying to conceive.

• Acne Treatment :
  Retinoids can further promote a reversal of an abnormal process called comedogenesis which may be a precursor to acne lesions. It is for this reason that tretinoin has been a mainstay of acne treatment for over 30 years. In this use, the retinoids tazarotene and adapalene appears to have the greatest anti-acne activity (tazarotene can even be used effectively in alternate-day, rather than daily, regimen), with adapalene perhaps showing the greatest tolerability.
  
  

• Other Uses :
  In addition, these agents have shown benefit and been successfully used across an impressively broad range of dermatological conditions (in addition to acne and skin photodamage) such as psoriasis, rosacea, hypertrophic scars and keloids, lichen planus (a dermatosis), melasma (a hyperpigmentation disorder), wound healing, and even alopecia areata (baldness) where topical tretinoin is sometimes coupled with topical minoxidil.

Vitamin A and Skin Antiaging

• Alpha-hydroxy Acids (AHAs)
  Alpha-hydroxy acids (AHAs) have been available as dermatological agents for over 20 years. However, the use of these agents for rejuvenation dates from ancient times (Cleopatra bathed in sour milk, which contains the AHA lactic acid). Most alpha-hydroxy acids are derived from foods (with those found in fruits being called fruit acids, but technically, AHAs are are carboxylic acids derived from fruit and milk sugars). Malic acid comes from apples and pears, citric acid from citrus fruits, lactic acid from milk, tartaric acid from grapes, and glycolic acid from sugar cane. Salicylic acid is, loosely speaking, a beta hydroxy acid (a BHA).
  
  Depending on the concentration, some have been shown to be effective as peeling agents and for rejuvenation, and all AHAs appear to act as both exfoliants and moisturizers. Products containing AHAs vary in concentration: consumer products usually have an AHA concentration of 10% or less, while those used by trained cosmetologists may be between 20% and 30%, and those used by physicians can be 50%-70% and are classified as medications. Although OTC (over-the-counter) commercial AHA-containing preparations are often synthetically derived, the efficacy and operation of synthetic AHAs is functionally equivalent to organic source derived preparations.
  
  AHAs contribute to a marked and visible improvement in skin quality - both tone and texture - through their exfoliative action, making the skin look smoother and more youthful.. Exfoliation removes dead skin cells from the skin's surface. Early studies demonstrated the age-reversal activity of glycolic acid, an alpha- hydroxy fruit acid, which sloughs off dead skin cells from the surface of the skin in order to allow the more youthful appearing underlying fresh cells to be visible. In effect, topical application of these fruit AHAs significantly reduces fine lines and wrinkles and produces a fresher looking tone to the skin. Thus AHAs perform chemical peeling of the human skin, a process in which the outermost layer of dead skin cells (the stratum corneum) is removed, exposing the fresh living cells of the underlying basal cell layer (these two layers of cells together constitute the skin's epidermis).
  
  Several studies attest to the antiaging benefits of AHAs and AHAs are not only exfoliants, but also stimulators of collagen production and cell proliferation (growth), with glycolic acid being significantly more effective than malic acid.
  
  In addition to their exfoliative action, AHAs also have moisturizing effects: they increase the moisture content of upper skin layers, thus smoothing out wrinkles and fine lines and relieving dryness as well.
  
  And AHAs also show keratolytic activity: photodamage (sun damage) to the skin results in hyperkeratosis; hyperkeratosis is a thickening of the skin's outer layer (the stratum corneum) containing keratin, a tough, protective protein (corns, calluses, and warts are all types of hyperkeratosis). The keratolytic activity of AHAs increases turnover of the stratum corneum, resulting in the skin appearing smoother.
  
  

• Other Uses of AHAs
  
  AHAs are of benefit in other skin disorders. One such disorder is psoriasis (a skin condition of increased epidermal production), especially when combined with a topical steroid.
  
  Another condition that benefits from AHAs is that of stretch marks (technically called striae rubra and striae alba): topical 20% glycolic acid is as effective as as the standard treatment with tretinoin (a retinoid, discussed in the previous issue of this newsletter), and both where found to be safe and effective with minimal irritation.
  
  

• A New Generation:
  Polyhydroxy Acids (PHAs)
  Given the potential of the current generation of hydroxy acids (alpha and beta) to increase skin sensitivity (see above), research has focused on match or exceed the efficacy of AHAs/BHAs yet reduce irritation that can limit the use of traditional AHAs. Gluconolactone represents the first of a new generation of hydroxy acids, the polyhydroxy acids (PHAs) that is as effective as an antiaging skin agent but less irritating than AHAs (lactobionic acid is another PHA being researched), and gluconolactone is now commercially available in OTC skin products.
  
  PHAs are better tolerated than AHAs, with stinging, burning and degree of sensitivity occurring significantly less than with AHA treatment, the antiaging benefits being otherwise roughly comparable. Furthermore, PHA-containing products were compatible with African American, Caucasian, and Hispanic/Asian skin, providing significant improvements in photoaging in all these populations.
  
  

• Some Cautions
  Be aware, however, that using exfoliants like the AHAs makes the skin more photosensitive, that is, sensitive to sunlight, and that such effects can persist up to a week after the products have been stopped. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) determined that a month of AHA use increased sensitivity to skin reddening by UV exposure (sunlight) by 18% (this photosensitivity is reversed within a week of terminating treatment). Therefore it is imperative to use a suitable sunscreen daily to protect the newly sensitized skin.
  
  Officially, the FDA position is: "Glycolic and Lactic Acid, their common salts and their simple esters, are safe for use in cosmetic products at concentrations <10%, at final formulation pH >3.5, when formulated to avoid increasing sun sensitivity or when directions for use include the daily use of sun protection."
  
  

• Consumer Guide to the Safe Use of AHAs/BHAs/PHAs:
  
  1. Concentration:
  Select a product with an AHA concentration of 10 percent or less.
  
  2. pH Range:
  Select a product with a pH of 3.5 or greater (remember: lower pH indicates greater acidity). Note: the natural pH of the skin is in the range of 4.2 - 5.7, so this physiologic pH is altered by AHA application.
  
  3. Photoprotection:
  Select a product with an added sunscreen, or one that has clear consumer advice to use an effective sunscreen.
  
  4. Initial Skin Test:
  Always first apply a small amount of an hydroxy acid containing preparation to a small area of skin, and monitor for a few days for any adverse sensitivity reaction; it is best even during this initial trial to either use a preparation that includes an effective sunscreen, or apply a sunscreen before any significant exposure of that area to sunlight. Discontinue use of a preparation if any significant sensitivity reaction occurs, and wait at least a week to 10 days before retrial of another preparation, after the skin has returned to normal.
  
  5. Product Switching:
  Response and reaction to hydroxy acid containing preparations may be fairly individual, and specific to the formulation of the product chosen, so it may be worth trying to switch to another preparation if any adverse reaction is encountered.
  
  6. Building Tolerance:
  It may be prudent to start with a low AHA concentration product and one with a relatively high pH (3.5 and above, higher is better, to a limit of about 5.7), in order to minimize the risk of sensitivity (always use a sunscreen with any such product if a sunscreen is not already included); then it may be possible after a week to 10 days, to switch to a more potent preparation (higher AHA concentration) after developing some tolerance to the initial milder preparation. This may be preferable to starting with a more potent preparation.
  
  

• Consumer Summary -Tthe Bottom Line:
  Hydroxy acids demonstrate exfoliative, moisturizing, and keratolytic activity which together result in significant antiaging benefits to the skin, improving skin quality as to tone and texture, and making the skin look smoother and more youthful, significantly reducing wrinkles and fine lines, as well as relieving skin dryness. If one follows our guidelines for use above, hydroxy acid containing preparations can be both safe and effective as antiaging agents.
  
  

• How to Recognize an
  AHA, BHA or PHA Ingredient:
  
  Alpha-hydroxy Acids (AHAs)
  alpha hydroxy and botanical complex alpha-hydroxycaprylic acid alpha-hydroxyethanoic acid + ammonium alpha-hydroxyethanoate alpha-hydroxyoctanoic acid citric acid glycolic acid glycolic acid + ammonium glycolate glycomer in crosslinked fatty acids alpha nutrium hydroxycaprylic acid L-alpha hydroxy acid lactic acid malic acid mixed fruit acid sugar cane extract triple fruit acid tri-alpha hydroxy fruit acids
  
  Beta-hydroxy Acids (BHAs)
  beta hydroxybutanoic acid
  salicylic acid
  tropic acid
  trethocanic acid
  
  Polyhydroxy Acids (PHAs)
  gluconolactone
  lactobionic acid

• Skin Anatomy :
  The skin is composed of two interdependent layers, the epidermis and dermis, which in turn rest on the fatty subcutaneous layer (sometimes called hypodermis or subcutis).
  
  

• Epidermis:
  The epidermis is the upper tough protective barrier layer of the skin, containing melanin which both protects against the skin from the harmful rays of the sun and gives the skin its unique color); melanin is produced by melanocytes within the epidermis. The epidermis is wholly dependent on the underlying dermis for both the delivery of nutrients and the disposal of waste products, and is composed of living epidermal cells called keratinocytes (the principal cell of the epidermis). Keratinocytes contain a structural protein called keratin (formed from dead cells).
  
  The epidermis itself is made up of three sub-layers:
  (1) status corneum or corneal (horny) layer
  This is the outermost protective layer of the epidermis layer and contains continually shedding, dead skin cells (keratinocytes) and is continually replaced by living skin (keratinocytes) cells. Keratin, a protein formed from these dead keratinocytes or skin cells aids in protecting the skin from harmful substances.
  (2) keratinocytes
  This layer contains living keratinocytes (squamous cells), which help provide the skin with what it needs to protect the rest of the body.
  (3) basal layer
  The basal layer is the inner layer of the epidermis, containing basal cells. Basal cells continually divide, forming new keratinocytes and replacing the old ones that are shed from the skin's surface.
  
  Note: More technically, the epidermis is actually subdivided into five layers or strata, the stratum germinativum (SG), the stratum spinosum(SS), the stratum granulosum(SGR), the stratum lucidum), and the stratum corneum(SC); however the above simplification suffices for our more accessible discussion.
  
  

• Dermis:
  The primary function of the dermis is to sustain and support the epidermis. It consists of the fibrous components collagen, and elastin, the two proteins responsible for the support and elasticity of the skin. Collagen is a fibrous protein and the main protein of connective tissue, ad it allows the skin to be plump and firm. Elastin helps maintain normal skin tension, giving it the ability to snap back after been stretched; deterioration of elastin yields the looseness and sagging of seen in aged skin.
  
  The dermis residing below the epidermis contains so-called epithelial appendages located deep within the dermis, and these include nerve endings, sweat glands, oil glands, and hair follicles. (In the face epithelial appendages may also be found in the fatty subcutaneous layer beneath the dermis). Hair follicles are tube-shaped sheaths surrounding the part of the hair under the skin. The hair is nourished by the follicle at its base, where the hair grows. The hair shaft is the part of the hair above the skin.
  
  Note that human skin contains three types of sweat glands: sebaceous, eccrine and apocrine.
  
  Sebaceous glands produce sebum, a complex natural skin oil which is a mixture of fats and waxes. Sebaceous glands are found at the side of hair follicles and secrete sebum through a small duct inside the hair shaft. The sebum acts to lock in the skin's natural moisture, preventing it from drying out.
  
  Eccrine glands are concentrated in the palms, soles and underarms, producing colorless and largely odorless sweat consisting mainly of water, with some inorganic chlorides and small amounts of fatty acids. Eccrine sweat glands assist in regulating body cooling and in some waste product removal.
  
  Apocrine glands, located primarily in the underarm and genital regions, like sebaceous glands secrete their contents through hair follicles to the skin surface. The sweat produced by these glands is rich in organic materials, and the breakdown of this secretion by bacteria on the surface of the skin is the primary cause of body odor.
  
  

• Subcutaneous Layer
  Consists of a network of collagen and fat (adipose tissue) cells, helping to conserve the body's heat, and protecting other organs from injury by acting as a natural "shock absorber."
  
  

• The Aging Skin:
  The skin undergoes atrophy with aging. Some changes occur in the epidermis. The outermost portion of the epidermis, the stratum corneum, becomes less effective as a protective barrier to the external environment. A gradual decline in the number of melanocytes populating the basal layer of the epidermis also occurs, thus providing the skin with less protection from photodamage. (For a more detailed and technical review, see Chau et al. in Dermatology Trends: Aging Skin).
  
  Most effects of aging and photodamage occur in the dermis. With aging the dermis retains less water and fat, so that the skin begins to look less plump and less supple, and it becomes less resilient. Oil flow slows considerably so that the skin is drier. Cell renewal rate of new skin cells (the keratinocytes) also slows, so that older cells may remain longer on the skin's surface. An overall loss of organization in the dermis occurs as the dermis thins with age. Elastic fibers degenerate, making the skin less resistant to deformational forces. Collagen also is lost.
  
  Actinic damage (from the sun's radiation causing photochemical reactions) produces changes in the skin, resulting in thickened skin. Actinic keratosis develops: this is a condition manifested in thick, warty, rough, reddish growths on sun-exposed skin areas (sometimes a precursor to squamous cell carcinoma). Lentigines (so-called liver or age spots) are formed. Dermal elastosis (a degenerative change in dermal collagen) results from the accumulation of thickened degraded collagen and elastic fibers, while mature forms of collagen are decreased.
  
  To summarize, wrinkles (technically, facial rhytids) and most of the effects of aging of the skin, are now considered to be the result of a combination of
  (1) aging (genetically programmed),
  (2) photodamage, especially to the supporting tissue of the dermis, by the cumulative everyday exposure to the sun's harmful UV (ultraviolet) rays, including the UV radiation associated with tanning booth use - photoaging is now thought to be responsible for the majority of age-associated changes in the skin’s appearance,
  (3) gravity,
  (4) wear and tear from the repeated use of facial muscles for facial expression, and
  (5) the effects of environmental factors (other than photodamage from UV radiation exposure), especially cigarette smoking, which contributes to the skin's aging effects by biochemical changes it brings about in skin tissues; also wind and chemical exposure.