This month’s column resumes my review of prevention and treatment strategies for aging skin using oral and topical cosmeceutical agents.
Preventing and treating inflammation
Skin aging can result from inflammation through several mechanisms, including the formation of reactive oxygen species. Inflammation itself arises from myriad etiologic pathways, with multiple inflammatory mediators potentially involved, including histamines, cytokines, eicosanoids (for example, prostaglandins, thromboxanes, and leukotrienes), complement cascade components, kinins, fibrinopeptide enzymes, nuclear factor–kappa B, and free radicals.
For example, an inflammatory chain of events can be triggered by UV light and free radicals when they oxidize cell membrane lipids, which leads to the release of arachidonic acid. The arachidonic acid cascade plays an important role in skin inflammation because it activates cyclooxygenase-2 (COX-2), which leads to the synthesis of substances such as prostaglandins and leukotrienes. These compounds cause inflammation and recruit inflammatory immune cells to the area. Nuclear factor–kappa B is another significant regulator of inflammation in the skin.1
Topically applied argan oil, caffeine, chamomile, feverfew, green tea, licorice extract, aloe, linoleic acid (found in high concentrations in argan oil and safflower oil), and niacinamide are among the anti-inflammatory ingredients that have been used successfully in topical skin care to reduce inflammation. The Food and Drug Administration does not allow cosmetics to make “anti-inflammatory” claims. For this reason, these products will state they have “soothing” effects or imply they improve of redness.
Oral polypodium leucotomos has been demonstrated to suppress the effect of UV radiation on COX-2 expression.2 Also, glycolic acid has exhibited the capacity to inhibit COX-2 signaling and other inflammatory mediators.3
Preventing and treating glycation
Glycation is produced by the Maillard reaction, a chemical reaction – particularly well known in cooking – between an amino acid and a sugar molecule that typically requires heat. This reaction was first described by Louis Camille Maillard in 1912 when he noted that amino acids can react with sugar to yield brown or golden-brown substances. It took until the 1980s for scientists to understand the importance of glycation in health.
When glycation occurs, sugar molecules attach to proteins, creating cross-linked proteins known as advanced glycation end products (or AGEs) and causing a series of chemical reactions. Glycation occurs in collagen fibers and results in the formation of cross-links that bind collagen fibers to each other, which leaves the skin stiffer. Glycosylated collagen is believed to be a factor in the appearance of aged skin.4 Glycation also can affect elastin: Recent research suggests that glycation can engender elastosis, which is elastin that is abnormally clumped together and presents more frequently in aged skin.
Several antiaging skin care products claim to treat glycation, but – unfortunately – glycation is not a reversible reaction. It must be prevented in the first place. Some studies suggest that antioxidants can prevent glycation, but it is more likely that they just divert the process down a different pathway that still leads to glycation. Reducing serum glucose levels is the optimum method of preventing glycation.5 Dietary intervention and oral metformin are recommended for lowering glycation.
REVERSING SKIN CELL AGING
Epidermal keratinocytes in aging
Young basal stem cells synthesize a plethora of new keratinocytes at a pace that leads to fast cell turnover and vigorous production of protective epidermal constituents. Old keratinocytes display less energy, show reduced responsiveness to cellular signals, and do not synthesize these protective components.6,7 Keratinocyte stem cell function declines over time while damage accumulates, as seen in a diminished response to growth factors, decreased keratinization, and impaired function.8
Dermal fibroblasts in cutaneous aging
Young fibroblasts produce key cellular constituents, including collagen, elastin, hyaluronic acid, and heparan sulfate. This production declines in older fibroblasts. Like aging keratinocytes, old fibroblasts lose energy and responsiveness to growth factors and other cellular signals.6,7
Rejuvenating aged skin with cosmeceuticals
Gene expression, growth factors, cytokines, chemokines, and receptor activation guide the function of keratinocytes and fibroblasts. To reverse or slow cellular skin aging, old keratinocytes and fibroblasts must be galvanized to respond to such signals or the signals must be enhanced.
Stimulating old keratinocytes and fibroblasts
Essential steps in stimulating aged keratinocytes and fibroblasts include: activating gene expression, adding growth factors, activating cytokines and chemokines, turning on receptors, and making cells more responsive to signals.
Influencing gene expression
Retinoids are known to affect collagen genes and increase activity of procollagen genes, thereby reducing the production of collagenase. Many studies have shown the efficacy of retinoids in treating aged skin and preventing cutaneous aging in both areas frequently exposed to the sun but also those that aren’t.9,10 Prescription retinoids (tretinoin, adapalene, tazarotene) and over-the-counter retinoids (retinol) are first-line options to treat and prevent aging by stimulating old keratinocytes and fibroblasts.10,11 However, exposing retinoic acid receptors to retinoids almost invariably leads to erythema and flaking in the first few weeks. Therefore, retinoids should be titrated slowly. Note that retinoid esters, such as retinyl palmitate and retinyl linoleate, do not penetrate well into the dermis;12 they also are not as effective as retinol, tretinoin, adapalene, and tazarotene. Compliance with retinoids is always an issue with patients. They should receive printed educational material about how to begin use and why it is important to use these products consistently.
Alpha hydroxy acids also can spur collagen genes to increase collagen synthesis.13-15 Ascorbic acid also has been demonstrated to stimulate collagen genes, yielding increased Type 1 collagen production by fibroblasts.16
Growth factors
The use of cosmetic formulations that contain growth factors can contribute to skin rejuvenation. There are various types of growth factors that have the capacity to stimulate old keratinocytes and fibroblasts to enhance function.17 Growth factors, which are inactive or vulnerable to degradation in their native, soluble form, can directly energize genes or act as a signaling mechanism. To exert their quintessential functions, growth factors must be transferred to the correct receptor site in order for the cell to respond to their signal.18
Heparan sulfate
Heparan sulfate (HS) plays a primary role in cell-to-cell communications. It increases cellular response to growth factors by facilitating the response of old, lazy fibroblasts to the cellular signals.18 HS binds, stores, and protects growth factors, which allows them to complete movement to their targets, and then presents them to the appropriate binding site.18,19 A topically applied analogue of HS has been demonstrated to rejuvenate aged skin.20
Stem cells
Stem cells included and pointedly marketed in cosmeceutical products are usually plant derived, are too large to penetrate the stratum corneum, display short shelf lives, and do not behave as human stem cells would. As a result, stem cells in cosmeceutical agents are essentially useless.
However, novel technologies have revealed ingredients that can incite native stem cells to repopulate the epidermis and dermis with young cells. Stem cells in skin include basal stem cells and 10 varieties of hair follicle stem cells. The LGR6+ hair follicle cells play a pivotal role in repopulating the epidermis after wounding has occurred.21,22 Aesthetic physicians have known for several years that inducing skin wounding with lasers, needles, and acidic peels leads to improvement in its appearance. Researchers have provided new data showing that wounding the skin prompts LGR6+ stem cells to repopulate the epidermis. Once wounding occurs, neutrophils release the peptide defensin, which stimulates the LGR6+ stem cells to repopulate the epidermis.23 Topical defensin that has been formulated to penetrate into hair follicles, where the LGR6+ stem cells reside, has been demonstrated to render a smoother, more youthful appearance to the skin.
Conclusion
It is important for practitioners to identify patients at risk for premature skin aging as early as possible and start them on an appropriate and consistent skin care regimen. This typically will include at least a daily sunscreen with an SPF 15 or higher, a nightly topical retinoid, and oral and topical antioxidants. The patient’s additional skin type proclivities (for example, dryness, inflammation, melanocyte activity) should guide the physician as to how to combine these baseline product types with cleansers, moisturizers, and formulations with hydroxy acids, growth factors, heparan sulfate, and defensin.
Several studies have revealed that patients exhibit poor compliance with recommended regimens.24 Informing patients about the need for skin protection and providing printed instructions can help to improve compliance.25 This can promote healthy lifestyle habits and compliance with scientifically proven antiaging therapies.
Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002) and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014); she also authored a New York Times Best Seller for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance Therapeutics. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.
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