Vitamin C

Topical vitamin C (ascorbic acid) has been shown to reduce UV-induced erythema, sunburn cell formation, and the appearance of wrinkles. A combination of topically applied water soluble vitamin C (ascorbic acid), and a lipid soluble form, tetrahexyldecyl ascorbate (THD), has also been shown to reduce wrinkling due to photodamage. Studies have shown that, at the same concentration, THD surpasses the depth of penetration of ascorbic acid by threefold and that its rate of penetration is greater, even when the concentration of ascorbic acid is 25 times that of THD. Vitamin C plays an important role in collagen production and has been shown to stimulate collagen production when added to cultures of human skin fibroblasts. Vitamin C also restores the antioxidant capacity of vitamin E, a much more potent inhibitor of lipid peroxidation.

Vitamin E

Vitamin E is lipid soluble and consists of eight active isomers (tocopherols and tocotrienols), with alpha-tocopherol showing the most biologic activity. Vitamin E reduces the number of sunburn cells, decreases UVB-induced photodamage, and can inhibit UV-induced tumor formation. Alpha-tocopherol, a membrane-bound antioxidant, protects cell membranes from damage caused by phospholipase A, lysophospholipids, and free fatty acids. Vitamin E has been shown to inhibit human macrophage metalloelastase, a matrix metalloproteinase (MMP) that degrades elastin. Furthermore, signs of photoaging were shown to improve in a study comparing the use of a vitamin E cream versus placebo.

Combined vitamins C and E

The combined application of Vitamins E and C that is commercially available in several product lines has been shown to provide more potent photoprotection compared with either agent alone. A limitation to topically applied vitamin E is the potential for contact dermatitis.

Green tea

Green tea antioxidants extracted from the leaves and buds of the plant Camellia sinensis include epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate (EGCG), the latter being the most abundant and potent. Animal studies have shown that topically applied green tea polyphenols can inhibit photocarcinogenesis as well as prevent UV-induced oxidative damage and induction of MMPs. In vivo application of green tea polyphenols to human backs 30 minutes before UV irradiation was shown to reduce erythema, the number of sunburn cells, immunosuppression, and DNA damage. Another study demonstrated the efficacy of topically applied EGCG in reducing UVB-induced inflammation. Although controlled clinical trials are lacking, green tea polyphenols are popular in cosmeceuticals given their ability to multitask. Vivian W. Bucay find them very helpful in mitigating the retinoid-induced irritation.

Vitamin B3

Topically applied niacinamide, the biologically active form of vitamin B3, not only exhibits antioxidant and antiinflammatory properties but also can improve hyperpigmentation by decreasing transfer of melanosomes to keratinocytes. The effects of topically applied niacinamide include improved skin texture and tone along with a reduction in fine lines and hyperpigmentation.

Prescription retinoids

Of the prescription retinoids, only tretinoin and tazarotene have FDA approval for the treatment of photodamage, although nonprescription retinol and retinaldehyde are commonly used for this indication. Wrinkle improvement is the result of retinoid-mediated effects that produce an increase in dermal collagen synthesis by increasing type I procollagen expression mediated by the inhibition of the UV-induction of c-Jun and an alteration of transforming growth factor (TGF)-β expression. Inhibition of dermal collagen degradation is accomplished by inhibition of transcriptional factor activator protein-1 activation of MMP-like collagenase.

Retinoids also improve dyschromia by inhibiting tyrosinase activity. This leads to a reduction of melanin synthesis, decrease in melanosome transfer, and increase in shedding of keratinocytes. Additionally, retinoids contribute to smoother skin and a reduction in tactile roughness by increasing epidermal proliferation and differentiation, compacting the stratum corneum, and increasing epidermal and dermal intercellular mucin deposition.

Over-the-counter retinoids

Over-the-counter alternatives include retinol that, although potentially less irritating than its metabolite retinoic acid (tretinoin), is also 20-fold less potent. Retinaldehyde, a naturally occurring metabolite of retinol and the precursor of retinoic acid, has demonstrated efficacy in treating photodamage but with less irritation than retinoic acid. Eye skin care products containing hyaluronic acid, ceramides, cholesterol, and dimethylaminoethanol (DMAE) lactate are useful in mitigating dryness and skin irritation, and maintaining an adequate skin barrier.

Peptides

Collagen boosters typically include compounds such as peptides and growth factors. A brief review of the pathogenesis of aging skin will aid in understanding the rationale for the use of these compounds in antiaging products:

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  Lines and wrinkles occur both in photoaged and chronologically aged skin

  
  
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  Coarser lines and wrinkles are characteristic of photoaging, whereas finer lines are more typical of chronologic aging

  
  
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  The pathogenesis of skin aging is characterized by a decrease in collagen synthesis coupled with an increase in collagen breakdown

  
  
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  A decrease in procollagen type I mRNA is seen in aging skin, with a greater reduction seen in photodamaged skin compared with nonexposed skin

  
  
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  UV radiation–induced upregulation of collagenase (MMP-1) leads to damage and degradation of collagen.

Mechanisms by which an improvement in lines and wrinkles can be achieved include the upregulation of collagen production coupled with the down-regulation of collagen degradation, with dermal fibroblasts being the target cell in this strategy. To this end, peptides (short chains of amino acid sequences) have been incorporated into cosmeceuticals to stimulate collagen production. Peptides can be subdivided into three categories:

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  Signal peptides

  
  
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  Carrier peptides

  
  
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  Neurotransmitter-inhibiting peptides.

Perhaps the most studied signal peptide is the five-amino-acid sequence Lys-Thr-Thr-Lys-Ser (KTTKS), which is found on type I procollagen and has been shown to increase the production of extracellular matrix proteins through the feedback regulation of collagen synthesis. Improved delivery of this hydrophilic peptide has been accomplished by adding palmitoyl, a 16-carbon fatty acid fragment, resulting in a compound known as Pal-KTTKS or, its commercial name, Matrixyl and is found in several commercially available products.

An example of a carrier peptide is the tripeptide glycyl-l-histidyl-l-lysine (GHK), which has been shown to facilitate copper uptake by cells and to stimulate fibroblast collagen synthesis. Additional effects of GHK include dermal remodeling by increasing levels of MMP-2 and MMP-2 mRNA and increasing levels of tissue inhibitors of metalloproteinase 1 and 2, increases in type I collagen and glycosaminoglycans, and increases in dermatan sulfate and cell layer-associated heparin sulfate.

In vitro studies have shown that acetyl hexapeptide-3, also known as argireline, functions as a neurotransmitter inhibiting peptide by interfering with sensory nerve action potential-25, thus mimicking the effects of clostridial botulinum neurotoxin. Although there is in vitro evidence of its ability to inhibit acetylcholine release, in vivo studies are limited, probably because of the inability of this compound to penetrate to the muscle. Nonetheless, argireline has been incorporated into several cosmeceutical products.

Additional peptides include tripeptide-1 (Aldenine), which acts by reducing glycation and advanced glycation end products by increasing superoxide dismutase and decreases collagen cross-linking and other peptides, and palmitoyl tetrapetide-7 and palmitoyl oligopeptide (together known as Matrixyl 3000), which act to stimulate type I collagen, fibronectin, and hyaluronic acid. Additional peptides will be covered under the topic of puffiness and dark circles.

Growth factors

Growth factors are high molecular weight peptides that regulate specific cellular activities, including tissue repair and growth and intercellular signaling. There is evidence to suggest that the following play a role in skin rejuvenation :

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  TGF

  
  
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  Epidermal growth factor

  
  
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  Platelet-derived growth factor

  
  
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  Insulin-like growth factor

  
  
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  Fibroblast growth factor

  
  
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  Vascular endothelial growth factor (VEGF).

A double-blind study involving 60 subjects examined the safety and efficacy of a proprietary mixture of more than 110 growth factors, cytokines, and soluble matrix proteins secreted by human fibroblasts in the treatment of mild to severe photodamage. Patients were randomized to receive either the active gel or the vehicle and were instructed to apply it twice daily. Both subjective and objective measurements at 3 months showed a greater reduction in fine lines and wrinkles by the active gel when compared with the vehicle, suggesting that a topical gel of growth factors and cytokines can improve the signs of photoaging when used with a sunscreen.

Alternatives to human growth factors are those derived from plants, such as N-furfuryladenine, and animal-derived growth factors, such as snail secretion filtrate, the most biologically active of which is derived from Cryptomphalus aspersa (SCA). This compound has been used successfully in Europe for over 15 years to treat radiation dermatitis. SCA is found in commercially available products used to treat the signs of photoaging and at least one published study has demonstrated its efficacy in the treatment of periocular wrinkles.

DNA repair liposomes have been shown to reduce the incidence of UV-induced skin cancer in mice, although to date, there are no controlled clinical studies in humans demonstrating the same. Despite the lack of clinical studies, incorporation of these compounds into antiaging products is becoming increasingly popular, and the author is aware of some ongoing studies involving some of the commercially available products.

DNA repair enzymes include photosomes, which are a plankton-derived form of photolyase and block the transcription of UV-induced pyrimidine dimers, roxisomes or oxoguanine glycosylase-1; a mitochondrial DNA repair enzyme obtained from the Arabidopsis thaliana (mustard) plant, which serves to excise damaged DNA; and ultrasomes, or T4 endonuclease, which is derived from Micrococcus lysate and acts by excising UV-induced dimers. Liposomal formulation of these enzymes allows for targeted delivery and enhanced efficacy. Photobiologist and cosmeceutical innovator Daniel Yarosh, PhD, has published more than 100 articles on the subject of DNA repair; his book, The New Science of Perfect Skin , is an excellent reference on the science of skin care.

Stem cells are a hot topic in many areas of medicine and their incorporation into skin care is an emerging trend. Plant stem cells, such as apple stem cells, can be found in currently available skin care products; however, the inclusion of autologous human cells in skin care heralds the latest advance in the treatment of photodamage. An additional application of the recent FDA approval of technology involving the injection of an autologous fibroblast suspension for the treatment of fine lines and wrinkles will extend to the use of these same cells to formulate personalized skin care. Controlled clinical trials will be necessary to prove their efficacy.

Shadowing

Shadowing due to intrinsic and extrinsic aging of the skin that leads to skin laxity, in combination with age-related changes in the soft tissue and skeleton, is another common cause of dark circles. The appearance of a “tear trough” depression secondary to loss of subcutaneous fat and thinning of the skin over the orbital rim ligament leads to hollowing of the orbital rim, leading to a dark shadow that can be further accentuated by pseudoherniation of the infraorbital fat pad. Short of addressing the issue of photodamaged skin as discussed earlier in this article, adjunctive skin care does not play a role in the treatment of this type of infraorbital dark circle.

Puffiness and bags

Under-eye puffiness and lower eyelid bags are also multifactorial in origin and another common aesthetic complaint, although published studies regarding this topic are scarce. In an analysis of 114 consecutive subjects (67 men and 47 women, mean age 52 years, age range 23–76 years) presenting for aesthetic consultation for lower eyelid bags, Goldman and colleagues conclude that there is not a single anatomic basis for their cause but, instead, identify six anatomic variables. These include

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  Cheek descent and hollow tear trough (52%)

  
  
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  Prolapsed of orbital fat (48%)

  
  
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  Skin laxity and sun damage (35%)

  
  
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  Eyelid fluid (32%)

  
  
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  Orbicularis hyperactivity (20%)

  
  
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  Triangular cheek festoon (13%).

Not surprising, tear trough depression, skin laxity, and triangular malar mound occurred with greater frequency in those older than 50 years, and linear regression analysis showed that a recommendation for surgery was based on the extent of fat prolapse, skin elasticity, and midface descent.

Surgical intervention, laser resurfacing, soft tissue fillers, neurotoxins, and energy-based skin tightening may be used in varying combinations to address this complaint. Nonetheless, despite the evidence in support of an anatomic basis for under-eye puffiness and bags, patients seek recommendations for cosmeceuticals that can diminish their appearance. Most products used for this indication contain ingredients to reduce fluid retention, strengthen the vasculature, and improve skin laxity.