The aging process is unavoidable and often augmented by extrinsic forces, such as ultraviolet radiation. The increasing middle-aged population is leading to the production of many new cosmetic products promising improvement of the various signs of aging, termed cosmeceuticals. Within this booming industry, several different types exist. This article focuses on updates in those involving peptides, growth factors, cytokines, and stem cells.
Key points
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Collagen, elastin, and other components of the skin diminish with age and may be replaced through the use of cosmeceuticals.
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Peptides induce neocollagenesis replacing lost extracellular matrix and reducing the appearance of wrinkles.
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Cosmeceuticals containing growth factors and cytokines involved in wound repair aid in the repair of chronic damage to the skin.
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Allogenic stem cells derived from human adipocytes produce growth factors which promote fibroblasts within the skin along with promoting wound healing.
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Xenogenic stem cells derived from plants have anti-senescent properties.
Introduction
As the population grows, there is a particular increase in the middle-aged and elderly population, the so-called “baby boomers.” Among this population is a continued increase in the desire for younger looking skin. Areas of particular concern include loss of elasticity, rhytides, irregular texture, pigmentation, and dryness. This desire has led to the development of cosmeceuticals, which are in between cosmetics and physiologically altering pharmaceuticals.
Aging occurs by two mechanisms: intrinsic and extrinsic aging. Intrinsic aging is inevitable and results in atrophy, fibroblast reduction, and thinning blood vessels. Collagen is particularly affected, as the synthesis steadily declines with age. Likewise, elastin also declines with age. Extrinsic aging primarily results from the effects of UV damage. Other causes include environmental factors, such as smoking, pollution, and poor nutrition. This type of damage leads to increased degradation of collagen and elastin. Aged skin shows a decrease in extracellular matrix (ECM) proteins, increased collagen degradation, and decreased fibroblasts. Furthermore, there is a reduction in the immune response, wound repair, and fiber synthesis. Extrinsic aging leads to the production of free radicals, which in turn activate matrix metalloproteinases (MMPs). This activation of MMPs also leads to ECM degradation. Additionally, free radicals inhibit the tissue inhibitors of metalloproteinase (TIMPs). The goal of cosmeceuticals is to mitigate some of these effects of aging.
Effective cosmeceuticals must be able to penetrate through the stratum corneum while maintaining their effectiveness. They also must have visible benefits without impacting the skin’s barrier function. There has been a recent surge of new cosmeceuticals, and this article discusses the functions, limits, and benefits of peptides, growth factors, cytokines, and stem cells used in these products.
Introduction
As the population grows, there is a particular increase in the middle-aged and elderly population, the so-called “baby boomers.” Among this population is a continued increase in the desire for younger looking skin. Areas of particular concern include loss of elasticity, rhytides, irregular texture, pigmentation, and dryness. This desire has led to the development of cosmeceuticals, which are in between cosmetics and physiologically altering pharmaceuticals.
Aging occurs by two mechanisms: intrinsic and extrinsic aging. Intrinsic aging is inevitable and results in atrophy, fibroblast reduction, and thinning blood vessels. Collagen is particularly affected, as the synthesis steadily declines with age. Likewise, elastin also declines with age. Extrinsic aging primarily results from the effects of UV damage. Other causes include environmental factors, such as smoking, pollution, and poor nutrition. This type of damage leads to increased degradation of collagen and elastin. Aged skin shows a decrease in extracellular matrix (ECM) proteins, increased collagen degradation, and decreased fibroblasts. Furthermore, there is a reduction in the immune response, wound repair, and fiber synthesis. Extrinsic aging leads to the production of free radicals, which in turn activate matrix metalloproteinases (MMPs). This activation of MMPs also leads to ECM degradation. Additionally, free radicals inhibit the tissue inhibitors of metalloproteinase (TIMPs). The goal of cosmeceuticals is to mitigate some of these effects of aging.
Effective cosmeceuticals must be able to penetrate through the stratum corneum while maintaining their effectiveness. They also must have visible benefits without impacting the skin’s barrier function. There has been a recent surge of new cosmeceuticals, and this article discusses the functions, limits, and benefits of peptides, growth factors, cytokines, and stem cells used in these products.
Peptides
Peptides are short amino acid chains with a functional ability to alter skin physiology. The basic cosmetic mechanism behind peptides is to increase collagen production, replacing lost ECM and reducing the size and appearance of wrinkles. Peptides are able to regulate fibroblast production of ECM components, mainly through the use of signal peptides. It is hypothesized that the introduction of subfragments of these components, such as elastin and collagen, will act as feedback stimulators inducing their own synthesis.
Use of peptides for topical application is limited by the ionic nature of the amino acid chains. However, this may be circumvented through the incorporation of a lipophilic derivative, such as palmitoyl. Peptides generally have a short half-life when delivered orally because of significant first-pass effect. By delivering them transdermally, fully functional peptides may be delivered to the desired site. The length and membrane permeability are important when assessing them for use in cosmeceuticals. Addition of peptides to products can get very costly; however, minimal compositions of peptides have shown significant results. Peptides are thus very potent and require only minor amounts, minimizing cost.
Signal Peptides
This discussion focuses on signal peptides, which stimulate ECM production, specifically increasing collagen synthesis. A list of functional peptides found in cosmeceuticals can be found in Table 1 . One of the longest used peptides, oligopeptide-20, consists of 12 amino acids. This peptide increases collagen and hyaluronic acid in cultured keratinocytes and fibroblasts. Another peptide shown to increase collagen production is palmitoyl pentapeptide-4 (Pal KTTKS). Pal KTTKS is a fragment of procollagen I. It increases production of collagen I and III through the stimulation of fibroblasts, and also stimulates production of fibronectin and elastin. The palmitoyl derivative was added to the pentapeptide, increasing its lipophilic properties and enhancing absorption. Pal KTTKS also inhibited the production of glycoasaminoglycans in the skin, an increase of which is associated with increased age and photodamaged skin.
| Antiaging Effect | Peptide Type | Peptide | Mechanism |
|---|---|---|---|
| Wrinkle and fine line reduction | Signal | Arg-gly-asp-ser | Increases cell-cell cohesion |
| Oligopeptide-20 | Increases collagen and hyaluronic acid | ||
| Pal-KTTKS | Increases collagen I and III, fibronectin, and elastin Inhibits glycoasaminoglycans formation | ||
| Pal-KT | Induces differentiation of the epidermis, BM zone, and fibroblasts Increases collagen I, collagen IV, and fibronectin | ||
| Amino acids val-gly-val-ala-pro-gly | Stimulates fibroblast proliferation | ||
| Carrier and signal | Glycyl-L-histidyl- l -lysine | Enhances collagen production Cu complex inhibits TIMP-1 and -2, increases levels of MMP-1 and -2, and increases synthesis of dermatan sulfate and heparin sulfate | |
| Enzyme inhibiting | Tyr-tyr-arg-ala-asp-asp-ala | Inhibits procollagen C proteinase | |
| Wrinkle improvement, firming | Signal | AcTP1 | Increases collagen I and lumican synthesis |
| AcTP2 | Stimulates keratinocyte growth and syndecan-1 synthesis | ||
| T10-C | Mimics decorin Increases collagen fiber uniformity and enhances cohesion | ||
| Skin firming | Signal | Peptamide-6 | Increases collagen synthesis Upregulates growth factors |
| Skin whitening | Signal | PKEK | Reduces IL-6, IL-8, tumor necrosis factor-α, proopiomelanocorticotropin, α-melanocyte-stimulating hormone, tyrosinase |
Palmitoyl-lysine-threonine (pal-KT) is one of the shortest peptides. When tested with human skin equivalents, it was found to enhance differentiation of the epidermis, basement membrane zone, and dermal fibroblasts. Within dermal fibroblasts, pal-KT increased collagen I, collagen IV, and fibronectin.
The hexapeptide, consisting of amino acids val-gly-val-ala-pro-gly, is an elastin fragment with chemotactic properties. It attracts cells to wound sites and significantly stimulates fibroblast proliferation within human skin. It also decreases the expression of elastin. Conversely, this peptide has been found in another study to induce proteolytic and inflammatory damage by upregulation of MMP-1 and MMP-3, requiring further study.
Tripeptide-10 citrulline (T10-C) is a decorin-like molecule. Decorin is a leucine-rich proteoglycan directly involved in matrix organization. By binding to the surface of collagen molecules, decorin regulates their interaction with other collagen molecules, stabilizing and orienting them, thus establishing a uniform tissue shape. This mechanism increases the tensile strength of collagen and reduces collagen disruption. With age, however, comes a lack of functional decorin within the skin. Instead, it is replaced with a truncated, nonfunctional fragment known as decorunt.
T10-C contains the collagen-binding site sequences of decorin and, like decorin, is able to regulate collagen fibers. Unlike other peptides, which increase the quantity of collagen, it increases the quality of the collagen, enhancing uniformity and increasing cohesion. T10-C showed a decrease in collagen fiber diameter, similar to decorin, which led to increased skin suppleness and firmness. Another peptide, arg-gly-asp-ser, enhances ECM structure. This tetrapeptide is a fragment of fibronectin and enhances cell and collagen cohesiveness.
Peptamide-6 is derived from the yeast Saccharomyces . It is a firming peptide that works by upregulation of growth factors and increasing collagen synthesis. This peptide has been shown to improve skin elasticity and deformation response.
Acetyl tetrapepide-9 and -11 (AcTP1 and AcTP2, respectively) increase skin thickness and firmness. AcTP1 increases collagen I and lumican synthesis. AcTP2 stimulates keratinocyte growth and syndecan-1 synthesis.
In addition to their effects on the ECM, peptides may also function as skin whitening agents. PKEK, a tetrapeptide of amino acids pro-lys-glu-lys, reduces pigmentation by reducing the expression of interleukin (IL) -6, IL-8, tumor necrosis factor-α, proopiomelanocorticotropin, α-melanocyte-stimulating hormone, and tyrosinase secondary to UVB upregulation of these genes. Skin pigmentation is thus decreased by reduction of UVB-induced proinflammatory reactions.
Sirtuin genes may also be altered through the application of peptides. A biopeptide developed from the yeast Kluyveromyces has been shown to stimulate sirtuins within human skin cells, specifically SIRT1. Sirtuins enhance cell longevity by allowing transcription to occur. This occurs through deacetylation of silenced genes. SIRT1 has also been shown to increase manganese superoxide dismutase, resulting in enhanced repair of oxidative stress. Sirtuins are decreased in aging skin and it can thus be hypothesized that increasing them will result in skin longevity. Topical application reduces wrinkles and pigmented spots, along with improving skin texture and hydration.
Enzyme-Inhibiting Peptides
Another type of peptide is the enzyme-inhibiting peptide. One of these is made up of the amino acid chain tyr-tyr-arg-ala-asp-asp-ala. This inhibits procollagen C proteinase, whose function is to cleave a portion of type I procollagen. By inhibiting this enzyme, there is a reduced destruction of procollagen.
Carrier Peptides
Carrier peptides are another subtype. Peptides, such as glycyl-L-histidyl- l -lysine, have been shown to facilitate copper uptake by cells. Copper has beneficial effects on the skin and is required for wound healing. Alone, this tripeptide also enhances collagen production. Together, the Cu-tripeptide complex facilitates dermal remodeling through inhibition of TIMPs 1 and 2, and increasing levels of MMP-1 and -2. Specifically within fibroblasts, this complex increases synthesis of dermatan sulfate and heparin sulfate.
Potency and Adverse Effects
Among the peptides discussed, effects are generally seen in about 8 weeks with twice daily application. Mixtures between 3 and 10 ppm exhibit efficacy, indicating high potency. PKEK required the most active ingredient, 40 ppm, to generate the desired effect. No significant adverse effects were seen, including redness, burning, or itching. Likewise, there was no impact on skin barrier function, based on transepidermal water loss measurements. Improvements were seen in wrinkles, fine lines, and skin roughness.
Growth factors and cytokines
Many growth factors are involved in wound healing, both chronic and acute. Growth factors have been introduced into the cosmeceutical world based on the hypothesis that the aging process of skin is similar to that of a chronic wound. Their ability to increase fibroblast and keratinocyte proliferation within the dermis, thus inducing ECM formation, supports this idea. Aging skin has reduced amounts of fibroblasts and decreased levels of growth factors. By supplementing these normal growth factors, we may allow for the natural repair of skin.
Growth factors are produced and secreted by many cell types of the skin, including fibroblasts, keratinocytes, and melanocytes. Included within these secreted growth factors are those that regulate the immune system, also known as cytokines. Cytokines are also involved in skin repair. Many growth factors are involved in wound repair and thus most of the topical products contain a combination of growth factors. It is important to combine growth factors and cytokines because they work together and regulate each other throughout the healing process. A general overview of the growth factors and cytokines found in cosmetic products and their functions can be found in Table 2 .
| Growth factors | Fibroblast growth factor | Activates fibroblasts, angiogenic, induces collagen synthesis |
| Heparin binding-epidermal growth factor | Keratinocyte and fibroblast mitogen | |
| Hepatocyte growth factor | Tissue regeneration and wound healing | |
| Insulin-like growth factor | Activates fibroblasts and endothelial cells | |
| Placenta growth factor | Activates fibroblasts, promotes endothelial growth | |
| Platelet-derived growth factor | Induces fibroblast migration, fibroblast mitogen, matrix production | |
| Transforming growth factor-β1 | Induces keratinocyte, fibroblast, and macrophage migration, and angiogenesis Initiates collagen and fibronectin synthesis; modulates degradation of matrix proteins | |
| Transforming growth factor-β2 | Induces keratinocyte, fibroblast, and macrophage migration; initiates collagen and fibronectin synthesis | |
| Transforming growth factor-β3 | Antiscarring | |
| Vascular endothelial growth factor | Inhibits collagen and hyaluronic acid degradation | |
| Cytokines | IL-1α and -1β | Activates growth factor expression in macrophages, keratinocytes, and fibroblasts |
| IL-1ra | Anti-inflammatory | |
| IL-10 | Anti-inflammatory | |
| IL-13 | Anti-inflammatory | |
| Tumor necrosis factor-α | Activates growth factor expression in macrophages, keratinocytes, and fibroblasts |
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