In recent years consumers have become increasingly interested in fighting the effects of ageing and in rejuvenating their appearance through products that lie between cosmetics and drugs. Industries encouraged and nurtured this need with the inception of ‘cosmeceuticals’. Cosmeceuticals are not a category that is either recognised or regulated by the US Food and Drug Administration (FDA), and cosmeceutical research is, for the most part, performed by the cosmetic industry.
Increasingly, patients are looking for cost-effective non-invasive methods to improve the appearance of their skin and are turning to cosmeceuticals and their purported ability to enhance an individual’s more youthful appearance. Topically applied products or oral formulations are leading the way in the growth of this industry, displacing prescription drugs or medical procedures as alternatives to slow the effects of ageing and improve the appearance of the skin. Recent research focusing on cosmeceutical products highlighted a rapid annual growth rate of 7.7%, and the global cosmeceutical market reaching $31.84 billion by 20161.
Albert Kligman coined the term ‘cosmeceutical’ in 1984 to refer to substances that exerted both cosmetic and therapeutic benefits2. According to Kligman, a product should address three main questions to qualify as a cosmeceutical: does the active ingredient penetrate the stratum corneum and reach in sufficient concentrations to its intended target in the skin; does it have a known specific biochemical mechanism of action in the target cell or tissue in human skin; and finally, are there published, peer-reviewed, double-blind, placebo-controlled, statistically significant, clinical trials to substantiate the efficacy claims? However, since cosmeceuticals remain an unrecognised category by the US Food and Drug Administration (FDA) stringent regulatory pathways do not exist to guide research and marketing. Efforts have only recently been initiated to address the issues surrounding quality control and to establish industry standards, since cosmeceuticals intend to deliver on a higher level than cosmetics that simply colour and scent the skin, and should be clinically tested for efficacy not only to insure a proven skin benefit but also to substantiate marketing claims3. There is limited research being done on cosmeceuticals in academic dermatology, and there have been no NIH grants available for cosmeceutical research to date. As a result, the best research comes from industry-sponsored studies, which may lead to the development of inherent biases.
Cosmeceuticals are developed in formulations around an active ingredient that is thought to have a functional benefit to skin health. Once a possible functional cosmeceutical active ingredient has been identified, it is synthesized and typically applied to a fibroblast cell culture to identify the key skin mediators that are modulated. The ingredient is usually tested in a rodent model for further elucidation of its mechanism of action and to confirm the desired skin benefits. After the active ingredient is placed in a vehicle suitable for human application clinical studies are undertaken, and successful human clinical studies pave the way for introduction into the marketplace via ingredient licensing arrangements.
The applications of cosmeceuticals are broad and include improving skin radiance and texture, acne reduction, and decreasing pigmentation. However, they are most well-known for combating the effects of ageing. In fact, deeper understanding of the skin ageing process has enabled manufacturers to design cosmeceuticals with active ingredients that mitigate or reverse the mechanisms of skin ageing. Both intrinsic and extrinsic ageing, the former largely determined by genetics and the latter by environmental factors such as UV exposure and lifestyle, result in reduction of skin collagen and elasticity, dermis thinning, heterogeneous pigmentation, and wrinkling4.
This article will focus on the clinical evidence available regarding the efficacy and safety of common active ingredients of cosmeceuticals including growth factors, peptides, stem cells, antioxidants and pigment/erythema reducing agents. The American Society of Plastic Surgeons rating scale of therapeutic studies was utilized to assign the relevant level of evidence (Table 1).
Growth factors (GF’s) comprise a large group of regulatory proteins that attach to cell surface receptors and mediate inter- and intracellular signaling pathways that control fibroblast and keratinocyte proliferation within the dermis, thus inducing extracellular matrix (ECM) formation5. Studies have shown minimal penetration of intact stratum corneum by hydrophilic molecules that have a molecular weight greater than 0.5 KDa6, and GFs are large, hydrophilic molecules with a molecular weight of over 15 KDa. However it is proposed that topical absorption occurs by way of hair follicles, sweat glands, and compromised skin 7, 8. In regards to their functionality outside their physiologic environment, it was shown they can retain stability for over 24 months9. FDA investigation into the carcinogenic potential of growth factors demonstrated that they do not pose any significant risk, since the levels used in topical cosmeceuticals is low and they minimally penetrate the skin6, 10.
Key growth factors used in topical cosmeceutical applications include platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and epidermal growth factor (EGF)11. They are derived from a variety of sources including humans, animals, plants, recombinant bacteria, and yeast12.
Commercially, they are available in various topical formulations such as a cell culture medium collected from a line of dermal fibroblasts originating from neonatal foreskin (NouriCel-MD, Allergan, Carlsbad, CA) and a formulation of processed skin cell proteins comprising a mixture of cytokines, GFs, and antioxidants harvested from fetal fibroblast cell lysate (PSP, Neocutis, Merz, Lausanne, Switzerland), GFs derived from the secretions of the snail Cryptomhalus aspersa (SCA) are also commercially available (Tensage, Biopelle, Inc., Ferndale, MI).
Numerous clinical studies have researched their skin rejuvenation potential and the most significant are summarised in Table 2.
Topical peptides have been studied for their therapeutic potential by the anti-ageing cosmeceutical market. These molecules are short amino acid chains with a functional ability to alter skin physiology by increasing collagen production and stimulating cells to replace extracellular matrix components13.
Peptide molecules are small enough to penetrate the skin and exert their effects, but topical application is limited due to their ionic nature. Incorporation of a lipophilic derivative, such as palmitoyl, can facilitate transdermal delivery to the desired site14. Four main families of peptides have been used in cosmeceuticals: carrier, signal, enzyme-inhibiting, and neurotransmitter peptides15 (Table 4).
These peptides were designed to facilitate transportation of an agent to an active site in the skin. GHK-Cu, composed of glycine and histidyl, and lysine hooked to copper, a trace element necessary for wound healing16,17, was commercialised into a line of skin care products to minimise the appearance of fine lines and wrinkles. Several controlled facial studies confirmed anti-ageing, firming and anti-wrinkle activity of copper peptide GHK-Cu. A facial cream containing GHK-Cu increased collagen by 70% in photoaged skin of 20 female volunteers, performing better than vitamin C (50%) and retinoic acid (40%)18. Another 12-week facial study of GHK-Cu on 71 females with mild to advanced signs of photoaging reported significant improvement of skin laxity, reduced fine lines and the depths of wrinkles and increased skin density and thickness comparing to placebo. A 12-week facial study on 67 women with advanced photoageing showed that GHK-Cu cream applied twice daily improved aged skin appearance, reduced wrinkles and strongly stimulated dermal keratinocyte proliferation as determined by histological analysis of biopsies. The same study found copper peptide GHK-Cu to be non-toxic and non-irritating18.
The most prevalent and widely used single peptide is palmitoyl pentapeptide (Pal-KTTKS) commercially known as Matrixyl (Sederma, Paris, France). This peptide is a procollagen I fragment that stimulates the production of collagen I, III, and IV in vitro. In a 4-month double-blind study enrolling 49 women that applied either (Pal- KTTKS) or vehicle twice daily showed significant improvement in skin roughness, rhytides, and depth compared to control. No adverse effects were noted19.
In a 12-week, double-blind, placebo-controlled, split-face, left-right randomised clinical study with 93 female subjects (aged 35-55) assessing two topical products with one containing 3 ppm pal-KTTKS, showed that Pal-KTTKS was well tolerated by the skin and provided significant improvement in wrinkle reduction, and fine lines through both quantitative technical and expert grader image analysis14.
Another signal peptide, melanostatin, studied in vitro but included in cosmeceuticals, is a synthesized peptide used to rid the skin of abnormal pigmentation by inhibiting the synthesis of melanin20. Tripeptide-10 citrulline (T10-C), a decorin-like molecule, regulates the interaction of collagen molecules in vitro to establish a uniform tissue shape, thus increasing the quality rather than quantity of collagen21.
Enzyme-modulating peptides directly or indirectly inhibit the function of a key enzyme in some metabolic processes of skin ageing. They are commonly extracted from botanical sources rather than engineered. For example, the extraction of certain peptides from rice proteins have shown an inhibitory effect on collagen degradation22.
Neurotransmitter peptides are similar to botulinum toxin in that they both selectively modulate synaptosome-associated proteins of 25 KDa, more commonly known as SNAP-25. Botulinum toxin A proteolytically degrades SNAP-25; whereas acetyl hexapeptide-3, commercially known as Argireline (Centerchem, Norwalk, CT, USA), inhibits its biologic function. Application of an emulsion containing 10% of the hexapeptide on healthy women volunteers reduced wrinkle depth up to 30% after 30 days treatment23. A randomised, placebo-controlled study of 60 volunteers applying acetyl hexapeptide-3 to their periorbital wrinkles twice daily for 4 weeks showed total anti-wrinkle efficacy in the acetyl hexapeptide-3 group of 48.9%, compared with 0% in the placebo group24. A second commercialised neurotransmitter peptide, pentapeptide-3, commercially known as VIALOX (Centerchem, Norwalk, CT, USA), is a competitive antagonist at the acetylcholine receptor. In a clinical study conducted by PentaPharm, women aged 30–60 years applied the compound twice daily to one half of the face for 28 days. Results demonstrated a subjective improvement in periorbital rhytides by almost 50%18.
Insights in stem cell biology and the relevant advances in harvesting and transplanting stem cells has let to expanding their clinical application in the field of skin rejuvenation. Cosmeceuticals have exploited the anti-ageing potential of stem cells by including the extracts in product emulsions touted as a ‘miracle’ active ingredient, but the marketing claims often push the limits of available science.
Cutaneous stem cells, residing in the basal layer of the epidermis, replenish skin during normal functions as well as through the course of wound repair25. Through ageing and with exposure to environmental insults, the stem cell’s ability to replicate and repair skin is reduced, thus supplementing the skin with additional stem cells could be a promising pathway. The proposed mechanism of action is based on the premise that the stem cells secrete growth factors that can affect the surrounding tissue, inducing fibroblast activation and collagen synthesis26. Sources of stem cells can be either human or plant-based, although the former faces numerous ethical issues making the production and distribution of products difficult27.
Adipose tissue is an abundant source of mesenchymal stem cells (MSC), which secrete collagen, fibronectin, VEGF, and other growth factors28. Conditioned media from these cells has been shown to have anti-ageing benefits when applied topically. Specifically, in a clinical case report, autologous, purified lipoaspirate was injected directly into the photoaged periorbital dermis of a patient yielding subjective improvement in the treated skin as well as an increase in dermal thickness as measured by ultrasonography at 2 month follow-up29. The same group also reported data from animal and in vitro models of the whitening effects of adipose-derived stem cells extracts via downregulation of tyrosinase30, anti-wrinkle effects induced by UV-B by stimulation of fibroblasts and collagen production31 and antioxidant benefits for control and prevention of skin damage from free radicals in various skin conditions32. Combined injection of stem cells and hyaluronic acid into deep facial folds of 15 female volunteers also proved beneficial in improving rhytides and skin tone33. No major adverse effects have been noted by analyzing data derived from 174 published cases of patients treated with adipose-derived stem cells and 121 patients enrolled in clinical trials in the plastic surgery literature34.
Plant stem cells have also been embraced as a viable and ethical option for formulating anti-ageing skin cosmeceuticals. Despite the broad potential of many botanical species the bulk of research has focused around stem cells of the lilac, the grape, and the swiss apple plant. In vitro studies have shown that lilac stem cell extracts have wound repair and anti-inflammatory properties35. Grape stem cell extracts, containing proanthocyanidins, are anti-inflammatory, prevent skin ageing and inhibit the action of radical oxygen species in both in vitro and in vivo models36,37. A trial with 20 subjects testing a cream containing swiss apple stem cell extract was found to reduce wrinkle depth by 8% after 2 weeks and 15% after 4 weeks38.
Although stem cells show promise and aspiration to join the cosmeceutical armamentarium, only sparse low-level clinical evidence is available to substantiate their efficacy. Considerable rigorous studies are required to justify their clinical utility in anti-ageing treatment (Table 5).
One of the most popular categories of cosmeceutical ingredients are antioxidants, as a major cause of ageing is oxidation of skin structures from reactive oxygen species. The primary source of cosmeceutical antioxidant ingredients is botanic extracts39.
Some antioxidants, mentioned in a separate section, have additional functions such as reduction of pigment and erythema (ascorbic acid, vitamin E, polypodium leucotomos). Carotenoids, flavonoids, and polyphenols are the major classes of antioxidants used by the cosmeceutical industry (Table 6).
Derivatives of Vitamin A are substances with a vital, established antioxidant role when ingested. Prescription tretinoid, the oxidized biologically active form of Vitamin A has had a well-documented role in anti-ageing and proven to repair photodamaged skin40. However, due to its irritancy, the natural forms of Vitamin A, retinol and retinaldehyde, have been exploited by cosmeceutical formulations to provide a less potent but safer alternative.
Flavonoids are yellow compounds found in plants that possess a variety of biologic functions. The most common flavonoids incorporated in cosmeceuticals are genistein contained in soybeans, pycnogenol, and ginkgo39.
Green tea, pomegranate fruit, and grape seeds are sources of polyphenols with high anti-oxidant activity. Although more commonly ingested rather than applied topically, clinical studies have indicated their beneficial potential for the skin41.
Cosmeceutical agents that selectively target hyperplastic melanocytes and inhibit key regulatory steps in melanin synthesis have been developed to treat various skin-pigmentation conditions. The gold standard and most effective agent for pigment-lightening was hydroquinone, however due to its side effects and safety profile its use has been restricted in cosmeceuticals41.
As an alternative, a variety of vitamins and botanics have also been evaluated and a summary of their clinical studies for pigment-reduction is presented in Table 7.
Vitamin C is a naturally occurring antioxidant, a property that has been shown to reduce tyrosinase activity and melanin synthesis42. Topical vitamin C derived from fruits and vegetables is unstable, hence derivatives such as magnesium-ascorbyl-phosphate (MAP) have been developed43.
Alpha tocopherol (vitamin E)
Vitamin E is a major lipophilic antioxidant and has been shown to cause depigmentation by interfering with the melanin metabolic pathway44. A double-blinded study on the therapeutic effects of a combination preparation of vitamins E and C in comparison with single preparations of both vitamins in the treatment of chloasma or pigmented contact dermatitis (PCD) revealed that the combination treatment resulted in significantly better clinical improvement as compared to vitamin C alone, in both diseases45.
Niacinamide is the active amide of vitamin B3 interferes with the interaction between keratinocytes and melanocytes, thereby inhibiting melanogenesis46.
Kojic acid is a fungal product derived from certain species of Acetobacter, Aspergillus, and Penicillium, and reduces hyperpigmentation by inhibiting the production of free tyrosinase47.
Various plant extracts have been studied for pigment-reduction due to the lack of side-effects. Grape seed, orchid, coffeeberry, soy, licorice or herbal blend extracts have shown inhibition of melanin synthesis through their antioxidant and other enzymatic properties48.
N-acetylglucosamine (NAG) is a monosaccharide that inhibits the conversion of protyrosinase to tyrosinase, thus decreasing pigmentation49.
Erythema, commonly associated with inflammation and UV-exposure, has been a treatment target for cosmeceutical agents (Table 8). Topical application of anti-inflammatory plant extracts immediately after irradiation can reduce erythema symptoms.
Polypodium leucotomos, marketed in some countries as Heliocare, comes from a tropical fern plant. The antioxidant and photoprotective properties of the plant extract have been used for the treatment of inflammatory disorders and skin diseases. Oral and topical administration has been clinically shown to prevent sunburn and UV-induced erythema. One possible molecular mechanism for this protection seems to be the inhibition of UV-induced photoisomerization of transurocanic acid, a common photoreceptor located in the stratum corneum50. Sage, witch hazel, carotenoids, lycopene, and grape seed extracts have also shown protection against erythema50.
Laboratory and clinical data suggest that the use of cosmeceuticals is a very promising field, and their potential applications in various disease and aesthetic conditions is bountiful. However, review of the current scientific literature pertaining to peptide, growth factor, stem cells, antioxidant and pigment/erythema reducing agents as having anti-ageing and rejuvenation effects produced a limited number of low-level evidence studies. Furthermore, since the majority of studies were conducted by the manufacturer of each cosmeceutical, the evident conflict of interest raises questions regarding the objective design and interpretation of the results.
Cosmeceutical products claim to affect the structure and function of skin, thus they are beholden to higher standards of scientific substantiation than cosmetic products. These standards should include at minimum being able to substantiate the three major questions proposed by Dr. Albert Kligman: a clear understanding that the ingredient penetrates into skin, a defined mechanism of action, and that it has specific clinical effects with continued topical use.
Therapies targeting optimal rejuvenation should be invariably geared toward addressing the intrinsic and extrinsic signs of ageing51. A solid rationale backed up by in vitro data or successful animal model research does not translate however into in vivo efficacy of the final formulation. Active ingredients must be physically, chemically, and photostable in the commercial formulation, and they must be able to penetrate the stratum corneum to reach their target in sufficient concentrations. Furthermore, even when designing a high-powered clinical trial, it may not be feasible to extrapolate statistically significant data between the treatment and control groups since anything applied to the skin will have an effect. Moreover, for modalities such as stem cell injection, mere volume-filling principles may be responsible for the improvement of facial rhytides rather than any specific anti-ageing effect52.
Apart from being stand-alone agents, cosmeceutical therapies can also be used in adjuvant to chemical peels, lasers, and injectables, making antiageing regimens less painful and requiring less postprocedural healing time53. Postinflammatory hyperpigmentation (PIH) can be decreased with some of the cosmeceuticals described, such as ascorbic acid54. Topical retinoids used prior to ablative laser treatments can aid re-epithelialization and reduce erythema55. Topical application of peptides can be used as an adjunct to intramuscular botulinum neurotoxin, to reduce the number of injections needed53.
Regardless of all the caveats, the study of active ingredients used in cosmeceutical agents remains fruitful and compelling. Ongoing research can advance the general understanding of dermal signaling mechanisms and provide deeper insights in the mechanism of action of existing cosmetic procedures, such as soft tissue fillers. Cosmeceutical studies can ameliorate the field by not only providing proof of clinical efficacy but by using gene, protein, and histologic evidence to ascertain their effectiveness. Consumers can have access to a better variety of non-invasive, cost and time-effective options tailored to their specific skin needs and conditions, and clinicians can access comprehensive information to counsel and treat their patients accordingly.