Therapeutic Peptides in Aged Skin

Editor’s note: The following article is adapted from the Textbook on Aging Skin, a Springer compilation edited by HI Maibach, MA Farage and KW Miller, which currently is in press. Farzam Garouhi, MD, is a volunteer research scholar with Maibach at the University of California School of Medicine, San Francisco; he is also an author featured in the textbook.

In the year 2000, individuals over the age of 65 represented 13% of the US population, and this number is expected to increase to 20% by 2030. This increase in the number of older individuals over younger individuals will transform the shape of age distribution from what currently is graphed as a pyramid into a rectangle.1 This demographic shift calls for increased efforts to prevent the aging process and to develop safe and effective drugs for the elderly.

In cosmetic dermatology, experts are exploring better anti-solar, antiaging, antiwrinkle and firming products. Pharmaceutical companies frequently use peptides as active ingredients in creams prescribed at medical and dermatology offices. Peptides can have different effects on the skin, especially for cosmetics purposes, but the most important concern regarding their topical use is their ability to penetrate skin.

Ideally, topical drugs have: a molecular weight less than 500 daltons; a moderate log of partition coefficient octanol/water between 1 and 3; a melting point of less than 200°C; a reasonable aqueous solubility (> 1 mg/mL); and few or no polar centers.2,3 The diffusivity of molecules into the stratum corneum (SC) is related to the number of hydrogen-bonding groups on a molecule; maximal diffusivity is achieved with small non-hydrogen-bonding molecules while minimal diffusivity occurs with molecules containing four hydrogen-bonding groups.4

Peptides and proteins contain many amide bonds as hydrogen-bond donor and acceptor groups. Due to their large molecular size, they have low diffusivity in skin. Furthermore, they are often charged at a physiological pH, making them intrinsically hydrophilic and hence, the lipophilic SC is a significant barrier to their penetration.5

Overall, topical peptides and proteins have successfully and widely been used. However, note that in the only published systematic review6 on interventions for photodamaged skin, no peptide therapy was included. Here, published work on peptides and proteins, their characteristics, and randomized efficacy data are examined.

Material and Methods
In an effort to examine different types of peptides and their efficacy in topical skin treatments, PubMed, Embase and Scopus were systematically searched within a date range of 1974 to June 15, 2008. Different search terms were used to locate peptides or proteins, to find all possible topical therapies, to locate all cosmeceutical-related papers, and to rule out irrelevant papers. All references of relevant articles were screened to find other eligible resources. In addition, some in vitro and in vivo data was collected from pharmaceutical company Web sites. For efficacy data, only randomized trials were included.

Results and Discussion
Surprisingly, scarce data regarding the permeation abilities of topical peptides was found. Only the permeation coefficients for three widely used topical cosmeceutical peptides—copper tripeptide-1 (GHK)7, glutathione (GSH)7 and melanocyte-stimulating hormone (MSH)8,9; some mono-peptides10,11 and their copper complexes were reported. Table 1 summarizes the randomized trials referenced.

GHK: Glycyl-L-histadyl-L-lysine or GHK is primarily known as a carrier peptide but it also acts as a signal peptide mainly to help stabilize and deliver copper. Signal peptides refer to all peptides that stimulate matrix protein production in general, specifically collagen synthesis. These peptides may be produced by growth and stimulation of different skin cells such as human skin fibroblasts. Signal peptides can also increase elastin, proteoglycan, glycosaminoglycans and fibronectin. By increasing matrix cell activities and therefore collagen production, the peptides make skin look firmer and younger.

In a randomized, double blind, placebo-controlled study of 67 volunteers, GHK-Cu and a placebo were applied twice daily for 12 weeks on facial skin.12 GHK-Cu improved skin laxity, clarity and appearance; reduced fine lines, coarse wrinkles and mottled hyperpigmentation; and increased skin density and thickness.

Pal-KTTKS: Palmitoyl pentapeptide-4 (Pal-KTTKS) is a synthetic signal peptide from pro-collagen I fragments. It stimulates collagen I, III and VI, in addition to fibronectin, elastin and glycosaminoglycan production.13 These effects have made it a popular ingredient in antiaging and antiwrinkle products.

In a study14 of 93 Caucasian females, Pal-KTTKS performed significantly better than a placebo, as assessed by expert graders and subjective observations, for the treatment of hyperpigmented age spots. Osborne et al. also showed a robust result for this peptide in reducing bumpy texture and fine wrinkles.15

Kinetin: Kinetin is another signal peptide that is derived naturally from plants. It exhibits antioxidant properties, delaying the onset of aging characteristics in human fibroblasts, and inhibits keratinocyte growth.16 Its cosmeceutical indication is mainly limited to antiaging, antiwrinkle and anti-solar purposes.

In a randomized, double-blind study, Chiu et al. compared topical kinetin with niacinamide to niacinamide alone and found significant reductions in spot, pore, wrinkle and erythema index and evenness counts in the kinetin with niacinamide group. Furthermore, significant increases in corneal hydration status were found in the same group.17 Several growth factors and cytokines have been applied to treat skin problems in elderly individuals.

Human growth factor: An antioxidant serum containing liposome-encapsulated transforming growth factor beta (TGF-β1), ascorbic acid and Cimicifuga racemosa extract in a silicone base was developeda, applied to the arms of test subjects, and compared with a placebo serum omitting the TGF-β1.18 The skin of subjects treated with TGF-β1 revealed a significant mean improvement (21.7%) in physician-rated wrinkle scores while the placebo-treated skin recorded a slight improvement (6.2%) over the baseline.

The trial then continued with a comparison of the test serum to a tissue nutrient solution (TNS) cream in 20 test subjects.18 TNS contains growth factors including vascular endothelial growth factor, platelet-derived growth factor A, granulocyte colony-stimulating factor, hepatocyte growth factor, interleukin-6, interleukin-8, and TGF-β1 without vitamin C. Both creams were found to significantly improve wrinkle scores.

Growth factor and cytokine mixture: A bio-restorative skin cream was developed containing a proprietary growth factor and cytokine mixture extracted from cultured, first trimester fetal human dermal fibroblasts. In a placebo-controlled trial, Gold and colleagues concluded that some skin roughness parameters were significantly better in the group treated with the cream but that no statistical difference between two groups was detected.19

Soybean proteins: Soybean proteins or peptides are enzyme inhibitor peptides extracted from soybean seeds. Soy proteins inhibit the formation of proteinases and increase trichoblast and atrichoblast numbers without changing their localization pattern;20 they are used as antiaging, skin moisturizer, anti-solar and hair-promoting agents.

In a randomized double blind placebo-controlled study, soy extract and placebo creams were applied to the forearms of 21 healthy women21 and overall, the papillae index increased greater with the application of the soy extract than with the placebo (p < 0.05).

Sericin: Another enzyme inhibitor protein, sericin or silk worm secretion, is extracted from the middle silk gland of the Bombyx mori silkworm. Sericin exhibits antioxidant properties and has a high affinity for chelating with copper. In addition, it inhibits lipid peroxidation, tyrosinase activity and keratinocyte apoptosis. In another study, silk protein was compared with bovine serum albumin in a vehicle found to better reduce UVB-induced symptoms in both short-term and chronic treatment courses.22

Lipopentapeptide: Another peptide, lipopentapeptide, in combination with white lupin peptide and antioxidants, significantly increased fibrillin-1 and procollagen I deposition at a 6% w/w concentration when compared with 2% tretinoin and the control.23

Keratin: Keratin is a major protein in the structure of hair and skin that can be extracted from human hair or sheep’s wool. It improves the hydration and elasticity of skin and hair when applied topically and thus is commonly used in moisturizers, firming agents and hair shine enhancers. Barba et al.24 conducted a randomized trial comparing 3% keratin peptides to water and a control in 16 healthy females and found the keratin peptide to be effective on disturbed but not undisturbed skin.

In another recent trial, significant improvements were achieved for elasticity parameters and especially skin capacitance with the application of the keratin samples.25 Among all the keratin creams tested, a combination of a keratin peptide with internal wool lipid liposomes provided the most significant benefits, compared with the aqueous solution.25

Some peptides have notable effects on chronologically aged and/or photodamaged skin. According to the current evidence, GHK-Cu, Pal-KTTKS, soybean protein and keratin peptides exhibit the best results among the peptides. There is a large gap in data regarding the permeability coefficient of cosmeceutical peptides and proteins, and researchers should focus on this ambiguity to identify substances with better permeability. Large high quality, randomized, double blind, active-controlled trials are required to calculate the exact effect of molecule size in this regard. Results from such trials will lead to an understanding of the best peptide for antiaging treatments.

Send e-mail to [email protected].
1. MG Kosmadaki and BA Gilchrest, The demographics of aging in the United States: implications for dermatology, Arch Dermatol, 138(11) 1427–8 (2002)
2. RH Guy, Current status and future prospects of transdermal drug delivery, Pharm Res, 13(12) 1765–9 (1996)
3. BE Vecchia and AL Bunge, Evaluating the transdermal permeability of chemicals, in Transdermal drug delivery (electronic resource), RH Guy and J Hadgraft, eds. Dekker: New York (2003)
4. MS Roberts, SE Cross and MA Pellett, Skin Transport, in Dermatological and transdermal formulations, AW Walters, ed. Dekker: New York (2002) p 121
5. C Cullander and RH Guy, Routes of delivery: Case studies (6). Trasdermal delivery of peptides and proteins, Adv Drug Deliv Rev 8 291–329 (1992)
6. M Samuel et al, Interventions for photodamaged skin, Cochrane Database Syst Rev 1 (2005) p CD001782
7. L Mazurowska and M Mojski, Biological activities of selected peptides: Skin penetration ability of copper complexes with peptides, J Cosmet Sci 59 1 59–69 (2008)
8. A Ruland, J Kreuter and JH Rytting, Transdermal delivery of the tetrapeptide hisetal (melanotropin (6-9)): II. Effect of various penetration enhancers, In vitro study across human skin, Intl J Pharmaceutics 103 1 77–80 (1994)
9. A Ruland, J Kreuter and JH Rytting, Transdermal delivery of the tetrapeptide hisetal (melanotropin (6-9)). I. Effect of various penetration enhancers: In vitro study across hairless mouse skin, Intl J Pharmaceutics, 101(1–2) 57–61 (1994)
10. L Mazurowska, K Nowak-Buciak and M Mojski, ESI-MS method for in vitro investigation of skin penetration by copper-amino acid complexes: From an emulsion through a model membrane, Analsis Bioanalasis Chem 388(5–6) 1157–63 (2007)
11. A Ruland and J Kreuter, Transdermal permeability and skin accumulation of amino acids, Intl J Pharm 72(2) 149–151 (1991)
12. MB Finkey, Y Appa and S Bhandarkar, Copper peptide and skin, in Cosmeceuticals and active cosmetics, P Elsner and HI Maibach, eds, Marcel Dekker: New York (2005) pp 549–564
13. K Lintner, Promoting production in the extracellular matrix without compromising barrier, Cutis, 70 (6 suppl) pp 13-6, discussion 21-3 (2002)
14. LR Robinson et al, Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin, Int J Cosmet Sci, 27(3) 155–60 (2005)
15. R Osborne et al, Use of a facial moisturizer containing palmitoyl pentapeptide improves the appreance of aging skin, J Am Acad Dermatol 52 (3 suppl 1) 96 (2005)
16. U Berge, P Kristensen and SI Rattan, Kinetin-induced differentiation of normal human keratinocytes undergoing aging in vitro, Ann NY Acad Sci, 1067 332–6 (2006) 1
7. PC Chiu et al, The clinical antiaging effects of topical kinetin and niacinamide, in Asians: A randomized, double-blind, placebo-controlled, split-face comparative trial, J Cosmet Dermatol 6(4) 243–9 (2007)
18. M Ehrlich et al, Improvement in the appearance of wrinkles with topical transforming growth factor beta(1) and l-ascorbic acid, Dermatol Surg 32(5) 618–25 (2006)
19. MH Gold, MP Goldman and J Biron, Efficacy of novel skin cream containing mixture of human growth factors and cytokines for skin rejuvenation, J Drugs Dermatol 6(2) 197–201 (2007)
20. Preregen, Centerchem, available at (accessed Jul 9, 2009)
21. KM Sudel et al, Novel aspects of intrinsic and extrinsic aging of human skin: Beneficial effects of soy extract, Photochem Photobiol 81(3) 581–7 (2005)
22. S Zhaorigetu, Inhibitory effects of silk protein, sericin on UVB-induced acute damage and tumor promotion by reducing oxidative stress in the skin of hairless mouse, J Photochem and Photobiology Biol 71(1–3) 11–17 (2003)
23. RE Watson et al, Repair of photo-aged dermal matrix by topical application of a cosmetic ‘antiaging’ product, Br J Dermatol 158(3) 472–7 (2008)
24. C Barba et al, Wool peptide derivatives for hand care, J Cosmet Sci 58(2) 99–107 (2007)
25. C Barba et al, Cosmetic effectiveness of topically applied hydrolyzed keratin peptides and lipids derived from wool, Skin Res Technol 14(2) 243–8 (2008)

More in Actives