Skip to main content

Advertisement

Log in

Revisiting the Effect of Aging on the Transport of Molecules through the Skin

  • Review Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Both intrinsic and extrinsic aging lead to a series of morphological changes in the skin including the flattening of the dermal–epidermal junction, increased stratum corneum dryness, reduction in sebaceous gland activity and enzyme activity as well as atrophy of blood vessels. In this study, the impact of these changes on the transport of molecules through the skin was revised. The increase in the number of transdermal formulations on the market in recent decades and life expectancy represent the main reasons for an in-depth discussion of this topic. Furthermore, elderly subjects have often been excluded from clinical trials due to polypharmacy, raising concerns in terms of efficacy and safety. In this way, ex vivo and in vivo studies comparing the transport of molecules through the mature and young skin were analyzed in detail. The reduced water content in mature skin had a significant impact on the transport rate of hydrophilic molecules. The lower enzymatic activity in aged skin, in turn, would explain changes in the activation of prodrugs. Interestingly, greater deposition of nanoparticles was also found in mature skin. In vivo models should be prioritized in future experimental studies as they allow to evaluate both absorption and metabolism simultaneously, providing more realistic information.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ageing and Health. Available at: https://www.who.int/news-room/fact-sheets/detail/ageing-and-health. Accessed 23 Jan 2023.

  2. Hughes MF. Percutaneous penetration of chemicals and aging skin. In: Farage MA et al, editor. Textb Aging Ski. Springer-Verlag Berlin Heidelberg; 2015. p. 1–14. https://doi.org/10.1007/978-3-642-27814-3_74-3.

  3. Sadick NS, Karcher C, Palmisano L. Cosmetic dermatology of the aging face. Clin Dermatol. 2009;27:S3–12. https://doi.org/10.1016/j.clindermatol.2008.12.003.

  4. Vierkötter A, Krutmann J. Environmental influences on skin aging and ethnic-specific manifestations. Dermatoendocrinol. 2012;4:227–31.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Holmgaard R, Benfeldt E, Sorensen JA, Nielsen JB. Chronological age affects the permeation of fentanyl through human skin in vitro. Skin Pharmacol Physiol. 2013;26:155–9.

    Article  CAS  PubMed  Google Scholar 

  6. Roskos KV, Maibach HI. Percutaneous absorption and age: implications for therapy. Drugs Aging. 1992;2:432–49.

    Article  CAS  PubMed  Google Scholar 

  7. Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm. 1989;17:617–30.

    Article  CAS  PubMed  Google Scholar 

  8. Perrie Y, Singh RK, Kirby DJ, Lowry D, Mohammed AR, Ouyang D. The impact of ageing on the barriers to drug delivery. J Control Release. 2012;161:389–98. https://doi.org/10.1016/j.jconrel.2012.01.020.

  9. Farlow MR, Somogyi M. Transdermal patches for the treatment of neurologic conditions in elderly patients: A review. Prim Care Companion CNS Disord. 2011;13:1–11.

    Google Scholar 

  10. Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26:1261–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kanitakis J. Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatology. 2001;12:1–12. Available from: https://www.researchgate.net/publication/11279803.

  12. Dąbrowska AK, Spano F, Derler S, Adlhart C, Spencer ND, Rossi RM. The relationship between skin function, barrier properties, and body-dependent factors. Ski Res Technol. 2018;24:165–74.

    Article  Google Scholar 

  13. Baroni A, Buommino E, De Gregorio V, Ruocco E, Ruocco V, Wolf R. Structure and function of the epidermis related to barrier properties. Clin Dermatol. 2012;30:257–62.

    Article  PubMed  Google Scholar 

  14. Kusuma S, Vuthoori RK, Piliang M, Zins JE. Skin anatomy and physiology. In: Siemionow MZ, Eisenmann-Klein M, editors. Plast Reconstr Surg. London: Springer-Verlag; 2010. p. 161–71. https://doi.org/10.1007/978-1-84882-513-0_13

  15. Losquadro WD. Anatomy of the skin and the pathogenesis of nonmelanoma skin cancer. Facial Plast Surg Clin North Am. 2017;25:283–9.

    Article  PubMed  Google Scholar 

  16. Wysocki AB. Skin anatomy, physiology, and pathophysiology. Nurs Clin North Am. 1999;34:777–97.

    Article  CAS  PubMed  Google Scholar 

  17. Feingold KR. The role of epidermal lipids in cutaneous permeability barrier homeostasis. J Lipid Res. 2007;48:2531–46. https://doi.org/10.1194/jlr.R700013-JLR200.

  18. Pyo SM, Maibach HI. Skin metabolism: relevance of skin enzymes for rational drug design. Skin Pharmacol Physiol. 2019;32:283–93.

    Article  CAS  PubMed  Google Scholar 

  19. Ventre M, Mollica F, Netti PA. The effect of composition and microstructure on the viscoelastic properties of dermis. J Biomech. 2009;42:430–5.

    Article  PubMed  Google Scholar 

  20. Park S. Biochemical, structural and physical changes in aging human skin, and their relationship. Biogerontology. 2022;23:275–88. https://doi.org/10.1007/s10522-022-09959-w.

  21. Yanez DA, Lacher RK, Vidyarthi A, Colegio OR. The role of macrophages in skin homeostasis. Pflügers Arch - Eur J Physiol. 2017;469:455–63.

    Article  CAS  Google Scholar 

  22. Thakur R, Batheja P, Kaushik D, Michniak B. Structural and biochemical changes in aging skin and their impact on skin permeability barrier. In: Dayan N, editor. Skin aging handbook: an integrated approach to biochemistry and product development. William Andrew Inc.; 2008. p. 55–90. Available at: https://doi.org/10.1016/B978-0-8155-1584-5.50008-9.

  23. Kolarsick PAJ, Kolarsick MA, Goodwin C. Anatomy and physiology of the skin. J Dermatol Nurses Assoc. 2011;3:203–13.

    Article  Google Scholar 

  24. Roberts MS, Cheruvu HS, Mangion SE, Alinaghi A, Benson HAE, Mohammed Y, et al. Topical drug delivery: History, percutaneous absorption, and product development. Adv Drug Deliv Rev. 2021;177:1–43. https://doi.org/10.1016/j.addr.2021.113929.

  25. Nafisi S, Maibach HI. Skin penetration of nanoparticles. Emerging Nanotechnologies in Immunology. 2018. p. 47–88. Available at: https://doi.org/10.1016/B978-0-323-40016-9.00003-8.

  26. Farage MA, Miller KW, Elsner P, Maibach HI. Functional and physiological characteristics of the aging skin. Aging Clin Exp Res. 2008;20:195–200.

    Article  PubMed  Google Scholar 

  27. Russell-Goldman E, Murphy GF. The pathobiology of skin aging: new insights into an old dilemma. Am J Pathol. 2020;190:1356–69. https://doi.org/10.1016/j.ajpath.2020.03.007.

  28. Potts RO, Buras EM, Chrisman DA. Changes with age in the moisture content of human skin. J Invest Dermatol. 1984;82:97–100.

    Article  CAS  PubMed  Google Scholar 

  29. Luebberding S, Krueger N, Kerscher M. Skin physiology in men and women: in vivo evaluation of 300 people including TEWL, SC hydration, sebum content and skin surface pH. Int J Cosmet Sci. 2013;35:477–83.

    Article  CAS  PubMed  Google Scholar 

  30. Harvell JD, Maibach HI. Percutaneous absorption and inflammation in aged skin: a review. J Am Acad Dermatol. 1994;31:1015–21. Available at: https://linkinghub.elsevier.com/retrieve/pii/S019096229470273X.

  31. Leyden JJ, McGinley KJ, Grove GL, Kligman AM. Age-related differences in the rate of desquamation of skin surface cells. Adv Exp Med Biol. 1978;97:297–8.

    CAS  PubMed  Google Scholar 

  32. Bonté F, Girard D, Archambault J-C, Desmoulière A. Skin changes during ageing. Subcell Biochem. 2019;91:249–80. https://doi.org/10.1007/978-981-13-3681-2_10.

    Article  CAS  PubMed  Google Scholar 

  33. Boireau-Adamezyk E, Baillet-Guffroy A, Stamatas GN. Age-dependent changes in stratum corneum barrier function. Ski Res Technol. 2014;20:409–15.

    Article  CAS  Google Scholar 

  34. Yamamura T, Tezuka T. Change in sphingomyelinase activity in human epidermis during aging. J Dermatol Sci. 1990;1:79–84.

    Article  CAS  PubMed  Google Scholar 

  35. Choi EH. Aging of the skin barrier. Clin Dermatol. 2019;37:336–45. https://doi.org/10.1016/j.clindermatol.2019.04.009.

  36. Ghadially R, Brown BE, Hanley K, Reed JT, Feingold KR, Elias PM. Decreased epidermal lipid synthesis accounts for altered barrier function in aged mice. J Invest Dermatol. 1996;106:1064–9.

    Article  CAS  PubMed  Google Scholar 

  37. Kim JC, Park TJ, Kang HY. Skin-aging pigmentation: Who is the real enemy? Cells. 2022;11. https://doi.org/10.3390/cells11162541.

  38. Lavker RM, Zheng P, Dong G. Morphology of aged skin. Dermatol Clin. 1986;4:379–89.

    Article  CAS  PubMed  Google Scholar 

  39. Waller JM, Maibach HI. Age and skin structure and function, a quantitative approach (I): blood flow, pH, thickness, and ultrasound echogenicity. Ski Res Technol. 2005;11:221–35.

    Article  Google Scholar 

  40. Shuster S, Black MM, McVitie E. The influence of age and sex on skin thickness, skin collagen and density. Br J Dermatol. 1975;93:639–43.

    Article  CAS  PubMed  Google Scholar 

  41. Varani J, Dame MK, Rittie L, Fligiel SEG, Kang S, Fisher GJ, et al. Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation. Am J Pathol. 2006;168:1861–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang H, Shyr T, Fevola MJ, Cula GO, Stamatas GN. Age-related morphological changes of the dermal matrix in human skin documented in vivo by multiphoton microscopy. J Biomed Opt. 2018;23:1–4.

    Article  PubMed  Google Scholar 

  43. Bentov I, Reed MJ. The effect of aging on the cutaneous microvasculature. Microvasc Res. 2015;100:25–31. https://doi.org/10.1016/j.mvr.2015.04.004.

  44. Wang Z, Man M-Q, Li T, Elias PM, Mauro TM. Aging-associated alterations in epidermal function and their clinical significance. Aging. 2020;12:5551–65.

  45. Choi E-H, Man M-Q, Xu P, Xin S, Liu Z, Crumrine DA, et al. Stratum corneum acidification is impaired in moderately aged human and murine skin. J Invest Dermatol. 2007;127:2847–56.

    Article  CAS  PubMed  Google Scholar 

  46. Kumar M, Sharma A, Mahmood S, Thakur A, Mirza MA, Bhatia A. Franz diffusion cell and its implication in skin permeation studies. J Dispers Sci Technol. 2023;1–14. https://doi.org/10.1080/01932691.2023.2188923.

  47. Hung CF, Chen WY, Aljuffali IA, Shih HC, Fang JY. The risk of hydroquinone and sunscreen over-absorption via photodamaged skin is not greater in senescent skin as compared to young skin: nude mouse as an animal model. Int J Pharm. 2014;471:135–45. https://doi.org/10.1016/j.ijpharm.2014.05.034.

  48. Schmook FP, Meingassner JG, Billich A. Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption. Int J Pharm. 2001;215:51–6.

  49. Qvist MH, Hoeck U, Kreilgaard B, Madsen F, Frokjaer S. Evaluation of Göttingen minipig skin for transdermal in vitro permeation studies. Eur J Pharm Sci. 2000;11:59–68.

    Article  CAS  PubMed  Google Scholar 

  50. Biondo NE, Argenta DF, Caon T. A comparative analysis of biological and synthetic skin models for drug transport studies. Pharm Res. 2023;40:1209–21. https://doi.org/10.1007/s11095-023-03499-9.

  51. Simon GA, Maibach HI. The pig as an experimental animal model of percutaneous permeation in man: Qualitative and quantitative observations – an overview. Skin Pharmacol Appl Skin Physiol. 2000;13:229–34.

    Article  CAS  PubMed  Google Scholar 

  52. Barber ED, Teetsel NM, Kolberg KF, Guest D. A comparative study of the rates of in vitro percutaneous absorption of eight chemicals using rat and human skin. Fundam Appl Toxicol. 1992;19:493–7.

  53. Van Ravenzwaay B, Leibold E. A comparison between in vitro rat and human and in vivo rat skin absorption studies. Hum Exp Toxicol. 2004;23:421–30.

  54. Jung JW, Cha SH, Lee SC, Chun IK, Kim YP. Age-related changes of water content in the rat skin. J Dermatol Sci. 1997;14:12–9.

    Article  CAS  PubMed  Google Scholar 

  55. Haratake A, Uchida Y, Mimura K, Elias PM, Holleran WM. Intrinsically aged epidermis displays diminished UVB-induced alterations in barrier function associated with decreased proliferation. J Invest Dermatol. 1997;108:319–23.

    Article  CAS  PubMed  Google Scholar 

  56. Dick IP, Scott RC. The influence of different strains and age on in vitro rat skin permeability to water and mannitol. Pharm Res. 1992;9:884–7. https://doi.org/10.1023/A:1015844714707.

  57. Ghadially R, Brown BE, Sequeira-Martin SM, Feingold KR, Elias PM. The aged epidermal permeability barrier. Structural, functional, and lipid biochemical abnormalities in humans and a senescent murine model. J Clin Invest. 1995;95:2281–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Umeda-Ikawa A, Shimokawa I, Doi K. Time-course expression profiles of hair cycle-associated genes in male mini rats after depilation of telogen-phase hairs. Int J Mol Sci. 2009;10:1967–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Behl CR, Flynn GL, Kurihara T, Smith WM, Bellantone NH, Gatmaitan O, et al. Age and anatomical site influences on alkanol permeation of skin of the male hairless mouse. J Soc Cosmet Chem. 1984;35:237–52.

    CAS  Google Scholar 

  60. Cheung C, Davies NG, Hoog J-O, Hotchkiss SAM, Smith Pease CK. Species variations in cutaneous alcohol dehydrogenases and aldehyde dehydrogenases may impact on toxicological assessments of alcohols and aldehydes. Toxicology. 2003;184:97–112.

    Article  CAS  PubMed  Google Scholar 

  61. Behl CR, Flynnx GL, Linn EE, Smith WM. Percutaneous absorption of corticosteroids: age, site, and skin-sectioning influences on rates of permeation of hairless mouse skin by hydrocortisone. J Pharm Sci. 1984;73:1287–90.

    Article  CAS  PubMed  Google Scholar 

  62. Hughes MF, Fishert HL, Birnbaum LS, Hallt LL. Effect of age on the in vitro percutaneous absorption of phenols in mice. Toxic Vitr. 1994;8:221–7.

  63. Ngawhirunpat T, Hatanaka T, Kawakami J, Adachi I. Age difference in simultaneous permeation and metabolism of ethyl nicotinate in rat skin. Biol Pharm Bull. 2001;24:414–7.

    Article  CAS  PubMed  Google Scholar 

  64. Hung CF, Chen WY, Aljuffali IA, Lin YK, Shih HC, Fang JY. Skin aging modulates percutaneous drug absorption: the impact of ultraviolet irradiation and ovariectomy. Age (Dordr). 2015;37:21. https://doi.org/10.1007/s11357-015-9757-1.

  65. Sator PG, Schmidt JB, Rabe T, Zouboulis CC. Skin aging and sex hormones in women - clinical perspectives for intervention by hormone replacemnt therapy. Exp Dermatol. 2004;13:36–40.

    Article  CAS  PubMed  Google Scholar 

  66. Jung EC, Maibach HI. Animal models for percutaneous absorption. J Appl Toxicol. 2015;35:1–10. https://doi.org/10.1002/jat.3004.

    Article  CAS  PubMed  Google Scholar 

  67. Fujii M, Yamanouchi S, Hori N, Iwanaga N, Kawaguchi N, Matsumoto M. Evaluation of Yucatan micropig skin for use as an in vitro model for skin permeation study. Biol Pharm Bull. 1997;20:249–54.

  68. Knorr F, Patzelt A, Darvin ME, Lehr C-M, Schäfer U, Gruber AD, et al. Penetration of topically applied nanocarriers into the hair follicles of dog and rat dorsal skin and porcine ear skin. Vet Dermatol. 2016;27:256-e60.

    Article  PubMed  Google Scholar 

  69. Lademann J, Richter H, Meinke M, Sterry W, Patzelt A. Which skin model is the most appropriate for the investigation of topically applied substances into the hair follicles? Skin Pharmacol Physiol. 2010;23:47–52.

    Article  CAS  PubMed  Google Scholar 

  70. Lademann J, Knorr F, Richter H, Blume-Peytavi U, Vogt A, Antoniou C, et al. Hair follicles - an efficient storage and penetration pathway for topically applied substances. Skin Pharmacol Physiol. 2008;21:150–5.

  71. Lademann J, Richter H, Schaefer UF, Blume-Peytavi U, Teichmann A, Otberg N, et al. Hair follicles - a long-term reservoir for drug delivery. Skin Pharmacol Physiol. 2006;19:232–6.

    Article  CAS  PubMed  Google Scholar 

  72. Lademann J, Richter H, Schanzer S, Knorr F, Meinke M, Sterry W, et al. Penetration and storage of particles in human skin: perspectives and safety aspects. Eur J Pharm Biopharm. 2011;77:465–8.

    Article  CAS  PubMed  Google Scholar 

  73. Lademann J, Richter H, Teichmann A, Otberg N, Blume-Peytavi U, Luengo J, et al. Nanoparticles – an efficient carrier for drug delivery into the hair follicles. Eur J Pharm Biopharm. 2007;66:159–64.

  74. Patzelt A, Richter H, Knorr F, Schäfer U, Lehr C-M, Dähne L, et al. Selective follicular targeting by modification of the particle sizes. J Control Release. 2011;150:45–8.

  75. Nastiti CMRR, Mohammed Y, Telaprolu KC, Liang X, Grice JE, Roberts MS, et al. Evaluation of quantum dot skin penetration in porcine skin: effect of age and anatomical site of topical application. Skin Pharmacol Physiol. 2019;32:182–91.

  76. Capt A, Luzy AP, Esdaile D, Blanck O. Comparison of the human skin grafted onto nude mouse model with in vivo and in vitro models in the prediction of percutaneous penetration of three lipophilic pesticides. Regul Toxicol Pharmacol. 2007;47:274–87.

  77. Banks YB, Brewster DW, Birnbaum LS. Age-related changes in dermal absorption of 2,3,7, 8-tetrachlorodibenzo-p-dioxin and 2,3,4,7,8-pentachlorodibenzofuran. Fundam Appl Toxicol. 1990;15:163–73.

  78. Hung CF, Fang CL, Al-Suwayeh SA, Yang SY, Fang JY. Evaluation of drug and sunscreen permeation via skin irradiated with UVA and UVB: Comparisons of normal skin and chronologically aged skin. J Dermatol Sci. 2012;68:135–48. https://doi.org/10.1016/j.jdermsci.2012.09.005.

  79. Thompson JP, Bower S, Liddle AM, Rowbotham DJ. Perioperative pharmacokinetics of transdermal fentanyl in elderly and young adult patients. Br J Anaesth. 1998;81:152–4.

    Article  CAS  PubMed  Google Scholar 

  80. Munce TA, Kenney WL. Age-specific skin blood flow responses to acute capsaicin. Journals Gerontol Ser A. 2003;58:B304-10. https://doi.org/10.1093/gerona/58.4.B304.

  81. Finnin B, Walters KA, Franz TJ. In vitro skin permeation methodology. In: Benson HAE, Watkinson AC, editors. Topical and Transdermal Drug Delivery. 2011. p. 85–108. https://doi.org/10.1002/9781118140505.ch5.

  82. García-Piqueras J, García-Mesa Y, Cárcaba L, Feito J, Torres-Parejo I, Martín-Biedma B, et al. Ageing of the somatosensory system at the periphery: age-related changes in cutaneous mechanoreceptors. J Anat. 2019;234:839–52.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Wargniez W, Connétable S, Bourokba N, Dufour O, Nouveau S, Grégoire S. In-vivo tape stripping study with caffeine for comparisons on body sites, age and washing. Pharm Res. 2022;39:1935–44.

Download references

Funding

No funding was received by the authors for the publication of this article.

Author information

Authors and Affiliations

Authors

Contributions

Tamires de Mello: Writing—original draft. Débora Fretes Argenta: Writing—review & editing. Thiago Caon: Conceptualization, Writing – review & editing, Supervision.

Corresponding author

Correspondence to Thiago Caon.

Ethics declarations

Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Mello, T., Argenta, D.F. & Caon, T. Revisiting the Effect of Aging on the Transport of Molecules through the Skin. Pharm Res (2024). https://doi.org/10.1007/s11095-024-03710-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-024-03710-5

Keywords

Navigation