Reversing Time with Peptides: Mechanisms, Classifications, and Innovations in Anti-aging Interventions

Öz

Anti-aging peptides are increasingly incorporated into cosmeceutical formulations because of their ability to target several biological mechanisms involved in skin aging and thereby improve overall skin appearance. Current research highlights various peptide categories, their modes of action, associated benefits, and the challenges and regulatory considerations linked to their cosmetic use. A literature search conducted through Web of Science and PubMed, including in vitro, in vivo, and clinical studies, provides insight into how these molecules function and their relevance in cosmetic science. Anti-aging peptides can stimulate extracellular matrix protein synthesis, inhibit matrix-degrading enzymes, improve skin barrier integrity, suppress inflammatory pathways, and modulate micro-muscle contractions, offering a broad range of skin-rejuvenating effects. Despite these promising properties, several limitations remain, including issues related to peptide stability, purity, effective skin penetration, and the scarcity of standardized clinical data supporting their efficacy. Overall, anti-aging peptides hold considerable promise as cosmetic actives due to their targeted and multifaceted actions combined with generally favorable safety profiles. However, future advances in delivery technologies and more rigorous clinical research are needed to fully overcome current barriers and enhance the effectiveness and reliability of peptide-based formulations.

Anahtar Kelimeler

• Skin Rejuvenation
• Extracellular Matrix
• Cosmeceuticals
• Bioactive Compounds

Zamanı Geri Çevirmek: Peptidler ile Yaşlanma Karşıtı Müdahaleler, Mekanizmalar, Sınıflandırma ve Yenilikler

Öz

Yaşlanma karşıtı peptitler, cilt yaşlanmasında rol oynayan çeşitli biyolojik mekanizmaları hedefleyebilme özellikleri nedeniyle kozmesötik formülasyonlarda giderek daha fazla kullanılmaktadır. Güncel araştırmalar; bu peptitlerin türleri, etki mekanizmaları, sağladıkları yararlar ile kozmetik alandaki kullanımına ilişkin mevcut zorluklar ve düzenleyici gereklilikler hakkında kapsamlı bilgi sunmaktadır. Web of Science ve PubMed veri tabanlarında yapılan taramada, yaşlanma karşıtı peptitlerle ilgili in vitro, in vivo ve klinik çalışmalar incelenmiş; peptit sınıflandırmaları, etki mekanizmaları, formülasyon zorlukları ve klinik önem temel değerlendirme başlıkları olarak ele alınmıştır. Yaşlanma karşıtı özelliklere sahip biyolojik olarak aktif peptitler, ekstrasellüler matriks proteinlerinin sentezini uyarmak, matriksi yıkan enzimleri inhibe etmek, cilt bariyerini güçlendirmek, inflamatuvar yolları baskılamak ve mikro kas kasılmalarını modüle etmek gibi çok yönlü yararlar sağlayabilir. Ancak stabilitelerinin sınırlı olması, saflık sorunları, cilde etkin şekilde nüfuz etmelerinin güçlüğü ve standartlaştırılmış klinik verilerin azlığı gibi etkenler, bu peptitlerin kullanımını kısıtlamaya devam etmektedir. Genel olarak yaşlanma karşıtı peptitler, hedefe yönelik ve çok boyutlu etkileri ile genellikle güvenli profilleri sayesinde kozmetik ürünlerde büyük potansiyele sahiptir. Bu potansiyelin tam olarak ortaya çıkarılabilmesi için gelecekte gelişmiş taşıyıcı sistemlere ve iyi tasarlanmış, standartlaştırılmış klinik çalışmalara daha fazla odaklanılması önem taşımaktadır.

Anahtar Kelimeler

• Cilt Gençleştirme
• Hücre Dışı Matriks
• Kozmesötikler
• Biyoaktif Bileşikler

Kaynakça

1. Acero, N., Muñoz-Mingarro, D., & Gradillas, A. (2024). Effects of Crocus sativus L. Floral Bio-Residues Related to Skin Protection. Antioxidants, 13(3), 358. https://doi.org/10.3390/antiox13030358
2. Adhikari, D., & Pokhrel, S. (2025). Microneedle Delivery of Protein and Peptides: Advances in Drug Delivery. Journal of Drug Delivery and Therapeutics, 15(2), 86–94. https://doi.org/10.22270/jddt.v15i2.6995
3. Akbarian, M., Khani, A., Eghbalpour, S., & Uversky, V.N. (2022). Bioactive Peptides: Synthesis, Sources, Applications, and Proposed Mechanisms of Action. International Journal of Molecular Sciences, 23(3), 1445. https://doi.org/10.3390/ijms23031445
4. Amer, R.I., Ezzat, S.M., Aborehab, N.M., Ragab, M.F., Mohamed, D., Hashad, A., Attia, D., Salama, M.M., & El Bishbishy, M.H. (2021). Downregulation of MMP1 expression mediates the anti-aging activity of Citrus sinensis peel extract nanoformulation in UV induced photoaging in mice. Biomedicine & Pharmacotherapy, 138, 111537. https://doi.org/10.1016/j.biopha.2021.111537
5. Arito, M., Mitsui, H., S Kurokawa, M., Yudoh, K., Kamada, T., Niki, H., & Kato, T. (2016). Effects of soy peptides on IL-1β-induced matrix-degrading enzymes in human articular chondrocytes. Integrative Molecular Medicine, 3(3), 661–665. https://doi.org/10.15761/IMM.1000219
6. Aruan, R.R., Hutabarat, H., Widodo, A.A., Firdiyono, M.T.C.C., Wirawanty, C., & Fransiska, L. (2023). Double-blind, Randomized Trial on the Effectiveness of Acetylhexapeptide-3 Cream and Palmitoyl Pentapeptide-4 Cream for Crow’s Feet. The Journal of Clinical and Aesthetic Dermatology, 16(2), 37–43.
7. Ashaolu, T. J. (2025). Applications of bioactive peptides in cosmeceuticals: A review. Journal of Zhejiang University-Science B, 26(6), 527-545. https://doi.org/10.1631/jzus.B2400029
8. Ashworth, J.C., Mehr, M., Buxton, P.G., Best, S.M., & Cameron, R.E. (2018). Optimising collagen scaffold architecture for enhanced periodontal ligament fibroblast migration. Journal of Materials Science: Materials in Medicine, 29(11), 166. https://doi.org/10.1007/s10856-018-6175-9

9. Avcil, M., Akman, G., Klokkers, J., Jeong, D., & Çelik, A. (2020). Efficacy of bioactive peptides loaded on hyaluronic acid microneedle patches: A monocentric clinical study. Journal of Cosmetic Dermatology, 19(2), 328–337. https://doi.org/10.1111/jocd.13009
10. Badenhorst, T., Svirskis, D., & Merrilees, M. (2016). Effects of GHK-Cu on MMP and TIMP Expression, Collagen and Elastin Production, and Facial Wrinkle Parameters. Journal of Aging Science, 04(03). https://doi.org/10.4172/2329-8847.1000166
11. Baker, P., Huang, C., Radi, R., Moll, S.B., Jules, E., & Arbiser, J.L. (2023). Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties. Cells, 12(23), 2745. https://doi.org/10.3390/cells12232745
12. Baliyan, S., Mukherjee, R., Priyadarshini, A., Vibhuti, A., Gupta, A., Pandey, R.P., & Chang, C.M. (2022). Determination of Antioxidants by DPPH Radical Scavenging Activity and Quantitative Phytochemical Analysis of Ficus religiosa. Molecules, 27(4), 1326. https://doi.org/10.3390/molecules27041326
13. Barbero, A., GrogFan, S., Schäfer, D., Heberer, M., Mainil-Varlet, P., & Martin, I. (2004). Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity. Osteoarthritis and Cartilage, 12(6), 476–484. https://doi.org/10.1016/j.joca.2004.02.010
14. Beach, M.A., Nayanathara, U., Gao, Y., Zhang, C., Xiong, Y., Wang, Y., & Such, G.K. (2024). Polymeric Nanoparticles for Drug Delivery. Chemical Reviews, 124(9), 5505–5616. https://doi.org/10.1021/acs.chemrev.3c00705
15. Biskanaki, F., Kefala, V., Lazaris, A.C., & Rallis, E. (2023). Aging and the Impact of Solar Ultraviolet Radiation on the Expression of Type I and Type VI Collagen. Cosmetics, 10(2), 48. https://doi.org/10.3390/cosmetics10020048
16. Bjørklund, G., Shanaida, M., Hangan, T., Kassym, L., Kussainova, A., Semenova, Y., Gheorghe, E., Gontova, T., Voloshyn, V., Lysiuk, R., Voloshyn, O., Shanaida, V., & Peana, M. (2025). The role of trace elements for the function and health of the skin. Journal of Trace Elements in Medicine and Biology, 89, 127674. https://doi.org/10.1016/j.jtemb.2025.127674
17. Blanes‐Mira, C., Clemente, J., Jodas, G., Gil, A., Fernández‐Ballester, G., Ponsati, B., Gutierrez, L., Pérez‐Payá, E., & Ferrer‐Montiel, A. (2002). A synthetic hexapeptide (Argireline) with antiwrinkle activity. International Journal of Cosmetic Science, 24(5), 303–310. https://doi.org/10.1046/j.1467-2494.2002.00153.x
18. Bourgeois, B., Spreitzer, E., Platero-Rochart, D., Paar, M., Zhou, Q., Usluer, S., de Keizer, P.L.J., Burgering, B.M.T., Sánchez-Murcia, P.A., & Madl, T. (2025). The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nature Communications, 16(1), 5672. https://doi.org/10.1038/s41467-025-60844-9
19. Bos, J. D., & Meinardi, M. M. (2000). The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology: Viewpoint, 9(3), 165-169. https://doi.org/10.1034/j.1600-0625.2000.009003165.x
20. Brand, R.M., Wipf, P., Durham, A., Epperly, M.W., Greenberger, J.S., & Falo, L.D. (2018). Targeting Mitochondrial Oxidative Stress to Mitigate UV-Induced Skin Damage. Frontiers in Pharmacology, 9. https://doi.org/10.3389/fphar.2018.00920
21. Buj, R., Leon, K.E., Anguelov, M.A., & Aird, K.M. (2021). Suppression of p16 alleviates the senescence-associated secretory phenotype. Aging, 13(3), 3290–3312. https://doi.org/10.18632/aging.202640
22. Cagan, A., Baez-Ortega, A., Brzozowska, N., Abascal, F., Coorens, T.H.H., Sanders, M.A., Lawson, A.R.J., Harvey, L.M.R., Bhosle, S., Jones, D., Alcantara, R.E., Butler, T.M., Hooks, Y., Roberts, K., Anderson, E., Lunn, S., Flach, E., Spiro, S., Januszczak, I., … Martincorena, I. (2022). Somatic mutation rates scale with lifespan across mammals. Nature, 604(7906), 517–524. https://doi.org/10.1038/s41586-022-04618-z
23. Cangul, I.T., Gul, N.Y., Topal, A., & Yilmaz, R. (2006). Evaluation of the effects of topical tripeptide‐copper complex and zinc oxide on open‐wound healing in rabbits. Veterinary Dermatology, 17(6), 417–423. https://doi.org/10.1111/j.1365-3164.2006.00551.x
24. Chen, W., Xiang, N., Huang, J., Xu, H., Wang, Z., Ruan, B., Zhang, J., Wu, C., Zhang, J., & Liang, Y. (2025). Supramolecular collagen nanoparticles for anti-wrinkle, skin whitening, and moisturizing effects. Colloids and Surfaces B: Biointerfaces, 245, 114275. https://doi.org/10.1016/j.colsurfb.2024.114275
25. Cheng, T., Tai, Z., Shen, M., Li, Y., Yu, J., Wang, J., Zhu, Q. & Chen, Z. (2023) Advance and challenges in the Treatment of Skin Diseases with the Transdermal Drug delivery System. Pharmaceutics. 15, 2165. https://doi.org/10.3390/pharmaceutics15082165
26. Cheng, J., Chen, Z., Lin, D., Yang, Y., Bai, Y., Wang, L., Li, J., Wang, Y., Wang, H., Chen, Y., Ye, J., & Liu, Y. (2025). A high clinically translatable strategy to anti-aging using hyaluronic acid and silk fibroin co-crosslinked hydrogels as dermal regenerative fillers. Acta Pharmaceutica Sinica B, 15(7), 3767–3787. https://doi.org/10.1016/j.apsb.2025.04.020
27. Cheung, P., Vallania, F., Warsinske, H.C., Donato, M., Schaffert, S., Chang, S.E., Dvorak, M., Dekker, C.L., Davis, M.M., Utz, P.J., Khatri, P., & Kuo, A.J. (2018). Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. Cell, 173(6), 1385-1397.e14. https://doi.org/10.1016/j.cell.2018.03.079
28. Corcuff, P., Chatenay, F., & Brun, A. (1985). Evaluation of anti‐wrinkle effects on humans. International Journal of Cosmetic Science, 7(3), 117–126. https://doi.org/10.1111/j.1467-2494.1985.tb00403.x
29. Cruz, A.M., Gonçalves, M.C., Marques, M.S., Veiga, F., Paiva-Santos, A. C., & Pires, P.C. (2023). In vitro Models for Anti-Aging Efficacy Assessment: A Critical Update in Dermocosmetic Research. Cosmetics, 10(2), 66. https://doi.org/10.3390/cosmetics10020066
30. Dall’Olmo, L., Papa, N., Surdo, N.C., Marigo, I., & Mocellin, S. (2023). Alpha-melanocyte stimulating hormone (α-MSH): biology, clinical relevance and implication in melanoma. Journal of Translational Medicine, 21(1), 562. https://doi.org/10.1186/s12967-023-04405-y
31. D'Arcangelis, A., Goswami Chatterjee, S., Diaz, I., Guehenneux, S., Namkoong, J., & Wu, J. (2025). In vitro, ex vivo, instrumental and clinical evaluation of a topical cream on the signs of periorbital ageing. International Journal of Cosmetic Science, 47(1), 18-30. https://doi.org/10.1111/ics.12987
32. Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology, 22(2), 75–95. https://doi.org/10.1038/s41580-020-00314-w
33. Dragicevic, N., Atkinson, J.P., & Maibach, H.I. (2015). Chemical Penetration Enhancers: Classification and Mode of Action. In Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement (pp. 11–27). Springer Berlin Heidelberg. https://doi.org/10.1007/978-3-662-47039-8_2
34. Duchardt, F., Fotin‐Mleczek, M., Schwarz, H., Fischer, R., & Brock, R. (2007). A Comprehensive Model for the Cellular Uptake of Cationic Cell‐penetrating Peptides. Traffic, 8(7), 848–866. https://doi.org/10.1111/j.1600-0854.2007.00572.x
35. Edgar, S., Hopley, B., Genovese, L., Sibilla, S., Laight, D., & Shute, J. (2018). Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts. Scientific Reports, 8(1), 10474. https://doi.org/10.1038/s41598-018-28492-w
36. Eskens, O., & Amin, S. (2021). Challenges and effective routes for formulating and delivery of epidermal growth factors in skin care. International Journal of Cosmetic Science, 43(2), 123–130. https://doi.org/10.1111/ics.12685
37. EU (2009) Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products. Off J L. 342, 22.12.2009, p 59–209
38. Filipczak, N., Yalamarty, S. S. K., Li, X., Khan, M. M., Parveen, F., & Torchilin, V. (2021). Lipid-based drug delivery systems in regenerative medicine. Materials, 14(18), 5371. https://doi.org/10.3390/ma14185371
39. Garre, A., Narda, M., Valderas-Martinez, P., Piquero, J., & Granger, C. (2018). Antiaging effects of a novel facial serum containing L-ascorbic acid, proteoglycans, and proteoglycan-stimulating tripeptide: ex vivo skin explant studies and in vivo clinical studies in women. Clinical, Cosmetic and Investigational Dermatology, 11, 253–263. https://doi.org/10.2147/CCID.S161352
40. Girardi, M., Sherling, M. A., Filler, R. B., Shires, J., Theodoridis, E., Hayday, A. C., & Tigelaar, R. E. (2003). Anti‐inflammatory effects in the skin of thymosin‐β4 splice‐variants. Immunology, 109(1), 1–7. https://doi.org/10.1046/j.1365-2567.2003.01616.x
41. Gomes, A., Bessa, L.J., Fernandes, I., Aguiar, L., Ferraz, R., Monteiro, C., Martins, M.C.L., Mateus, N., Gameiro, P., Teixeira, C., & Gomes, P. (2022). Boosting Cosmeceutical Peptides: Coupling Imidazolium-Based Ionic Liquids to Pentapeptide-4 Originates New Leads with Antimicrobial and Collagenesis-Inducing Activities. Microbiology Spectrum, 10(4). https://doi.org/10.1128/spectrum.02291-21
42. González‐Gualda, E., Baker, A.G., Fruk, L., & Muñoz‐Espín, D. (2021). A guide to assessing cellular senescence in vitro and in vivo. The FEBS Journal, 288(1), 56–80. https://doi.org/10.1111/febs.15570
43. Gul, N.Y., Topal, A., Cangul, I.T., & Yanik, K. (2008). The effects of topical tripeptide copper complex and helium‐neon laser on wound healing in rabbits. Veterinary Dermatology, 19(1), 7–14. https://doi.org/10.1111/j.1365-3164.2007.00647.x
44. Guo, H., Guo, S., & Liu, H. (2020). Antioxidant activity and inhibition of ultraviolet radiation-induced skin damage of Selenium-rich peptide fraction from selenium-rich yeast protein hydrolysate. Bioorganic Chemistry, 105, 104431. https://doi.org/10.1016/j.bioorg.2020.104431
45. Haftek, M., Abdayem, R., & Guyonnet-Debersac, P. (2022). Skin Minerals: Key Roles of Inorganic Elements in Skin Physiological Functions. International Journal of Molecular Sciences, 23(11), 6267. https://doi.org/10.3390/ijms23116267
46. Hahn, H. J., Jung, H. J., Schrammek-Drusios, M. C., Lee, S. N., Kim, J. H., Kwon, S. B., ... & Ahn, K. J. (2016). Instrumental evaluation of anti-aging effects of cosmetic formulations containing palmitoyl peptides, Silybum marianum seed oil, vitamin E and other functional ingredients on aged human skin. Experimental and Therapeutic Medicine, 12(2), 1171-1176. https://doi.org/10.3892/etm.2016.3447
47. Han, F., Luo, D., Qu, W., Chen, D., Hong, Y., Sheng, J., Yang, X., & Liu, W. (2020). Nanoliposomes codelivering bioactive peptides produce enhanced anti-aging effect in human skin. Journal of Drug Delivery Science and Technology, 57, 101693. https://doi.org/10.1016/j.jddst.2020.101693
48. Harada, M., Su-Harada, K., Kimura, T., Ono, K., & Ashida, N. (2024). Sustained activation of NF-κB through constitutively active IKKβ leads to senescence bypass in murine dermal fibroblasts. Cell Cycle, 23(3), 308–327. https://doi.org/10.1080/15384101.2024.2325802
49. He, Q., Liao, Y., Wu, Y., Zhang, H., Long, X., & Zhang, Y. (2025). Bioactive oligopeptides and the application in skin regeneration and rejuvenation. Journal of Applied Biomaterials & Functional Materials, 23. https://doi.org/10.1177/22808000251330974
50. Heremans, J., Ballet, S., & Martin, C. (2025). The versatility of peptide hydrogels: From self‐assembly to drug delivery applications. Journal of Peptide Science, 31(2). https://doi.org/10.1002/psc.3662
51. Herrera-Lavados, C., Tabilo-Munizaga, G., Carvajal-Mena, N., Jara-Quijada, E., Martínez-Oyanedel, J., & Pérez-Won, M. (2025). Obtaining bioactive peptides by enhancing enzymatic hydrolysis of salmon by-product proteins through pulsed electric fields (PEF). Food Research International, 208, 116103. https://doi.org/10.1016/j.foodres.2025.116103
52. Höhn, A., Weber, D., Jung, T., Ott, C., Hugo, M., Kochlik, B., Kehm, R., König, J., Grune, T., & Castro, J.P. (2017). Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence. Redox Biology, 11, 482–501. https://doi.org/10.1016/j.redox.2016.12.001
53. Huang, Y., He, Y., Makarcyzk, M.J., & Lin, H. (2021). Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Frontiers in Bioengineering and Biotechnology, 9. https://doi.org/10.3389/fbioe.2021.677576
54. Hussain, M., & Goldberg, D.J. (2007). Topical manganese peptide in the treatment of photodamaged skin. Journal of Cosmetic and Laser Therapy, 9(4), 232–236. https://doi.org/10.1080/14764170701704668
55. Ita, K. (2015). Chemical Penetration Enhancers for Transdermal Drug Delivery- Success and Challenges. Current Drug Delivery, 12(6), 645–651. https://doi.org/10.2174/1567201812666150804104600
56. Jones, D., Caballero, S., & Davidov-Pardo, G. (2019). Bioavailability of nanotechnology-based bioactives and nutraceuticals (pp. 235–273). https://doi.org/10.1016/bs.afnr.2019.02.014
57. Juhl, P., Bondesen, S., Hawkins, C.L., Karsdal, M.A., Bay-Jensen, A.C., Davies, M.J., & Siebuhr, A.S. (2020). Dermal fibroblasts have different extracellular matrix profiles induced by TGF-β, PDGF and IL-6 in a model for skin fibrosis. Scientific Reports, 10(1), 17300. https://doi.org/10.1038/s41598-020-74179-6
58. Kennedy, K., Cal, R., Casey, R., Lopez, C., Adelfio, A., Molloy, B., Wall, A. M., Holton, T. A., & Khaldi, N. (2020). The anti‐ageing effects of a natural peptide discovered by artificial intelligence. International Journal of Cosmetic Science, 42(4), 388–398. https://doi.org/10.1111/ics.12635
59. Kim, D.J., Chang, S.S., & Lee, J. (2019). Anti-Aging Potential of Substance P-Based Hydrogel for Human Skin Longevity. International Journal of Molecular Sciences, 20(18), 4453. https://doi.org/10.3390/ijms20184453
60. Kim, M.K., Kim, M.J., Kim, J.W., & Kim, J.H. (2021). Control Effect of Palmitoyl Teterapeptide-7 Gel to Inflammatory Responses Elicited by PM10. Asian Journal of Beauty and Cosmetology, 19(2), 165–174. https://doi.org/10.20402/ajbc.2021.0144
61. Kim, Y.H., Lee, Y.K., Park, S.S., Park, S.H., Eom, S.Y., Lee, Y.S., Lee, W. J., Jang, J., Seo, D., Kang, H.Y., Kim, J.C., Lim, S. Bin, Yoon, G., Kim, H. S., Kim, J.H., & Park, T.J. (2023). Mid-old cells are a potential target for anti-aging interventions in the elderly. Nature Communications, 14(1), 7619. https://doi.org/10.1038/s41467-023-43491-w
62. Kirmit, A., Kader, S., Aksoy, M., Bal, C., Nural, C., & Aslan, O. (2020). Trace elements and oxidative stress status in patients with psoriasis. Advances in Dermatology and Allergology, 37(3), 333–339. https://doi.org/10.5114/ada.2020.94265
63. Kobiela, T., Milner-Krawczyk, M., Pasikowska-Piwko, M., Bobecka-Wesołowska, K., Eris, I., Święszkowski, W., & Dulinska-Molak, I. (2018). The Effect of Anti-aging Peptides on Mechanical and Biological Properties of HaCaT Keratinocytes. International Journal of Peptide Research and Therapeutics, 24(4), 577–587. https://doi.org/10.1007/s10989-017-9648-7
64. Lane, M.E. (2024). In vitro permeation testing for the evaluation of drug delivery to the skin. European Journal of Pharmaceutical Sciences, 201, 106873. https://doi.org/10.1016/j.ejps.2024.106873
65. Lansdown, A.B.G., Mirastschijski, U., Stubbs, N., Scanlon, E., & Ågren, M. S. (2007). Zinc in wound healing: Theoretical, experimental, and clinical aspects. Wound Repair and Regeneration, 15(1), 2–16. https://doi.org/10.1111/j.1524-475X.2006.00179.x
66. Lee, J.S., Kang, H.Y., Lee, R., Oh, H., Son, P., Rhim, J.H., Kim, J.H., & Choi, W.Il. (2024c). Transdermal peptide delivery using solvent-free thermosponge nanoparticles to improve the anti-aging efficacy of peptides in clinical trials. European Polymer Journal, 215, 113208. https://doi.org/10.1016/j.eurpolymj.2024.113208
67. Lee, M.S., Bui, H.D., Kim, S.J., Lee, J.B., & Yoo, H.S. (2024a). Liposome-assisted penetration and antiaging effects of collagen in a 3D skin model. Journal of Cosmetic Dermatology, 23(1), 236–243. https://doi.org/10.1111/jocd.15912
68. Lee, S.G., Ham, S., Lee, J., Jang, Y., Suk, J., Lee, Y.I., & Lee, J.H. (2024b). Evaluation of the anti‐aging effects of Zinc‐α2‐glycoprotein peptide in clinical and in vitro study. Skin Research and Technology, 30(3). https://doi.org/10.1111/srt.13609
69. Levi, N., Papismadov, N., Solomonov, I., Sagi, I., & Krizhanovsky, V. (2020). The ECM path of senescence in aging: components and modifiers. The FEBS Journal, 287(13), 2636–2646. https://doi.org/10.1111/febs.15282
70. Li, Y., Ji, T., Torre, M., Shao, R., Zheng, Y., Wang, D., Li, X., Liu, A., Zhang, W., Deng, X., Yan, R., & Kohane, D.S. (2023). Aromatized liposomes for sustained drug delivery. Nature Communications, 14(1), 6659. https://doi.org/10.1038/s41467-023-41946-8
71. Li, Y., Xiang, L., & Qi, J. (2025). Procyanidin A1 from Peanut Skin Exerts Anti-Aging Effects and Attenuates Senescence via Antioxidative Stress and Autophagy Induction. Antioxidants, 14(3), 322. https://doi.org/10.3390/antiox14030322
72. Lim, S.H., Sun, Y., Thiruvallur Madanagopal, T., Rosa, V., & Kang, L. (2018). Enhanced Skin Permeation of Anti-wrinkle Peptides via Molecular Modification. Scientific Reports, 8(1), 1596. https://doi.org/10.1038/s41598-017-18454-z
73. Lim, S., Song, H.Y., Park, H.R., & Ahn, K.B. (2024). A Novel Deinococcus Antioxidant Peptide Mitigates Oxidative Stress in Irradiated CHO-K1 Cells. Microorganisms, 12(11), 2161. https://doi.org/10.3390/microorganisms12112161
74. Lima, A., Oliveira, J., Saúde, F., Mota, J., & Ferreira, R. (2017). Proteins in Soy Might Have a Higher Role in Cancer Prevention than Previously Expected: Soybean Protein Fractions Are More Effective MMP-9 Inhibitors Than Non-Protein Fractions, Even in Cooked Seeds. Nutrients, 9(3), 201. https://doi.org/10.3390/nu9030201
75. Liu, Y., Hou, Q., Wang, R., Liu, Y., & Cheng, Z. (2023). FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice. Naunyn-Schmiedeberg’s Archives of Pharmacology, 396(10), 2393–2403. https://doi.org/10.1007/s00210-023-02452-2
76. Liu, Y., Li, M., Xie, D., Chen, G., Zhao, N., & Luo, Z. (2025). Research progress of penetration enhancers in transdermal drug delivery systems: Multidimensional exploration from mechanisms to clinical application. International Journal of Pharmaceutics: X, 100468. https://doi.org/10.1016/j.ijpx.2025.100468
77. Magrode, N., Poomanee, W., Kiattisin, K., & Ampasavate, C. (2024). Microemulsions and Nanoemulsions for Topical Delivery of Tripeptide-3: From Design of Experiment to Anti-Sebum Efficacy on Facial Skin. Pharmaceutics, 16(4), 554. https://doi.org/10.3390/pharmaceutics16040554
78. Marianni, B., Mansourian, M., Koulouridas, S., & Polonini, H. (2024). Compatibility of Active Pharmaceutical Ingredients in CleodermTM: A Comprehensive Study for Enhanced Topical Dermatological Treatments. International Journal of Pharmaceutical Compounding, 28(5), 413–422.
79. McCabe, M.C., Hill, R.C., Calderone, K., Cui, Y., Yan, Y., Quan, T., Fisher, G.J., & Hansen, K.C. (2020). Alterations in extracellular matrix composition during aging and photoaging of the skin. Matrix Biology Plus, 8, 100041. https://doi.org/10.1016/j.mbplus.2020.100041
80. Md Fadilah, N. I., Shahabudin, N. A., Mohd Razif, R. A., Sanyal, A., Ghosh, A., Baharin, K. I., ... & Fauzi, M. B. (2024). Discovery of bioactive peptides as therapeutic agents for skin wound repair. Journal of Tissue Engineering, 15, 20417314241280359.. https://doi.org/10.1177/20417314241280359
81. Mia, M.M., Boersema, M., & Bank, R.A. (2014). Interleukin-1β Attenuates Myofibroblast Formation and Extracellular Matrix Production in Dermal and Lung Fibroblasts Exposed to Transforming Growth Factor-β1. Plos One, 9(3), e91559. https://doi.org/10.1371/journal.pone.0091559
82. Mochida, S., Sheng, Z.H., Baker, C., Kobayashi, H., & Catterall, W.A. (1996). Inhibition of Neurotransmission by Peptides Containing the Synaptic Protein Interaction Site of N-Type Ca2+ Channels. Neuron, 17(4), 781–788. https://doi.org/10.1016/S0896-6273(00)80209-3
83. Mondon, P., Hillion, M., Peschard, O., Andre, N., Marchand, T., Doridot, E., Feuilloley, M.G., Pionneau, C., & Chardonnet, S. (2015). Evaluation of dermal extracellular matrix and epidermal–dermal junction modifications using matrix‐assisted laser desorption/ionization mass spectrometric imaging, in vivo reflectance confocal microscopy, echography, and histology: effect of age and peptide applications. Journal of Cosmetic Dermatology, 14(2), 152–160. https://doi.org/10.1111/jocd.12135
84. Murphrey, M.B., Miao, J.H., & Zito, P.M. (2025). Histology, Stratum Corneum.
85. Naseri, N., Valizadeh, H., & Zakeri-Milani, P. (2015). Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Structure, Preparation and Application. Advanced Pharmaceutical Bulletin, 5(3), 305–313. https://doi.org/10.15171/apb.2015.043
86. Negahdaripour, M., Owji, H., Eslami, M., Zamani, M., Vakili, B., Sabetian, S., ... & Ghasemi, Y. (2019). Selected application of peptide molecules as pharmaceutical agents and in cosmeceuticals. Expert opinion on biological therapy, 19(12), 1275-1287. https://doi.org/10.1080/14712598.2019.1652592
87. Ngoc, L.T.N., Moon, J.Y., & Lee, Y.C. (2023). Insights into Bioactive Peptides in Cosmetics. Cosmetics, 10(4), 111. https://doi.org/10.3390/cosmetics10040111
88. Obrenovich, M.E.M. (2018). Leaky Gut, Leaky Brain? Microorganisms, 6(4), 107. https://doi.org/10.3390/microorganisms6040107
89. Ogórek, K., Nowak, K., Wadych, E., Ruzik, L., Timerbaev, A.R., & Matczuk, M. (2025). Are We Ready to Measure Skin Permeation of Modern Antiaging GHK–Cu Tripeptide Encapsulated in Liposomes? Molecules, 30(1), 136. https://doi.org/10.3390/molecules30010136
90. Ogiso, T., Iwaki, M., Tanino, T., Yono, A., & Ito, A. (2000). In vitro Skin Penetration and Degradation of Peptides and Their Analysis Using a Kinetic Model. Biological and Pharmaceutical Bulletin, 23(11), 1346–1351. https://doi.org/10.1248/bpb.23.1346
91. Olsson, S. E., Sreepad, B., Lee, T., Fasih, M., & Fijany, A. (2024). Public Interest in Acetyl Hexapeptide-8: Longitudinal Analysis. JMIR Dermatology, 7, e54217. https://doi.org/10.2196/54217
92. Pai, V., Bhandari, P., & Shukla, P. (2017). Topical peptides as cosmeceuticals. Indian Journal of Dermatology, Venereology, and Leprology, 83(1), 9. https://doi.org/10.4103/0378-6323.186500
93. Pavlicevic, M., Marmiroli, N., & Maestri, E. (2022). Immunomodulatory peptides—A promising source for novel functional food production and drug discovery. Peptides, 148, 170696. https://doi.org/10.1016/j.peptides.2021.170696
94. Pennington, M. W., Czerwinski, A., & Norton, R. S. (2018). Peptide therapeutics from venom: Current status and potential. Bioorganic & medicinal chemistry, 26(10), 2738-2758.
95. Perugini, P., Bleve, M., Redondi, R., Cortinovis, F., & Colpani, A. (2020). In vivo evaluation of the effectiveness of biocellulose facial masks as active delivery systems to skin. Journal of Cosmetic Dermatology, 19(3), 725–735. https://doi.org/10.1111/jocd.13051
96. Pickart, L., & Margolina, A. (2018). Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data. International Journal of Molecular Sciences, 19(7), 1987. https://doi.org/10.3390/ijms19071987
97. Pintea, A., Manea, A., Pintea, C., Vlad, R.-A., Bîrsan, M., Antonoaea, P., Rédai, E.M., & Ciurba, A. (2025). Peptides: Emerging Candidates for the Prevention and Treatment of Skin Senescence: A Review. Biomolecules, 15(1), 88. https://doi.org/10.3390/biom15010088
98. Rinnerthaler, M., Bischof, J., Streubel, M. K., Trost, A., & Richter, K. (2015). Oxidative stress in aging human skin. Biomolecules, 5(2), 545-589. https://doi.org/10.3390/biom5020545
99. Qin, Z., Robichaud, P., & Quan, T. (2016). Oxidative stress and CCN1 protein in human skin connective tissue aging. AIMS Molecular Science, 3(2), 269–279. https://doi.org/10.3934/molsci.2016.2.269
100. Quiles, J., Cabrera, M., Jones, J., Tsapekos, M., & Caturla, N. (2022). In vitro Determination of the Skin Anti-Aging Potential of Four-Component Plant-Based Ingredient. Molecules, 27(22), 8101. https://doi.org/10.3390/molecules27228101
101. Raikou, V., Varvaresou, A., Panderi, I., & Papageorgiou, E. (2017). The efficacy study of the combination of tripeptide‐10‐citrulline and acetyl hexapeptide‐3. A prospective, randomized controlled study. Journal of Cosmetic Dermatology, 16(2), 271–278. https://doi.org/10.1111/jocd.12314
102. Sadgrove, N.J., & Simmonds, M.S.J. (2021). Topical and nutricosmetic products for healthy hair and dermal antiaging using “dual‐acting” (2 for 1) plant‐based peptides, hormones, and cannabinoids. FASEB BioAdvances, 3(8), 601–610. https://doi.org/10.1096/fba.2021-00022
103. Saewan, N., Jimtaisong, A., Panyachariwat, N., & Chaiwut, P. (2023). In vitro and In vivo Anti-Aging Effect of Coffee Berry Nanoliposomes. Molecules, 28(19), 6830. https://doi.org/10.3390/molecules28196830
104. Safta, D. A., Bogdan, C., & Moldovan, M. L. (2024). SLNs and NLCs for skin applications: enhancing the bioavailability of natural bioactives. Pharmaceutics, 16(10), 1270. https://doi.org/10.3390/pharmaceutics16101270
105. Sanz, M.T., Campos, C., Milani, M., Foyaca, M., Lamy, A., Kurdian, K., & Trullas, C. (2016). Biorevitalizing effect of a novel facial serum containing apple stem cell extract, pro‐collagen lipopeptide, creatine, and urea on skin aging signs. Journal of Cosmetic Dermatology, 15(1), 24–30. https://doi.org/10.1111/jocd.12173
106. Schagen, S. (2017). Topical Peptide Treatments with Effective Anti-Aging Results. Cosmetics, 4(2), 16. https://doi.org/10.3390/cosmetics4020016
107. Schmidt, J.J., & Weinstein, S.A. (1995). Structure-function studies of waglerin I, a lethal peptide from the venom of wagler’s pit viper, Trimeresurus wagleri. Toxicon, 33(8), 1043–1049. https://doi.org/10.1016/0041-0101(95)00043-L
108. SCCS (Scientific Committee on Consumer Safety), 2023. The SCCS notes of guidance for the testing of cosmetic ingredients and their safety evaluation 12th revision. European Commission, Brussels.
109. Sebaaly, C., Greige-Gerges, H., Stainmesse, S., Fessi, H., & Charcosset, C. (2016). Effect of composition, hydrogenation of phospholipids and lyophilization on the characteristics of eugenol-loaded liposomes prepared by ethanol injection method. Food Bioscience, 15, 1–10. https://doi.org/10.1016/j.fbio.2016.04.005
110. Seo, M.Y., Chung, S.Y., Choi, W.K., Seo, Y.K., Jung, S.H., Park, J.M., Seo, M.J., Park, J.K., Kim, J.W., & Park, C.S. (2009). Anti-aging effect of rice wine in cultured human fibroblasts and keratinocytes. Journal of Bioscience and Bioengineering, 107(3), 266–271. https://doi.org/10.1016/j.jbiosc.2008.11.016
111. Shin, K.O. & Park, H.S. (2019). Antiaging cosmeceuticals in Korea and open innovation in the era of the 4th industrial revolution: from research to business. Sustainability, 11(3), 898. https://doi.org/10.3390/su11030898
112. Siméon, A., Wegrowski, Y., Bontemps, Y., & Maquart, F.-X. (2000). Expression of Glycosaminoglycans and Small Proteoglycans in Wounds: Modulation by the Tripeptide–Copper Complex Glycyl-L-Histidyl-L-Lysine-Cu2+. Journal of Investigative Dermatology, 115(6), 962–968. https://doi.org/10.1046/j.1523-1747.2000.00166.x
113. Skibska, A., & Perlikowska, R. (2021). Signal Peptides - Promising Ingredients in Cosmetics. Current Protein & Peptide Science, 22(10), 716–728. https://doi.org/10.2174/1389203722666210812121129
114. Subroto, E., Andoyo, R., & Indiarto, R. (2023). Solid lipid nanoparticles: review of the current research on encapsulation and delivery systems for active and antioxidant compounds. Antioxidants, 12(3), 633. https://doi.org/10.3390/antiox12030633
115. Souto, E.B., Cano, A., Martins-Gomes, C., Coutinho, T. E., Zielińska, A., & Silva, A.M. (2022). Microemulsions and Nanoemulsions in Skin Drug Delivery. Bioengineering, 9(4), 158. https://doi.org/10.3390/bioengineering9040158
116. Suh, M.G., Bae, G.Y., Jo, K., Kim, J.M., Hong, K.B., & Suh, H.J. (2020). Photoprotective Effect of Dietary Galacto-Oligosaccharide (GOS) in Hairless Mice via Regulation of the MAPK Signaling Pathway. Molecules, 25(7), 1679. https://doi.org/10.3390/molecules25071679
117. Supe, S., & Takudage, P. (2021). Methods for evaluating penetration of drug into the skin: A review. Skin research and technology, 27(3), 299-308.. https://doi.org/10.1111/srt.12968
118. Tarroux, R., Assalit, M.F., Hemmerle, J., & Ginestar, J. (2000). Influence of applied quantity, water-immersion and air-drying on covering and microstructure of physical sunscreen films. International Journal of Cosmetic Science, 22(6), 447–458. https://doi.org/10.1111/j.1468-2494.2000.00043.x
119. Turlier, V., Darde, M.‐S., Loustau, J., & Mengeaud, V. (2021). Assessment of the effects of a hair lotion in women with acute telogen effluvium: a randomized controlled study. Journal of the European Academy of Dermatology and Venereology, 35(S2), 12–20. https://doi.org/10.1111/jdv.17245
120. U.S. Food and Drug Administration (if desired—sometimes auto-filled). (2024, May 2). Cosmetics & U.S. Law. Van Doren, S.R. (2015). Matrix metalloproteinase interactions with collagen and elastin. Matrix Biology, 44–46, 224–231. https://doi.org/10.1016/j.matbio.2015.01.005
121. Varvaresou, A., Papageorgiou, S., Protopapa, E., & Katsarou, A. (2011). Efficacy and Tolerance Study of an Oligopeptide with Potential Anti-Aging Activity. Journal of Cosmetics, Dermatological Sciences and Applications, 01(04), 133–140. https://doi.org/10.4236/jcdsa.2011.14020
122. Veiga, E., Ferreira, L., Correia, M., Pires, P.C., Hameed, H., Araújo, A.R.T. S., Cefali, L.C., Mazzola, P.G., Hamishehkar, H., Veiga, F., & Paiva-Santos, A.C. (2023). Anti-aging peptides for advanced skincare: Focus on nanodelivery systems. Journal of Drug Delivery Science and Technology, 89, 105087. https://doi.org/10.1016/j.jddst.2023.1050ö87
123. Verma, D. (2003). Particle size of liposomes influences dermal delivery of substances into skin. International Journal of Pharmaceutics, 258(1–2), 141–151. https://doi.org/10.1016/S0378-5173(03)00183-2
124. Vincenti, M.P., & Brinckerhoff, C.E. (2002). Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Research & Therapy, 4(3), 157. https://doi.org/10.1186/ar401
125. Waszkielewicz, A.M., & Mirosław, K. (2024). Peptides and Their Mechanisms of Action in the Skin. Applied Sciences, 14(24), 11495. https://doi.org/10.3390/app142411495
126. Wissing, S.A., & Müller, R.H. (2003). The influence of solid lipid nanoparticles on skin hydration and viscoelasticity – in vivo study. European Journal of Pharmaceutics and Biopharmaceutics, 56(1), 67–72. https://doi.org/10.1016/S0939-6411(03)00040-7
127. WMA. (2024). WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Participants General Principles. https://www.wma.net/policies-post/wma-declaration-of-helsinki/
128. Xing, H., Pan, X., Hu, Y., Yang, Y., Zhao, Z., Peng, H., Wang, J., Li, S., Hu, Y., Li, G., & Ma, D. (2024). High molecular weight hyaluronic acid-liposome delivery system for efficient transdermal treatment of acute and chronic skin photodamage. Acta Biomaterialia, 182, 171–187. https://doi.org/10.1016/j.actbio.2024.05.026
129. Yan, J., Chen, S., Yi, Z., Zhao, R., Zhu, J., Ding, S., & Wu, J. (2024). The role of p21 in cellular senescence and aging-related diseases. Molecules and Cells, 47(11), 100113. https://doi.org/10.1016/j.mocell.2024.100113
130. Yang, C.Y., Pan, C.C., Tseng, C.H., & Yen, F.L. (2022). Antioxidant, Anti-Inflammation and Antiaging Activities of Artocarpus altilis Methanolic Extract on Urban Particulate Matter-Induced HaCaT Keratinocytes Damage. Antioxidants, 11(11), 2304. https://doi.org/10.3390/antiox11112304
131. Yang, F., Zhang, X., Wang, H., Guo, M., Zhang, J., Feng, X., Yu, J., Yang, J., Zhu, J., & Wang, Y. (2024). Comprehensive evaluation of the efficacy and safety of a new multi‐component anti‐aging topical eye cream. Skin Research and Technology, 30(7). https://doi.org/10.1111/srt.13790
132. Yousef, H., Alhajj, M., Fakoya, A.O., & Sharma, S. (2025). Anatomy, Skin (Integument), Epidermis.
133. Zdrada-Nowak, J., Surgiel-Gemza, A., & Szatkowska, M. (2025). Acetyl Hexapeptide-8 in Cosmeceuticals—A Review of Skin Permeability and Efficacy. International Journal of Molecular Sciences, 26(12), 5722. https://doi.org/10.3390/ijms26125722
134. Zhang, Y., Feurino, L.W., Zhai, Q., Wang, H., Fisher, W.E., Chen, C., Yao, Q., & Li, M. (2008). Thymosin beta 4 is overexpressed in human pancreatic cancer cells and stimulates proinflammatory cytokine secretion and JNK activation. Cancer Biology & Therapy, 7(3), 419–423. https://doi.org/10.4161/cbt.7.3.5415
135. Zonari, A., Brace, L.E., Al-Katib, K., Porto, W.F., Foyt, D., Guiang, M., Cruz, E.A.O., Marshall, B., Gentz, M., Guimarães, G.R., Franco, O.L., Oliveira, C.R., Boroni, M., & Carvalho, J.L. (2023). Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models. Npj Aging, 9(1), 10. https://doi.org/10.1038/s41514-023-00109-1
136. Zonari, A., Brace, L. E., Harder, N. H., Harker, C., Oliveira, C. R., Boroni, M., & Carvalho, J. L. (2024). Double‐blind, vehicle‐controlled clinical investigation of peptide OS‐01 for skin rejuvenation. Journal of Cosmetic Dermatology, 23(6), 2135-2144. https://doi.org/10.1111/jocd.16242
137. Zou, Z., Long, X., Zhao, Q., Zheng, Y., Song, M., Ma, S., Jing, Y., Wang, S., He, Y., Esteban, C.R., Yu, N., Huang, J., Chan, P., Chen, T., Izpisua Belmonte, J.C., Zhang, W., Qu, J., & Liu, G.H. (2021). A Single-Cell Transcriptomic Atlas of Human Skin Aging. Developmental Cell, 56(3), 383-397.e8. https://doi.org/10.1016/j.devcel.2020.11.002