Peptide-Based Approaches for Extracellular Matrix Remodeling, Senescence Modulation, and Topical Delivery in Adult and Aging Skin
Abstract
This study synthesizes current knowledge on bioactive peptides for adult and aging skin, integrating skin structure, aging biology, peptide classes, formulation science, preclinical models and clinical evaluation to inform evidence-based topical strategies. Skin architecture and ageing mechanisms are summarized to contextualize peptide interventions that target epidermal renewal, dermal extracellular matrix, pigmentation and inflammation. Peptide categories covered include signal peptides that promote collagen, elastin and glycosaminoglycan synthesis, carrier peptides that deliver trace metals such as copper, neurotransmitter-modulating peptides for expression lines, and enzyme-inhibiting sequences that reduce MMP and tyrosinase activity. Case examples describe Pal-KTTKS, Pal-GHK, Cu-GHK, tripeptide-10 citrulline, SA1-III (KP1) and Pep 14, highlighting modes of action from collagen fibrillogenesis control and MMP activity reduction to modulation of PP2A/AKT and senescence-associated signaling. Formulation considerations examine physicochemical constraints on cutaneous delivery, lipidation strategies, nanocarriers, cell-penetrating peptides, stability challenges and vehicle design that balance penetration with safety. Mechanistic assays spanning fibroblast and keratinocyte monolayers, 3D skin equivalents and ex vivo human skin are presented alongside clinical and instrumental endpoints including profilometry, ultrasound, histology and DNA methylation age metrics. Safety, sensitization, regulatory labeling and claim frameworks are discussed with recommendations for rigorous trial design, standardized measurements and population-specific risk assessment for aging skin. Practical guidance addresses regimen sequencing, combination with retinoids and procedures such as laser, microneedling and fillers, emphasizing controlled evaluation to optimize matrix remodeling, repair and tolerability in mature skin.
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Introduction
Adult and aging skin comprises discrete yet tightly interconnected layers with specialized cell populations and extracellular matrices that are directly relevant to peptide-based interventions. The outer compartment, the epidermis, is a stratified epithelium populated primarily by keratinocytes. Its innermost portion contains proliferating basal keratinocytes, above which lie three differentiated strata: stratum spinosum, stratum granulosum and stratum corneum. The most superficial stratum corneum consists of anucleate corneocytes embedded in a lipid-rich matrix, a configuration that is central to barrier function and to the limitation of transcutaneous penetration of many hydrophilic molecules [1].
Epidermal renewal depends on distinct epidermal stem cell populations distributed within the basal layer and the hair follicle. These stem cells support continuous regeneration of the epidermis on top of the collagen-rich dermal extracellular matrix (ECM). The dermis lies beneath the basal epidermal layer and contains vasculature and adnexal structures within an ECM produced by dermal fibroblasts, which are terminally differentiated cells of mesenchymal origin. Collagen and elastin fibers within this matrix provide mechanical integrity, firmness and tensile strength, and are key targets of aging-associated degradation processes. Histologic and molecular analyses of photoaged skin show dermal loss of collagen and elastin accompanied by increased dermal inflammation and elevated gene expression of matrix metalloproteinases (MMPs), with concomitant decreases in ECM components such as collagen and elastin [1,2,3].
Extrinsic aging driven by ultraviolet (UV) radiation particularly affects epidermal and dermal structure. UVB, with higher energy and shorter wavelength, primarily damages the epidermis through direct absorption by chromophores including nucleic acids and amino acids, leading to the formation of cyclobutane pyrimidine dimers and photoproducts. These lesions interfere with RNA transcription, activate p53, and induce keratinocyte apoptosis. Photosensitization mechanisms further generate reactive oxygen species (ROS) and reactive nitrogen species that penetrate nuclei and induce oxidative DNA damage and strand breaks. Downstream, oxidative stress activates inflammatory pathways and upregulates MMPs such as MMP-1, MMP-3 and MMP-9, which degrade collagen and elastin, with clinical consequences including wrinkle formation, loss of elasticity, hyperpigmented lesions and impaired barrier function [3].
Within the dermal ECM, fragmented collagen acquires a central role in propagating aging-related signaling. Photoaging is strongly associated with collagen degradation initiated by UV-induced increases in MMP secretion from basal keratinocytes and dermal fibroblasts, linked to activation of AP-1 signaling. In vitro, dermal fibroblasts cultured on synthetically degraded collagen exhibit increased ROS generation, elevated MMP secretion and reduced collagen production. Co-culture experiments show that MMP expression in fibroblasts decreases regenerative capacity and longevity of overlying epidermal stem cells, highlighting bidirectional communication between dermal ECM and epidermal progenitors. These interactions position ECM composition and integrity as critical determinants of both structural and functional aspects of skin aging, including barrier maintenance and repair potential [1].
Structural differences between intrinsically aged and photoaged skin further clarify how tissue architecture underlies clinical phenotypes. Intrinsic aging typically presents with fine wrinkles, some deepening of surface markings, modest loss of elasticity, and relatively smooth but sagging skin. Photoaged skin, in contrast, shows nodular, leathery surfaces, coarse wrinkles, severe loss of elasticity, yellowish mottled pigmentation and a reddened appearance. At the epidermal level, intrinsic aging involves thinning with lower cell growth and minor keratinocyte irregularities, while photoaging is characterized by marked acanthosis followed by cellular atrophy, high basal keratinocyte irregularity, a compact stratum corneum and loss of rete pegs in both states. In the dermis, intrinsic aging features a thinner reticular dermis with decreased fibroblasts and collagen fibers, whereas photoaging produces a thickened dermis with elastosis, increased and hyperactive fibroblasts and mast cells, excessive and disorganized elastin, collagen fiber thickening followed by wear, and formation of a grenz zone associated with solar elastosis. Collagen bundles are thick but disoriented in intrinsic aging, and markedly decreased in photoaging, while glycosaminoglycans are slightly decreased versus markedly increased, respectively. Microvascular loss is moderate in intrinsic aging but pronounced, abnormal and telangiectatic in photoaging [2].
Conclusion
This synthesis highlights how short bioactive peptides interact with key cutaneous compartments to modify extracellular matrix turnover, cell signaling and repair pathways. Signal and carrier sequences such as palmitoyl-conjugated collagen fragments, Cu-GHK and decorin-mimetic tripeptides have demonstrable effects on collagen, elastin and glycosaminoglycan dynamics, while modulators like SA1-III can reduce proteolytic collagen loss by attenuating MMP activity. Senotherapeutic sequences exemplified by Pep 14 influence PP2A/AKT and FoxO-related networks to reduce late-stage senescence markers and support DNA repair without triggering apoptosis, producing favorable ex vivo tissue responses including increased epidermal thickness and reduced methylation age metrics.
Delivery constraints imposed by the stratum corneum demand physicochemical modification, lipidation, nanoparticulate encapsulation or transient barrier disruption for deeper dermal targeting; each approach alters spatial distribution and bioavailability and therefore must be matched to the intended molecular target and safety profile. Translational pathways benefit from a staged evaluation framework that integrates molecular, cellular and tissue models with rigorous clinical and instrumental endpoints. In vitro and ex vivo assays clarify mechanism of action and off-target signals, three-dimensional skin equivalents connect cellular responses to organ-level outcomes, and randomized human trials with profilometry, ultrasound and biochemical readouts validate functional benefits such as wrinkle depth reduction, elasticity improvement and increased procollagen synthesis.
Safety assessment should prioritize irritation, sensitization and potential photoallergic effects in older, barrier-compromised cohorts, and regulatory labeling must reflect the level of evidence supporting claims. Future work should refine delivery systems to balance epidermal versus dermal exposure, expand controlled comparative trials that isolate peptide effects within complex formulations, and apply standardized endpoints including epigenetic clocks and objective imaging to establish durable, reproducible benefits for adult and aging skin.
References
- AK, M. (2019). Skin aging & modern age anti-aging strategies. International Journal of Clinical Dermatology & Research. https://doi.org/10.19070/2332-2977-1900052
- Aluko, R. (2012). Bioactive peptides. In Functional foods and nutraceuticals (Food Science Text Series). Springer. https://doi.org/10.1007/978-1-4614-3480-1_3
- Arab, H., Sadeghi, S., Shahtalebi, M. A., Siadat, A. H., Tahvilian, B., & Mofid, M. R. (2025). Anti-wrinkle effect of an emulsion based on the hexapeptide argireline. Pilot study. Aesthetic Cosmetology and Medicine, *14*(4). https://doi.org/10.52336/acm.2025.030
- Escobar, S., Valois, A., Nielsen, M., Closs, B., & Kerob, D. (2020). Effectiveness of a formulation containing peptides and vitamin c in treating signs of facial ageing: Three clinical studies. International Journal of Cosmetic Science, *43*(2). https://doi.org/10.1111/ics.12665
- Farage, M. A., Miller, K. W., Elsner, P., & Maibach, H. I. (2007). Structural characteristics of the aging skin: A review. Cutaneous and Ocular Toxicology, *26*(4). https://doi.org/10.1080/15569520701622951
- Ferreira, M. S., Magalhães, M. C., Sousa-Lobo, J. M., & Almeida, I. F. (2020). Trending anti-aging peptides. Cosmetics, *7*(4). https://doi.org/10.3390/cosmetics7040091
- Fu, T.-K., Kuo, P.-H., Lu, Y.-C., Lin, H.-N., Wang, L. H.-C., Lin, Y.-C., Kao, Y.-C., Lai, H.-M., & Chang, M. D.-T. (2020). Cell penetrating peptide as a high safety anti-inflammation ingredient for cosmetic applications. Biomolecules, *10*(1). https://doi.org/10.3390/biom10010101
- Gazitaeva, Z., Drobintseva, A., Chung, Y., Polyakova, V., & Kvetnoy, I. (2017). Cosmeceutical product consisting of biomimetic peptides: Antiaging effects in vivo and in vitro. Clinical, Cosmetic and Investigational Dermatology, Volume 10. https://doi.org/10.2147/ccid.s97573
- Gorouhi, F., & Maibach, H. I. (2009). Role of topical peptides in preventing or treating aged skin. International Journal of Cosmetic Science, *31*(5). https://doi.org/10.1111/j.1468-2494.2009.00490.x
- Kluczyk, A., Ludwiczak, J., Modzel, M., Kuczer, M., Cebrat, M., Biernat, M., & Bąchor, R. (2021). Chemical and biological properties of anti-wrinkle peptide argireline. Aesthetic Cosmetology and Medicine, *10*(3). https://doi.org/10.52336/acm.2021.10.3.05
- Moazzam, M., Mehboob, T., Bashir, I., Aslam, R., Tabassam, N., & Jamshaid, M. (2018). Constituents of cosmeceuticals and implication of nanotechnology in cosmetics. RADS Journal of Pharmacy and Pharmaceutical Sciences, *6*(4).
- Naharro-Rodriguez, J., Bacci, S., Hernandez-Bule, M. L., Perez-Gonzalez, A., & Fernandez-Guarino, M. (2025). Decoding skin aging: A review of mechanisms, markers, and modern therapies. Cosmetics, *12*(4). https://doi.org/10.3390/cosmetics12040144
- Patlolla, R. R., Desai, P. R., Belay, K., & Singh, M. S. (2010). Translocation of cell penetrating peptide engrafted nanoparticles across skin layers. Biomaterials, *31*(21). https://doi.org/10.1016/j.biomaterials.2010.03.010
- Rovero, P., Malgapo, D. M. H., Sparavigna, A., Beilin, G., Wong, V., & Lao, M. P. (2022). The clinical evidence-based paradigm of topical anti-aging skincare formulations enriched with bio-active peptide SA1-III (KP1) as collagen modulator: From bench to bedside. Clinical, Cosmetic and Investigational Dermatology, Volume 15. https://doi.org/10.2147/ccid.s374295
- Sánchez, A., & Vázquez, A. (2017). Bioactive peptides: A review. Food Quality and Safety, *1*(1). https://doi.org/10.1093/fqs/fyx006
- Schagen, S. (2017). Topical peptide treatments with effective anti-aging results. Cosmetics, *4*(2). https://doi.org/10.3390/cosmetics4020016
- Singh, S., Singh, V., & Patel, S. (2024). Cosmeceuticals; the fusion of cosmetics and pharmaceuticals. Journal of Community Pharmacy Practice, *42*. https://doi.org/10.55529/jcpp.42.16.27
- TATARINGA, G., & ZBANCIOC, A. M. (2021). Antirid peptides in cosmeceutical formula. Romanian Journal of Pharmaceutical Practice, *14*(3-4). https://doi.org/10.37897/rjphp.2021.3.1
- Umeyor, C. E., Shelke, V., Pol, A., Kolekar, P., Jadhav, S., Tiwari, N., Anure, A., Nayak, A., Bairagi, G., Agale, A., Raut, V., Bahadure, S., Chaudhari, A., & Patravale, V. B. (2023). Biomimetic microneedles: Exploring the recent advances on a microfabricated system for precision delivery of drugs, peptides, and proteins. Future Journal of Pharmaceutical Sciences, *9*(1). https://doi.org/10.1186/s43094-023-00553-6
- Vandiver, A. R., & Hogan, S. R. (2020). Aging skin and non-surgical procedures: A basic science overview. Plastic and Aesthetic Research, *7*. https://doi.org/10.20517/2347-9264.2020.159
- West, B. J., Alabi, I., & Deng, S. (2021). A face serum containing palmitoyl tripeptide-38, hydrolyzed hyaluronic acid, bakuchiol and a polyherbal and vitamin blend improves skin quality. Journal of Cosmetics, Dermatological Sciences and Applications, *11*(3). https://doi.org/10.4236/jcdsa.2021.113020
- Zonari, A., Brace, L. E., Al-Katib, K. Z., Porto, W. F., Foyt, D., Guiang, M., Cruz, E. A. O., Marshall, B., Salgueiro, W. G., Inan, M. D., Rahman, M., Anupom, T., Vanapalli, S., Mori, M. A., Franco, O. L., Oliveira, C. R., Boroni, M., & Carvalho, J. L. (2020). Senotherapeutic peptide reduces skin biological age and improves skin health markers. https://doi.org/10.1101/2020.10.30.362822
- 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). https://doi.org/10.1038/s41514-023-00109-1.