The skin is continuously exposed to environmental changes, rendering it vulnerable to damage from external stressors that contribute to premature skin aging. This study aims to explore skin longevity pathways stimulated by a rose extract (RE) derived from petals. Human keratinocytes treated with RE exhibited a significant increase in NRF2 (NF-E2-related factor 2; ≈2–4% of induction) and LAMP2A (Lysosome-Associated Membrane Protein 2A; ≈6–12% of induction) levels. The presence of RE significantly mitigated the increase in carbonylation levels (≈34–37% of protection) and the number of labeled P16^INK4A cells (≈60–72% of protection), associated with proliferation arrest, both induced by exposure to BAP (Benzo[a]pyrene) coupled with UV-A (Ultraviolet A) irradiation. The beneficial effects mediated by RE were inhibited by Compound C, a specific AMPK inhibitor (AMP-activated protein kinase). The involvement of the AMPK pathway in mediating the beneficial effects of RE has been confirmed by assessing its activation through the evaluation of its phosphorylation state which was significantly elevated in the presence of RE compared to the stress condition. In conclusion, the activation of the AMPK pathway enhances antioxidant defenses and promotes autophagy. This dual action, mediated by RE, helps protect skin cells from oxidative damage and senescence while maintaining proteostasis, skin integrity, and cellular proliferation under pollution-induced stress (BAP + UV-A). These findings highlight the potential in mitigating age-related skin changes through the modulation of longevity pathways.

Maintaining a balanced skin microbiota is essential for preserving epidermal barrier integrity and overall skin health. Dysbiosis, particularly the opportunistic overgrowth of Staphylococcus aureus, is associated with barrier dysfunction and inflammatory dermatoses such as atopic dermatitis, psoriasis, and acne. In dysbiotic states, microbial regulatory mechanisms become disrupted, enabling pathogenic strains to proliferate and release proteases that degrade structural components of the skin barrier, increasing epidermal permeability in a manner analogous to ‘leaky gut’ physiopathology. Microbiota dysbiosis has further been proposed as an emerging hallmark of aging, contributing to chronic low-grade inflammation, impaired tissue repair, and progressive barrier decline. Current strategies predominantly target the microbiota itself, leaving the host tissue response to protease-mediated barrier disruption comparatively underaddressed. To fill this gap, an ex vivo human skin model was developed based on topical application of purified S. aureus serine protease SspA to skin explants, enabling controlled investigation of early host–microbiota interaction events. Barrier function, junctional integrity, inflammatory mediators, and proteostasis were assessed through a panel of complementary biomarkers—Lucifer Yellow permeability, claudin-1, desmoglein-1, filaggrin, IL-31, S100A8/A9, PGE2, and protein carbonylation. SspA induced measurable barrier disruption, junctional protein loss, inflammatory mediator upregulation, and proteostasis impairment without overt tissue damage. A biotic culture filtrate of Bifidobacterium adolescentis partially attenuated SspA-induced protein carbonylation. This model provides the scientific community with a controlled, biologically relevant platform for identifying biomarkers of early barrier impairment and evaluating host-targeted interventions aimed at preventing or counteracting protease-driven barrier damage in dysbiosis-associated skin conditions. A better understanding of the early molecular mechanisms through which microbial virulence factors drive barrier disruption and proteostasis decline may further contribute to broader strategies aimed at preserving skin integrity during aging.

Hair follicle homeostasis is influenced by hormonal pathways, the scalp microenvironment, and environmental stressors such as pollution, UV radiation, and oxidative stress. Elissara^®, a polyphenol-enriched botanical ingredient, has shown benefits for scalp moisturization, barrier function, sebum regulation, and redness. Building on these scalp-level benefits, we investigated Elissara’s effects on follicular signaling, survival-associated biomarkers, oxidative damage, and androgen-related pathways as potential contributors to follicular health, using in silico, in vitro, and ex vivo models. Molecular docking (AutoDock Vina) of the main Elissara bioactives (oleuropein, hydroxytyrosol, verbascoside, carnosic acid, carnosol, and quercetin) identified SRD5A2 as a favorable predicted target, with individual binding energies ranging from −8.70 to −9.73 kcal/mol, approaching finasteride/dutasteride reference values. As an exploratory approach, simultaneous multi-ligand docking showed favorable global docking outputs for several targets, indicating that multiple bioactives could be structurally accommodated within complementary regions of the binding site. In human follicle dermal papilla cells, Elissara significantly increased BrdU incorporation to 245.70% of control at 0.002% and reduced SRD5A2 protein levels by 18.48% at 0.006%. In human scalp explants, Elissara at 200 µg/mL increased β-catenin, Bcl-2, and collagen IV under basal conditions and counteracted acute PM_2.5/UVA-induced alterations in β-catenin, Ki67-positive cells, Bcl-2, IGF-1, collagen IV, and protein carbonylation. Together, these findings support the potential of Elissara as a promising nutricosmetic ingredient for supporting follicular resilience through multiple follicle-relevant pathways. Clinical studies assessing hair growth outcomes are needed to determine whether these preclinical findings translate into measurable benefits.

This study supports the use of human skin explants as a versatile and translational model for evaluating pharmacologic skin responses and topical bioactivity. The approach allows mechanistic insight beyond single biomarkers and may serve as a scalable pharmacologic platform for efficacy testing, particularly when expanded to include multiple donors and broader readouts.