A Well-Tolerated Supercritical CO2 Extract Derived from Helichrysum italicum Distillation Co-Products with Retinoid-Associated Anti-Aging Activity

Skin aging is characterized by various changes, including epidermal thinning, barrier dysfunction, dermis alteration, and dermal–epidermal junction flattening. These changes lead to wrinkles and loss of skin radiance. This study investigates the potential of a supercritical CO2 extract derived from Helichrysum italicum distillation co-products (CO2SC extract) to serve as a botanical anti-aging product, targeting epidermal renewal, barrier reinforcement, dermal–epidermal junction organization, and engagement of retinoid-related gene networks. CO2SC extract’s effects were examined at 0.005% in aged-human-skin equivalents via histology, immunohistology, and transcriptomics. Furthermore, CO2SC extract was investigated at 0.1% in human skin explants using label-free proteomics in comparison with retinol (ROL) at 0.1% and 0.3%. The clinical effectiveness and tolerability of 0.1% CO2SC extract were determined by conducting a randomized, intra-individual comparison with a 0.1% ROL formulation. In aged-human-skin equivalents, CO2SC extract at 0.005% increased epidermal thickness, enhanced expression of differentiation- and barrier-related genes, and stimulated dermal remodeling by increasing type I and III collagens while promoting type VII collagen at the dermal–epidermal junction. Transcriptomic analysis revealed upregulation of genes involved in ROL metabolism and retinoic-acid-responsive signaling. Proteomic profiling further highlighted treatment-associated molecular signatures in comparison with ROL. Clinically, 0.1% CO2SC extract significantly improved wrinkles by day 28, with improvements of comparable magnitude to those observed with the 0.1% ROL arm under the tested conditions and good tolerability, with no signs of irritation reported, including in sensitive-skin participants. CO2SC extract displays anti-aging activity at the molecular, histological, and clinical levels under the tested conditions, modulating gene networks related to ROL metabolism and retinoid signaling while reinforcing barrier integrity and dermal regeneration. Together with its favorable tolerability profile, these findings suggest that this CO2SC extract triggers retinoid-associated programs while maintaining a molecular profile distinct from that of ROL, supporting further evaluation as a botanical anti-aging ingredient agent.