Abstract
Novel senotherapeutics are needed to reverse aging-related skin decline. The research question addressed was whether mesoglycan, a clinically approved glycosaminoglycan formulation known to enhance perfusion, angiogenesis, and VEGF-A signaling, possesses therapeutic potential for rejuvenating photo aged human skin. To test this, we treated full-thickness photoaged facial human skin samples (mean age: 72 ± 5 years) from seven women ex vivo. The samples were treated with topical or medium-delivered mesoglycan (100, 200, and 300 µM) for 6 days under serum-free conditions that accelerate skin aging. Biomarkers associated with aging were assessed using quantitative immunohistomorphometry. Mesoglycan treatment improved key skin aging biomarkers at all doses. Compared to vehicle-treated skin, mesoglycan broadly enhanced epidermal structure and function, improved pigmentation-related markers, reduced cellular senescence, boosted mitochondrial performance and antioxidant defenses, and improved dermal matrix structure and microvasculature density. Notably, mesoglycan also upregulated VEGF-A and VEGFR2, promoting skin rejuvenation. Medium-delivered mesoglycan produced stronger overall effects, while rete ridge reappearance was observed exclusively after topical application. Mesoglycan demonstrates senotherapeutic potential in photoaged human skin, acting via complementary pathways, including VEGF-A upregulation. Although medium-delivered mesoglycan yielded the greatest biomarker improvements topical application restored rete ridges, a sign of epidermal reorganization and also significantly enhanced basement membrane structure, pigmentation, mitochondrial function and antioxidant defenses, while avoiding systemic exposure, making it the safer and more feasible route for localized skin anti-aging.