Targeting skin ageing at the source: a novel cellular reprogramming approach using natural extract combinations

Abstract

Cellular senescence is a driver of skin ageing that leads to structural deterioration and aesthetic changes. This study evaluated a novel senomorphic strategy, using synergistic combinations of natural small molecules to target RNA splicing regulation via upstream ERK/AKT signaling pathways. Nature-identical synthetic molecules, and corresponding extracts were assessed for cytotoxicity, impact on senescent cell load, proliferation, DNA damage load and SASP markers in naturally aged human primary skin cells. A topical, simple formulation was evaluated for impact on senescence and skin structure using 3D human ex vivo full-thickness skin explants exposed to 1.5 J/cm2 UVC irradiation. Combination of H. lupulus and G. biloba extracts produced a dose-dependent senomorphic impact of up to 45% in aged dermal fibroblasts and 10% in aged human primary keratinocytes (p [≤] 0.0001 & 0.001), without inducing cell proliferation. A 50% decrease in DNA damage load was also observed (p [≤] 0.0001). Qualitatively, the simple formulation mitigated UV-induced epidermal hyperplasia, restored collagen fiber organization, and reduced markers of senescence and inflammation. Targeting cellular senescence is an emerging traction point to address the root biological causes of skin ageing. Targeting the splicing dysregulation/senescence axis using combinations of natural plant extracts may provide a novel mode of action to reprogram senescent cells for repair and protection of skin structure and function.