Akhbari, P. | bioRxiv Science

bioRxiv2026

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

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.

cell biology↗

bioRxiv2025

Small things matter: Lack of extra-islet beta cells in Type 1 diabetes

Recent 3D analyses reported abundant, small beta-cell-rich endocrine objects (EOs) in the human pancreas. Here, we assessed morphological parameters of >262,000 EOs in pancreas sections from 220 donors with or without type 1 diabetes (T1D), ranging in age and disease duration. We observe many insulin (Ins)+/glucagon (Gluc)-EOs in donors without diabetes. Their relative contribution to the total endocrine area is greatest in early life (0-2y) but reduces thereafter. Strikingly, we show the virtual absence of Ins+Gluc- EOs in individuals with T1D, where only the medium and large EOs retain beta cells. We also report a lower EO density in T1D, especially in individuals diagnosed in early life. These findings suggest that extra-islet beta cells are impacted in the development of T1D, and their early loss is a characteristic feature. This new understanding has important implications for defining beta-cell mass, which may inform future screening and treatment strategies in T1D. HighlightsO_LIThe present extensive 2D studies confirm and extend recent 3D analyses of human pancreata, demonstrating that 50% of endocrine objects (EOs) are much smaller than classical islets of Langerhans and consist predominantly of beta cells (Ins+). C_LIO_LISmall insulin+ EOs comprise the largest proportion of the total endocrine area in early childhood and persist throughout the life course in donors without diabetes. C_LIO_LIThere is a shift towards larger EO size with increasing age, with the most pronounced changes in size occurring in the first few years of life. C_LIO_LISmall Ins+ EOs are virtually absent in individuals with type 1 diabetes, while the persisting EOs with beta cells are larger, suggesting a selective destruction of beta cells in small EOs. C_LIO_LIDevelopment of type 1 diabetes, particularly at an early age, is associated with fewer larger EOs in adulthood. This implies that the lack or early destruction of small Ins+ EOs may be detrimental to the generation of larger EOs. C_LI

pathology↗