Dysregulation of extracellular fibronectin and α5-integrin in dermal aging

Dermal aging is a complex process characterized by structural and functional changes in the extracellular matrix (ECM) and the resident cells, such as dermal fibroblasts. Fibronectin (FN) ECM is a crucial component of the dermis, yet its role in natural aging remains poorly understood. Here, we demonstrate a significant reduction in FN ECM in aged, otherwise healthy, mouse dermis. To explore whether aging dermal fibroblasts contribute to this decline in FN levels, we examined human dermal fibroblasts (HDF) from aged skin and observed that they produce lower extracellular FN densities in vitro than young HDFs. This age-associated deficiency correlates with reduced level of α5-integrin, a cell-surface FN receptor essential for extracellular FN assembly. Knockdown of α5-integrin (α5KD) in young HDFs impairs FN ECM formation and induces phenotypes characteristic of cellular senescence. Interestingly, the proliferation defect in α5KD fibroblasts is largely restored by cell-derived matrices (CDMs) in vitro, highlighting the importance of ECM organization. These findings underscore the essential role of α5-integrin in maintaining proper ECM formation, which in turn protects against fibroblast senescence during dermal aging.