Age-Associated Increase in Skin Fibroblast-Derived Prostaglandin E₂Contributes to Reduced Collagen Levels in Elderly Human Skin

Production of type I collagen declines during aging, leading to skin thinning and impaired function. Prostaglandin E₂(PGE₂) is a pleiotropic lipid mediator that is synthesized from arachidonic acid by the sequential actions of cyclooxygenases (COX) and PGE synthases (PTGES). PGE₂inhibits collagen production by fibroblasts in vitro. We report that PTGES1 and COX2 progressively increase with aging in sun-protected human skin. PTGES1 and COX2 mRNA were increased 3.4-fold and 2.7-fold, respectively, in the dermis of elderly (>80 years) versus young (21-30 years) individuals. Fibroblasts were the major cell source of both enzymes. PGE₂levels were increased 70% in elderly skin. Fibroblasts in aged skin display reduced spreading due to collagen fibril fragmentation. To investigate the relationship between spreading and PGE₂synthesis, fibroblasts were cultured on micropost arrays or hydrogels of varying mechanical compliance. Reduced spreading/mechanical force resulted in increased expression of both PTGES1 and COX2 and elevated levels of PGE 2. Inhibition of PGE₂synthesis by diclofenac enhanced collagen production in skin organ cultures. These data suggest that reduced spreading/mechanical force of fibroblasts in aged skin elevates PGE₂production, contributing to reduced collagen production. Inhibition of PGE₂production may be therapeutically beneficial for combating age-Associated collagen deficit in human skin.