Age-dependent dysregulation of collagen metabolism in primary cardiac fibroblasts in vitro

Abstract Introduction Fibroblast-driven collagen remodelling is a key process in cardiac aging and fibrosis, yet how age and sex alter fibroblast collagen handling remains poorly characterized. This proof-of-concept study aimed to address this knowledge gap, as currently the effects of age and sex on cardiac fibroblast (cFb) collagen metabolism remain incompletely understood. Methods/Results cFbs were isolated from young (4-week) and aged (18-month) Sprague-Dawley rats and cultured in vitro. Unhydroxylated (immature) and hydroxylated (mature) collagen synthesis was estimated using cis- and trans-4-18Ffluoro-L-proline PET radiotracers as a proxy measure of collagen synthesis. Insoluble and soluble collagen deposition was assessed using colorimetric assays. No sex differences were observed in hydroxylated and hydroxylated collagen synthesis. Aging resulted in increased hydroxylated and unhydroxylated collagen synthesis in males. Insoluble collagen deposition was higher in young males than females and decreased with aging. Conclusion Collagen metabolism in cFbs is influenced by age, with aging uncoupling synthesis and deposition. These findings provide preliminary mechanistic insight and intrinsic fibroblast-level differences that may underlie age- and sex-dependent cardiac remodelling.