Muscle collagen accumulation is not a universal feature of human aging: a systematic review

The extracellular matrix is critical to skeletal muscle structure and function, with collagen its largest component. Fibrosis, excessive collagen accumulation, disrupts muscle function. While animal studies consistently report age-related intramuscular collagen accumulation, human findings are inconsistent. This systematic review evaluated primary, peer-reviewed studies to assess if collagen accumulation is a universal feature of human aging. The review was registered on PROSPERO (CRD42024569964). Following PRISMA guidelines, five databases (MEDLINE [Ovid], Web of Science, SCOPUS, CINAHL, SPORTDiscus) were searched in January 2026 for studies comparing intramuscular collagen/extracellular matrix content in healthy young and older (> 60 years) adults. Eligible studies used histological or hydroxyproline techniques to quantify collagen/extracellular matrix content. Study screening, review, data extraction, and risk of bias were performed independently by two reviewers. Results were synthesized narratively. Nine studies (including 122 young and 119 older adults) were included. Four reported no age-related differences, four showed age-related intramuscular collagen accumulation, and one found equivocal results when distinguishing perimysial from endomysial collagen. Considerable heterogeneity was observed in collagen quantification methods and control of mediators including hypertension, diabetes, aerobic fitness and physical activity. Studies with rigorous control generally found no age-related differences, whereas those with limited control generally reported age-related collagen accumulation. Collagen accumulation is not an inevitable feature of human chronological aging. Observed differences may instead reflect comorbidities or lifestyle factors associated with aging; thus, through these mediators, muscle collagen accumulation may be elevated in older populations. Future studies should control mediators and investigate mechanisms regulating collagen in skeletal muscle.