The circadian clock and extracellular matrix homeostasis in ageing and age-related diseases

The extracellular matrix (ECM) is the non-cellular scaffolding component present within all tissues and organs. It provides crucial biochemical and biomechanical cues to instruct cellular behaviour and has been shown to be under circadian clock regulation, a highly conserved cell-intrinsic time keeping mechanism that has evolved with the 24-hour rhythmic environment. Ageing is a major risk factor for many diseases, including cancer, fibrosis and neurodegenerative disorders. Both ageing and our modern 24/7 society disrupt circadian rhythms, which could contribute to altered ECM homeostasis. Understanding the daily dynamics of ECM and how this mechanism changes with age will have profound impact on tissue health, disease prevention and improving treatments. Maintaining rhythmic oscillations has been proposed as a hallmark of health. On the other hand, many hallmarks of ageing turn out to be key regulators of circadian timekeeping mechanisms. In this review, we summarise new work linking the ECM with circadian clocks and tissue ageing. We discuss how the changes in the biomechanical and biochemical properties of ECM during ageing may contribute to circadian clock dysregulation. We also consider how dampening of clocks with age could compromise daily dynamic regulation of ECM homeostasis in matrix rich tissues. This review aims to encourage new concepts and testable hypotheses about the two-way interactions between circadian clocks and ECM in the context of ageing.