Extracellular Matrix Aging

The extracellular matrix is a dynamic microenvironment of tissues such as the vessel wall that, from early development through to ageing, undergoes various biochemical and biomechanical alterations in response to diverse environmental cues and exerts precise regulatory control over tissue remodelling. ^[1] Extracellular-matrix aging is characterized by loss, fragmentation, or fragility of extracellular matrix fibers, which in skin is manifested macroscopically by wrinkling, laxity, and pigmentary abnormalities. ^[2]

Senescent fibroblasts enhance degradation of the extracellular matrix through activation of matrix metalloproteinases, which contributes to age-related tissue changes. ^[3] Matrix metalloproteinases are zinc-containing endopeptidases that collectively degrade the various components of extracellular matrix proteins, and the alterations they make to the ECM contribute to skin wrinkling, a characteristic of premature skin aging. ^[4] Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for further degradation of the extracellular matrix by means of positive feedback regulation. ^[5] Excessive accumulation of ECM components, especially collagens, whether due to excessive ECM production, alteration in ECM-degrading activities, or a combination of both, is defined as fibrosis, a hallmark of aging and severe muscle injuries. ^[6]

Age-related changes in the extracellular matrix drive alterations in cell signalling that, together with inflammaging, cellular senescence, and mitochondrial dysfunction, promote a proinflammatory catabolic state contributing to osteoarthritis. ^[7] During ageing the microenvironment undergoes biophysical alterations in the extracellular matrix along with changes in secreted factors and the immune system, contributing to a tumour-permissive microenvironment. ^[8] Age-related changes in fibre and extracellular matrix composition, alongside signaling pathway disruptions and mitochondrial dysfunction, are implicated in the deterioration of healthy muscle into sarcopenia. ^[9]

Advances in technologies that enable comprehensive evaluation of extracellular matrix components and cell-matrix interactions have led to the emergence of therapeutic strategies that specifically target this fine-tuned network in vascular diseases. ^[1] Because senescent cells accumulate in aged skin and contribute to degradation of the extracellular matrix, senolytic intervention strategies that selectively target skin senescent cells are being explored to counter premature skin aging. ^[2] Accumulating evidence on the molecular mechanisms of skin aging, including MMP activity and extracellular-matrix degradation, has provided clinicians with a wide range of therapeutic targets for treating aging skin. ^[3]