The senescence-stiffening loop: How extracellular matrix remodeling, vascular decline, and mitochondrial dysfunction collectively drive tissue aging
By
Luigi Ferrucci1 Send email to [email protected]
Summary
This article presents a unified perspective on tissue aging through a "senescence-stiffening loop" — a self-reinforcing cycle involving extracellular matrix (ECM) stiffening, microvascular hypoperfusion, and mitochondrial dysfunction. As tissues age, collagen crosslinking, elastin degradation, and basement membrane thickening cause ECM stiffening, which reduces vascular compliance and impairs angiogenesis. This leads to capillary rarefaction and diminished blood flow, creating chronic or intermittent hypoxia. Hypoxia in turn triggers transcriptional and proteomic changes that suppress oxidative phosphorylation and promote glycolysis, further impairing mitochondrial function. The article outlines a matrix-vascular-metabolic axis as a unifying framework for understanding tissue aging and identifies potential therapeutic entry points to preserve tissue resilience and function with age.
Source
Twitter / XThe senescence-stiffening loop: How extracellular matrix remodeling, vascular decline, and mitochondrial dysfunction collectively drive tissue agingcell.comKey quotes
· 3 pulledStiffening of the extracellular matrix that results from collagen crosslinking, elastin loss, and basement membrane thickening reduces vascular compliance and impairs local angiogenesis.
The consequent reduction in capillaries and diminished endothelial reactivity leads to ongoing or intermittent hypoxia, which triggers changes in transcriptomic and proteomic programs that inhibit oxidative phosphorylation.
This perspective outlines a unifying matrix-vascular-metabolic axis and highlights potential entry points to preserve tissue resilience and function with age.
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