The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging

Aging tissues experience a gradual decline in perfusion and metabolic resilience due to complex interactions among extracellular matrix (ECM) remodeling, vascular dysfunction, and mitochondrial impairment. Stiffening of the ECM 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 and facilitate the production of reactive oxygen species. Under these conditions, mitochondria produce less ATP than is needed for homeostatic repair. This energetic breakdown triggers cellular senescence and inflammation, further increasing ECM stiffening, and thus creating a self-sustaining feedback loop that accelerates tissue aging and functional decline. Such a continuum from ECM stiffening to mitochondrial dysfunction may be considered a new therapeutic target for strategies aimed at maintaining vascular integrity, mitochondrial health, and cellular homeostasis during aging.