Aging is characterized by a progressive decline in cellular and tissue function, shaped in part by disruptions in communication between the extracellular matrix (ECM) and intracellular signaling networks. The cell surface receptor CD44 functions as a molecular hub, integrating signals from a remodeled ECM to regulate core aging programs including senescence, inflammation, and metabolic balance. This review synthesizes evidence that CD44, through its structural domains, isoform diversity, and proteolytic processing, integrates extracellular cues to modulate key pathways such as STAT3, NF-κB, and the class III PI3K complex. Mechanistically, HA-fragment engagement of CD44 activates the CD44-STAT3 axis in vascular tissue, suppressing autophagic flux and promoting endothelial senescence. Concurrently, ECM-derived ligand binding to CD44 drives NF-κB signaling that amplifies chronic inflammation in a tissue and context-dependent manner, contributing to inflammaging. Functional outcomes are context-dependent, shaped by isoform switching and γ-secretase-mediated release of CD44-ICD, which may drive degeneration or support repair and proteostasis. Emerging single-cell and spatial transcriptomics reveal spatiotemporal CD44 dysregulation across vasculature, brain, adipose tissue, kidney, and liver. This review establishes CD44 as a mechanistic link connecting ECM remodeling to nuclear responses in aging and outlines therapeutic strategies including ligand competition, antibody blockade, and γ-secretase modulation to mitigate age-related pathology and extend health span. These insights provide a coherent framework for understanding aging biology and guiding future translational interventions targeting CD44 signaling pathways effectively.
