Signals from the extracellular matrix: Region- and sex-specificity in cardiac aging.

During aging, the cardiac extracellular matrix (ECM) undergoes gradual remodeling that reduces the heart's ability to function. Specific ECM changes cause alterations in cellular signaling pathways, eliciting maladaptive responses. Here, we provide insight into the current knowledge of how age-specific ECM changes contribute to altered ligand-receptor interactions, dysregulated mechanotransduction, and the propagation of pro-fibrotic signaling cascades that underpin dysfunction. We also highlight regional and sex differences that new biomolecular and bioengineered technologies have recently uncovered. We call for new biomaterial strategies that mimic spatiotemporal and sex-specific ECM alterations to equip researchers with the tools to unravel complex cellular signaling events. We believe this can be achieved through interdisciplinary cooperation amongst researchers spanning matrix biology, biomaterials, spatial omics, and biomedical engineering.