Arterial stiffening, at least, reflects gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media of large arteries and occurs independently of atherosclerosis. The arterial compliance is determined by the ratio of elastin and collagen. Aging is associated with a decreased ratio of elastin/collagen, which is because of, in part, an enhanced degradation of elastin and increased accumulation of stiffer collagen. Elastin degradation is associated with progressive aortic stiffening and all-cause mortality. 20 Upregulation of MMPs may be involved in aging-associated elastin fragmentation and collagen deposition (Figure). 21 Inhibition of MMPs results in preservation of intact elastin fibers, abolishes collagen deposition, and blunts an age-associated increase in arterial blood pressure. 21 Higher serum levels of MMP2, cathepsin S, and elastin-derived peptides are independently associated with baseline pulse wave velocity and changes in arterial stiffness in patients with chronic kidney disease. 20 A recent study indicated that the expression and activity of MMP2 may be regulated by calpain-1. 2 Overexpression of calpain-1 activates MMP2 resulting in elastin degradation and increased production of collagen I and III. 2 Calpain-1 also induces TGFβ1/Smad signaling and alkaline phosphatase activation and increases total calcium content but reduces the expression of calcification inhibitors, osteopontin, and osteonectin, in cultured SMCs in vitro and arterial rings ex vivo. The cross-talk of calpain-1 and MMP2 leads to secretion of active MMP2, which remodels extracellular matrix via increasing collagen deposition and vascular calcification, 2 resulting in increased arterial stiffness. Calpain-1 levels are upregulated with aging within human aortic intima, establishing it as a potential molecular candidate to attenuate age-associated extracellular matrix remodeling and hypertension.