Arterial stiffness is a hallmark of vascular ageing that precedes and strongly predicts the development of cardiovascular diseases, including atherosclerotic cardiovascular disease. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. In this outstanding study, Diaz-Canestro and Puspitasari show that MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, the authors conclude that MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases. Full study results are now up Cardiovascular Research.