Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001. It is known that calcified extracellular matrix (ECM) is a salient feature of the aged arterial wall, which is contributed mainly by a synthetic shift of vascular smooth muscle cells (VSMC) phenotype. Secreted matrices from aged VSMC produce a favorable microenviroment of vascular calcification (VC): abnormal mineral metabolism with enhanced phosphatase activity while osteopontin (OPN) and osteonectin (ON) are decreased. In this study, dual immunostaining shows that calpain-1 colocalized with collagen I (Col I) or III (Col III), which increases in early passage VSMC with aging. Further, over-expression of calpain-1 by a recombinant adenovirus (pAd/CANP1) infection in young VSMC increased Col I by 2.18- fold and Col III by 1.99-fold compared to control virus (pAd/GFP), up to levels of old control cells. In cultured young VSMC, over-expression of calpain-1 increased both secreted alkaline phosphotase activity by 35% and intracellular calcium content (7.9 0.4 vs 4.6 0.3 ug Ca2+/mg total protein, N=3) compared with pAd/GFP infection. Interestingly, over-expression of calpain-1 in young VSMC decreases the OPN by 65% and ON by 30% over control cells, which mimics aging. Conversely, young VSMC infected with recombinant adenovirus containing calpastatain cDNA (pAd/CAST), an endogenous inhibitor of calpain-1, increases OPN by 48% and ON by 54% over control cells. Thus, Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring and VSMC migration and to procalcification. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling and arterial calcification that underlies age-associated diseases i.e. atherosclerosis.