Extracellular matrix (ECM), mainly composed of elastin and collagens, is a fundamental structural component participating in vascular function. Previously, our group demonstrated that LTBP-4 and Fibulin-5 are key molecules in regulating elastic fiber formation. Here, we analysed quantitative changes of LTBP-4 and Fibulin-5 with aging in mice. Thoracic aortas were resected from wild-type (WT) mice from two- to 48-weeks of age and Ltbp4S-ko or Fbln5-ko mice at four-months after birth. Expression of LTBP-4 or Fibulin-5 was evaluated by Western blot. Three-dimentional structures of elastin and collagen were visualized using two-photon microscopy. In WT mice, LTBP-4- and Fibulin-5 protein levels in aorta decreased with aging. Compared to young WT mice, higher degree of elastin break and collagen accumulation were found in ascending aortic wall of old WT, Ltbp4- and Fbln5-ko mice, suggesting a similar pathophysiology of increased aortic stiffness in these mice. In accordance, pulse pressure in old WT- and ko mice was higher than that in WT young mice. Further, higher incidence of aortic disease (aneurysm or dissection) induced by angiotensin Ⅱ infusion was found in Fbln5-ko than WT mice. Thus, ECM remodeling caused by progressive decrease in intrinsic LTBP-4 and Fibulin-5 levels may induce age-related atrial stiffening and vascular disease such as dissection and aneurysm.