Previous studies from our laboratories showed lung development differences between inbred mouse strains. In the current study, C57BL/6J (B6) and DBA/2J (D2) strains were examined for senescent-dependent differences in lung structure and function. We hypothesize that senescent changes in lung vary between strains due to identifiable gene expression differences. Quasi-static pressure-volume (P-V) curves and respiratory impedance measurements were performed on 2- and 20-month old B6 and D2 mice. Lung volume at 30cmH₂O (V₃₀) pressure was significantly (P<0.01) increased with age in both strains, but the increase was proportionally greater in D2 (68%) than in B6 (40%) mice. Elastic recoil pressure at 50% of V₃₀ and airway resistance as a function of PEEP were decreased in 20-month old D2 mice, but not in B6 mice. The lung parenchyma showed significant age-dependent decreases in elastic fiber content in both strains, but collagen content was significantly (P<0.01) greater in D2 than in B6 mice at 20-months. Using quantitative RT-PCR methods, gene expression differences between strains suggested that D2 mice significantly (P<0.05) down-regulate elastin and procollagen levels in lung tissue at 20-months of age. These age-dependent changes were accompanied by increased gene expression in matrix metalloproteinase 9 in D2, and increases in tissue inhibitor of matrix metalloproteinase in B6 mice. The results from the present study demonstrate that lung mechanics of both strains show significant age-dependent changes; however, changes in D2 mice are accelerated relative to B6 mice. Moreover, gene expression differences appear to be involved in the strain-specific changes of lung mechanic properties.