Aging and lung disease are recognized factors that increase mortality risk in subjects exposed to ambient particulate matter (PM). In an effort to understand the mechanisms of enhanced susceptibility, the present study examined an inbred mouse model of senescence to: 1) determine changes in lung permeability as animals approach the end-of-life, and 2) characterize age-dependent changes in lung mechanics in pre-senescent and terminally senescent mice. The clearance of ^99mTc-DTPA was used to test the hypothesis that lung permeability increases with age and enhances PM uptake principally during the period several weeks prior to death in AKR/J mice. Quasistatic pressure-volume (PV) curves were conducted on robust and on terminally senescent AKR/J mice several weeks prior to death to assess the relative importance of lung mechanics. Abrupt body weight loss was used to signal imminent death because it accompanies indices of physiological aging and terminal senescence. ^99mTc-DTPA clearance from the lung 30-min after tracheal instillation was significantly (P < 0.05) enhanced in senescent mice. Age-dependent changes in lung mechanics were indicative of significant (P < 0.05) decrements in lung volume and compliance several weeks before death. Thus, during a period of homeostatic instability toward natural death, AKR/J mice showed enhanced permeability of soluble particles despite a decrease in lung volume and concomitant alveolar surface area. These results suggest that pulmonary epithelial-endothelial barrier dysfunction occurs in terminally-senescent mice just before death. Furthermore, this senescent-dependent increase in lung permeability appears to be a contributing factor for increased PM susceptibility in the elderly and patients with lung disease.