Rationale: Cigarette-smoke (CS) exposure and aging are the leading causes of chronic obstructive pulmonary disease (COPD)-emphysema development, although the molecular mechanism that mediates disease pathogenesis remains poorly understood. Objectives: To investigate the impact of CS-exposure and aging on autophagy, and pathophysiological changes associated with lung aging (senescence) and emphysema progression. Methods: Beas2b cells, C57BL/6 mice and human (GOLD 0-IV) lung tissues were used to determine the central mechanism involved in CS/age-related COPD-emphysema pathogenesis. Results: Beas2b cells and murine lungs exposed to CSE/CS showed a significant (p<0.05) accumulation of poly-ubiquitinated proteins and impaired-autophagy marker, p62, in aggresome-bodies. Moreover, treatment with autophagy-inducing antioxidant drug, cysteamine significantly (p<0.001) decreased CSE/CS-induced aggresome-bodies. We also found a significant (p<0.001) increase in levels of aggresome-bodies in the lungs of smokers and COPD-subjects in comparison to non-smoker controls. Furthermore, the presence and levels of aggresome-bodies statistically correlated with severity of emphysema and alveolar senescence. In addition to CS exposure, lungs from old mice also showed accumulation of aggresome-bodies, suggesting this as a common mechanism to initiate cellular senescence and emphysema. Additionally, Beas2b cells and murine lungs exposed to CSE/CS showed cellular apoptosis and senescence, which were both controlled by cysteamine treatment. In parallel, we evaluated the impact of CS on pulmonary exacerbation, using mice exposed to CS and/or infected with Pseudomonas aeruginosa (Pa), and confirmed cysteamine's potential as an autophagy-inducing antibacterial drug, based on its ability to control CS-induced pulmonary exacerbation (Pa-bacterial counts) and resulting inflammation. Conclusion: CS induced autophagy-impairment accelerates lung aging, COPD-emphysema exacerbations and pathogenesis.