Telomere integrity is essential for cell and organ function. In the presence of short telomeres, cells activate a DNA damage response that signals apoptosis and senescence. Clinically, these cellular programs manifest as progressive, degenerative organ failure. Because short telomeres accumulate with aging and impair tissue repair even when telomerase is wildtype, they have been implicated in mediating age-related disease. However, the consequences of telomere shortening in the lung are not fully understood. Aside from cigarette smoke exposure, age is the biggest risk factor for the development of emphysema. Emphysema incidence increases steadily with age and accounts for the fourth most common cause of mortality in the United States. The genetic mechanisms that lead to the age-related increase in emphysema are however not fully known. This proposal examines the role of short telomeres in emphysema susceptibility and pathogenesis in a relevant and genetically defined model, the telomerase knockout mouse. We hypothesize that short telomeres cooperate with cigarette smoke-related DNA damage to induce molecular defects that provoke the emphysema phenotype. Understanding the role of short telomeres in emphysema pathogenesis is particularly significant given recent observations that, in cigarette smokers, short telomeres are associated with the emphysema phenotype. The proposed studies therefore have the potential to advance knowledge about the genetic factors associated with aging that mediate the emphysema phenotype. PUBLIC HEALTH RELEVANCE: This project examines the role of short telomeres in the pathogenesis of chronic obstructive pulmonary disease and the mechanism by which telomere shortening may be a susceptibility factor in emphysema.