In their study, mice were exposed to more severe levels of cigarette smoke over a shorter period, than the chronic experimental conditions that we selected. The Espinosa-Heidmann et al protocol had higher levels of total suspended particulate and carbon monoxide compared to our levels of 90 mg/m3 and 350 ppm, respectively. In addition,R428 they used significantly older mice than in our study. We selected our protocol based on evidence that this model induces emphysema in mice, and that AMD lesions are thought to develop over a long period of time. The younger age allows us to isolate the effect of cigarette smoke on the RPE from the complex factors related to chronological aging, which remains the most common risk factor for AMD. It is difficult to determine what factors caused preferential injury to the RPE over Bruch membrane in our study. Interestingly, Espinosa-Heidmann et al did not find compelling ultrastructural evidence of RPE cell injury. However, they did not specifically study apoptosis. Given their more acute exposure of higher concentrations of cigarette smoke, it is possible that cells could die before showing ultrastructural evidence of injury. Alternatively, because of the significant anti-oxidant capability of the RPE, a chronic exposure to the oxidants in cigarette smoke might be necessary to cause RPE injury and apoptosis. While this study provides data in support of a role for chronic cigarette smoke in RPE cell injury and apoptosis as it related to AMD,Rapamycin further work is necessary to provide a causal link. It is clear that other factors such as genetic susceptibility, the role of lipids, and chronic inflammation are important factors in the develop-ment of AMD. The value of this model is that each of these factors can be studied to determine whether cigarette smoking has a synergistic effect on important endpoints of AMD. The incidence of cancer increases with age, suggesting that physiological changes associated with aging contribute to carci-nogenesis. Cellular proliferation over the course of a lifetime coincides with a progressive loss of DNA from the ends of chromosomes, or telomeres, which culminates in a cessation of cell division known as replicative senescence.