Aging and cigarette smoke: fueling the fire.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality in North America, accounting for approximately 120,000 of 400,000 total cigarette smoke–related deaths in 2002. COPD preferentially affects elderly individuals, with those 65 or older having 2.6-fold and 35.4-fold higher disease rates than those in the 45 to 64 and 18 to 44 age groups, respectively. Age contributes to the prevalence of COPD independently of the ratio of pack/years. This clear relationship raises the broader question of the nature of the relationship between a patient’s age, the process of aging, and emphysema, which with chronic bronchitis accounts for COPD. Theoretically, all humans surviving beyond 105 yr of age would eventually develop COPD (as assessed by airflow limitation and increase lung compliance [1]) or senile emphysema (as assessed morphologically [1]). Both aging and COPD share intriguing resemblances, including cardiovascular morbidity and mortality, obstructive pulmonary physiology, and underlying mechanisms of alveolar enlargement. Most importantly, cellular damage caused by aging and cigarette smoking might involve interrelated pathogenetic mechanisms, as aging may lower the injury threshold or amplify mechanisms involved in lung destruction by cigarette smoke (see Figure E1 in the online supplement). A better understanding of these mechanisms may aid us in defining risk groups and providing potential platforms for novel therapies. The experimental work by Sato and coworkers in this issue of AJRCCM (pp. 530–537) starts to address this important interaction between aging and COPD, particularly cigarette smoke–induced emphysema (2). This group reports that mice deficient in senescence marker protein-30 (SMP30-m), a model of aging, showed airspace enlargement at 3 mo of age and, most importantly, enhanced susceptibility to developing cigarette smoke–induced emphysema when compared with wild-type mice (SMP30 m). Several hypotheses to explain aging center broadly on whether aging is programmed (i.e., driven by “aging” genes) or results from stochastic events (rather than being driven by evolution). Among the latter, aging would result from the accumulation of mutations through several generations (mutation accumulation hypothesis), or result from the paradoxical effect of pleiotropic genes, beneficial early in life but detrimental as individuals age beyond reproductive age (antagonist pleiotrophy hypothesis). In line with these concepts, investigations have focused on the identification of a set of genes present in the younger but absent in the elderly, such as SMP30. SMP30 was initially identified in screening of liver proteins downregulated in aging rats (3). Its expression in the liver and kidney peaked at 3 to 6 mo of age (12 mo in the lungs), and progressively decreased by 60% in aged rats (24–26 mo of age) (4). Initial studies revealed that SMP30 might control intracellular calcium homeostasis and, more recently, SMP30 was found to act as a gluconolactase in the synthesis of L-ascorbic acid biosynthesis (5). Studies in knockout mice provided the most revealing functions of this protein, as SMP30-m showed decreased protection to liver cell apoptosis caused by Fas antibody (6), decreased life span (mean survival of 6 mo in SMP30-m versus 2 yr in SMP30 m) (7), and marked alveolar enlargement (2). This airspace enlargement fulfilled the criteria of hu-