© 2006 American Thoracic Society doi: 10.1164/rccm.200607-924ED
Aging and Cigarette Smoke: Fueling the FireDivision of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine Baltimore, Maryland 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 human senile emphysema, in that it was interpreted as "nondestructive," homogeneously distributed within the lung lobes, and unrelated to alveolar inflammation. However, senile emphysema might involve alveolar destruction akin to that proposed for cigarette smoke. Fragmented alveolar elastin in aged lungs (1) may activate neutrophil-type elastase and potentially cause alveolar cell apoptosis (8) (Figure E1). Mice deleted of the anti-aging Klotho protein also develop early-onset emphysema, with evidence of activation of metalloprotease (MMP) 9 (9). Consistent with the proposed role of oxidative stress in aging (10), SMP30– lungs showed age-dependent increases in oxidative stress as assessed by protein carbonylation. As oxidative stress is clearly present in human lungs exposed to cigarette smoke (11), and recent studies linked the master antioxidant transcription factor NRF-2 to cigarette smoke–induced emphysema in mice (12), lack of SMP30 may further enhance lung oxidative stress imposed by cigarette smoke, an abundant source of highly toxic oxidants (Figure E1). The bidirectional interaction between aging and cigarette smoke is perhaps best illustrated by the recent evidence of decreased telomerase activity (a characteristic event in senescent cells) in circulating peripheral blood cells of patients with COPD (13) and markers of senescence in cigarette smoke–exposed cells and lungs (14). Senescent cells may release MMPs and trigger inflammation. The aggregate of these data suggest that cigarette smoke may be closely related to aging, acting as an environmental factor that challenges organ maintenance and repair, also a leading hypothesis in aging.
The most relevant finding by Sato and colleagues was the enhanced emphysema caused by chronic cigarette smoke exposure of SMP30– mice when compared with SMP30+ (2). In con- trast to senile airspace enlargement seen in aging SMP30– lungs, cigarette smoke–damaged lungs had a marked increase in the destructive index (number of alveolar septal breaks), consistent with active alveolar septal destruction. These findings suggest that aging directly enhances lung injury by cigarette smoke. An alternative possibility is that SMP30 interferes directly in how cigarette smoke ultimately damages alveolar septa, particularly protease/antiprotease imbalance, oxidative stress, or apoptosis. Interestingly, there were no differences in lung inflammation due to cigarette smoke in SMP30-m when compared with SMP+ lungs, based on analysis of bronchoalveolar lavage. Extracellular matrix protease activation was not investigated, but enhanced oxidative stress might lead to activation of MMPs (as MMP-9) or decrease antiproteases as Alveolar cell apoptosis, recently linked to enhanced alveolar destruction in both humans and animal models of emphysema (15, 16), might interact with alveolar oxidative stress and contribute to alveolar destruction (16). While SMP+m had mild increases in apoptotic bronchial, peribronchial, and alveolar cells due to cigarette smoke exposure, SMP30– lungs showed marked increase in apoptotic lung cells, which with enhanced oxidative stress might ultimately explain their remarkable susceptibility to cigarette smoke–induced injury (Figure E1). However, given the findings of Sato and coworkers (2), it remains to be elucidated how aging might shift the interaction between oxidative stress and apoptosis, and its potential contribution of inflammation and protease/antiprotease imbalance to emphysema due to cigarette smoke. In light of the high conservation of the amino acid sequence of SMP30 among species, data on its expression in both aging humans and in smokers, coupled with functional studies, will speed the translation of this fascinating area of investigation into human disease. FOOTNOTES This editorial has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: R.T. has received lecture fees from AstraZeneca in April 2006. REFERENCES
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