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1 Department of Respiratory Medicine, Juntendo University, Tokyo, Japan
Correspondence and requests for reprints should be addressed to Yoshinosuke Fukuchi, M.D., Ph.D., Department of Respiratory Medicine, CRD Research Institute, Juntendo University, Bunkyo-ku Hongo 2-9-8, Tokyo 113-0033, Japan. E-mail: yfukuchi{at}tea.ocn.ne.jp
ABSTRACT
There is growing evidence of higher prevalence of chronic obstructive pulmonary disease (COPD) in the elderly. Age-associated changes in the structure and function of the lung may increase a pathogenetic susceptibility to COPD. The lung may directly develop COPD in old age. Suitable animal models are required to test this hypothesis. Senescence-accelerated mice (SAM), Klotho gene depleted mice, and SMP-30 knockout mice were investigated with their short lifespan associated with premature aging in systemic organs. The structural and physiological changes demonstrated senile lung, not emphysema, without alveolar wall destruction. Tobacco smoke exposure resulted in the development of emphysema. These findings support the hypothesis that premature aging is not the direct cause of emphysema, but that premature aging enhances the susceptibility of the lung to extrinsic insults including tobacco smoke in these animal models. The mechanism of this enhancement needs further investigation and its elucidation should advance COPD management.
Key Words: aging lung • COPD • animal models • accelerated senescence
There is a growing concern for the rapid increase in the chronic obstructive pulmonary disease (COPD) burden worldwide. A meta-analysis using epidemiologic data from 28 countries indicates that the prevalence of COPD based on spirometry is 9 to 10% in those over 40 years of age (1). Two contributing factors may be responsible for this global surge of this disease. As the prevalence is reported to be two to three times higher in the elderly (persons over 60 years of age) (2–3), progressive graying of the global population is playing a role in the increase of the disease. Tobacco smoking is the greatest risk factor for COPD, and smoking is still poorly controlled both in industrialized and developing countries despite public anti-smoking campaigns (4). Greater burden of COPD among the elderly may be attributable to two hypotheses. First, age-associated changes in the structure and function of the lung per se may increase a pathogenetic susceptibility to COPD. At the extreme of this hypothesis, aging of the lung may directly cause COPD. To test this hypothesis, we need to find a suitable animal model because longitudinal studies using human cohorts are virtually impossible to complete. Second, cumulative insults from outside may make the old more vulnerable to hazardous injury of the lung during long life. This is related to the unique structure of the organ in that it is directly open to the external environment. This complicates assessment of the proportional contribution of intrinsic (aging dependent on genes) and/or extrinsic (epigenetic environmental influence) factor in the development of lung disease. Dissection of these two factors becomes possible only when we can control the environmental exposures. This can only be accomplished in animal experiments.
We therefore aimed to answer following questions. What type of animal models are satisfactory to find out whether maximum aging can produce COPD (emphysema)? How much is due to the effects of tobacco smoke exposure on top of the aging of the animal? Can we provide any means by which we can modulate the progression of COPD in these animals?
AGING LUNG, SENILE LUNG, AND SENILE EMPHYSEMA
Aging phenomena of tissues and organs are defined as a condition that satisfy four principles: it is intrinsic (gene dependent), universal, progressive, and usually detrimental to the host (5). Aging lung results in the lung having both structural and functional changes compatible with these four principles in healthy subjects. The aging process includes all biological events after birth, namely development, maturation, and postmaturation decline. The term "aging lung" is usually applied to designate the organ in the decline stage. The aging lung is characterized by notable changes both in structure and function (6–8). Morphologic changes consist of alveolar enlargement without wall destruction and distal duct ectasia. This finding resembles emphysema except for absence of destructive wall changes of the alveoli. The descriptive term "senile emphysema" was used to describe this finding. Aging lung was suggested as an alternative term to acknowledge that senile emphysema might be misleading since it lacks alveolar wall destruction, a pathologic hallmark of emphysema (9). In this context, the term senile lung seems more appropriate to describe these structural alterations associated with normal aging (10, 11). Thus the aging lung should be clearly distinguished from senile emphysema. Senile emphysema is associated with a notion that extreme senility may induce pulmonary emphysema. The scientific validation of this concept remains undemonstrated, and we need to test this hypothesis. Physiologic changes with normal aging are characterized by significant reduction in the elastic recoil of the lung, greater chest wall rigidity, and loss of power in the respiratory muscles (12, 13). These changes are responsible for lowered FVC/FEV1, and greater residual volume (RV). COPD is diagnosed by spirometry in the presence of air flow limitation (AFL). Aging lung is associated with progressive reduction in FEV. As a result there is considerable overdiagnosis of COPD in healthy elderly, which has become a problem in epidemiologic studies. This is particularly noteworthy when AFL is defined by a fixed ratio of FEV1/FVC (14).
ANIMAL MODELS OF AGING LUNG
There are advantages and limitations to be considered regarding the various animal models for studies of aging lung in relation to emphysema (Table 1). The most important is that the target animal must develop prominent senile changes in major organs during a relatively short life span. This will enable the investigator to observe normal aging of the target organ (lung) and examine age changes at planned times throughout the lifetime of the animal. Animal models with accelerated senescence should facilitate this requirement. Representative models that were confirmed to be compatible with this prerequisite will be discussed.
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Klotho Mouse
Mice deficient in a Klotho gene exhibit premature aging with a short life span, infertility, arteriosclerosis, and osteoporosis (25). Earlier studies in homozygous mutant klotho mice were conflicting regarding the features of air space enlargement. Reduction of elastic recoil was common but air space enlargement was inhomogenous with an increased DI, indicating development of emphysema (26). In contrast, fractal analysis suggested that the enlarged alveoli were homogenous, a result compatible with aged lung, not with emphysema (27). These investigations examined the lung only after 4 to 8 weeks of age. More recent investigation evaluated the age changes in the lung through entire lifespan of 12 weeks. The result confirmed that the lung showed aging lung, not emphysema, with DI in the normal range even at maximum age for this animal model (28).
SMP30 Knockout Mice
A novel age-associated protein was found and designated Senescence Marker Protein-30 (SMP30) (29). It has a molecular weight of 30 kD, and the amino acid sequence among humans, rats, and mice of SMP30 is highly preserved. The amount of this protein significantly decreases with aging in an androgen-independent manner. The liver of SMP30 knockout mice (SMP30 KO mice) is highly susceptible to apoptosis, and SMP30 reduces cell death from apoptosis induced by high calcium concentration.
Little is known about the changes of the lung with age in SMP30 KO mice. Mori and coworkers examined morphologic changes of the lung of SMP30 KO mice and found that MLI was significantly increased until 12 months as compared with C57BL/6 control mice. Enlarged alveoli were not associated with wall destruction with DI lower than 10% (30). When exposed to tobacco smoke for 8 weeks, SMP KO mice developed greater MI, DI, total protein carbonyls, total glutathione, and apoptosis in the lung compared with age-matched wild strains (31). SMP30 was recently identified as a key enzyme (gluconolactonase) involved in the production of vitamin C (32). Complete depletion of Vitamin C in SMP30 KO mice results in enlarged MLI and greater than 10% of DI, suggesting the development of emphysema (33).
LESSONS FROM ACCELERATED AGING ANIMAL MODELS
All three of these animal models exhibit accelerated aging, with short lifespan and characteristic aging phenomena. Their lungs are consistent with aging lung (senile lung) without pathologic changes associated with emphysema. Therefore, senile emphysema, implying the formation of emphysema with aging, is misleading and should not be used to describe the lungs of these mice. Accelerated aging may be a significant factor to increase a susceptibility of the lung to develop COPD, but not in directly causing COPD itself.
Elucidation of the cellular and molecular mechanisms responsible for the enhanced susceptibility is now extensively being investigated, and the clinical implications of the results should advance COPD management (34, 35).
FOOTNOTES
Conflict of Interest Statement: Y.F. has received reimbursement for consultancies with Novartis Japan Co. ($5,001–$10,000), Tanabe Mitsubishi Pharmaceutical Co. ($10,001–$50,000), Ohtsuka Pharmaceutical Co. ($5,001–$10,000), Kyorin Pharmaceutical Co. ($10,001–$50,000), and also has served on Advisory Boards for Tokyo CRO. Co. ($10,001–$50,000). He has also received reimbursement for lectures with Boehringer Ingelheim Japan Co. ($10,001–$50,000), GSK Japan Co. ($5,001–$10,000), and Abbott Japan Co. ($5,001–$10,000).
(Received in original form September 9, 2009; accepted in final form September 23, 2009)
REFERENCES
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