Idiopathic pulmonary fibrosis is, at least in part, a disease of aging. The evidence is both epidemiological and biological. The study by Fell and colleagues in this issue of the Journal (pp. 832–837) supports a growing literature suggesting that age-related changes at both the cellular and clinical level play a central role in the disease (1).

The association of age with idiopathic pulmonary fibrosis has been clear for decades (2). Well-characterized cohorts have consistently found the mean age of patients to be around 65 years; idiopathic pulmonary fibrosis is exceedingly rare in younger adults (3). Fell and colleagues expand these observations, and in doing so, show that age is a useful diagnostic tool. In a retrospective cohort of 135 patients with biopsy-proven interstitial lung disease, they show that the combination of increased age and an elevated high-resolution computed tomography scan “interstitial score” identifies patients with idiopathic pulmonary fibrosis. The study is simple and elegant, and the findings potentially obviate the need for surgical lung biopsy in selected cases.

There are, of course, limitations to this study. First, the reported findings apply only to a select population of patients with suspected idiopathic pulmonary fibrosis: those who, at the time of presentation, have a nondiagnostic clinical evaluation and a high-resolution computed tomography scan without honeycombing. Second, the prevalence of idiopathic pulmonary fibrosis in this study group was quite high (72%); this may not be representative of the true prevalence of idiopathic pulmonary fibrosis in a similar population of patients drawn from general practice. The positive predictive value of the model derived from these data is reduced if the prevalence is lowered. Finally, the absence of an independent validation cohort limits any firm conclusions, particularly given the dramatic findings. Although possible, it is seems improbable that a 55-year-old patient with only modest amounts of unexplained fibrosis by high-resolution computed tomography scan is guaranteed to have idiopathic pulmonary fibrosis, as these data suggest. Additional independent confirmation will be important. Nonetheless, this study may change the way we approach the clinical diagnosis of idiopathic pulmonary fibrosis in the future.

The link between older age and idiopathic pulmonary fibrosis highlighted by Fell and colleagues is likely important to disease management beyond its role in facilitating diagnosis. On a cellular level, emerging data suggest idiopathic pulmonary fibrosis may represent a primary failure of the alveolar epithelium, due in part to age-related changes in cellular function. The potential impact of age-related telomere shortening on the alveolar epithelium's ability to regenerate has been discussed in these editorial pages before (4). Abnormally short telomeres have been documented in the alveolar epithelium of patients with idiopathic pulmonary fibrosis (5) and mutations in the enzyme responsible for maintaining telomere length (telomerase) have been linked to familial disease (6). Protein folding in the endoplasmic reticulum becomes less efficient and reliable with aging (7). This may lead to the pathological accumulation of unfolded or aggregated proteins that trigger the unfolded protein response, endoplasmic reticulum stress, and apoptosis of the affected cell. Markers of the unfolded protein response and apoptosis are increased in the alveolar epithelium of patients with idiopathic pulmonary fibrosis (8, 9) and abnormalities in surfactant protein A2 processing (which could lead to the accumulation of unfolded protein) have been recently identified in a large affected family (10). Aging is also associated with oxidation of proteins, such as glutathione, and alterations in mesenchymal stem cell function, both of which may contribute to abnormalities of alveolar epithelial regeneration (11, 12). These preliminary observations raise the possibility that novel therapeutic approaches targeting telomerase activation, stabilization of protein folding, antioxidents, stem cell recruitment, or the modification of other age-related phenomena may have a role in idiopathic pulmonary fibrosis.

On a clinical level, the link between aging and idiopathic pulmonary fibrosis suggests patients with this disease are best approached from a geriatric perspective, as the impact of aging-related morbidity on the experience and course of disease may be substantial. Depression and debility are common geriatric conditions described in patients with idiopathic pulmonary fibrosis, and treatments aimed at improving emotional support and physical function in idiopathic pulmonary fibrosis patients have led to significant improvements in dyspnea and walk distance (13, 14). Indeed, unpublished data from our laboratory suggest that dyspnea is more strongly associated with depression and debility than with pulmonary function. It is likely that other age-related conditions (e.g., cognitive impairment, malnutrition, frailty) contribute to symptom severity and possibly even disease progression. These observations suggest that the comprehensive management of idiopathic pulmonary fibrosis should include careful attention to geriatric comorbidities and an increased focus on symptom-based management techniques as a complement to emerging disease-modifying therapies.

In recognition of the link between aging and idiopathic pulmonary fibrosis, the National Institute on Aging, the National Heart, Lung, and Blood Institute, the John A. Hartford Foundation, the Association of Specialty Professors, the American College of Chest Physicians, and the American Geriatrics Society recently cosponsored a workshop designed to stimulate the development of collaborative research in this field. This is an important development for those who study both aging and fibrosis that will surely accelerate basic and clinical investigation. It is hoped that this and other such innovative research initiatives will lead to novel scientific discoveries that directly improve the lives of patients with this devastating disease.

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