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Is Telomere Length Associated with Survival in IPF?
IPF is an age-associated disease with presentation typically occurring in the sixth and seventh decades of life.1-3 An important hallmark of aging is the progressive shortening of telomeres with increasing age.4 Telomeres are protective structures at the ends of chromosomes,5 and when telomeres reach a critically short length, persistent DNA damage results in induction of cellular senescence or apoptosis.6 Therefore, maintaining telomere length is critical for ongoing cell proliferation. Telomerase (Tert, telomerase reverse transcriptase) is an enzyme that compensates the telomere attrition produced by telomere degradation. A number of diseases have been associated with mutations in telomerase and other telomere-related genes,7 with the most frequent being IPF.8 In addition to genetic factors,9 telomere shortening has been shown to be influenced by environmental factors (eg, cigarette smoking).10 This prospective, population-based study sought to determine whether telomere length is associated with survival in IPF.11
What They Did
The study population included 94 consecutive patients with a clinical and high-resolution computed tomography-confirmed diagnosis of IPF admitted to a single hospital. All patients underwent pulmonary function testing (percent-predicted forced vital capacity [FVC % predicted] and percent-predicted diffusing capacity for carbon monoxide [DLCO % predicted]). Patients were prospectively followed for at least 1 month or until death. Eighty-five unrelated, age-matched, healthy individuals constituted a control group. Telomere length was determined with power SYBR green PCR master mix (Applied Biosystems, Foster City, CA, USA).
What They Found
The median age of patients with IPF was 67 ± 10 years (range, 37-84 years), while the median age of the age-matched control group was 68 ± 10 years (range, 45-78 years). The mean age-adjusted telomere length of patients with IPF was substantially shorter than age-matched controls (0.85 ± 0.50 vs 1.15 ± 0.60, respectively, P=.001). For patients with IPF, the median follow-up was 26 months, during which time 43 patients died. The median time to death was 6 months. Compared with survivors, non-survivors had shorter mean age-adjusted telomere length (1.03 ± 0.59 vs 0.61 ± 0.53, respectively, P=.005). In a Cox proportional hazards model in which patients were stratified by telomere length quartiles (Q) and adjustments made for relevant individual covariates (age, sex, FVC% predicted and DLCO% predicted), telomere length was found to be independently associated with survival time in patients with IPF (hazard ratio [HR], 0.47; 95% CI, 0.25-0.89; P=.019) (Figure 1).
In a subsequent analysis that excluded 6 patients with telomerase gene mutations, telomere length remained an independent predictor for survival time in patients with IPF (HR, 0.46; 95% CI, 0.24-0.88; P=.018).
What It Means
This study suggests that telomere length may be associated with the pathogenesis and progression of IPF. These findings indicate that future research should focus on the molecular mechanism underlying the shortening of telomere length in IPF. Further, it opens the door to the possibility of blocking telomere shortening as a new therapeutic target for IPF.
Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/26073170
- Gribbin J, Hubbard RB, Le J, I, et al. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006;61:980-985.
- Scott J, Johnston I, Britton J. What causes cryptogenic fibrosing alveolitis? A case-control study of environmental exposure to dust. BMJ. 1990;301:1015-1017.
- Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J. 2006;27:136-142.
- Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153:1194-1217.
- O'Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010;11:171-181.
- Povedano JM, Martinez P, Flores JM, Mulero F, Blasco MA. Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction. Cell Rep. 2015;12:286-299.
- Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest. 2013;123:996-1002.
- Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res. 2012;730:52-58.
- Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012;13:693-704.
- Alder JK, Guo N, Kembou F, et al. Telomere length is a determinant of emphysema susceptibility. Am J Respir Crit Care Med. 2011;184:904-912.
- Dai J, Cai H, Li H, et al. Association between telomere length and survival in patients with idiopathic pulmonary fibrosis. Respirology. 2015;20:947-952.