Abstract
Our understanding of the biology of aging has advanced significantly in recent years. This has resulted in the recent formulation of the “hallmarks of aging” that include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that results from the accumulation of scar tissue in the lungs of affected individuals. IPF is a disease of aging that most commonly affects human subjects older than 60 years of age. While progress has been made in elucidating key pathological processes in IPF, the relationship of these processes to those that occur during aging are not well defined. In this review, we explore existing and emerging paradigms in the pathogenesis of IPF in light of the recently defined hallmarks of aging.
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Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA 3rd, Lansdorp PM, Loyd JE, Armanios MY (2008) Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA 105(35):13051–13056. doi:10.1073/pnas.0804280105
Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, Yanagisawa H, Kobayashi K, Tsurushige C, Kawaishi M, Kamiya N, Hirano J, Odaka M, Morikawa T, Nishimura SL, Kawabata Y, Hano H, Nakayama K, Kuwano K (2013) Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 304(1):L56–L69. doi:10.1152/ajplung.00213.2012
Armanios M (2012) Telomerase and idiopathic pulmonary fibrosis. Mutat Res 730(1–2):52–58. doi:10.1016/j.mrfmmm.2011.10.013
Armanios M (2013) Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest 123(3):996–1002. doi:10.1172/JCI66370
Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips JA 3rd, Lansdorp PM, Greider CW, Loyd JE (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356(13):1317–1326. doi:10.1056/NEJMoa066157
Baker DJ, Dawlaty MM, Wijshake T, Jeganathan KB, Malureanu L, van Ree JH, Crespo-Diaz R, Reyes S, Seaburg L, Shapiro V, Behfar A, Terzic A, van de Sluis B, van Deursen JM (2013) Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15(1):96–102. doi:10.1038/ncb2643
Block K, Gorin Y, Abboud HE (2009) Subcellular localization of Nox4 and regulation in diabetes. Proc Natl Acad Sci USA 106(34):14385–14390. doi:10.1073/pnas.0906805106
Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11(8):567–578. doi:10.1038/nrm2944
Chapman HA (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73:413–435. doi:10.1146/annurev-physiol-012110-142225
Chen ZH, Kim HP, Sciurba FC, Lee SJ, Feghali-Bostwick C, Stolz DB, Dhir R, Landreneau RJ, Schuchert MJ, Yousem SA, Nakahira K, Pilewski JM, Lee JS, Zhang Y, Ryter SW, Choi AM (2008) Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease. PLoS One 3(10):e3316. doi:10.1371/journal.pone.0003316
Chilosi M, Poletti V, Murer B, Lestani M, Cancellieri A, Montagna L, Piccoli P, Cangi G, Semenzato G, Doglioni C (2002) Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63. Lab Invest 82(10):1335–1345
Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, Pedron S, Bertaso M, Scarpa A, Murer B, Cancellieri A, Maestro R, Semenzato G, Doglioni C (2003) Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol 162(5):1495–1502
Chilosi M, Doglioni C, Murer B, Poletti V (2010) Epithelial stem cell exhaustion in the pathogenesis of idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 27(1):7–18
Chilosi M, Carloni A, Rossi A, Poletti V (2013) Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res. doi:10.1016/j.trsl.2013.06.004
Cisneros J, Hagood J, Checa M, Ortiz-Quintero B, Negreros M, Herrera I, Ramos C, Pardo A, Selman M (2012) Hypermethylation-mediated silencing of p14(ARF) in fibroblasts from idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 303(4):L295–L303. doi:10.1152/ajplung.00332.2011
Collard HR (2010) The age of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 181(8):771–772. doi:10.1164/rccm.201001-0049ED
Coward WR, Watts K, Feghali-Bostwick CA, Jenkins G, Pang L (2010) Repression of IP-10 by interactions between histone deacetylation and hypermethylation in idiopathic pulmonary fibrosis. Mol Cell Biol 30(12):2874–2886. doi:10.1128/MCB.01527-09
Crespo FL, Sobrado VR, Gomez L, Cervera AM, McCreath KJ (2010) Mitochondrial reactive oxygen species mediate cardiomyocyte formation from embryonic stem cells in high glucose. Stem Cells 28(7):1132–1142. doi:10.1002/stem.441
Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, Garcia CK (2008) Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med 178(7):729–737. doi:10.1164/rccm.200804-550OC
Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lu J (2010) MIR-29 is a major regulator of genes associated with pulmonary fibrosis. Am J Respir Cell Mol Biol. doi:10.1165/rcmb.2010-0323OC
Dakhlallah D, Batte K, Wang Y, Cantemir-Stone CZ, Yan P, Nuovo G, Mikhail A, Hitchcock CL, Wright VP, Nana-Sinkam SP, Piper MG, Marsh CB (2013) Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 187(4):397–405. doi:10.1164/rccm.201205-0888OC
de Grey AD (2005) Resistance to debate on how to postpone ageing is delaying progress and costing lives. Open discussions in the biogerontology community would attract public interest and influence funding policy. EMBO reports 6 Spec No:S49–53. doi:10.1038/sj.embor.7400399
Degryse AL, Xu XC, Newman JL, Mitchell DB, Tanjore H, Polosukhin VV, Jones BR, McMahon FB, Gleaves LA, Phillips JA 3rd, Cogan JD, Blackwell TS, Lawson WE (2012) Telomerase deficiency does not alter bleomycin-induced fibrosis in mice. Exp Lung Res 38(3):124–134. doi:10.3109/01902148.2012.658148
Dimmeler S, Nicotera P (2013) MicroRNAs in age-related diseases. EMBO Mol Med 5(2):180–190. doi:10.1002/emmm.201201986
Fell CD, Martinez FJ, Liu LX, Murray S, Han MK, Kazerooni EA, Gross BH, Myers J, Travis WD, Colby TV, Toews GB, Flaherty KR (2010) Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 181(8):832–837. doi:10.1164/rccm.200906-0959OC
Fontana L, Partridge L, Longo VD (2010) Extending healthy life span–from yeast to humans. Science 328(5976):321–326. doi:10.1126/science.1172539
Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254
Hecker L, Vittal R, Jones T, Jagirdar R, Luckhardt TR, Horowitz JC, Pennathur S, Martinez FJ, Thannickal VJ (2009) NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med 15(9):1077–1081. doi:10.1038/nm.2005
Hernandez-Gea V, Friedman SL (2012) Autophagy fuels tissue fibrogenesis. Autophagy 8(5):849–850. doi:10.4161/auto.19947
Huang SK, Scruggs AM, Donaghy J, Horowitz JC, Zaslona Z, Przybranowski S, White ES, Peters-Golden M (2013) Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. Cell Death Dis 4:e621. doi:10.1038/cddis.2013.146
Hwang JW, Chung S, Sundar IK, Yao H, Arunachalam G, McBurney MW, Rahman I (2010) Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 500(2):203–209. doi:10.1016/j.abb.2010.05.013
Jain M, Rivera S, Monclus EA, Synenki L, Zirk A, Eisenbart J, Feghali-Bostwick C, Mutlu GM, Budinger GR, Chandel NS (2013) Mitochondrial reactive oxygen species regulate transforming growth factor-beta signaling. J Biol Chem 288(2):770–777. doi:10.1074/jbc.M112.431973
Jun JI, Lau LF (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12(7):676–685. doi:10.1038/ncb2070
Kirkwood TB, Kowald A (2012) The free-radical theory of ageing–older, wiser and still alive: modelling positional effects of the primary targets of ROS reveals new support. Bioessays 34(8):692–700. doi:10.1002/bies.201200014
Koga H, Kaushik S, Cuervo AM (2011) Protein homeostasis and aging: the importance of exquisite quality control. Ageing Res Rev 10(2):205–215. doi:10.1016/j.arr.2010.02.001
Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A (2008) Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178(8):838–846. doi:10.1164/rccm.200802-313OC
Korfei M, Schmitt S, Ruppert C, Henneke I, Markart P, Loeh B, Mahavadi P, Wygrecka M, Klepetko W, Fink L, Bonniaud P, Preissner KT, Lochnit G, Schaefer L, Seeger W, Guenther A (2011) Comparative proteomic analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and lung transplant donor lungs. J Proteome Res 10(5):2185–2205. doi:10.1021/pr1009355
Korfhagen TR, Le Cras TD, Davidson CR, Schmidt SM, Ikegami M, Whitsett JA, Hardie WD (2009) Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 41(5):562–572. doi:10.1165/rcmb.2008-0377OC
Koziel R, Pircher H, Kratochwil M, Lener B, Hermann M, Dencher NA, Jansen-Durr P (2013) Mitochondrial respiratory chain complex I is inactivated by NADPH oxidase Nox4. Biochem J 452(2):231–239. doi:10.1042/BJ20121778
Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114(9):1299–1307. doi:10.1172/JCI22475
Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134(4):657–667. doi:10.1016/j.cell.2008.06.049
Kropski JA, Lawson WE, Young LR, Blackwell TS (2013) Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis Model Mech 6(1):9–17. doi:10.1242/dmm.010736
Kuwano K, Kunitake R, Kawasaki M, Nomoto Y, Hagimoto N, Nakanishi Y, Hara N (1996) P21Waf1/Cip1/Sdi1 and p53 expression in association with DNA strand breaks in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 154(2 Pt 1):477–483. doi:10.1164/ajrccm.154.2.8756825
Lawson WE, Crossno PF, Polosukhin VV, Roldan J, Cheng DS, Lane KB, Blackwell TR, Xu C, Markin C, Ware LB, Miller GG, Loyd JE, Blackwell TS (2008) Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol 294(6):L1119–L1126. doi:10.1152/ajplung.00382.2007
Liu T, Chung MJ, Ullenbruch M, Yu H, Jin H, Hu B, Choi YY, Ishikawa F, Phan SH (2007) Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice. J Clin Invest 117(12):3800–3809. doi:10.1172/JCI32369
Liu G, Beri R, Mueller A, Kamp DW (2010a) Molecular mechanisms of asbestos-induced lung epithelial cell apoptosis. Chem Biol Interact 188(2):309–318. doi:10.1016/j.cbi.2010.03.047
Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E (2010b) miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 207(8):1589–1597. doi:10.1084/jem.20100035
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217. doi:10.1016/j.cell.2013.05.039
Madala SK, Maxfield MD, Davidson CR, Schmidt SM, Garry D, Ikegami M, Hardie WD, Glasser SW (2011) Rapamycin regulates bleomycin-induced lung damage in SP-C-deficient mice. Pulm Med 2011:653524. doi:10.1155/2011/653524
Maitra M, Cano CA, Garcia CK (2012) Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-beta1 secretion. Proc Natl Acad Sci USA 109(51):21064–21069. doi:10.1073/pnas.1217069110
Mora AL, Rojas M (2013) Adult stem cells for chronic lung diseases. Respirology. doi:10.1111/resp.12112
Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, Fraifeld VE (2013) The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 12(2):661–684. doi:10.1016/j.arr.2012.02.001
Park CB, Larsson NG (2011) Mitochondrial DNA mutations in disease and aging. J Cell Biol 193(5):809–818. doi:10.1083/jcb.201010024
Park CS, Bang BR, Kwon HS, Moon KA, Kim TB, Lee KY, Moon HB, Cho YS (2012) Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase. Biochem Pharmacol 84(12):1660–1670. doi:10.1016/j.bcp.2012.09.025
Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, Rosas IO, Morse D (2012) Autophagy in idiopathic pulmonary fibrosis. PLoS One 7(7):e41394. doi:10.1371/journal.pone.0041394
Powers ET, Morimoto RI, Dillin A, Kelly JW, Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annu Rev Biochem 78:959–991. doi:10.1146/annurev.biochem.052308.114844
Rabinovich EI, Kapetanaki MG, Steinfeld I, Gibson KF, Pandit KV, Yu G, Yakhini Z, Kaminski N (2012) Global methylation patterns in idiopathic pulmonary fibrosis. PLoS One 7(4):e33770. doi:10.1371/journal.pone.0033770
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G (2006) Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 174(7):810–816. doi:10.1164/rccm.200602-163OC
Rando TA, Chang HY (2012) Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148(1–2):46–57. doi:10.1016/j.cell.2012.01.003
Ricci A, Cherubini E, Scozzi D, Pietrangeli V, Tabbi L, Raffa S, Leone L, Visco V, Torrisi MR, Bruno P, Mancini R, Ciliberto G, Terzano C, Mariotta S (2012) Decreased expression of autophagic beclin 1 protein in idiopathic pulmonary fibrosis fibroblasts. J Cell Physiol. doi:10.1002/jcp.24307
Ricci A, Cherubini E, Ulivieri A, Lavra L, Sciacchitano S, Scozzi D, Mancini R, Ciliberto G, Bartolazzi A, Bruno P, Graziano P, Mariotta S (2013) Homeodomain-interacting protein kinase2 in human idiopathic pulmonary fibrosis. J Cell Physiol 228(1):235–241. doi:10.1002/jcp.24129
Robinson CM, Neary R, Levendale A, Watson CJ, Baugh JA (2012) Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype. Respir Res 13:74. doi:10.1186/1465-9921-13-74
Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192(4):547–556. doi:10.1083/jcb.201009094
Rubinsztein DC, Marino G, Kroemer G (2011) Autophagy and aging. Cell 146(5):682–695. doi:10.1016/j.cell.2011.07.030
Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP, Hagood JS (2008) Thy-1 promoter hypermethylation: a novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol 39(5):610–618. doi:10.1165/rcmb.2007-0322OC
Sanders YY, Tollefsbol TO, Varisco BM, Hagood JS (2011) Epigenetic regulation of thy-1 by histone deacetylase inhibitor in rat lung fibroblasts. Am J Respir Cell Mol Biol 45(1):16–23. doi:10.1165/rcmb.2010-0154OC
Sanders YY, Ambalavanan N, Halloran B, Zhang X, Liu H, Crossman DK, Bray M, Zhang K, Thannickal VJ, Hagood JS (2012) Altered DNA methylation profile in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 186(6):525–535. doi:10.1164/rccm.201201-0077OC
Sanders YY, Liu H, Zhang X, Bernard K, Hecker L, Desai L, Liu G, Thannickal VJ (2013) Histone modifications in senescence-associated resistance to apoptosis by oxidative stress. Redox biol 1:8–16. doi:http://dx.doi.org/10.1016/j.redox.2012.11.004
Schroeder SA, Swift M, Sandoval C, Langston C (2005) Interstitial lung disease in patients with ataxia-telangiectasia. Pediatr Pulmonol 39(6):537–543. doi:10.1002/ppul.20209
Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, Dave A, Engelhardt JF, Liu X, White ES, Thannickal VJ, Moore BB, Christensen PJ, Simon RH (2010) Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med 181(3):254–263. doi:10.1164/rccm.200810-1615OC
Thannickal VJ, Horowitz JC (2006) Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 3(4):350–356. doi:10.1513/pats.200601-001TK
Thannickal VJ, Loyd JE (2008) Idiopathic pulmonary fibrosis: a disorder of lung regeneration? Am J Respir Crit Care Med 178(7):663–665. doi:10.1164/rccm.200807-1127ED
Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ (2004) Mechanisms of pulmonary fibrosis. Annu Rev Med 55:395–417. doi:10.1146/annurev.med.55.091902.103810
Thomas AQ, Lane K, Phillips J 3rd, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, Roberts R, Haines J, Stahlman M, Loyd JE (2002) Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 165(9):1322–1328. doi:10.1164/rccm.200112-123OC
Vassilakis DA, Sourvinos G, Spandidos DA, Siafakas NM, Bouros D (2000) Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 162(3 Pt 1):1115–1119. doi:10.1164/ajrccm.162.3.9911119
Vece TJ, Schecter MG, Gatti RA, Tunuguntla R, Garcia CK, Langston C, Dishop MK, Moore RH, Fan LL (2012) Rapid and progressive pulmonary fibrosis in 2 families with DNA repair deficiencies of undetermined etiology. J Pediatr 160(4):700–702. doi:10.1016/j.jpeds.2011.12.001 e703
Warner H, Anderson J, Austad S, Bergamini E, Bredesen D, Butler R, Carnes BA, Clark BF, Cristofalo V, Faulkner J, Guarente L, Harrison DE, Kirkwood T, Lithgow G, Martin G, Masoro E, Melov S, Miller RA, Olshansky SJ, Partridge L, Pereira-Smith O, Perls T, Richardson A, Smith J, von Zglinicki T, Wang E, Wei JY, Williams TF (2005) Science fact and the SENS agenda. What can we reasonably expect from ageing research? EMBO Rep 6(11):1006–1008. doi:10.1038/sj.embor.7400555
Wolin MS (2013) Evidence for novel aspects of Nox4 oxidase regulation of mitochondrial function and peroxide generation in an endothelial cell model of senescence. Biochem J 452(2):e1–e2. doi:10.1042/BJ20130484
Yang S, Banerjee S, de Freitas A, Sanders YY, Ding Q, Matalon S, Thannickal VJ, Abraham E, Liu G (2012) Participation of miR-200 in pulmonary fibrosis. Am J Pathol 180(2):484–493. doi:10.1016/j.ajpath.2011.10.005
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This work was funded by National Institutes of Health grants, R01 HL067967, R01 HL094230 and P50 HL107181.
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Thannickal, V.J. Mechanistic links between aging and lung fibrosis. Biogerontology 14, 609–615 (2013). https://doi.org/10.1007/s10522-013-9451-6
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DOI: https://doi.org/10.1007/s10522-013-9451-6