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Recent Advances in Molecular Basis of Lung Aging and Its Associated Diseases

  • Kang, Min-Jong (Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine)
  • Received : 2020.01.18
  • Accepted : 2020.02.19
  • Published : 2020.04.30

Abstract

Aging is often viewed as a progressive decline in fitness due to cumulative deleterious alterations of biological functions in the living system. Recently, our understanding of the molecular mechanisms underlying aging biology has significantly advanced. Interestingly, many of the pivotal molecular features of aging biology are also found to contribute to the pathogenesis of chronic lung disorders such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, for which advanced age is the most crucial risk factor. Thus, an enhanced understanding of how molecular features of aging biology are intertwined with the pathobiology of these aging-related lung disorders has paramount significance and may provide an opportunity for the development of novel therapeutics for these major unmet medical needs. To serve the purpose of integrating molecular understanding of aging biology with pulmonary medicine, in this review, recent findings obtained from the studies of aging-associated lung disorders are summarized and interpreted through the perspective of molecular biology of aging.

References

  1. Kaeberlein M, Rabinovitch PS, Martin GM. Healthy aging: the ultimate preventative medicine. Science 2015;350:1191-3. https://doi.org/10.1126/science.aad3267
  2. Gladyshev VN. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 2016;15:594-602. https://doi.org/10.1111/acel.12480
  3. Kirkwood TB. Understanding the odd science of aging. Cell 2005;120:437-47. https://doi.org/10.1016/j.cell.2005.01.027
  4. Fukuchi Y. The aging lung and chronic obstructive pulmonary disease: similarity and difference. Proc Am Thorac Soc 2009;6:570-2. https://doi.org/10.1513/pats.200909-099RM
  5. Lowery EM, Brubaker AL, Kuhlmann E, Kovacs EJ. The aging lung. Clin Interv Aging 2013;8:1489-96.
  6. Skloot GS. The effects of aging on lung structure and function. Clin Geriatr Med 2017;33:447-57. https://doi.org/10.1016/j.cger.2017.06.001
  7. Thannickal VJ, Murthy M, Balch WE, Chandel NS, Meiners S, Eickelberg O, et al. Blue journal conference: aging and susceptibility to lung disease. Am J Respir Crit Care Med 2015;191:261-9. https://doi.org/10.1164/rccm.201410-1876PP
  8. Budinger GR, Kohanski RA, Gan W, Kobor MS, Amaral LA, Armanios M, et al. The intersection of aging biology and the pathobiology of lung diseases: a Joint NHLBI/NIA Workshop. J Gerontol A Biol Sci Med Sci 2017;72:1492-500. https://doi.org/10.1093/gerona/glx090
  9. MacNee W. Is chronic obstructive pulmonary disease an accelerated aging disease? Ann Am Thorac Soc 2016;13 Suppl 5:S429-37. https://doi.org/10.1513/AnnalsATS.201602-124AW
  10. Mora AL, Bueno M, Rojas M. Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis. J Clin Invest 2017;127:405-14. https://doi.org/10.1172/JCI87440
  11. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153:1194-217. https://doi.org/10.1016/j.cell.2013.05.039
  12. Szilard L. On the nature of the aging process. Proc Natl Acad Sci U S A 1959;45:30-45. https://doi.org/10.1073/pnas.45.1.30
  13. Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev 2013;12:661-84. https://doi.org/10.1016/j.arr.2012.02.001
  14. Niedernhofer LJ, Gurkar AU, Wang Y, Vijg J, Hoeijmakers JH, Robbins PD. Nuclear genomic instability and aging. Annu Rev Biochem 2018;87:295-322. https://doi.org/10.1146/annurev-biochem-062917-012239
  15. Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 2015;350:1193-8. https://doi.org/10.1126/science.aab3389
  16. Brunet A, Berger SL. Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci 2014;69 Suppl 1:S17-20. https://doi.org/10.1093/gerona/glu042
  17. Sen P, Shah PP, Nativio R, Berger SL. Epigenetic mechanisms of longevity and aging. Cell 2016;166:822-39. https://doi.org/10.1016/j.cell.2016.07.050
  18. Kaushik S, Cuervo AM. Proteostasis and aging. Nat Med 2015;21:1406-15. https://doi.org/10.1038/nm.4001
  19. Most J, Tosti V, Redman LM, Fontana L. Calorie restriction in humans: an update. Ageing Res Rev 2017;39:36-45. https://doi.org/10.1016/j.arr.2016.08.005
  20. Redman LM, Smith SR, Burton JH, Martin CK, Il'yasova D, Ravussin E. Metabolic slowing and reduced oxidative damage with sustained caloric restriction support the rate of living and oxidative damage theories of aging. Cell Metab 2018;27:805-15. https://doi.org/10.1016/j.cmet.2018.02.019
  21. Fontana L, Partridge L, Longo VD. Extending healthy life span: from yeast to humans. Science 2010;328:321-6. https://doi.org/10.1126/science.1172539
  22. Rizza W, Veronese N, Fontana L. What are the roles of calorie restriction and diet quality in promoting healthy longevity? Ageing Res Rev 2014;13:38-45. https://doi.org/10.1016/j.arr.2013.11.002
  23. Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell 2016;61:654-66. https://doi.org/10.1016/j.molcel.2016.01.028
  24. Akbari M, Kirkwood TB, Bohr VA. Mitochondria in the signaling pathways that control longevity and health span. Ageing Res Rev 2019;54:100940. https://doi.org/10.1016/j.arr.2019.100940
  25. Dela Cruz CS, Kang MJ. Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases. Mitochondrion 2018;41:37-44. https://doi.org/10.1016/j.mito.2017.12.001
  26. Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular senescence: aging, cancer, and injury. Physiol Rev 2019;99:1047-78. https://doi.org/10.1152/physrev.00020.2018
  27. Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell 2019;179:813-27. https://doi.org/10.1016/j.cell.2019.10.005
  28. He S, Sharpless NE. Senescence in health and disease. Cell 2017;169:1000-11. https://doi.org/10.1016/j.cell.2017.05.015
  29. Prata L, Ovsyannikova IG, Tchkonia T, Kirkland JL. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin Immunol 2018;40:101275. https://doi.org/10.1016/j.smim.2019.04.003
  30. Brunauer R, Alavez S, Kennedy BK. Stem cell models: a guide to understand and mitigate aging? Gerontology 2017;63:84-90. https://doi.org/10.1159/000449501
  31. Schultz MB, Sinclair DA. When stem cells grow old: phenotypes and mechanisms of stem cell aging. Development 2016;143:3-14. https://doi.org/10.1242/dev.130633
  32. Neves J, Sousa-Victor P, Jasper H. Rejuvenating strategies for stem cell-based therapies in aging. Cell Stem Cell 2017;20:161-75. https://doi.org/10.1016/j.stem.2017.01.008
  33. Riera CE, Merkwirth C, De Magalhaes Filho CD, Dillin A. Signaling networks determining life span. Annu Rev Biochem 2016;85:35-64. https://doi.org/10.1146/annurev-biochem-060815-014451
  34. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244-54.
  35. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for agerelated diseases. Nat Rev Endocrinol 2018;14:576-90. https://doi.org/10.1038/s41574-018-0059-4
  36. Fulop T, Witkowski JM, Olivieri F, Larbi A. The integration of inflammaging in age-related diseases. Semin Immunol 2018;40:17-35. https://doi.org/10.1016/j.smim.2018.09.003
  37. Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, et al. Interventions to slow aging in humans: are we ready? Aging Cell 2015;14:497-510. https://doi.org/10.1111/acel.12338
  38. Lopez-Lluch G, Navas P. Calorie restriction as an intervention in ageing. J Physiol 2016;594:2043-60. https://doi.org/10.1113/JP270543
  39. Fontana L, Partridge L. Promoting health and longevity through diet: from model organisms to humans. Cell 2015;161:106-18. https://doi.org/10.1016/j.cell.2015.02.020
  40. Hegab AE, Ozaki M, Meligy FY, Nishino M, Kagawa S, Ishii M, et al. Calorie restriction enhances adult mouse lung stem cells function and reverses several ageing-induced changes. J Tissue Eng Regen Med 2019;13:295-308. https://doi.org/10.1002/term.2792
  41. Hegab AE, Ozaki M, Meligy FY, Kagawa S, Ishii M, Betsuyaku T. High fat diet activates adult mouse lung stem cells and accelerates several aging-induced effects. Stem Cell Res 2018;33:25-35. https://doi.org/10.1016/j.scr.2018.10.006
  42. Bishai JM, Mitzner W. Effect of severe calorie restriction on the lung in two strains of mice. Am J Physiol Lung Cell Mol Physiol 2008;295:L356-62. https://doi.org/10.1152/ajplung.00514.2007
  43. Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol 2012;22:546-54. https://doi.org/10.1016/j.tcb.2012.07.004
  44. Parikh N, Chakraborti AK. Phosphodiesterase 4 (PDE4) inhibitors in the treatment of COPD: promising dug candidates and future directions. Curr Med Chem 2016;23:129-41. https://doi.org/10.2174/0929867323666151117121334
  45. Teumer A, Qi Q, Nethander M, Aschard H, Bandinelli S, Beekman M, et al. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on agerelated traits. Aging Cell 2016;15:811-24. https://doi.org/10.1111/acel.12490
  46. Stormann S, Gutt B, Roemmler-Zehrer J, Bidlingmaier M, Huber RM, Schopohl J, et al. Assessment of lung function in a large cohort of patients with acromegaly. Eur J Endocrinol 2017;177:15-23. https://doi.org/10.1530/EJE-16-1080
  47. Burdet L, de Muralt B, Schutz Y, Pichard C, Fitting JW. Administration of growth hormone to underweight patients with chronic obstructive pulmonary disease: a prospective, randomized, controlled study. Am J Respir Crit Care Med 1997;156:1800-6. https://doi.org/10.1164/ajrccm.156.6.9704142
  48. Pape GS, Friedman M, Underwood LE, Clemmons DR. The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease. Chest 1991;99:1495-500. https://doi.org/10.1378/chest.99.6.1495
  49. Krein PM, Winston BW. Roles for insulin-like growth factor I and transforming growth factor-beta in fibrotic lung disease. Chest 2002;122(6 Suppl):289S-93S. https://doi.org/10.1378/chest.122.6_suppl.289S
  50. Pilewski JM, Liu L, Henry AC, Knauer AV, Feghali-Bostwick CA. Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition. Am J Pathol 2005;166:399-407. https://doi.org/10.1016/S0002-9440(10)62263-8
  51. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013;493:338-45. https://doi.org/10.1038/nature11861
  52. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017;168:960-76. https://doi.org/10.1016/j.cell.2017.02.004
  53. Yoshida T, Mett I, Bhunia AK, Bowman J, Perez M, Zhang L, et al. Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 2010;16:767-73. https://doi.org/10.1038/nm.2157
  54. Houssaini A, Breau M, Kebe K, Abid S, Marcos E, Lipskaia L, et al. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight 2018;3:93203. https://doi.org/10.1172/jci.insight.93203
  55. Saito N, Araya J, Ito S, Tsubouchi K, Minagawa S, Hara H, et al. Involvement of lamin B1 reduction in accelerated cellular senescence during chronic obstructive pulmonary disease pathogenesis. J Immunol 2019;202:1428-40. https://doi.org/10.4049/jimmunol.1801293
  56. Wang Y, Liu J, Zhou JS, Huang HQ, Li ZY, Xu XC, et al. MTOR suppresses cigarette smoke-induced epithelial cell death and airway inflammation in chronic obstructive pulmonary disease. J Immunol 2018;200:2571-80. https://doi.org/10.4049/jimmunol.1701681
  57. Wu YF, Li ZY, Dong LL, Li WJ, Wu YP, Wang J, et al. Inactivation of MTOR promotes autophagy-mediated epithelial injury in particulate matter-induced airway inflammation. Autophagy 2020;16:435-50. https://doi.org/10.1080/15548627.2019.1628536
  58. Pasini E, Flati V, Comini L, Olivares A, Bertella E, Corsetti G, et al. Mammalian target of rapamycin: is it relevant to COPD pathogenesis or treatment? COPD 2019;16:89-92. https://doi.org/10.1080/15412555.2019.1583726
  59. Romero Y, Bueno M, Ramirez R, Alvarez D, Sembrat JC, Goncharova EA, et al. mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 2016;15:1103-12. https://doi.org/10.1111/acel.12514
  60. Allen RJ, Guillen-Guio B, Oldham JM, Ma SF, Dressen A, Paynton ML, et al. Genome-wide association study of susceptibility to idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2019 Nov 11 [Epub]. https://doi.org/10.1164/rccm.201905-1017OC.
  61. Gokey JJ, Sridharan A, Xu Y, Green J, Carraro G, Stripp BR, et al. Active epithelial Hippo signaling in idiopathic pulmonary fibrosis. JCI Insight 2018;3:98738. https://doi.org/10.1172/jci.insight.98738
  62. Moya IM, Halder G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol 2019;20:211-26. https://doi.org/10.1038/s41580-018-0086-y
  63. Woodcock HV, Eley JD, Guillotin D, Plate M, Nanthakumar CB, Martufi M, et al. The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis. Nat Commun 2019;10:6. https://doi.org/10.1038/s41467-018-07858-8
  64. Lukey PT, Harrison SA, Yang S, Man Y, Holman BF, Rashidnasab A, et al. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis. Eur Respir J 2019;53:1801992. https://doi.org/10.1183/13993003.01992-2018
  65. Mercer PF, Woodcock HV, Eley JD, Plate M, Sulikowski MG, Durrenberger PF, et al. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax 2016;71:701-11. https://doi.org/10.1136/thoraxjnl-2015-207429
  66. Lawrence J, Nho R. The role of the mammalian target of rapamycin (mTOR) in pulmonary fibrosis. Int J Mol Sci 2018;19:E778. https://doi.org/10.3390/ijms19030778
  67. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 2018;19:121-35.
  68. O'Callaghan C, Vassilopoulos A. Sirtuins at the crossroads of stemness, aging, and cancer. Aging Cell 2017;16:1208-18. https://doi.org/10.1111/acel.12685
  69. Lee SH, Lee JH, Lee HY, Min KJ. Sirtuin signaling in cellular senescence and aging. BMB Rep 2019;52:24-34. https://doi.org/10.5483/BMBRep.2019.52.1.290
  70. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009;458:1056-60. https://doi.org/10.1038/nature07813
  71. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:861-70. https://doi.org/10.1164/rccm.200708-1269OC
  72. Yao H, Chung S, Hwang JW, Rajendrasozhan S, Sundar IK, Dean DA, et al. SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice. J Clin Invest 2012;122:2032-45. https://doi.org/10.1172/JCI60132
  73. Takasaka N, Araya J, Hara H, Ito S, Kobayashi K, Kurita Y, et al. Autophagy induction by SIRT6 through attenuation of insulin-like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence. J Immunol 2014;192:958-68. https://doi.org/10.4049/jimmunol.1302341
  74. Minagawa S, Araya J, Numata T, Nojiri S, Hara H, Yumino Y, et al. Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-beta-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2011;300:L391-401. https://doi.org/10.1152/ajplung.00097.2010
  75. Wyman AE, Noor Z, Fishelevich R, Lockatell V, Shah NG, Todd NW, et al. Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2017;312:L945-58. https://doi.org/10.1152/ajplung.00473.2016
  76. Hwang JW, Yao H, Caito S, Sundar IK, Rahman I. Redox regulation of SIRT1 in inflammation and cellular senescence. Free Radic Biol Med 2013;61:95-110. https://doi.org/10.1016/j.freeradbiomed.2013.03.015
  77. Piskovatska V, Stefanyshyn N, Storey KB, Vaiserman AM, Lushchak O. Metformin as a geroprotector: experimental and clinical evidence. Biogerontology 2019;20:33-48. https://doi.org/10.1007/s10522-018-9773-5
  78. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab 2014;20:953-66. https://doi.org/10.1016/j.cmet.2014.09.018
  79. Bishwakarma R, Zhang W, Lin YL, Kuo YF, Cardenas VJ, Sharma G. Metformin use and health care utilization in patients with coexisting chronic obstructive pulmonary disease and diabetes mellitus. Int J Chron Obstruct Pulmon Dis 2018;13:793-800. https://doi.org/10.2147/COPD.S150047
  80. Zhu A, Teng Y, Ge D, Zhang X, Hu M, Yao X. Role of metformin in treatment of patients with chronic obstructive pulmonary disease: a systematic review. J Thorac Dis 2019;11:4371-8. https://doi.org/10.21037/jtd.2019.09.84
  81. Rangarajan S, Bone NB, Zmijewska AA, Jiang S, Park DW, Bernard K, et al. Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 2018;24:1121-7. https://doi.org/10.1038/s41591-018-0087-6
  82. Kheirollahi V, Wasnick RM, Biasin V, Vazquez-Armendariz AI, Chu X, Moiseenko A, et al. Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis. Nat Commun 2019;10:2987. https://doi.org/10.1038/s41467-019-10839-0
  83. Spagnolo P, Kreuter M, Maher TM, Wuyts W, Bonella F, Corte TJ, et al. Metformin does not affect clinically relevant outcomes in patients with idiopathic pulmonary fibrosis. Respiration 2018;96:314-22. https://doi.org/10.1159/000489668
  84. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 2013;123:966-72. https://doi.org/10.1172/JCI64098
  85. Royce GH, Brown-Borg HM, Deepa SS. The potential role of necroptosis in inflammaging and aging. Geroscience 2019;41:795-811. https://doi.org/10.1007/s11357-019-00131-w
  86. Canan CH, Gokhale NS, Carruthers B, Lafuse WP, Schlesinger LS, Torrelles JB, et al. Characterization of lung inflammation and its impact on macrophage function in aging. J Leukoc Biol 2014;96:473-80. https://doi.org/10.1189/jlb.4A0214-093RR
  87. John-Schuster G, Gunter S, Hager K, Conlon TM, Eickelberg O, Yildirim AO. Inflammaging increases susceptibility to cigarette smoke-induced COPD. Oncotarget 2016;7:30068-83. https://doi.org/10.18632/oncotarget.4027