1932

Abstract

Chronic obstructive pulmonary disease (COPD) is regarded as a disease of accelerated lung aging. This affliction shows all of the hallmarks of aging, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence, and a low-grade chronic inflammation (inflammaging). Many of these pathways are driven by chronic exogenous and endogenous oxidative stress. There is also a reduction in antiaging molecules, such as sirtuins and Klotho, which further accelerate the aging process. COPD is associated with several comorbidities (multimorbidity), such as cardiovascular and metabolic diseases, that share the same pathways of accelerated aging. Understanding these mechanisms has helped identify several novel therapeutic targets, and several drugs and dietary interventions are now in development to treat multimorbidity.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-022516-034314
2017-02-10
2024-10-06
Loading full text...

Full text loading...

/deliver/fulltext/physiol/79/1/annurev-physiol-022516-034314.html?itemId=/content/journals/10.1146/annurev-physiol-022516-034314&mimeType=html&fmt=ahah

Literature Cited

  1. Barnes PJ, Burney PGJ, Silverman EK, Celli BR, Vestbo J. 1.  et al. 2015. Chronic obstructive pulmonary disease. Nat. Rev. Primers 1:1–21 [Google Scholar]
  2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K. 2.  et al. 2012. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380:2095–128 [Google Scholar]
  3. Salvi SS, Barnes PJ. 3.  2009. Chronic obstructive pulmonary disease in non-smokers. Lancet 374:733–43 [Google Scholar]
  4. Gordon SB, Bruce NG, Grigg J, Hibberd PL, Kurmi OP. 4.  et al. 2014. Respiratory risks from household air pollution in low and middle income countries. Lancet Resp. Med. 2:823–60 [Google Scholar]
  5. Burney P, Jithoo A, Kato B, Janson C, Mannino D. 5.  et al. 2014. Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty—a BOLD analysis. Thorax 69:465–73 [Google Scholar]
  6. Hogg JC, Timens W. 6.  2009. The pathology of chronic obstructive pulmonary disease. Annu. Rev. Pathol. 4:435–59 [Google Scholar]
  7. Lange P, Celli B, Agusti A, Boje Jensen G, Divo M. 7.  et al. 2015. Lung-function trajectories leading to chronic obstructive pulmonary disease. N. Engl. J. Med. 373:111–22 [Google Scholar]
  8. Barnes PJ. 8.  2013. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 131:636–45 [Google Scholar]
  9. Barnes PJ. 9.  2016. Inflammatory mechanisms in COPD. J. Allergy Clin. Immunol. 138:16–27 [Google Scholar]
  10. Barnes PJ. 10.  2009. Role of HDAC2 in the pathophysiology of COPD. Annu. Rev. Physiol. 71:451–64 [Google Scholar]
  11. Barnes PJ. 11.  2014. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin. Chest Med. 35:71–86 [Google Scholar]
  12. Kirkham PA, Barnes PJ. 12.  2013. Oxidative stress in COPD. Chest 144:266–73 [Google Scholar]
  13. Ito K, Barnes PJ. 13.  2009. COPD as a disease of accelerated lung aging. Chest 135:173–80 [Google Scholar]
  14. Mercado N, Ito K, Barnes PJ. 14.  2015. Accelerated ageing in chronic obstructive pulmonary disease: new concepts. Thorax 70:482–89 [Google Scholar]
  15. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM. 15.  et al. 2014. Geroscience: linking aging to chronic disease. Cell 159:709–13 [Google Scholar]
  16. Kirkwood TB. 16.  2005. Understanding the odd science of aging. Cell 120:437–47 [Google Scholar]
  17. Harman D. 17.  2006. Free radical theory of aging: an update: increasing the functional life span. Ann. N.Y. Acad. Sci. 1067:10–21 [Google Scholar]
  18. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. 18.  2006. The molecular inflammatory process in aging. Antioxid. Redox Signal. 8:572–81 [Google Scholar]
  19. Hekimi S, Lapointe J, Wen Y. 19.  2011. Taking a “good” look at free radicals in the aging process. Trends Cell Biol 21:569–76 [Google Scholar]
  20. Hayflick L. 20.  1965. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37:614–36 [Google Scholar]
  21. Williams GC. 21.  1957. Pleiotropy, natural selection, and the evolution of senescence evolution. Evolution 11:398–411 [Google Scholar]
  22. Salama R, Sadaie M, Hoare M, Narita M. 22.  2014. Cellular senescence and its effector programs. Genes Dev 28:99–114 [Google Scholar]
  23. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. 23.  2013. The hallmarks of aging. Cell 153:1194–217 [Google Scholar]
  24. Meiners S, Eickelberg O, Konigshoff M. 24.  2015. Hallmarks of the ageing lung. Eur. Respir. J. 45:807–27 [Google Scholar]
  25. Armanios M. 25.  2013. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J. Clin. Investig. 123:996–1002 [Google Scholar]
  26. Fyhrquist F, Saijonmaa O, Strandberg T. 26.  2013. The roles of senescence and telomere shortening in cardiovascular disease. Nat. Rev. Cardiol. 10:274–83 [Google Scholar]
  27. Monickaraj F, Aravind S, Gokulakrishnan K, Sathishkumar C, Prabu P. 27.  et al. 2012. Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes. Mol. Cell Biochem. 365:343–50 [Google Scholar]
  28. Lee J, Sandford AJ, Connett JE, Yan J, Mui T. 28.  et al. 2012. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD). PLOS ONE 7:e35567 [Google Scholar]
  29. Houben JM, Mercken EM, Ketelslegers HB, Bast A, Wouters EF. 29.  et al. 2009. Telomere shortening in chronic obstructive pulmonary disease. Respir. Med. 103:230–36 [Google Scholar]
  30. Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L. 30.  et al. 2009. Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 179:566–71 [Google Scholar]
  31. Rutten EP, Gopal P, Wouters EF, Franssen FM, Hageman GJ. 31.  et al. 2016. Various mechanistic pathways representing the aging process are altered in COPD. Chest 149:53–61 [Google Scholar]
  32. Tsuji T, Aoshiba K, Nagai A. 32.  2006. Alveolar cell senescence in patients with pulmonary emphysema. Am. J. Respir. Crit. Care Med. 174:886–93 [Google Scholar]
  33. Tomita K, Caramori G, Ito K, Lim S, Sano H. 33.  et al. 2010. Telomere shortening in alveolar macrophages of smokers and COPD patients. Open. Path. J. 4:23–29 [Google Scholar]
  34. Birch J, Anderson RK, Correia-Melo C, Jurk D, Hewitt G. 34.  et al. 2015. DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am. J. Physiol. Lung. Cell Mol. Physiol. 309:L1124–37 [Google Scholar]
  35. Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ. 35.  et al. 2011. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 184:904–12 [Google Scholar]
  36. Stanley SE, Chen JJ, Podlevsky JD, Alder JK, Hansel NN. 36.  et al. 2015. Telomerase mutations in smokers with severe emphysema. J. Clin. Investig. 125:563–70 [Google Scholar]
  37. Chen R, Zhang K, Chen H, Zhao X, Wang J. 37.  et al. 2015. Telomerase deficiency causes alveolar stem cell senescence-associated low-grade inflammation in lungs. J. Biol. Chem. 290:30813–29 [Google Scholar]
  38. Amsellem V, Gary-Bobo G, Marcos E, Maitre B, Chaar V. 38.  et al. 2011. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 184:1358–66 [Google Scholar]
  39. Janssens JP, Pache JC, Nicod LP. 39.  1999. Physiological changes in respiratory function associated with ageing. Eur. Respir. J. 13:197–205 [Google Scholar]
  40. Muñoz-Espín D, Serrano M. 40.  2014. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15:482–96 [Google Scholar]
  41. Coppede F. 41.  2012. Premature aging syndrome. Adv. Exp. Med. Biol 724317–31 [Google Scholar]
  42. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG. 42.  et al. 2011. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–36 [Google Scholar]
  43. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ. 43.  et al. 2016. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530:184–89 [Google Scholar]
  44. Sorrentino JA, Krishnamurthy J, Tilley S, Alb JG Jr., Burd CE, Sharpless NE. 44.  2014. p16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J. Clin. Investig. 124:169–73 [Google Scholar]
  45. Correia-Melo C, Hewitt G, Passos JF. 45.  2014. Telomeres, oxidative stress and inflammatory factors: Partners in cellular senescence?. Longev. Healthspan 3:1 [Google Scholar]
  46. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A. 46.  et al. 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–18 [Google Scholar]
  47. Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H. 47.  et al. 2006. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8:1291–97 [Google Scholar]
  48. Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER. 48.  et al. 2015. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. PNAS 112:E6301–10 [Google Scholar]
  49. Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S. 49.  et al. 2015. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17:1205–17 [Google Scholar]
  50. Chilosi M, Carloni A, Rossi A, Poletti V. 50.  2013. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl. Res. J. Lab. Clin. Med. 162:156–73 [Google Scholar]
  51. Tomita K, Caramori G, Lim S, Ito K, Hanazawa T. 51.  et al. 2002. Increased p21CIP1/WAF1 and B cell lymphoma leukemia-xL expression and reduced apoptosis in alveolar macrophages from smokers. Am. J. Respir. Crit. Care Med. 166:724–31 [Google Scholar]
  52. Barnes PJ. 52.  2004. Mediators of chronic obstructive pulmonary disease. Pharm. Rev. 56:515–48 [Google Scholar]
  53. Johnson SC, Rabinovitch PS, Kaeberlein M. 53.  2013. mTOR is a key modulator of ageing and age-related disease. Nature 493:338–45 [Google Scholar]
  54. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM. 54.  et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–95 [Google Scholar]
  55. Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A. 55.  et al. 2015. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17:1049–61 [Google Scholar]
  56. To Y, Ito K, Kizawa Y, Failla M, Ito M. 56.  et al. 2010. Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid insensitivity in COPD. Am. J. Resp. Crit. Care Med. 182:897–904 [Google Scholar]
  57. Mitani A, Ito K, Vuppusetty C, Barnes PJ, Mercado N. 57.  2015. Inhibition of mTOR restores corticosteroid sensitivity in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 193:143–53 [Google Scholar]
  58. Hosgood HD III, Menashe I, He X, Chanock S, Lan Q. 58.  2009. PTEN identified as important risk factor of chronic obstructive pulmonary disease. Respir. Med. 103:1866–70 [Google Scholar]
  59. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG. 59.  et al. 2008. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7:2769–73 [Google Scholar]
  60. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. 60.  2014. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5:3557 [Google Scholar]
  61. Lamming DW, Ye L, Sabatini DM, Baur JA. 61.  2013. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Investig. 123:980–89 [Google Scholar]
  62. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. 62.  2000. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162:369–73 [Google Scholar]
  63. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M. 63.  et al. 2000. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am. J. Respir. Crit. Care Med. 162:1175–77 [Google Scholar]
  64. Rahman I, van Schadewijk AA, Crowther AJ, Hiemstra PS, Stolk J. 64.  et al. 2002. 4-Hydroxy-2-nonenal, a specific lipid peroxidation product, is elevated in lungs of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 166:490–95 [Google Scholar]
  65. Wang CH, Wu SB, Wu YT, Wei YH. 65.  2013. Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp. Biol. Med. 238:450–60 [Google Scholar]
  66. Osoata GO, Hanazawa T, Brindicci C, Ito M, Barnes PJ. 66.  et al. 2009. Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine. Chest 135:1513–20 [Google Scholar]
  67. Osoata G, Yamamura S, Ito M, Vuppusetty C, Adcock IM. 67.  et al. 2009. Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem. Biophy. Res. Commun. 384:366–71 [Google Scholar]
  68. Ito K, Ito M, Elliott WM, Cosio B, Caramori G. 68.  et al. 2005. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352:1967–76 [Google Scholar]
  69. Kirkham PA, Caramori G, Casolari P, Papi A, Edwards M. 69.  et al. 2011. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of COPD. Am. J. Respir. Crit. Care Med. 184:796–802 [Google Scholar]
  70. Caramori G, Adcock IM, Casolari P, Ito K, Jazrawi E. 70.  et al. 2011. Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax 66:521–27 [Google Scholar]
  71. Aoshiba K, Zhou F, Tsuji T, Nagai A. 71.  2012. DNA damage as a molecular link in the pathogenesis of COPD in smokers. Eur. Respir. J. 39:1368–76 [Google Scholar]
  72. Sorheim IC, DeMeo DL, Washko G, Litonjua A, Sparrow D. 72.  et al. 2010. Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD. COPD 7:262–68 [Google Scholar]
  73. Kensler TW, Wakabayashi N, Biswal S. 73.  2007. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47:89–116 [Google Scholar]
  74. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M. 74.  et al. 2008. Decline in NRF2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am. J. Respir. Crit. Care Med. 178:592–604 [Google Scholar]
  75. Mercado N, Thimmulappa R, Thomas CM, Fenwick PS, Chana KK. 75.  et al. 2011. Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem. Biophys. Res. Commun. 406:292–98 [Google Scholar]
  76. Malhotra D, Thimmulappa RK, Mercado N, Ito K, Kombairaju P. 76.  et al. 2011. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J. Clin. Investig. 121:4289–302 [Google Scholar]
  77. Correia-Melo C, Passos JF. 77.  2015. Mitochondria: Are they causal players in cellular senescence?. Biochim. Biophys. Acta 1847:1373–79 [Google Scholar]
  78. Sureshbabu A, Bhandari V. 78.  2013. Targeting mitochondrial dysfunction in lung diseases: emphasis on mitophagy. Front. Physiol. 4:384 [Google Scholar]
  79. Zheng S, Wang C, Qian G, Wu G, Guo R. 79.  et al. 2012. Role of mtDNA haplogroups in COPD susceptibility in a southwestern Han Chinese population. Free Rad. Biol. Med. 53:473–81 [Google Scholar]
  80. Wanagat J, Dai DF, Rabinovitch P. 80.  2010. Mitochondrial oxidative stress and mammalian healthspan. Mech. Ageing Devel. 131:527–35 [Google Scholar]
  81. Meyer A, Zoll J, Charles AL, Charloux A, de Blay F. 81.  et al. 2013. Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target. Exp. Physiol. 98:1063–78 [Google Scholar]
  82. Artal-Sanz M, Tavernarakis N. 82.  2009. Prohibitin and mitochondrial biology. Trends Endocrinol. Metab. 20:394–401 [Google Scholar]
  83. Soulitzis N, Neofytou E, Psarrou M, Anagnostis A, Tavernarakis N. 83.  et al. 2012. Downregulation of lung mitochondrial prohibitin in COPD. Respir. Med. 106:954–61 [Google Scholar]
  84. Hoffmann RF, Zarrintan S, Brandenburg SM, Kol A, de Bruin HG. 84.  et al. 2013. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 14:97 [Google Scholar]
  85. Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M. 85.  et al. 2014. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Investig. 124:3987–4003 [Google Scholar]
  86. Li J, Dai A, Hu R, Zhu L, Tan S. 86.  2010. Positive correlation between PPARγ/PGC-1α and γ-GCS in lungs of rats and patients with chronic obstructive pulmonary disease. Acta Biochim. Biophys. Sin. 42:603–14 [Google Scholar]
  87. Mizumura K, Cloonan SM, Haspel JA, Choi AM. 87.  2012. The emerging importance of autophagy in pulmonary diseases. Chest 142:1289–99 [Google Scholar]
  88. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. 88.  2008. Autophagy fights disease through cellular self-digestion. Nature 451:1069–75 [Google Scholar]
  89. Murrow L, Debnath J. 89.  2013. Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu. Rev. Pathol. Mech. Dis. 8:105–37 [Google Scholar]
  90. Monick MM, Powers LS, Walters K, Lovan N, Zhang M. 90.  et al. 2010. Identification of an autophagy defect in smokers' alveolar macrophages. J. Immunol. 185:5425–35 [Google Scholar]
  91. Chen ZH, Lam HC, Jin Y, Kim HP, Cao J. 91.  et al. 2010. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. PNAS 107:18880–85 [Google Scholar]
  92. Fujii S, Hara H, Araya J, Takasaka N, Kojima J. 92.  et al. 2012. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. Oncoimmunology 1:630–41 [Google Scholar]
  93. Donnelly LE, Barnes PJ. 93.  2012. Defective phagocytosis in airways disease. Chest 141:1055–62 [Google Scholar]
  94. Dunlop EA, Tee AR. 94.  2014. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Sem. Cell Devel. Biol. 36C:121–29 [Google Scholar]
  95. Kubo H. 95.  2012. Concise review: clinical prospects for treating chronic obstructive pulmonary disease with regenerative approaches. Stem. Cell Translat. Med. 1:627–31 [Google Scholar]
  96. Fujino N, Kubo H, Suzuki T, Ota C, Hegab AE. 96.  et al. 2011. Isolation of alveolar epithelial type II progenitor cells from adult human lungs. Lab. Investig. 91:363–78 [Google Scholar]
  97. Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D. 97.  et al. 2011. Evidence for human lung stem cells. N. Engl. J. Med. 364:1795–806 [Google Scholar]
  98. Lindsey JY, Ganguly K, Brass DM, Li Z, Potts EN. 98.  et al. 2011. c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am. J. Respir. Crit. Care Med. 183:1644–52 [Google Scholar]
  99. Fadini GP, Losordo D, Dimmeler S. 99.  2012. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ. Res. 110:624–37 [Google Scholar]
  100. Paschalaki KE, Starke RD, Hu Y, Mercado N, Margariti A. 100.  et al. 2013. Dysfunction of endothelial progenitor cells from smokers and COPD patients due to increased DNA damage and senescence. Stem Cells 31:2813–26 [Google Scholar]
  101. Sousounis K, Baddour JA, Tsonis PA. 101.  2014. Aging and regeneration in vertebrates. Curr. Top. Dev. Biol. 108:217–46 [Google Scholar]
  102. Oh J, Lee YD, Wagers AJ. 102.  2014. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20:870–80 [Google Scholar]
  103. Behrens A, van Deursen JM, Rudolph KL, Schumacher B. 103.  2014. Impact of genomic damage and ageing on stem cell function. Nat. Cell Biol. 16:201–7 [Google Scholar]
  104. Gorospe M, Abdelmohsen K. 104.  2011. MicroRegulators come of age in senescence. Trends Genet 27:233–41 [Google Scholar]
  105. Noren Hooten N, Abdelmohsen K, Gorospe M, Ejiogu N, Zonderman AB, Evans MK. 105.  2010. microRNA expression patterns reveal differential expression of target genes with age. PLOS ONE 5:e10724 [Google Scholar]
  106. Dimmeler S, Nicotera P. 106.  2013. MicroRNAs in age-related diseases. EMBO Mol. Med. 5:180–90 [Google Scholar]
  107. Feser J, Tyler J. 107.  2011. Chromatin structure as a mediator of aging. FEBS Lett 585:2041–48 [Google Scholar]
  108. McCauley BS, Dang W. 108.  2014. Histone methylation and aging: lessons learned from model systems. Biochim. Biophys. Acta 1839:1454–62 [Google Scholar]
  109. Sarker RS, John-Schuster G, Bohla A, Mutze K, Burgstaller G. 109.  et al. 2015. Coactivator-associated arginine methyltransferase-1 function in alveolar epithelial senescence and elastase-induced emphysema susceptibility. Am. J. Respir. Cell Mol. Biol. 53:769–81 [Google Scholar]
  110. Armstrong L, Al-Aama J, Stojkovic M, Lako M. 110.  2014. Concise review: the epigenetic contribution to stem cell ageing: can we rejuvenate our older cells?. Stem Cells 32:2291–98 [Google Scholar]
  111. Horvath S. 111.  2013. DNA methylation age of human tissues and cell types. Genome Biol 14:R115 [Google Scholar]
  112. Shaw AC, Goldstein DR, Montgomery RR. 112.  2013. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13:875–87 [Google Scholar]
  113. Mahbub S, Brubaker AL, Kovacs EJ. 113.  2011. Aging of the innate immune system: an update. Curr. Immunol. Rev. 7:104–15 [Google Scholar]
  114. Arnold CR, Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-Loebenstein B. 114.  2011. Gain and loss of T cell subsets in old age–age-related reshaping of the T cell repertoire. J. Clin. Immunol. 31:137–46 [Google Scholar]
  115. Hodge G, Jersmann H, Tran HB, Roscioli E, Holmes M. 115.  et al. 2015. Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes. Respir. Res. 16:130 [Google Scholar]
  116. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW. 116.  et al. 2008. Autoantibodies in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 177:156–63 [Google Scholar]
  117. Karayama M, Inui N, Suda T, Nakamura Y, Nakamura H, Chida K. 117.  2010. Antiendothelial cell antibodies in patients with COPD. Chest 138:1303–8 [Google Scholar]
  118. Kirkham PA, Caramori G, Casolari P, Papi AA, Edwards M. 118.  et al. 2011. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 184:796–802 [Google Scholar]
  119. Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ. 119.  2013. Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17A ratio in patients with COPD. Thorax 68:330–37 [Google Scholar]
  120. Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M. 120.  et al. 2014. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20:62–8 [Google Scholar]
  121. Sapey E, Greenwood H, Walton G, Mann E, Love A. 121.  et al. 2014. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123:239–48 [Google Scholar]
  122. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J. 122.  et al. 2014. mTOR inhibition improves immune function in the elderly. Sci. Translat. Med. 6:268ra179 [Google Scholar]
  123. Finkel T, Deng CX, Mostoslavsky R. 123.  2009. Recent progress in the biology and physiology of sirtuins. Nature 460:587–91 [Google Scholar]
  124. Guarente L. 124.  2011. Sirtuins, aging, and metabolism. Cold Spring Harb. Symp. Quant. Biol. 76:81–90 [Google Scholar]
  125. Nakamaru Y, Vuppusetty C, Wada H, Milne JC, Ito M. 125.  et al. 2009. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 23:2810–19 [Google Scholar]
  126. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. 126.  2008. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 177:861–70 [Google Scholar]
  127. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J. 127.  et al. 2008. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. PNAS 105:3374–79 [Google Scholar]
  128. Hubbard BP, Sinclair DA. 128.  2014. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci. 35:146–54 [Google Scholar]
  129. Kugel S, Mostoslavsky R. 129.  2014. Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem. Sci. 39:72–81 [Google Scholar]
  130. Takasaka N, Araya J, Hara H, Ito S, Kobayashi K. 130.  et al. 2014. 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. 192:958–68 [Google Scholar]
  131. Dermaku-Sopjani M, Kolgeci S, Abazi S, Sopjani M. 131.  2013. Significance of the anti-aging protein Klotho. Mol. Membr. Biol. 30:369–85 [Google Scholar]
  132. Gao W, Yuan C, Zhang J, Li L, Yu L. 132.  et al. 2015. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury. Clin. Sci. 129:1011–23 [Google Scholar]
  133. Feng D, Kondo Y, Ishigami A, Kuramoto M, Machida T, Maruyama N. 133.  2004. Senescence marker protein-30 as a novel antiaging molecule. Ann. N. Y. Acad. Sci. 1019:360–64 [Google Scholar]
  134. Sato T, Seyama K, Sato Y, Mori H, Souma S. 134.  et al. 2006. Senescence marker protein-30 protects mice lungs from oxidative stress, aging and smoking. Am. J. Respir. Crit. Care Med. 174:530–37 [Google Scholar]
  135. Barnes PJ, Celli BR. 135.  2009. Systemic manifestations and comorbidities of COPD. Eur. Respir. J. 33:1165–85 [Google Scholar]
  136. Burgel PR, Paillasseur JL, Caillaud D, Tillie-Leblond I, Chanez P. 136.  et al. 2010. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur. Respir. J. 36:531–39 [Google Scholar]
  137. Burgel PR, Paillasseur JL, Peene B, Dusser D, Roche N. 137.  et al. 2012. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLOS ONE 7:e51048 [Google Scholar]
  138. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP. 138.  et al. 2013. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 187:728–35 [Google Scholar]
  139. Barnes PJ. 139.  2015. Mechanisms of development of multimorbidity in the elderly. Eur. Respir. J. 45:790–806 [Google Scholar]
  140. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. 140.  2012. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 380:37–43 [Google Scholar]
  141. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. 141.  2014. The search for antiaging interventions: from elixirs to fasting regimens. Cell 157:1515–26 [Google Scholar]
  142. Ito K, Colley T, Mercado N. 142.  2012. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease. Int. J. Chronic Obstr. Pulm. Dis. 7:641–52 [Google Scholar]
  143. Bjedov I, Partridge L. 143.  2011. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem. Soc. Trans. 39:460–65 [Google Scholar]
  144. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL. 144.  et al. 2013. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4:2192 [Google Scholar]
  145. Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C. 145.  et al. 2013. Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br. J. Pharmacol. 168:1506–18 [Google Scholar]
  146. Leaker BR, Barnes PJ, O'Connor BJ, Ali FY, Tam P. 146.  et al. 2014. The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. Clin. Exp. Allergy 44:1146–53 [Google Scholar]
  147. Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C. 147.  et al. 2009. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11:1305–14 [Google Scholar]
  148. Saso L, Firuzi O. 148.  2014. Pharmacological applications of antioxidants: lights and shadows. Curr. Drug Targets 15:1177–99 [Google Scholar]
  149. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP. 149.  2012. The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging 4:686–94 [Google Scholar]
  150. Jiang ZY, Lu MC, Xu LL, Yang TT, Xi MY. 150.  et al. 2014. Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J. Med. Chem 572736–45 [Google Scholar]
  151. Fontana L, Partridge L, Longo VD. 151.  2010. Extending healthy life span—from yeast to humans. Science 328:321–26 [Google Scholar]
  152. Longo VD, Mattson MP. 152.  2014. Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181–92 [Google Scholar]
  153. Pérez-López FR, Chedraui P, Haya J, Cuadros JL. 153.  2009. Effects of the Mediterranean diet on longevity and age-related morbid conditions. Maturitas 64:67–79 [Google Scholar]
  154. Marín C, Yubero-Serrano EM, López-Miranda J, Pérez-Jiménez F. 154.  2013. Endothelial aging associated with oxidative stress can be modulated by a healthy Mediterranean diet. Internat. J. Mol. Sci. 14:8869–89 [Google Scholar]
  155. Gulsvik AK, Thelle DS, Samuelsen SO, Myrstad M, Mowe M, Wyller TB. 155.  2012. Ageing, physical activity and mortality—a 42-year follow-up study. Int. J. Epidemiol. 41:521–30 [Google Scholar]
  156. Fleg JL. 156.  2012. Aerobic exercise in the elderly: a key to successful aging. Discov. Med. 13:223–28 [Google Scholar]
  157. Casaburi R, ZuWallack R. 157.  2009. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N. Engl. J. Med. 360:1329–35 [Google Scholar]
/content/journals/10.1146/annurev-physiol-022516-034314
Loading
/content/journals/10.1146/annurev-physiol-022516-034314
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error