Mechanisms of development of multimorbidity in the elderly

European Respiratory Journal

Volumn 45, Issue 3, 2015, Pages 790-806

  Barnes, Peter J ^a,b  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^b Airways Disease Section   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMOKINE RECEPTOR CXCR2; CXCL1 CHEMOKINE; CYCLIN DEPENDENT KINASE INHIBITOR 2A; DYSKERIN; HISTONE DEACETYLASE 2; HISTONE H4; INTERLEUKIN 6; INTERLEUKIN 8; KLOTHO PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MICRORNA; MONOCYTE CHEMOTACTIC PROTEIN 1; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN P21; PROTEIN P53; RAPAMYCIN; REGUCALCIN; SIRTUIN 1; SIRTUIN 6; SUPEROXIDE DISMUTASE; TELOMERASE; TELOMERASE REVERSE TRANSCRIPTASE; TELOMERASE RNA COMPONENT; TRANSCRIPTION FACTOR NRF2; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AGING; ANEMIA; APOPTOSIS; ARTICLE; AUTOPHAGY; CALORIC RESTRICTION; CARDIOVASCULAR DISEASE; CELL DAMAGE; CELLULAR PARAMETERS; CELLULAR SENESCENCE; CHRONIC OBSTRUCTIVE LUNG DISEASE; COMORBIDITY ASSESSMENT; CYTOKINE RELEASE; DISEASE ASSOCIATION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA DAMAGE; DRUG EFFECT; ELDERLY CARE; ENDOTHELIAL PROGENITOR CELL; ENZYME ACTIVATION; EPIGENETICS; EXOSOME; FIBROSING ALVEOLITIS; HUMAN; IMMUNOLOGICAL PARAMETERS; IMMUNOSENESCENCE; MEDITERRANEAN DIET; METABOLIC DISORDER; MOLECULARLY TARGETED THERAPY; NERVE DEGENERATION; OXIDATIVE STRESS; PHYSICAL INACTIVITY; PNEUMONIA; PRIORITY JOURNAL; PROTEIN EXPRESSION; SENESCENCE; STEM CELL EXHAUSTION; TELOMERE SHORTENING; WOUND HEALING IMPAIRMENT; AGED; CARDIOVASCULAR DISEASES; CELL AGING; GENETICS; IMMUNOLOGY; METABOLIC DISEASES; METABOLISM; NEOPLASMS; PHYSIOLOGY; PREVENTIVE MEDICINE; PROCEDURES; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; SIGNAL TRANSDUCTION;

AGED; AGING; CARDIOVASCULAR DISEASES; CELL AGING; EPIGENOMICS; HUMANS; METABOLIC DISEASES; NEOPLASMS; OXIDATIVE STRESS; PREVENTIVE MEDICINE; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; SIGNAL TRANSDUCTION;

EID: 84924006883     PISSN: 09031936     EISSN: 13993003     Source Type: Journal    
DOI: 10.1183/09031936.00229714     Document Type: Article

References (152)

1. Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 2012; 380: 37-43.
2. Burgel PR, Paillasseur JL, Caillaud D, et al. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur Respir J 2010; 36: 531-539.
3. Burgel PR, Paillasseur JL, Peene B, et al. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS One 2012; 7: e51048.
4. Vanfleteren LE, Spruit MA, Groenen M, et al. Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187: 728-735.
5. Young RP, Hopkins RJ. Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities. Expert Rev Respir Med 2013; 7: 533-544.
6. Wang MT, Lo YW, Tsai CL, et al. Statin use and risk of COPD exacerbation requiring hospitalization. Am J Med 2013; 126: 598-606.
7. Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest 2013; 123: 996-1002.
8. Fyhrquist F, Saijonmaa O, Strandberg T. The roles of senescence and telomere shortening in cardiovascular disease. Nat Rev Cardiol 2013; 10: 274-283.
9. Monickaraj F, Aravind S, Gokulakrishnan K, et al. Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes. Mol Cell Biochem 2012; 365: 343-350.
10. Lee J, Sandford AJ, Connett JE, et al. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD). PLoS One 2012; 7: e35567.
11. Houben JM, Mercken EM, Ketelslegers HB, et al. Telomere shortening in chronic obstructive pulmonary disease. Respir Med 2009; 103: 230-236.
12. Savale L, Chaouat A, Bastuji-Garin S, et al. Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 179: 566-571.
13. Tsuji T, Aoshiba K, Nagai A. Alveolar cell senescence in patients with pulmonary emphysema. Am J Respir Crit Care Med 2006; 174: 886-893.
14. Tomita K, Caramori G, Ito K, et al. Telomere shortening in alveolar macrophages of smokers and COPD patients. Open Pathol J 2010; 4: 23-29.
15. 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.
16. Tsakiri KD, Cronkhite JT, Kuan PJ, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA 2007; 104: 7552-7557.
17. Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA 2008; 105: 13051-13056.
18. Amsellem V, Gary-Bobo G, Marcos E, et al. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2011; 184: 1358-1366.
19. Coppedè F. Premature aging syndrome. Adv Exp Med Biol 2012; 724: 317-331.
20. Salama R, Sadaie M, Hoare M, et al. Cellular senescence and its effector programs. Genes Dev 2014; 28: 99-114.
21. Correia-Melo C, Hewitt G, Passos JF. Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence? Longev Healthspan 2014; 3: 1.
22. Acosta JC, O'Loghlen A, Banito A, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008; 133: 1006-1018.
23. Takahashi A, Ohtani N, Yamakoshi K, et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 2006; 8: 1291-1297.
24. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011; 479: 232-236.
25. Naylor RM, Baker DJ, van Deursen JM. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther 2013; 93: 105-116.
26. Chilosi M, Carloni A, Rossi A, et al. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res 2013; 162: 156-173.
27. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013; 493: 338-345.
28. Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460: 392-395.
29. To Y, Ito K, Kizawa Y, et al. Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid insensitivity in COPD. Am J Respir Crit Care Med 2010; 182: 897-904.
30. Hosgood HD 3rd, Menashe I, He X, et al. PTEN identified as important risk factor of chronic obstructive pulmonary disease. Respir Med 2009; 103: 1866-1870.
31. Anisimov VN, Berstein LM, Egormin PA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 2008; 7: 2769-2773.
32. Colman RJ, Beasley TM, Kemnitz JW, et al. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun 2014; 5: 3557.
33. Lamming DW, Ye L, Sabatini DM, et al. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J Clin Invest 2013; 123: 980-989.
34. Paredi P, Kharitonov SA, Leak D, et al. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 162: 369-373.
35. Montuschi P, Collins JV, Ciabattoni G, et al. 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 2000; 162: 1175-1177.
36. Rahman I, van Schadewijk AA, Crowther AJ, et al. 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 2002; 166: 490-495.
37. Lambeth JD. Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radical Biol Med 2007; 43: 332-347.
38. Wang CH, Wu SB, Wu YT, et al. Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp Biol Med 2013; 238: 450-460.
39. Kirkham PA, Barnes PJ. Oxidative stress in COPD. Chest 2013; 144: 266-273.
40. Osoata GO, Hanazawa T, Brindicci C, et al. Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine. Chest 2009; 135: 1513-1520.
41. Osoata G, Yamamura S, Ito M, et al. Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem Biophy Res Commun 2009; 384: 366-371.
42. Ito K, Ito M, Elliott WM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005; 352: 1967-1976.
43. Kirkham PA, Caramori G, Casolari P, et al. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of COPD. Am J Respir Crit Care Med 2011; 184: 796-802.
44. Harman D. Free radical theory of aging: an update: increasing the functional life span. Ann N Y Acad Sci 2006; 1067: 10-21.
45. Caramori G, Adcock IM, Casolari P, et al. Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax 2011; 66: 521-527.
46. Aoshiba K, Zhou F, Tsuji T, et al. DNA damage as a molecular link in the pathogenesis of COPD in smokers. Eur Respir J 2012; 39: 1368-1376.
47. Xiang F, Shuanglun X, Jingfeng W, et al. Association of serum 8-hydroxy-2'-deoxyguanosine levels with the presence and severity of coronary artery disease. Coron Artery Dis 2011; 22: 223-227.
48. Serdar M, Sertoglu E, Uyanik M, et al. Comparison of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels using mass spectrometer and urine albumin creatinine ratio as a predictor of development of diabetic nephropathy. Free Radical Res 2012; 46: 1291-1295.
49. Valdiglesias V, Giunta S, Fenech M, et al. γH2AX as a marker of DNA double strand breaks and genomic instability in human population studies. Mutat Res 2013; 753: 24-40.
50. Sørheim IC, DeMeo DL, Washko G, et al. Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD. COPD 2010; 7: 262-268.
51. Grammer TB, Renner W, Hoffmann MM, et al. SOD3 R231G polymorphism associated with coronary artery disease and myocardial infarction. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Free Radical Res 2009; 43: 677-684.
52. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007; 47: 89-116.
53. Malhotra D, Thimmulappa R, Navas-Acien A, et al. Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 2008; 178: 592-604.
54. Mercado N, Thimmulappa R, Thomas CM, et al. Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem Biophys Res Commun 2011; 406: 292-298.
55. Malhotra D, Thimmulappa RK, Mercado N, et al. Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J Clin Invest 2011; 121: 4289-4302.
56. Howden R. Nrf2 and cardiovascular defense. Oxid Med Cell Longev 2013; 2013: 104308.
57. Chartoumpekis DV, Kensler TW. New player on an old field; the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome. Curr Diabetes Rev 2013; 9: 137-145.
58. Ruiz S, Pergola PE, Zager RA, et al. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 2013; 83: 1029-1041.
59. Sureshbabu A, Bhandari V. Targeting mitochondrial dysfunction in lung diseases: emphasis on mitophagy. Frontiers Physiol 2013; 4: 384.
60. Zheng S, Wang C, Qian G, et al. Role of mtDNA haplogroups in COPD susceptibility in a southwestern Han Chinese population. Free Radical Biol Med 2012; 53: 473-481.
61. Wanagat J, Dai DF, Rabinovitch P. Mitochondrial oxidative stress and mammalian healthspan. Mech Ageing Devel 2010; 131: 527-535.
62. Meyer A, Zoll J, Charles AL, et al. Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target. Exp Physiol 2013; 98: 1063-1078.
63. Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab 2009; 20: 394-401.
64. Soulitzis N, Neofytou E, Psarrou M, et al. Downregulation of lung mitochondrial prohibitin in COPD. Respir Med 2012; 106: 954-961.
65. Schleicher M, Shepherd BR, Suarez Y, et al. Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence. J Cell Biol 2008; 180: 101-112.
66. Theiss AL, Sitaraman SV. The role and therapeutic potential of prohibitin in disease. Biochim Biophys Acta 2011; 1813: 1137-1143.
67. Hoffmann RF, Zarrintan S, Brandenburg SM, et al. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir Res 2013; 14: 97.
68. Mizumura K, Cloonan SM, Nakahira K, et al. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest 2014; 124: 3987-4003.
69. Li J, Dai A, Hu R, et al. Positive correlation between PPARγ/PGC-1α and γ-GCS in lungs of rats and patients with chronic obstructive pulmonary disease. Acta Biochim Biophys Sin 2010; 42: 603-614.
70. Dillon LM, Rebelo AP, Moraes CT. The role of PGC-1 coactivators in aging skeletal muscle and heart. IUBMB Life 2012; 64: 231-241.
71. Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 2011; 1813: 1269-1278.
72. Mizumura K, Cloonan SM, Haspel JA, et al. The emerging importance of autophagy in pulmonary diseases. Chest 2012; 142: 1289-1299.
73. Mizushima N, Levine B, Cuervo AM, et al. Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069-1075.
74. Murrow L, Debnath J. Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Ann Rev Pathol 2013; 8: 105-137.
75. Monick MM, Powers LS, Walters K, et al. Identification of an autophagy defect in smokers' alveolar macrophages. J Immunol 2010; 185: 5425-5435.
76. Chen ZH, Lam HC, Jin Y, et al. Autophagy protein microtubule-associated protein 1 light chain-3B (LC3B) activates extrinsic apoptosis during cigarette smoke-induced emphysema. Proc Natl Acad Sci USA 2010; 107: 18880-18885.
77. Fujii S, Hara H, Araya J, et al. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. Oncoimmunology 2012; 1: 630-641.
78. Donnelly LE, Barnes PJ. Defective phagocytosis in airways disease. Chest 2012; 141: 1055-1062.
79. Dunlop EA, Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol 2014; 36C: 121-129.
80. Schneider JL, Cuervo AM. Autophagy and human disease: emerging themes. Curr Opin Genet Dev 2014; 26C: 16-23.
81. López-Otín C, Blasco MA, Partridge L, et al. The hallmarks of aging. Cell 2013; 153: 1194-1217.
82. Kubo H. Concise review: clinical prospects for treating chronic obstructive pulmonary disease with regenerative approaches. Stem Cell Transl Med 2012; 1: 627-631.
83. Fujino N, Kubo H, Suzuki T, et al. Isolation of alveolar epithelial type II progenitor cells from adult human lungs. Lab Invest 2011; 91: 363-378.
84. Kajstura J, Rota M, Hall SR, et al. Evidence for human lung stem cells. N Engl J Med 2011; 364: 1795-1806.
85. Lindsey JY, Ganguly K, Brass DM, et al. c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am J Respir Crit Care Med 2011; 183: 1644-1652.
86. Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 2012; 110: 624-637.
87. Paschalaki KE, Starke RD, Hu Y, et al. Dysfunction of endothelial progenitor cells from smokers and COPD patients due to increased DNA damage and senescence. Stem Cells 2013; 31: 2813-2826.
88. Lee PS, Poh KK. Endothelial progenitor cells in cardiovascular diseases. World J Stem Cells 2014; 6: 355-366.
89. Yiu KH, Tse HF. Specific role of impaired glucose metabolism and diabetes mellitus in endothelial progenitor cell characteristics and function. Arterioscler Thromb Vasc Biol 2014; 34: 1136-1143.
90. Kramann R, Humphreys BD. Kidney pericytes: roles in regeneration and fibrosis. Semin Nephrol 2014; 34: 374-383.
91. Sousounis K, Baddour JA, Tsonis PA. Aging and regeneration in vertebrates. Curr Top Dev Biol 2014; 108: 217-246.
92. Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med 2014; 20: 870-880.
93. Behrens A, van Deursen JM, Rudolph KL, et al. Impact of genomic damage and ageing on stem cell function. Nat Cell Biol 2014; 16: 201-207.
94. Salani S, Donadoni C, Rizzo F, et al. Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies. J Cell Mol Med 2012; 16: 1353-1364.
95. Gorospe M, Abdelmohsen K. MicroRegulators come of age in senescence. Trends Genet 2011; 27: 233-241.
96. Noren Hooten N, Abdelmohsen K, Gorospe M, et al. microRNA expression patterns reveal differential expression of target genes with age. PLoS One 2010; 5: e10724.
97. Dimmeler S, Nicotera P. MicroRNAs in age-related diseases. EMBO Mol Med 2013; 5: 180-190.
98. Hunter MP, Ismail N, Zhang X, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS One 2008; 3: e3694.
99. Schiro A, Wilkinson FL, Weston R, et al. Endothelial microparticles as conveyors of information in atherosclerotic disease. Atherosclerosis 2014; 234: 295-302.
100. Takahashi T, Kubo H. The role of microparticles in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2014; 9: 303-314.
101. Thomashow MA, Shimbo D, Parikh MA, et al. Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study. Am J Respir Crit Care Med 2013; 188: 60-68.
102. Gordon C, Gudi K, Krause A, et al. Circulating endothelial microparticles as a measure of early lung destruction in cigarette smokers. Am J Respir Crit Care Med 2011; 184: 224-232.
103. Li CJ, Liu Y, Chen Y, et al. Novel proteolytic microvesicles released from human macrophages after exposure to tobacco smoke. Am J Pathol 2013; 182: 1552-1562.
104. Markiewicz M, Richard E, Marks N, et al. Impact of endothelial microparticles on coagulation, inflammation, and angiogenesis in age-related vascular diseases. J Aging Res 2013; 2013: 734509.
105. Hulsmans M, Holvoet P. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc Res 2013; 100: 7-18.
106. Feser J, Tyler J. Chromatin structure as a mediator of aging. FEBS Lett 2011; 585: 2041-2048.
107. McCauley BS, Dang W. Histone methylation and aging: lessons learned from model systems. Biochim Biophys Acta 2014; 1839: 1454-1462.
108. Armstrong L, Al-Aama J, Stojkovic M, et al. Concise review: the epigenetic contribution to stem cell ageing: can we rejuvenate our older cells? Stem Cell 2014; 32: 2291-2298.
109. Chambers SM, Shaw CA, Gatza C, et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol 2007; 5: e201.
110. Horvath S. DNA methylation age of human tissues and cell types. Genome Biol 2013; 14: R115.
111. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nat Rev Immunol 2013; 13: 875-887.
112. Mahbub S, Brubaker AL, Kovacs EJ. Aging of the innate immune system: an update. Curr Immunol Rev 2011; 7: 104-115.
113. Arnold CR, Wolf J, Brunner S, et al. Gain and loss of T cell subsets in old age - age-related reshaping of the T cell repertoire. J Clin Immunol 2011; 31: 137-146.
114. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, et al. Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008; 177: 156-163.
115. Karayama M, Inui N, Suda T, et al. Antiendothelial cell antibodies in patients with COPD. Chest 2010; 138: 1303-1308.
116. Wang H, Ying H, Wang S, et al. Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease. Clin Respir J 2014 [In press DOI: 10.1111/crj.12147].
117. Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A, et al. Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17A ratio in patients with COPD. Thorax 2013; 68: 330-337.
118. Potekhina AV, Pylaeva E, Provatorov S, et al. Treg/Th17 balance in stable CAD patients with different stages of coronary atherosclerosis. Atherosclerosis 2015; 238: 17-21.
119. Komatsu N, Okamoto K, Sawa S, et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 2014; 20: 62-68.
120. Sapey E, Greenwood H, Walton G, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 2014; 123: 239-248.
121. Azzi J, Moore RF, Elyaman W, et al. The novel therapeutic effect of phosphoinositide 3-kinase-γ inhibitor AS605240 in autoimmune diabetes. Diabetes 2012; 61: 1509-1518.
122. Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008; 105: 7797-7802.
123. Ito K, Barnes PJ. COPD as a disease of accelerated lung aging. Chest 2009; 135: 173-180.
124. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature 2009; 460: 587-591.
125. Nakamaru Y, Vuppusetty C, Wada H, et al. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 2009; 23: 2810-2819.
126. Guarente L, Franklin H. Epstein lecture: sirtuins, aging, and medicine. N Engl J Med 2011; 364: 2235-2244.
127. Lee IH, Cao L, Mostoslavsky R, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 2008; 105: 3374-3379.
128. Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci 2014; 35: 146-154.
129. Kugel S, Mostoslavsky R. Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem Sci 2014; 39: 72-81.
130. Dërmaku-Sopjani M, Kolgeci S, Abazi S, et al. Significance of the anti-aging protein Klotho. Mol Membr Biol 2013; 30: 369-385.
131. Feng D, Kondo Y, Ishigami A, et al. Senescence marker protein-30 as a novel antiaging molecule. Ann N Y Acad Sci 2004; 1019: 360-364.
132. Sato T, Seyama K, Sato Y, et al. Senescence marker protein-30 protects mice lungs from oxidative stress, aging and smoking. Am J Respir Crit Care Med 2006; 174: 530-537.
133. Misaka T, Suzuki S, Miyata M, et al. Deficiency of senescence marker protein 30 exacerbates angiotensin II-induced cardiac remodelling. Cardiovasc Res 2013; 99: 461-470.
134. de Cabo R, Carmona-Gutierrez D, Bernier M, et al. The search for antiaging interventions: from elixirs to fasting regimens. Cell 2014; 157: 1515-1526.
135. Ito K, Colley T, Mercado N. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease. Int J Chron Obstruct Pulmon Dis 2012; 7: 641-652.
136. Bjedov I, Partridge L. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem Soc Trans 2011; 39: 460-465.
137. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4: 2192.
138. Stenton GR, Mackenzie LF, Tam P, et al. 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 2013; 168: 1506-1518.
139. Leaker BR, Barnes PJ, O'Connor BJ, et al. The effects of the novel SHIP1 activator AQX-1125 on allergen-induced responses in mild-to-moderate asthma. Clin Exp Allergy 2014; 44: 1146-1153.
140. Eisenberg T, Knauer H, Schauer A, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 2009; 11: 1305-1314.
141. Baur JA, Ungvari Z, Minor RK, et al. Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov 2012; 11: 443-461.
142. Saso L, Firuzi O. Pharmacological applications of antioxidants: lights and shadows. Curr Drug Targets 2014; 15: 1177-1199.
143. Kolosova NG, Stefanova NA, Muraleva NA, et al. The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging 2012; 4: 686-694.
144. Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci 2013; 34: 340-346.
145. Jiang ZY, Lu MC, Xu LL, et al. Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 2014; 57: 2736-2745.
146. Fontana L, Partridge L, Longo VD. Extending healthy life span - from yeast to humans. Science 2010; 328: 321-326.
147. Longo VD, Mattson MP. Fasting: molecular mechanisms and clinical applications. Cell Metab 2014; 19: 181-192.
148. Pérez-López FR, Chedraui P, Haya J, et al. Effects of the Mediterranean diet on longevity and age-related morbid conditions. Maturitas 2009; 64: 67-79.
149. Marín C, Yubero-Serrano EM, López-Miranda J, et al. Endothelial aging associated with oxidative stress can be modulated by a healthy mediterranean diet. Int J Mol Sci 2013; 14: 8869-8889.
150. Gulsvik AK, Thelle DS, Samuelsen SO, et al. Ageing, physical activity and mortality - a 42-year follow-up study. Int J Epidemiol 2012; 41: 521-530.
151. Fleg JL. Aerobic exercise in the elderly: a key to successful aging. Discov Med 2012; 13: 223-228.
152. Casaburi R, ZuWallack R. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N Engl J Med 2009; 360: 1329-1335.