Senescence in COPD and Its Comorbidities

Annual Review of Physiology

Volumn 79, Issue , 2017, Pages 517-539

  Barnes, Peter J ^a  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

Autophagy; Cellular senescence; Immunosenescence; Mitochondria; Oxidative stress; Sirtuins

Indexed keywords

KLOTHO PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MICRORNA; PHOSPHATIDYLINOSITOL 3 KINASE; REGUCALCIN; SIRTUIN;

AUTOPHAGY; CARDIOVASCULAR DISEASE; CELL AGING; CHRONIC INFLAMMATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; COMORBIDITY ASSESSMENT; DISORDERS OF MITOCHONDRIAL FUNCTIONS; ENZYME ACTIVATION; EPIGENETICS; HUMAN; IMMUNOSENESCENCE; LIFESTYLE; LUNG; METABOLIC DISORDER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; STEM CELL; TELOMERE SHORTENING; ANIMAL; COMORBIDITY; INFLAMMATION; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY;

ANIMALS; CELL AGING; COMORBIDITY; HUMANS; INFLAMMATION; LUNG; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 85013098594     PISSN: 00664278     EISSN: 15451585     Source Type: Book Series    
DOI: 10.1146/annurev-physiol-022516-034314     Document Type: Review

References (157)

1. Barnes PJ, Burney PGJ, Silverman EK, Celli BR, Vestbo J, et al. 2015. Chronic obstructive pulmonary disease. Nat. Rev. Primers 1:1-21
2. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, 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
3. Salvi SS, Barnes PJ. 2009. Chronic obstructive pulmonary disease in non-smokers. Lancet 374:733-43
4. Gordon SB, Bruce NG, Grigg J, Hibberd PL, Kurmi OP, et al. 2014. Respiratory risks from household air pollution in low and middle income countries. Lancet Resp. Med. 2:823-60
5. Burney P, Jithoo A, Kato B, Janson C, Mannino D, et al. 2014. Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty-A BOLD analysis. Thorax 69:465-73
6. Hogg JC, TimensW. 2009. The pathology of chronic obstructive pulmonary disease. Annu. Rev. Pathol. 4:435-59
7. Lange P, Celli B, Agusti A, Boje Jensen G, Divo M, et al. 2015. Lung-function trajectories leading to chronic obstructive pulmonary disease. N. Engl. J. Med. 373:111-22
8. Barnes PJ. 2013. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 131:636-45
9. Barnes PJ. 2016. Inflammatory mechanisms in COPD. J. Allergy Clin. Immunol. 138:16-27
10. Barnes PJ. 2009. Role of HDAC2 in the pathophysiology of COPD. Annu. Rev. Physiol. 71:451-64
11. Barnes PJ. 2014. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin. Chest Med. 35:71-86
12. Kirkham PA, Barnes PJ. 2013. Oxidative stress in COPD. Chest 144:266-73
13. Ito K, Barnes PJ. 2009. COPD as a disease of accelerated lung aging. Chest 135:173-80
14. Mercado N, Ito K, Barnes PJ. 2015. Accelerated ageing in chronic obstructive pulmonary disease: new concepts. Thorax 70:482-89
15. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, et al. 2014. Geroscience: linking aging to chronic disease. Cell 159:709-13
16. Kirkwood TB. 2005. Understanding the odd science of aging. Cell 120:437-47
17. Harman D. 2006. Free radical theory of aging: an update: increasing the functional life span. Ann. N.Y. Acad. Sci. 1067:10-21
18. Chung HY, Sung B, Jung KJ, Zou Y, Yu BP. 2006. The molecular inflammatory process in aging. Antioxid. Redox Signal. 8: 572-81
19. Hekimi S, Lapointe J, Wen Y. 2011. Taking a "good" look at free radicals in the aging process. Trends Cell Biol. 21:569-76
20. Hayflick L. 1965. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37:614-36
21. Williams GC. 1957. Pleiotropy, natural selection, and the evolution of senescence evolution. Evolution 11:398-411
22. Salama R, Sadaie M, Hoare M, Narita M. 2014. Cellular senescence and its effector programs. Genes Dev. 28:99-114
23. Ĺopez-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. 2013. The hallmarks of aging. Cell 153:1194-217
24. Meiners S, Eickelberg O, Konigshoff M. 2015. Hallmarks of the ageing lung. Eur. Respir. J. 45:807-27
25. Armanios M. 2013. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J. Clin. Investig. 123:996-1002
26. Fyhrquist F, Saijonmaa O, Strandberg T. 2013. The roles of senescence and telomere shortening in cardiovascular disease. Nat. Rev. Cardiol. 10:274-83
27. Monickaraj F, Aravind S, Gokulakrishnan K, Sathishkumar C, Prabu P, 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
28. Lee J, Sandford AJ, Connett JE, Yan J, Mui T, et al. 2012. The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD). PLOS ONE 7:e35567
29. Houben JM, Mercken EM, Ketelslegers HB, Bast A,Wouters EF, et al. 2009. Telomere shortening in chronic obstructive pulmonary disease. Respir. Med. 103:230-36
30. Savale L, Chaouat A, Bastuji-Garin S, Marcos E, Boyer L, et al. 2009. Shortened telomeres in circulating leukocytes of patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 179:566-71
31. Rutten EP, Gopal P,Wouters EF, Franssen FM, Hageman GJ, et al. 2016. Various mechanistic pathways representing the aging process are altered in COPD. Chest 149:53-61
32. Tsuji T, Aoshiba K, Nagai A. 2006. Alveolar cell senescence in patients with pulmonary emphysema. Am. J. Respir. Crit. Care Med. 174:886-93
33. Tomita K, CaramoriG, Ito K, Lim S, SanoH, et al. 2010. Telomere shortening in alveolar macrophages of smokers and COPD patients. Open. Path. J. 4:23-29
34. Birch J, Anderson RK, Correia-Melo C, Jurk D, Hewitt G, 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
35. Alder JK, Guo N, Kembou F, Parry EM, Anderson CJ, et al. 2011. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 184:904-12
36. Stanley SE, Chen JJ, Podlevsky JD, Alder JK, Hansel NN, et al. 2015. Telomerase mutations in smokers with severe emphysema. J. Clin. Investig. 125:563-70
37. Chen R, Zhang K, Chen H, Zhao X, Wang J, et al. 2015. Telomerase deficiency causes alveolar stem cell senescence-associated low-grade inflammation in lungs. J. Biol. Chem. 290:30813-29
38. Amsellem V, Gary-Bobo G, Marcos E, Maitre B, Chaar V, et al. 2011. Telomere dysfunction causes sustained inflammation in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 184:1358-66
39. Janssens JP, Pache JC, Nicod LP. 1999. Physiological changes in respiratory function associated with ageing. Eur. Respir. J. 13:197-205
40. Muñoz-Espín D, Serrano M. 2014. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15:482-96
41. Coppede F. 2012. Premature aging syndrome. Adv. Exp. Med. Biol. 724:317-31
42. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, et al. 2011. Clearance of p16Ink4apositive senescent cells delays ageing-associated disorders. Nature 479:232-36
43. Baker DJ, Childs BG, DurikM,WijersME, Sieben CJ, et al. 2016. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530:184-89
44. Sorrentino JA, Krishnamurthy J, Tilley S, Alb JG Jr., Burd CE, Sharpless NE. 2014. p16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J. Clin. Investig. 124:169-73
45. Correia-Melo C, Hewitt G, Passos JF. 2014. Telomeres, oxidative stress and inflammatory factors: Partners in cellular senescence? Longev. Healthspan 3:1
46. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, et al. 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006-18
47. Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, et al. 2006. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8:1291-97
48. Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, et al. 2015. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. PNAS 112:6301-10
49. Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, et al. 2015. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17:1205-17
50. 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. J. Lab. Clin. Med. 162:156-73
51. Tomita K, Caramori G, Lim S, Ito K, Hanazawa T, 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
52. Barnes PJ. 2004. Mediators of chronic obstructive pulmonary disease. Pharm. Rev. 56:515-48
53. Johnson SC, Rabinovitch PS, Kaeberlein M. 2013. mTOR is a key modulator of ageing and age-related disease. Nature 493:338-45
54. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392-95
55. Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, et al. 2015. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17:1049-61
56. To Y, Ito K, Kizawa Y, Failla M, Ito M, et al. 2010. Targeting phosphoinositide-3-kinase-δ with theophylline reverses corticosteroid insensitivity in COPD. Am. J. Resp. Crit. Care Med. 182:897-904
57. Mitani A, ItoK,Vuppusetty C, Barnes PJ,MercadoN. 2015. Inhibition ofmTORrestores corticosteroid sensitivity in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 193:143-53
58. Hosgood HD, Menashe I, He X, Chanock S, Lan Q. 2009. PTEN identified as important risk factor of chronic obstructive pulmonary disease. Respir. Med. 103:1866-70
59. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, et al. 2008. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7:2769-73
60. Colman RJ, Beasley TM, Kemnitz JW, Johnson SC, Weindruch R, Anderson RM. 2014. Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 5:3557
61. Lamming DW, Ye L, Sabatini DM, Baur JA. 2013. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Investig. 123:980-89
62. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. 2000. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 162:369-73
63. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, 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
64. Rahman I, van Schadewijk AA, Crowther AJ, Hiemstra PS, Stolk J, 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
65. Wang CH, Wu SB, Wu YT, Wei YH. 2013. Oxidative stress response elicited by mitochondrial dysfunction: implication in the pathophysiology of aging. Exp. Biol. Med. 238:450-60
66. Osoata GO, Hanazawa T, Brindicci C, Ito M, Barnes PJ, et al. 2009. Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine. Chest 135:1513-20
67. Osoata G, Yamamura S, Ito M, Vuppusetty C, Adcock IM, et al. 2009. Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem. Biophy. Res. Commun. 384:366-71
68. Ito K, Ito M, Elliott WM, Cosio B, Caramori G, et al. 2005. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352:1967-76
69. Kirkham PA, CaramoriG, CasolariP,PapiA,Edwards M, 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
70. Caramori G, Adcock IM, Casolari P, Ito K, Jazrawi E, et al. 2011. Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer. Thorax 66:521-27
71. Aoshiba K, Zhou F, Tsuji T, Nagai A. 2012. DNA damage as a molecular link in the pathogenesis of COPD in smokers. Eur. Respir. J. 39:1368-76
72. Sorheim IC, DeMeo DL, Washko G, Litonjua A, Sparrow D, et al. 2010. Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD. COPD 7:262-68
73. Kensler TW, Wakabayashi N, Biswal S. 2007. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol. 47:89-116
74. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, 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
75. Mercado N, Thimmulappa R, Thomas CM, Fenwick PS, Chana KK, et al. 2011. Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem. Biophys. Res. Commun. 406:292-98
76. Malhotra D, Thimmulappa RK,MercadoN, Ito K, KombairajuP, et al. 2011. Denitrosylation ofHDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients. J. Clin. Investig. 121:4289-302
77. Correia-Melo C, Passos JF. 2015. Mitochondria: Are they causal players in cellular senescence? Biochim. Biophys. Acta 1847:1373-79
78. Sureshbabu A, Bhandari V. 2013. Targeting mitochondrial dysfunction in lung diseases: emphasis on mitophagy. Front. Physiol. 4:384
79. Zheng S,Wang C, Qian G, Wu G, Guo R, et al. 2012. Role of mtDNA haplogroups in COPD susceptibility in a southwestern Han Chinese population. Free Rad. Biol. Med. 53:473-81
80. Wanagat J, Dai DF, Rabinovitch P. 2010. Mitochondrial oxidative stress and mammalian healthspan. Mech. Ageing Devel. 131:527-35
81. Meyer A, Zoll J, Charles AL, Charloux A, Blay F, et al. 2013. Skeletal muscle mitochondrial dysfunction during chronic obstructive pulmonary disease: central actor and therapeutic target. Exp. Physiol. 98:1063-78
82. Artal-Sanz M, Tavernarakis N. 2009. Prohibitin and mitochondrial biology. Trends Endocrinol. Metab. 20:394-401
83. Soulitzis N, Neofytou E, PsarrouM, Anagnostis A, TavernarakisN, et al. 2012. Downregulation of lung mitochondrial prohibitin in COPD. Respir. Med. 106:954-61
84. Hoffmann RF, Zarrintan S, Brandenburg SM, Kol A, Bruin HG, et al. 2013. Prolonged cigarette smoke exposure alters mitochondrial structure and function in airway epithelial cells. Respir. Res. 14:97
85. Mizumura K, Cloonan SM, Nakahira K, Bhashyam AR, Cervo M, et al. 2014. Mitophagy-dependent necroptosis contributes to the pathogenesis of COPD. J. Clin. Investig. 124:3987-4003
86. Li J, Dai A, Hu R, Zhu L, Tan S. 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
87. Mizumura K, Cloonan SM, Haspel JA, Choi AM. 2012. The emerging importance of autophagy in pulmonary diseases. Chest 142:1289-99
88. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. 2008. Autophagy fights disease through cellular self-digestion. Nature 451:1069-75
89. MurrowL,Debnath J. 2013. Autophagy as a stress-response and quality-controlmechanism: implications for cell injury and human disease. Annu. Rev. Pathol. Mech. Dis. 8:105-37
90. Monick MM, Powers LS, Walters K, Lovan N, Zhang M, et al. 2010. Identification of an autophagy defect in smokers' alveolar macrophages. J. Immunol. 185:5425-35
91. Chen ZH,Lam HC, Jin Y, Kim HP, Cao J, 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
92. Fujii S, Hara H, Araya J, Takasaka N, Kojima J, et al. 2012. Insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease. Oncoimmunology 1:630-41
93. Donnelly LE, Barnes PJ. 2012. Defective phagocytosis in airways disease. Chest 141:1055-62
94. Dunlop EA, Tee AR. 2014. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Sem. Cell Devel. Biol. 36:121-29
95. Kubo H. 2012. Concise review: clinical prospects for treating chronic obstructive pulmonary disease with regenerative approaches. Stem. Cell Translat. Med. 1:627-31
96. Fujino N, Kubo H, Suzuki T, Ota C, Hegab AE, et al. 2011. Isolation of alveolar epithelial type II progenitor cells from adult human lungs. Lab. Investig. 91:363-78
97. Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D, et al. 2011. Evidence for human lung stem cells. N. Engl. J. Med. 364:1795-806
98. Lindsey JY, Ganguly K, Brass DM, Li Z, Potts EN, 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
99. Fadini GP,Losordo D, Dimmeler S. 2012. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ. Res. 110:624-37
100. Paschalaki KE, Starke RD, Hu Y, Mercado N, Margariti A, 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
101. Sousounis K, Baddour JA, Tsonis PA. 2014. Aging and regeneration in vertebrates. Curr. Top. Dev. Biol. 108:217-46
102. Oh J, Lee YD, Wagers AJ. 2014. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20:870-80
103. Behrens A, van Deursen JM, Rudolph KL, Schumacher B. 2014. Impact of genomic damage and ageing on stem cell function. Nat. Cell Biol. 16:201-7
104. GorospeM, AbdelmohsenK. 2011. MicroRegulators come of age in senescence. TrendsGenet. 27:233-41
105. NorenHooten N, AbdelmohsenK,Gorospe M, Ejiogu N, Zonderman AB, EvansMK. 2010. microRNA expression patterns reveal differential expression of target genes with age. PLOS ONE 5:e10724
106. Dimmeler S, Nicotera P. 2013. MicroRNAs in age-related diseases. EMBO Mol. Med. 5:180-90
107. Feser J, Tyler J. 2011. Chromatin structure as a mediator of aging. FEBS Lett. 585:2041-48
108. McCauley BS, Dang W. 2014. Histone methylation and aging: lessons learned from model systems. Biochim. Biophys. Acta 1839:1454-62
109. Sarker RS, John-Schuster G, Bohla A, Mutze K, Burgstaller G, 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
110. Armstrong L, Al-Aama J, Stojkovic M, Lako M. 2014. Concise review: the epigenetic contribution to stem cell ageing: can we rejuvenate our older cells? Stem Cells 32:2291-98
111. Horvath S. 2013. DNA methylation age of human tissues and cell types. Genome Biol. 14:R115
112. Shaw AC, Goldstein DR, Montgomery RR. 2013. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13:875-87
113. Mahbub S, Brubaker AL, Kovacs EJ. 2011. Aging of the innate immune system: an update. Curr. Immunol. Rev. 7:104-15
114. Arnold CR,Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-Loebenstein B. 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
115. Hodge G, Jersmann H, Tran HB, Roscioli E, Holmes M, et al. 2015. Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes. Respir. Res. 16:130
116. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW, et al. 2008. Autoantibodies in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 177:156-63
117. KarayamaM, InuiN, Suda T, Nakamura Y, Nakamura H, ChidaK. 2010. Antiendothelial cell antibodies in patients with COPD. Chest 138:1303-8
118. Kirkham PA, Caramori G, Casolari P, Papi AA, Edwards M, 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
119. Maneechotesuwan K, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ. 2013. Decreased indoleamine 2,3-dioxygenase activity and IL-10/IL-17A ratio in patients with COPD. Thorax 68:330-37
120. Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, et al. 2014. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20:62-8
121. Sapey E, Greenwood H, Walton G, Mann E, Love A, et al. 2014. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123:239-48
122. Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, et al. 2014. mTOR inhibition improves immune function in the elderly. Sci. Translat. Med. 6:268ra179
123. Finkel T, Deng CX, Mostoslavsky R. 2009. Recent progress in the biology and physiology of sirtuins. Nature 460:587-91
124. Guarente L. 2011. Sirtuins, aging, and metabolism. Cold Spring Harb. Symp. Quant. Biol. 76:81-90
125. Nakamaru Y, Vuppusetty C, Wada H, Milne JC, Ito M, et al. 2009. A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J. 23:2810-19
126. Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. 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
127. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, et al. 2008. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. PNAS 105:3374-79
128. Hubbard BP, Sinclair DA. 2014. Small molecule SIRT1 activators for the treatment of aging and agerelated diseases. Trends Pharmacol. Sci. 35:146-54
129. Kugel S,MostoslavskyR. 2014. Chromatin and beyond: the multitasking roles for SIRT6. Trends Biochem. Sci. 39:72-81
130. Takasaka N, Araya J, Hara H, Ito S, Kobayashi K, 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
131. Dermaku-SopjaniM, Kolgeci S, Abazi S, SopjaniM. 2013. Significance of the anti-aging protein Klotho. Mol. Membr. Biol. 30:369-85
132. Gao W, Yuan C, Zhang J, Li L, Yu L, et al. 2015. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury. Clin. Sci. 129:1011-23
133. Feng D, Kondo Y, Ishigami A, Kuramoto M, Machida T, Maruyama N. 2004. Senescence marker protein-30 as a novel antiaging molecule. Ann. N. Y. Acad. Sci. 1019:360-64
134. Sato T, Seyama K, Sato Y, Mori H, Souma S, 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
135. Barnes PJ, Celli BR. 2009. Systemic manifestations and comorbidities of COPD. Eur. Respir. J. 33:1165-85
136. Burgel PR, Paillasseur JL, Caillaud D, Tillie-Leblond I, Chanez P, et al. 2010. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur. Respir. J. 36:531-39
137. Burgel PR, Paillasseur JL, Peene B, Dusser D, Roche N, et al. 2012. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLOS ONE 7:e51048
138. Vanfleteren LE, Spruit MA, Groenen M, Gaffron S, van Empel VP, 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
139. Barnes PJ. 2015. Mechanisms of development ofmultimorbidity in the elderly. Eur. Respir. J. 45:790-806
140. BarnettK,Mercer SW, NorburyM,WattG,Wyke S,Guthrie B. 2012. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 380:37-43
141. de Cabo R, Carmona-Gutierrez D, Bernier M, Hall MN, Madeo F. 2014. The search for antiaging interventions: from elixirs to fasting regimens. Cell 157:1515-26
142. Ito K, Colley T, Mercado N. 2012. Geroprotectors as a novel therapeutic strategy for COPD, an accelerating aging disease. Int. J. Chronic Obstr. Pulm. Dis. 7:641-52
143. Bjedov I, Partridge L. 2011. A longer and healthier life with TOR down-regulation: genetics and drugs. Biochem. Soc. Trans. 39:460-65
144. Martin-Montalvo A,Mercken EM,Mitchell SJ, Palacios HH, Mote PL, et al. 2013. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4:2192
145. Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, 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
146. Leaker BR, Barnes PJ, O'Connor BJ, Ali FY, Tam P, 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
147. Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, et al. 2009. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11:1305-14
148. Saso L, Firuzi O. 2014. Pharmacological applications of antioxidants: lights and shadows. Curr. Drug Targets 15:1177-99
149. Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP. 2012. The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. Aging 4:686-94
150. Jiang ZY, Lu MC,Xu LL, Yang TT, Xi MY, et al. 2014. Discovery of potentKeap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J. Med. Chem. 57:2736-45
151. Fontana L, Partridge L, Longo VD. 2010. Extending healthy life span-from yeast to humans. Science 328:321-26
152. Longo VD, Mattson MP. 2014. Fasting: molecular mechanisms and clinical applications. Cell Metab. 19:181-92
153. Pérez-López FR, Chedraui P, Haya J, Cuadros JL. 2009. Effects of the Mediterranean diet on longevity and age-related morbid conditions. Maturitas 64:67-79
154. Marín C, Yubero-Serrano EM, Ĺopez-Miranda J, Pérez-Jiménez F. 2013. Endothelial aging associated with oxidative stress can be modulated by a healthy Mediterranean diet. Internat. J.Mol. Sci. 14:8869-89
155. Gulsvik AK, Thelle DS, Samuelsen SO,Myrstad M, Mowe M, WyllerTB. 2012. Ageing, physical activity and mortality-A 42-year follow-up study. Int. J. Epidemiol. 41:521-30
156. Fleg JL. 2012. Aerobic exercise in the elderly: a key to successful aging. Discov. Med. 13:223-28
157. Casaburi R, ZuWallack R. 2009. Pulmonary rehabilitation for management of chronic obstructive pulmonary disease. N. Engl. J. Med. 360:1329-35