Aging, obesity, and inflammatory age-related diseases

Frontiers in Immunology

Volumn 8, Issue DEC, 2017, Pages

  Frasca, Daniela ^a   Blomberg, Bonnie B ^a   Paganelli, Roberto ^b  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF CHIETI   (Italy)

Author keywords

Aging; Inflammation; Obesity; Rheumatoid arthritis; Type 2 diabetes

Indexed keywords

ADAPTIVE IMMUNITY; ADIPOSE TISSUE; AGING; ARTICLE; B LYMPHOCYTE; BODY MASS; CELL INFILTRATION; COGNITIVE DEFECT; DEMENTIA; DIABETES MELLITUS; HOMEOSTASIS; HUMAN; HYPOXIA; IMMUNOCOMPETENT CELL; INFLAMMATION; INNATE IMMUNITY; INSULIN RESISTANCE; NUTRITIONAL STATUS; OBESITY; OSTEOARTHRITIS; PHENOTYPE; RHEUMATOID ARTHRITIS;

EID: 85037666279     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2017.01745     Document Type: Article

References (140)

1. Collaborators GBD, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med (2017) 377(1):13-27. doi:10.1056/NEJMoa1614362
2. Hruby A, Hu FB. The epidemiology of obesity: a big picture. Pharmacoeconomics (2015) 33(7):673-89. doi:10.1007/s40273-014-0243-x
3. Ottaviani S, Allanore Y, Tubach F, Forien M, Gardette A, Pasquet B, et al. Body mass index influences the response to infliximab in ankylosing spondylitis. Arthritis Res Ther (2012) 14(3):R115. doi:10.1186/ar3841
4. Sandberg ME, Bengtsson C, Kallberg H, Wesley A, Klareskog L, Alfredsson L, et al. Overweight decreases the chance of achieving good response and low disease activity in early rheumatoid arthritis. Ann Rheum Dis (2014) 73(11):2029-33. doi:10.1136/annrheumdis-2013-205094
5. George MD, Baker JF. The obesity epidemic and consequences for rheumatoid arthritis care. Curr Rheumatol Rep (2016) 18(1):6. doi:10.1007/s11926-015-0550-z
6. Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology (2016) 17(1):7-19. doi:10.1007/s10522-015-9578-8
7. Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med (2010) 16(5):238-46. doi:10.1016/j.molmed.2010.03.003
8. Olivieri F, Lazzarini R, Recchioni R, Marcheselli F, Rippo MR, Di Nuzzo S, et al. MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling. Age (Dordr) (2013) 35(4):1157-72. doi:10.1007/s11357-012-9440-8
9. Lanna A, Henson SM, Escors D, Akbar AN. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB 1 drives the senescence of human T cells. Nat Immunol (2014) 15(10):965-72. doi:10.1038/ni.2981
10. Muller-Durovic B, Lanna A, Covre LP, Mills RS, Henson SM, Akbar AN. Killer cell lectin-like receptor G1 inhibits NK cell function through activation of adenosine 5'-monophosphate-activated protein kinase. J Immunol (2016) 197(7):2891-9. doi:10.4049/jimmunol.1600590
11. Frasca D, Diaz A, Romero M, Blomberg BB. Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways. Exp Gerontol (2017) 87(Pt A):113-20. doi:10.1016/j.exger.2016.12.001
12. Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature (2017) 542(7640):177-85. doi:10.1038/nature21363
13. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest (2003) 112(12):1796-808. doi:10.1172/JCI19246
14. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med (2009) 15(8):921-9. doi:10.1038/nm.2001
15. Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med (2011) 17(5):610-7. doi:10.1038/nm.2353
16. Grant RW, Dixit VD. Adipose tissue as an immunological organ. Obesity (Silver Spring) (2015) 23(3):512-8. doi:10.1002/oby.21003
17. Boulenouar S, Michelet X, Duquette D, Alvarez D, Hogan AE, Dold C, et al. Adipose type one innate lymphoid cells regulate macrophage homeostasis through targeted cytotoxicity. Immunity (2017) 46(2):273-86. doi:10.1016/j.immuni.2017.01.008
18. Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest (2008) 118(9):2992-3002. doi:10.1172/JCI34260
19. Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes (2004) 53(Suppl 3):S16-21. doi:10.2337/diabetes.53.suppl_3.S16
20. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature (2001) 414(6865):813-20. doi:10.1038/414813a
21. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest (2006) 116(7):1793-801. doi:10.1172/JCI29069
22. Langin D, Arner P. Importance of TNFalpha and neutral lipases in human adipose tissue lipolysis. Trends Endocrinol Metab (2006) 17(8):314-20. doi:10.1016/j.tem.2006.08.003
23. Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A (1994) 91(11):4854-8. doi:10.1073/pnas.91.11.4854
24. Bezaire V, Mairal A, Anesia R, Lefort C, Langin D. Chronic TNFalpha and cAMP pre-treatment of human adipocytes alter HSL, ATGL and perilipin to regulate basal and stimulated lipolysis. FEBS Lett (2009) 583(18):3045-9. doi:10.1016/j.febslet.2009.08.019
25. Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab (2012) 15(5):585-94. doi:10.1016/j.cmet.2012.04.002
26. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med (2009) 15(8):914-20. doi:10.1038/nm.1964
27. O'Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II, et al. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes (Lond) (2009) 33(9):978-90. doi:10.1038/ijo.2009.133
28. Chen Y, Tian J, Tian X, Tang X, Rui K, Tong J, et al. Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One (2014) 9(3):e92450. doi:10.1371/journal.pone.0092450
29. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes (2009) 58(3):718-25. doi:10.2337/db08-1098
30. Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose tissue hypoxia, inflammation, and fibrosis in obese insulin-sensitive and obese insulin-resistant subjects. J Clin Endocrinol Metab (2016) 101(4):1422-8. doi:10.1210/jc.2015-4125
31. Imtiyaz HZ, Simon MC. Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol (2010) 345:105-20. doi:10.1007/82_2010_74
32. Franceschi C. Healthy ageing in 2016: obesity in geroscience-is cellular senescence the culprit? Nat Rev Endocrinol (2017) 13(2):76-8. doi:10.1038/nrendo.2016.213
33. Wu L, Parekh VV, Hsiao J, Kitamura D, Van Kaer L. Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance. Proc Natl Acad Sci U S A (2014) 111(43):E4638-47. doi:10.1073/pnas.1324052111
34. Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, et al. Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature (2015) 519(7542):242-6. doi:10.1038/nature14115
35. Kolodin D, van Panhuys N, Li C, Magnuson AM, Cipolletta D, Miller CM, et al. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab (2015) 21(4):543-57. doi:10.1016/j.cmet.2015.03.005
36. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest (1995) 95(5):2111-9. doi:10.1172/JCI117899
37. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem (2014) 289(11):7884-96. doi:10.1074/jbc.M113.522037
38. Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol (2017) 17(12):774-85. doi:10.1038/nri.2017.103
39. Wen H, Ting JP, O'Neill LA. A role for the NLRP3 inflammasome in metabolic diseases-did Warburg miss inflammation? Nat Immunol (2012) 13(4):352-7. doi:10.1038/ni.2228
40. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol (2011) 12(5):408-15. doi:10.1038/ni.2022
41. Lee HM, Kim JJ, Kim HJ, Shong M, Ku BJ, Jo EK. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes (2013) 62(1):194-204. doi:10.2337/db12-0420
42. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest (2007) 117(1):175-84. doi:10.1172/JCI29881
43. Galic S, Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR, et al. Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest (2011) 121(12):4903-15. doi:10.1172/JCI58577
44. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol (2011) 186(6):3299-303. doi:10.4049/jimmunol.1003613
45. Neumann B, Emmanuilidis K, Stadler M, Holzmann B. Distinct functions of interferon-gamma for chemokine expression in models of acute lung inflammation. Immunology (1998) 95(4):512-21. doi:10.1046/j.1365-2567.1998.00643.x
46. Singh UP, Singh S, Iqbal N, Weaver CT, McGhee JR, Lillard JW Jr. IFN-gamma-inducible chemokines enhance adaptive immunity and colitis. J Interferon Cytokine Res (2003) 23(10):591-600. doi:10.1089/107999003322485099
47. O'Rourke RW, White AE, Metcalf MD, Winters BR, Diggs BS, Zhu X, et al. Systemic inflammation and insulin sensitivity in obese IFN-gamma knockout mice. Metabolism (2012) 61(8):1152-61. doi:10.1016/j.metabol.2012.01.018
48. McGillicuddy FC, Chiquoine EH, Hinkle CC, Kim RJ, Shah R, Roche HM, et al. Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. J Biol Chem (2009) 284(46):31936-44. doi:10.1074/jbc.M109.061655
49. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell (2000) 100(6):655-69. doi:10.1016/S0092-8674(00)80702-3
50. Stolarczyk E, Vong CT, Perucha E, Jackson I, Cawthorne MA, Wargent ET, et al. Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet. Cell Metab (2013) 17(4):520-33. doi:10.1016/j.cmet.2013.02.019
51. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature (2006) 444(7122):1022-3. doi:10.1038/4441022a
52. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A (2007) 104(3):979-84. doi:10.1073/pnas.0605374104
53. Neurath MF, Weigmann B, Finotto S, Glickman J, Nieuwenhuis E, Iijima H, et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J Exp Med (2002) 195(9):1129-43. doi:10.1084/jem.20011956
54. Garrett WS, Lord GM, Punit S, Lugo-Villarino G, Mazmanian SK, Ito S, et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell (2007) 131(1):33-45. doi:10.1016/j.cell.2007.08.017
55. DeFuria J, Belkina AC, Jagannathan-Bogdan M, Snyder-Cappione J, Carr JD, Nersesova YR, et al. B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile. Proc Natl Acad Sci U S A (2013) 110(13):5133-8. doi:10.1073/pnas.1215840110
56. Frasca D, Diaz A, Romero M, Vazquez T, Blomberg BB. Obesity induces pro-inflammatory B cells and impairs B cell function in old mice. Mech Ageing Dev (2017) 162:91-9. doi:10.1016/j.mad.2017.01.004
57. Benezech C, Luu NT, Walker JA, Kruglov AA, Loo Y, Nakamura K, et al. Inflammation-induced formation of fat-associated lymphoid clusters. Nat Immunol (2015) 16(8):819-28. doi:10.1038/ni.3215
58. Roubenoff R, Roubenoff RA, Ward LM, Holland SM, Hellmann DB. Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. J Rheumatol (1992) 19(10):1505-10.
59. Summers GD, Deighton CM, Rennie MJ, Booth AH. Rheumatoid cachexia: a clinical perspective. Rheumatology (Oxford) (2008) 47(8):1124-31. doi:10.1093/rheumatology/ken146
60. Roubenoff R. Rheumatoid cachexia: a complication of rheumatoid arthritis moves into the 21st century. Arthritis Res Ther (2009) 11(2):108. doi:10.1186/ar2658
61. Rall LC, Roubenoff R. Rheumatoid cachexia: metabolic abnormalities, mechanisms and interventions. Rheumatology (Oxford) (2004) 43(10):1219-23. doi:10.1093/rheumatology/keh321
62. Giles JT, Ling SM, Ferrucci L, Bartlett SJ, Andersen RE, Towns M, et al. Abnormal body composition phenotypes in older rheumatoid arthritis patients: association with disease characteristics and pharmacotherapies. Arthritis Rheum (2008) 59(6):807-15. doi:10.1002/art.23719
63. Roubenoff R. Sarcopenia: a major modifiable cause of frailty in the elderly. J Nutr Health Aging (2000) 4(3):140-2.
64. Kalinkovich A, Livshits G. Sarcopenic obesity or obese sarcopenia: a cross talk between age-associated adipose tissue and skeletal muscle inflammation as a main mechanism of the pathogenesis. Ageing Res Rev (2017) 35:200-21. doi:10.1016/j.arr.2016.09.008
65. Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y, Kitas GD. Obesity in rheumatoid arthritis. Rheumatology (Oxford) (2011) 50(3):450-62. doi:10.1093/rheumatology/keq266
66. Iannone F, Lopalco G, Rigante D, Orlando I, Cantarini L, Lapadula G. Impact of obesity on the clinical outcome of rheumatologic patients in biotherapy. Autoimmun Rev (2016) 15(5):447-50. doi:10.1016/j.autrev.2016.01.010
67. Gonzalez-Gay MA, Gonzalez-Juanatey C. Rheumatoid arthritis: obesity impairs efficacy of anti-TNF therapy in patients with RA. Nat Rev Rheumatol (2012) 8(11):641-2. doi:10.1038/nrrheum.2012.158
68. Iannone F, Courvoisier DS, Gottenberg JE, Hernandez MV, Lie E, Canhao H, et al. Body mass does not impact the clinical response to intravenous abatacept in patients with rheumatoid arthritis. Analysis from the "pan-European registry collaboration for abatacept (PANABA)". Clin Rheumatol (2017) 36(4):773-9. doi:10.1007/s10067-016-3505-5
69. Alvarez-Nemegyei J, Buenfil-Rello FA, Pacheco-Pantoja EL. Association between body composition and disease activity in rheumatoid arthritis. A systematic review. Reumatol Clin (2016) 12(4):190-5. doi:10.1016/j.reuma.2015.09.001
70. Liu Y, Hazlewood GS, Kaplan GG, Eksteen B, Barnabe C. Impact of obesity on remission and disease activity in rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) (2017) 69(2):157-65. doi:10.1002/acr.22932
71. Hallajzadeh J, Safiri S, Mansournia MA, Khoramdad M, Izadi N, Almasi-Hashiani A, et al. Metabolic syndrome and its components among rheumatoid arthritis patients: a comprehensive updated systematic review and meta-analysis. PLoS One (2017) 12(3):e0170361. doi:10.1371/journal.pone.0170361
72. Chung CP, Oeser A, Solus JF, Avalos I, Gebretsadik T, Shintani A, et al. Prevalence of the metabolic syndrome is increased in rheumatoid arthritis and is associated with coronary atherosclerosis. Atherosclerosis (2008) 196(2):756-63. doi:10.1016/j.atherosclerosis.2007.01.004
73. Wolfe F, Michaud K. Effect of body mass index on mortality and clinical status in rheumatoid arthritis. Arthritis Care Res (Hoboken) (2012) 64(10):1471-9. doi:10.1002/acr.21627
74. Sattar N, McInnes IB. Rheumatoid arthritis: debunking the obesity-mortality paradox in RA. Nat Rev Rheumatol (2015) 11(8):445-6. doi:10.1038/nrrheum.2015.93
75. Baker JF, George M, Baker DG, Toedter G, Von Feldt JM, Leonard MB. Associations between body mass, radiographic joint damage, adipokines and risk factors for bone loss in rheumatoid arthritis. Rheumatology (Oxford) (2011) 50(11):2100-7. doi:10.1093/rheumatology/ker294
76. Caplan L, Davis LA, Bright CM, Kerr GS, Lazaro DM, Khan NA, et al. Body mass index and the rheumatoid arthritis swollen joint count: an observational study. Arthritis Care Res (Hoboken) (2013) 65(1):101-6. doi:10.1002/acr.21734
77. Fukuda W, Omoto A, Ohta T, Majima S, Kimura T, Tanaka T, et al. Low body mass index is associated with impaired quality of life in patients with rheumatoid arthritis. Int J Rheum Dis (2013) 16(3):297-302. doi:10.1111/1756-185X.12079
78. Baker JF, Billig E, Michaud K, Ibrahim S, Caplan L, Cannon GW, et al. Weight loss, the obesity paradox, and the risk of death in rheumatoid arthritis. Arthritis Rheumatol (2015) 67(7):1711-7. doi:10.1002/art.39136
79. Vidal C, Barnetche T, Morel J, Combe B, Daien C. Association of body mass index categories with disease activity and radiographic joint damage in rheumatoid arthritis: a systematic review and metaanalysis. J Rheumatol (2015) 42(12):2261-9. doi:10.3899/jrheum.150224
80. Muller R, Kull M, Polluste K, Aart A, Eglit T, Lember M, et al. The metabolic profile in early rheumatoid arthritis: a high prevalence of metabolic obesity. Rheumatol Int (2017) 37(1):21-7. doi:10.1007/s00296-016-3464-9
81. Kerekes G, Nurmohamed MT, Gonzalez-Gay MA, Seres I, Paragh G, Kardos Z, et al. Rheumatoid arthritis and metabolic syndrome. Nat Rev Rheumatol (2014) 10(11):691-6. doi:10.1038/nrrheum.2014.121
82. McGrath CM, Young SP. Lipid and metabolic changes in rheumatoid arthritis. Curr Rheumatol Rep (2015) 17(9):57. doi:10.1007/s11926-015-0534-z
83. Ormseth MJ, Lipson A, Alexopoulos N, Hartlage GR, Oeser AM, Bian A, et al. Association of epicardial adipose tissue with cardiometabolic risk and metabolic syndrome in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) (2013) 65(9):1410-5. doi:10.1002/acr.22027
84. Giles JT, Ferrante AW, Broderick R, Zartoshti A, Rose J, Downer K, et al. Adipose tissue macrophages in rheumatoid arthritis: prevalence, disease related indicators, and associations with cardiometabolic risk factors. Arthritis Care Res (Hoboken) (2017). doi:10.1002/acr.23253
85. Stavropoulos-Kalinoglou A, Metsios GS, Panoulas VF, Nightingale P, Koutedakis Y, Kitas GD. Anti-tumour necrosis factor alpha therapy improves insulin sensitivity in normal-weight but not in obese patients with rheumatoid arthritis. Arthritis Res Ther (2012) 14(4):R160. doi:10.1186/ar3900
86. Lemmey AB, Wilkinson TJ, Clayton RJ, Sheikh F, Whale J, Jones HS, et al. Tight control of disease activity fails to improve body composition or physical function in rheumatoid arthritis patients. Rheumatology (Oxford) (2016) 55(10):1736-45. doi:10.1093/rheumatology/kew243
87. Scrivo R, Vasile M, Muller-Ladner U, Neumann E, Valesini G. Rheumatic diseases and obesity: adipocytokines as potential comorbidity biomarkers for cardiovascular diseases. Mediators Inflamm (2013) 2013:808125. doi:10.1155/2013/808125
88. Tolusso B, Alivernini S, Gigante MR, Ferraccioli G, Gremese E. Biomolecular features of inflammation in obese rheumatoid arthritis patients: management considerations. Expert Rev Clin Immunol (2016) 12(7):751-62. doi:10.1586/1744666X.2016.1159132
89. Gomez R, Conde J, Scotece M, Gomez-Reino JJ, Lago F, Gualillo O. What's new in our understanding of the role of adipokines in rheumatic diseases? Nat Rev Rheumatol (2011) 7(9):528-36. doi:10.1038/nrrheum.2011.107
90. Weyand CM, Goronzy JJ. Immunometabolism in early and late stages of rheumatoid arthritis. Nat Rev Rheumatol (2017) 13(5):291-301. doi:10.1038/nrrheum.2017.49
91. Yang Z, Shen Y, Oishi H, Matteson EL, Tian L, Goronzy JJ, et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med (2016) 8(331):331ra338. doi:10.1126/scitranslmed.aad7151
92. Weyand CM, Yang Z, Goronzy JJ. T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol (2014) 26(1):93-100. doi:10.1097/BOR.0000000000000011
93. Fulop T Jr, Larbi A, Dupuis G, Pawelec G. Ageing, autoimmunity and arthritis: perturbations of TCR signal transduction pathways with ageing-a biochemical paradigm for the ageing immune system. Arthritis Res Ther (2003) 5(6):290-302. doi:10.1186/ar1019
94. Weyand CM, Fulbright JW, Goronzy JJ. Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol (2003) 38(8):833-41. doi:10.1016/S0531-5565(03)00090-1
95. Boots AM, Maier AB, Stinissen P, Masson P, Lories RJ, De Keyser F. The influence of ageing on the development and management of rheumatoid arthritis. Nat Rev Rheumatol (2013) 9(10):604-13. doi:10.1038/nrrheum.2013.92
96. van Onna M, Boonen A. The challenging interplay between rheumatoid arthritis, ageing and comorbidities. BMC Musculoskelet Disord (2016) 17:184. doi:10.1186/s12891-016-1038-3
97. Weyand CM, Fujii H, Shao L, Goronzy JJ. Rejuvenating the immune system in rheumatoid arthritis. Nat Rev Rheumatol (2009) 5(10):583-8. doi:10.1038/nrrheum.2009.180
98. Cejka D, Hayer S, Niederreiter B, Sieghart W, Fuereder T, Zwerina J, et al. Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum (2010) 62(8):2294-302. doi:10.1002/art.27504
99. Steiner G, Smolen J. Autoantibodies in rheumatoid arthritis and their clinical significance. Arthritis Res (2002) 4(Suppl 2):S1-5. doi:10.1186/ar551
100. Abdul Wahab A, Mohammad M, Rahman MM, Mohamed Said MS. Anti-cyclic citrullinated peptide antibody is a good indicator for the diagnosis of rheumatoid arthritis. Pak J Med Sci (2013) 29(3):773-7.
101. Rapetti L, Chavele KM, Evans CM, Ehrenstein MR. B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis. Ann Rheum Dis (2015) 74(1):294-302. doi:10.1136/annrheumdis-2013-204049
102. Baker K, Rath T, Lencer WI, Fiebiger E, Blumberg RS. Cross-presentation of IgG-containing immune complexes. Cell Mol Life Sci (2013) 70(8):1319-34. doi:10.1007/s00018-012-1100-8
103. Adlowitz DG, Barnard J, Biear JN, Cistrone C, Owen T, Wang W, et al. Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of B cell depletion therapy, and biomarkers of response. PLoS One (2015) 10(6):e0128269. doi:10.1371/journal.pone.0128269
104. Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Poe JC, et al. Therapeutic B cell depletion impairs adaptive and autoreactive CD4+ T cell activation in mice. Proc Natl Acad Sci U S A (2007) 104(52):20878-83. doi:10.1073/pnas.0709205105
105. Byng-Maddick R, Ehrenstein MR. The impact of biological therapy on regulatory T cells in rheumatoid arthritis. Rheumatology (Oxford) (2015) 54(5):768-75. doi:10.1093/rheumatology/keu487
106. Salomon S, Guignant C, Morel P, Flahaut G, Brault C, Gourguechon C, et al. Th17 and CD24hiCD27+ regulatory B lymphocytes are biomarkers of response to biologics in rheumatoid arthritis. Arthritis Res Ther (2017) 19(1):33. doi:10.1186/s13075-017-1244-x
107. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol (2007) 7(6):429-42. doi:10.1038/nri2094
108. Meednu N, Zhang H, Owen T, Sun W, Wang V, Cistrone C, et al. Production of RANKL by memory B cells: a link between B cells and bone erosion in rheumatoid arthritis. Arthritis Rheumatol (2016) 68(4):805-16. doi:10.1002/art.39489
109. Abyad A, Boyer JT. Arthritis and aging. Curr Opin Rheumatol (1992) 4(2):153-9. doi:10.1097/00002281-199204000-00004
110. Tutuncu Z, Kavanaugh A. Rheumatic disease in the elderly: rheumatoid arthritis. Rheum Dis Clin North Am (2007) 33(1):57-70. doi:10.1016/j.rdc.2006.12.006
111. Hough AJ Jr, Webber RJ. Aging phenomena and osteoarthritis: cause or coincidence? Claude P. Brown memorial lecture. Ann Clin Lab Sci (1986) 16(6):502-10.
112. Aigner T, Rose J, Martin J, Buckwalter J. Aging theories of primary osteoarthritis: from epidemiology to molecular biology. Rejuvenation Res (2004) 7(2):134-45. doi:10.1089/1549168041552964
113. Jorgensen AEM, Kjaer M, Heinemeier KM. The effect of aging and mechanical loading on the metabolism of articular cartilage. J Rheumatol (2017) 44(4):410-7. doi:10.3899/jrheum.160226
114. Li YS, Xiao WF, Luo W. Cellular aging towards osteoarthritis. Mech Ageing Dev (2017) 162:80-4. doi:10.1016/j.mad.2016.12.012
115. Hugle T, Geurts J, Nuesch C, Muller-Gerbl M, Valderrabano V. Aging and osteoarthritis: an inevitable encounter? J Aging Res (2012) 2012:950192. doi:10.1155/2012/950192
116. Toh WS, Brittberg M, Farr J, Foldager CB, Gomoll AH, Hui JH, et al. Cellular senescence in aging and osteoarthritis. Acta Orthop (2016) 87(Suppl 363):6-14. doi:10.1080/17453674.2016.1235087
117. Appelt CJ, Burant CJ, Siminoff LA, Kwoh CK, Ibrahim SA. Arthritis-specific health beliefs related to aging among older male patients with knee and/or hip osteoarthritis. J Gerontol A Biol Sci Med Sci (2007) 62(2):184-90. doi:10.1093/gerona/62.2.184
118. Wang F, Cai F, Shi R, Wang XH, Wu XT. Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthritis Cartilage (2016) 24(3):398-408. doi:10.1016/j.joca.2015.09.019
119. Loeser RF. Aging and osteoarthritis. Curr Opin Rheumatol (2011) 23(5):492-6. doi:10.1097/BOR.0b013e3283494005
120. Loeser RF. Aging processes and the development of osteoarthritis. Curr Opin Rheumatol (2013) 25(1):108-13. doi:10.1097/BOR.0b013e32835a9428
121. Loeser RF. The role of aging in the development of osteoarthritis. Trans Am Clin Climatol Assoc (2017) 128:44-54.
122. de SSMV, Valadares AL, Costa-Paiva LH, Osis MJ, Sousa MH, Pinto-Neto AM. Aging, obesity, and multimorbidity in women 50 years or older: a population-based study. Menopause (2013) 20(8):818-24. doi:10.1097/GME.0b013e31827fdd8c
123. Barbour KE, Helmick CG, Boring M, Brady TJ. Vital signs: prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United States, 2013-2015. MMWR Morb Mortal Wkly Rep (2017) 66(9):246-53. doi:10.15585/mmwr.mm6609e1
124. Barbour KE, Helmick CG, Boring M, Qin J, Pan L, Hootman JM. Obesity trends among US adults with doctor-diagnosed arthritis 2009-2014. Arthritis Care Res (Hoboken) (2017) 69(3):376-83. doi:10.1002/acr.22958
125. Bliddal H, Leeds AR, Christensen R. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons-a scoping review. Obes Rev (2014) 15(7):578-86. doi:10.1111/obr.12173
126. Rahmati M, Nalesso G, Mobasheri A, Mozafari M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res Rev (2017) 40:20-30. doi:10.1016/j.arr.2017.07.004
127. Langa KM, Larson EB, Crimmins EM, Faul JD, Levine DA, Kabeto MU, et al. A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Intern Med (2017) 177(1):51-8. doi:10.1001/jamainternmed.2016.6807
128. Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol (2008) 7(9):812-26. doi:10.1016/S1474-4422(08)70169-8
129. Rizzi L, Rosset I, Roriz-Cruz M. Global epidemiology of dementia: Alzheimer's and vascular types. Biomed Res Int (2014) 2014:908915. doi:10.1155/2014/908915
130. Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. Global prevalence of dementia: a Delphi consensus study. Lancet (2005) 366(9503):2112-7. doi:10.1016/S0140-6736(05)67889-0
131. Vos SJB, van Boxtel MPJ, Schiepers OJG, Deckers K, de Vugt M, Carriere I, et al. Modifiable risk factors for prevention of dementia in midlife, late life and the oldest-old: validation of the libra index. J Alzheimers Dis (2017) 58(2):537-47. doi:10.3233/JAD-161208
132. Villringer A. The path from obesity and hypertension to dementia. Adv Exp Med Biol (2015) 821:5. doi:10.1007/978-3-319-08939-3_3
133. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol (2005) 62(10):1556-60. doi:10.1001/archneur.62.10.1556
134. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology (2008) 71(14):1057-64. doi:10.1212/01.wnl.0000306313.89165.ef
135. Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth WT Jr, et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol (2009) 66(3):336-42. doi:10.1001/archneurol.2008.582
136. Pedditizi E, Peters R, Beckett N. The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age Ageing (2016) 45(1):14-21. doi:10.1093/ageing/afv151
137. Albanese E, Launer LJ, Egger M, Prince MJ, Giannakopoulos P, Wolters FJ, et al. Body mass index in midlife and dementia: systematic review and meta-regression analysis of 589,649 men and women followed in longitudinal studies. Alzheimers Dement (Amst) (2017) 8:165-78. doi:10.1016/j.dadm.2017.05.007
138. Kiliaan AJ, Arnoldussen IA, Gustafson DR. Adipokines: a link between obesity and dementia? Lancet Neurol (2014) 13(9):913-23. doi:10.1016/S1474-4422(14)70085-7
139. Arnoldussen IA, Kiliaan AJ, Gustafson DR. Obesity and dementia: adipokines interact with the brain. Eur Neuropsychopharmacol (2014) 24(12):1982-99. doi:10.1016/j.euroneuro.2014.03.002
140. Naseer MI, Bibi F, Alqahtani MH, Chaudhary AG, Azhar EI, Kamal MA, et al. Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease. CNS Neurol Disord Drug Targets (2014) 13(2):305-11. doi:10.2174/18715273113126660147