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Interleukin 6 in aging and age­-related diseases

https://doi.org/10.17650/1818-8338-2020-14-3-4-K633

Abstract

Modern concepts about the importance of subclinical inflammation in various age-associated pathology are described in the review. The term “inflammaging” (inflammation due to aging) refers to the special role of inflammation in the aging processes. This type of inflammation is low-grade, controlled, asymptomatic, chronic and systemic. Inflammaging determines the rate of aging and life expectancy. The balance of pro-inflammatory and anti-inflammatory cytokines plays a significant role in aging processes. The increased levels of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α in the elderly are associated with different diseases, disability and mortality. Interleukin-6 is a multifunctional cytokine involved in the regulation of acute phase response and other immunological reactions, in the hematopoiesis and in chronic inflammation. This cytokine is important in the pathogenesis of chronic inflammation diseases, as well as different oncological disorders. Interleukin-6 is often called the “cytokine of gerontologists”, since it is one of the main signaling pathways associated with aging and age-related diseases. This cytokine also plays an important role in the pathogenesis of atherosclerosis, coronary artery disease, chronic heart failure and increases the risk of death from cardiovascular diseases and overall mortality. Interleukin-6 is a key proinflammatory cytokine responsible for the “metabolic inflammation”, obesity, insulin resistance and diabetes mellitus. This cytokine has a significant impact on the development of sarcopenia and frailty. The serum levels of interleukin-6 negatively correlate with muscle mass and skeletal muscle function in the elderly, so it is considered as a biomarker of sarcopenia and functional decline. Interleukin-6 may contribute to the development of osteoporosis by stimulating osteoclastogenesis and bone resorption. The modern data indicate the diverse effects of interleukin-6 and confirm the significant role of this cytokine in aging and in different age-associated pathology.

About the Author

S. V. Topolyanskaya
Sechenov First Moscow State Medical University, Ministry of Health of Russia
Russian Federation
Build 2, 8 Trubetskaya St., Moscow 119991


References

1. Franceschi C., Bonafé M., Valentin S. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244–54. DOI: 10.1111/j.1749-6632.2000.tb06651.x.

2. Xia S., Zhang X., Zheng S. et al. An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res 2016;8:8426874. DOI: 10.1155/2016/8426874.

3. Ferrucci L., Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018;15(9):505–22. DOI: 10.1038/S41569-018-0064-2.

4. Chung H.Y., Kim D.H., Lee E.K. et al. Redefining chronic inflammation in aging and age-related diseases: proposal of the senoinflammation concept. Aging Dis 2019;10(2):367–82. DOI: 10.14336/AD.2018.0324.

5. Fulop T., Witkowski J.M., Olivieri F., Larbi A. The integration of inflammaging in age-related diseases. Semin Immunol 2018;40:17–35. DOI: 10.1016/j.smim.2018.09.003.

6. Baylis D., Bartlett D.B., Patel H.P., Roberts H.C. Understanding how we age: insights into inflammaging. Longev Heal 2013;2(1):1–8. DOI: 10.1186/2046-2395-2-8.

7. Brüünsgaard H., Pedersen B.K. Agerelated inflammatory cytokines and disease. Immunol Allergy Clin North Am 2003;23(1):15–39. DOI: 10.1016/S0889-8561(02)00056-5.

8. Franceschi C., Campisi J. Chronic inflammation(Inflammaging) and its potential contribution to age-associated diseases. J Gerontol Ser A Biol Sci Med Sci 2014;69(Suppl.1):4–9. DOI: 10.1093/gerona/glu057.

9. Duggal N.A. Reversing the immune ageing clock: lifestyle modifications and pharmacological interventions. Biogerontology 2018;19(6):481–96. DOI: 10.1007/s10522-018-9771-7.

10. Rea I.M., Gibson D.S., McGilligan V. et al. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol 2018;9(9):586. DOI: 10.3389/fimmu.2018.00586.

11. Minciullo P.L., Catalano A., Mandraffino G. et al. Inflammaging and Anti-Inflammaging: The role of cytokines in extreme longevity. Arch Immunol Ther Exp 2016;64(2):111–26. DOI: 10.1007/s00005-015-0377-3.

12. Franceschi C., Capri M., Monti D. et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007;128(1):92–105. DOI: 10.1016/j.mad.2006.11.016.

13. Tanaka T., Narazaki M., Kishimoto T. Il-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014;6(10):016295. DOI: 10.1101/cshperspect.a016295.

14. Maggio M., Guralnik J.M., Longo D.L., Ferrucci L. Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci 2006;61(6):575–84. DOI: 10.1093/gerona/61.6.575.

15. Mauer J., Denson J.L., Brüning J.C. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol 2015;36(2):92–101. DOI: 10.1016/j.it.2014.12.008.

16. Kany S., Vollrath J.T., Relja B. Cytokines in inflammatory disease. Int J Mol Sci 2019;20(23):6008. DOI: 10.3390/ijms20236008.

17. Narazaki M., Kishimoto T. The Two-Faced Cytokine IL-6 in host defense and diseases. Int J Mol Sci 2018;19(11):3528. DOI: 10.3390/ijms19113528.

18. Bruunsgaard H., Ladelund S., Pedersen A.N. et al. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clin Exp Immunol 2003;132(1):24–31. DOI: 10.1046/j.1365-2249.2003.02137.x.

19. Ferrucci L., Corsi A., Lauretani F. et al. The origins of age-related proinflammatory state. Blood 2005;105(6):2294–9. DOI: 10.1182/blood-2004-07-2599.

20. Palmeri M., Misiano G., Malaguarnera M. et al. Cytokine Serum Profile in a Group of Sicilian Nonagenarians. J Immunoasay Immunochem 2012;33(1):82–90. DOI: 10.1080/15321819.2011.601781.

21. Sansoni P., Vescovini R., Fagnoni F. et al. The immune system in extreme longevity. Exp Gerontol 2008;43(2):61–5. DOI: 10.1016/j.exger.2007.06.008.

22. Mikó A., Pótó L., Márai P. et al. Gender difference in the effects of interleukin-6 on grip strength-a systematic review and meta-analysis. BMC Geriatr 2018;18(1):107. DOI: 10.1186/s12877-018-0798-z.

23. Legrand D., Adriaensen W., Vaes B. et al. The relationship between grip strength and muscle mass (MM), inflammatory biomarkers and physical performance in community-dwelling very old persons. Arch Gerontol Geriatr 2013;57(3):345–51. DOI: 10.1016/j.archger.2013.06.003.

24. Giovannini S., Onder G., Liperoti R. et al. Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha as predictors of mortality in frail, community-living elderly individuals. J Am Geriatr Soc 2011;59(9):1679–85. DOI: 10.1111/j.1532-5415.2011.03570.x.

25. Bruunsgaard H. Effects of tumor necrosis factor-α and interleukin-6 in elderly populations. Eur Cytokine Netw 2002;13(4):389–91.

26. Di Bona D., Vasto S., Capurso C. et al. Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res Rev 2009;8(1):36–42. DOI: 10.1016/j.arr.2008.09.001.

27. Su D., Li Z., Li X. et al. Association between serum interleukin-6 concentration and mortality in patients with coronary artery disease. Mediators Inflamm 2013;2013:726178. DOI: 10.1155/2013/726178.

28. Shinohara T., Takahashi N., Okada N. et al. Interleukin-6 as an independent predictor of future cardiovascular events in patients with type-2 diabetes without structural heart disease. J Clin Exp Cardiology 2012;3(9):209. DOI: 10.4172/2155-9880.1000209.

29. Qu D., Liu J., Lau C.W., Huang Y. IL-6 in diabetes and cardiovascular complications. Br J Pharmacol 2014;171(15):3595–603. DOI: 10.1111/bph.12713.

30. Ridker P.M. From CRP to IL-6 to IL-1: moving upstream to identify novel targets for atheroprotection. Circ Res 2016;118(1):145–56. DOI: 10.1161/CIRCRESAHA.115.306656.

31. Danesh J., Kaptoge S., Mann A.G. et al. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Med 2008;5(4):78. DOI: 10.1371/journal.pmed.0050078.

32. Tehrani D.M., Gardin J.M., Yanez D. et al. Impact of inflammatory biomarkers on relation of high density lipoproteincholesterol with incident coronary heart disease: Cardiovascular Health Study. Atherosclerosis 2013;231(2):246–51. DOI: 10.1016/j.atherosclerosis.2013.08.036.

33. Kaptoge S., Seshasai S.R.K., Gao P. et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J 2014;35(9):578–89. DOI: 10.1093/eurheartj/eht367.

34. Sarwar N., Butterworth A.S., Freitag D.F. et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012;379(9822):1205–13. DOI: 10.1016/S0140-6736(11)61931-4.

35. Eskandari V., Amirzargar A.A., Mahmoudi M.J. et al. Gene expression and levels of IL-6 and TNFα in PBMCs correlate with severity and functional class in patients with chronic heart failure. Ir J Med Sci 2018;187(2):359–68. DOI: 10.1007/s11845-017-1680-2.

36. Markousis-Mavrogenis G., Tromp J., Ouwerkerk W. et al. The clinical significance of interleukin-6 in heart failure: results from the BIOSTAT-CHF study. Eur J Heart Fail 2019;21(8):965–73. DOI: 10.1002/ejhf.1482.

37. Volpato S., Guralnik J.M., Ferrucci L. et al. Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women’s health and aging study. Circulation 2001;103(7):947–53. DOI: 10.1161/01.cir.103.7.947.

38. Arai Y., Takayama M., Gondo Y. et al. Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age. J Gerontol A Biol Sci Med Sci 2008;63(11):1209–18. DOI: 10.1093/gerona/63.11.1209.

39. Hamzic-Mehmedbasic A. Inflammatory cytokines as risk factors for mortality after acute cardiac events. Med Arch 2016;70(4):252–5. DOI: 10.5455/medarh.2016.70.252-255.

40. Pudil R., Tichý M., Andrýs C. et al. Plasma interleukin-6 level is associated with NT-proBNP level and predicts short- and long-term mortality in patients with acute heart failure. Acta Medica (Hradec Králové) 2010;53(4):225–8. DOI: 10.14712/18059694.2016.81.

41. Haugen E., Gan L.-M., Isic A. et al. Increased interleukin-6 but not tumour necrosis factor-alpha predicts mortality in the population of elderly heart failure patients. Exp Clin Cardiol 2008;13(1):19–24.

42. Puzianowska-Kuźnicka M., Owczarz M., Wieczorowska-Tobis K. et al. Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun Ageing 2016;13:21. DOI: 10.1186/s12979-016-0076-x.

43. Li H., Sun K., Zhao R. et al. Inflammatory biomarkers of coronary heart disease. Front Biosci (Schol Ed) 2018;10(1):185–96. DOI: 10.2741/s508.

44. Kim H.J., Higashimori T., Park S.-Y. et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 2004;53(4):1060–7. DOI: 10.2337/diabetes.53.4.1060.

45. Lowe G., Woodward M., Hillis G. et al. Circulating inflammatory markers and the risk of vascular complications and mortality in people with type 2 diabetes and cardiovascular disease or risk factors: the advance study. Diabetes 2014;63(3):1115–23. DOI: 10.2337/db12-1625.

46. Wang X., Bao W., Liu J. et al. Inflammatory markers and risk of type 2 diabetes: a systematic review and metaanalysis. Diabetes Care 2013;36(1):166–75. DOI: 10.2337/dc12-0702.

47. D’Elia H.F., Mattsson L.-A., Ohlsson C. et al. Hormone replacement therapy in rheumatoid arthritis is associated with lower serum levels of soluble IL-6 receptor and higher insulin-like growth factor 1. Arthritis Res Ther 2003;5(4):202–9. DOI: 10.1186/ar761.

48. Maggio M., Basaria S., Ble A. et al. Correlation between testosterone and the inflammatory marker soluble interleukin-6 receptor in older men. J Clin Endocrinol Metab 2006;91(1):345–7. DOI: 10.1210/jc.2005-1097.

49. Felicio D.C., Pereira D.S., Assumpcão A.M. et al. Inflammatory mediators, muscle and functional performance of communitydwelling elderly women. Arch Gerontol Geriatr 2014;59(3):549–53. DOI: 10.1016/j.archger.2014.08.004.

50. Patel H.P., Al-Shanti N., Davies L.C. et al. Lean mass, muscle strength and gene expression in community dwelling older men: findings from the Hertfordshire Sarcopenia Study (HSS). Calcif Tissue Int 2014;95(4):308–16. DOI: 10.1007/s00223-014-9894-z.

51. Volaklis K.A., Halle M., Koenig W. et al. Association between muscular strength and inflammatory markers among elderly persons with cardiac disease: results from the KORA-Age study. Clin Res Cardiol 2015;104(11):982–9. DOI: 10.1007/s00392-015-0867-7.

52. Nieman D.C., Davis J.M., Henson D.A. et al. Muscle cytokine mRNA changes after 2.5 h of cycling: Influence of carbohydrate. Med Sci Sports Exerc 2005;37(8):1283–90. DOI: 10.1249/01.mss.0000175054.99588.b1.

53. Febbraio M.A., Pedersen B.K. Musclederived interleukin-6: mechanisms for activation and possible biological roles. FASEB J 2002;16(11):1335–47. DOI: 10.1096/fj.01-0876rev.

54. Cappola A.R., Xue Q.-L., Ferrucci L. et al. Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J Clin Endocrinol Metab 2003;88(5):2019–25. DOI: 10.1210/jc.2002-021694.

55. Harmer D., Falank C., Reagan M.R. Interleukin-6 interweaves the bone marrow microenvironment, bone loss, and multiple myeloma. Front Endocrinol (Lausanne) 2019;9:788. DOI: 10.3389/fendo.2018.00788.

56. Donzis E.J., Tronson N.C. Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences. Neurobiol Learn Mem 2014;115:68–77. DOI: 10.1016/j.nlm.2014.08.008.

57. Lai K.S.P., Liu C.S., Rau A. et al. Peripheral inflammatory markers in Alzheimer’s disease: A systematic review and meta-analysis of 175 studies. J Neurol Neurosurg Psychiatry 2017;88(10):876–82. DOI: 10.1136/jnnp-2017-316201.

58. Bradburn S., Sarginson J., Murgatroyd C.A. Association of peripheral interleukin-6 with global cognitive decline in non-demented adults: a meta-analysis of prospective studies. Front Aging Neurosci 2018;9:438. DOI: 10.3389/fnagi.2017.00438.


Review

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Topolyanskaya S.V. Interleukin 6 in aging and age­-related diseases. The Clinician. 2020;14(3-4):10-17. (In Russ.) https://doi.org/10.17650/1818-8338-2020-14-3-4-K633

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ISSN 1818-8338 (Print)