Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press125310.17650/1726-9784-2021-20-2-10-18REVIEWSОБЗОРЫ ЛИТЕРАТУРЫCHRONIC INFLAMMATION IN THE ELDERLY: MECHANISMS AND ASSOCIATION WITH ATHEROSCLEROSISХРОНИЧЕСКОЕ ВОСПАЛЕНИЕ У ПОЖИЛЫХ: МЕХАНИЗМЫ РАЗВИТИЯ И СВЯЗЬ С АТЕРОСКЛЕРОЗОМhttps://orcid.org/0000-0001-5355-7943ZinovevP. A.ЗиновьевП. А.
Russian Federation

Pavel Andreevich Zinovev

1, A. A. Vishnevskiy 3 CMCH, Noviy village, Krasnogorsk, Moscow region 143420

Павел Андреевич Зиновьев

143420 Московская обл., городской округ Красногорск, п. Новый, терр. 3 ЦВКГ им. А. А. Вишневского, 1

pashaz_1991@mail.ruhttps://orcid.org/0000-0002-9374-3158ShubinaI. Zh.ШубинаИ. Ж.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

YamenskovV. V.ЯменсковВ. В.
Russian Federation

1, A. A. Vishnevskiy 3 CMCH, Noviy village, Krasnogorsk, Moscow region 143420

143420 Московская обл., городской округ Красногорск, п. Новый, терр. 3 ЦВКГ им. А. А. Вишневского, 1

https://orcid.org/0000-0002-0132-167XKiselevskiyM. V.КиселевскийМ. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

A.A. Vishnevskiy 3 Central Military Clinical Hospital, Ministry of Defense of RussiaФГБУ «3 Центральный военный клинический госпиталь им. А. А. Вишневского» Минобороны РоссииN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России1407202120210181307202113072021https://bioterapevt.abvpress.ru/jour/article/view/1253

In 2000 Claudio Franceschi first used the term “inflammageing” derived from the English words “inflammation” and “age”. This term refers to the development of chronic inflammation in the elderly, which is characterized by a high level of pro-inflammatory markers of cells and tissues. Cellular aging can be triggered by a variety of factors: critical telomere shortening, permanent DNA damage, epigenetic damage, mitochondrial dysfunction, and an increase in the number of molecular fragments associated with cell damage.A large number of markers have been found to reveal the pro-inflammatory status, such as interleukin (IL) 1, IL-1ra (IL-1 receptor antagonist protein), IL-6, -8, -13, -18, C-reactive protein, interferons α, β, transforming growth factor β, tumor necrosis factor α and its soluble receptors and SAA-1 (serum amyloid А1). The molecular mechanisms associated with aging and age-related diseases are not clear yet, while sluggish chronic inflammation is one of the leading mechanisms for the atherosclerosis development. Remodeling of the immune system with the increasing production of pro-inflammatory cytokines and NLRP3 inflammasomes also play a key role in the maintenance of chronic inflammation due to its ability to pick up a variety of age-related dangerous signals that trigger the immune response and subsequent inflammation and may act as a factor of the atherosclerosis development.Thus, pro-inflammatory factors of the immune system play an important role in pathogenesis of atherosclerosis,especially at an early stage, involving various mechanisms of action that boost atherosclerotic changes.

В  2000  г. Claudio Franceschi впервые использовал термин “inflammageing”, который является производным от английских слов inflammation (воспаление) и age (возраст). Этим термином обозначается состояние, при котором у лиц пожилого возраста развивается хроническое воспаление и  которое характеризуется высоким уровнем провоспалительных медиаторов клеток и тканей. Клеточное старение может быть запущено различными факторами: критическим укорочением теломер, постоянным повреждением ДНК, эпигенетическими повреждениями, митохондриальной дисфункцией и увеличением количества молекулярных фрагментов, ассоциированных с повреждениями клеток.Обнаружено большое количество маркеров, изменение которых говорит о наличии воспалительного статуса, характеризующегося высоким уровнем провоспалительных факторов, включающих интерлейкин (ИЛ) 1, ИЛ-1ra (белок антагониста рецептора ИЛ-1), ИЛ-6, -8, -13, -18, С-реактивный белок, интерфероны α, β, трансформирующий фактор роста β, фактор некроза опухоли α и его растворимые рецепторы и SAA-1 (сывороточный амилоид А1). Молекулярные механизмы, связанные со старением и болезнями, обусловленными возрастными изменениями, не до  конца ясны, при  этом вялотекущее хроническое воспаление является одним из  ведущих механизмов развития атеросклероза и других патологических процессов у лиц пожилого возраста. Инфламмасомы NLRP3 и  состояние иммунной системы в  целом, а  именно ее ремоделирование в  сторону увеличения продукции провоспалительных цитокинов, играют ключевую роль в поддержании хронического воспаления и могут быть факторами развития атеросклероза.Таким образом, на всех стадиях патогенеза атеросклероза, особенно на  начальном его этапе, важную роль играют провоспалительные факторы иммунной системы, которые через различные механизмы действия стимулируют атеросклеротические изменения сосудов.

cellular ageing, inflammationatherosclerosisinflammageingклеточное старение4 воспалениеатеросклерозинфламэйджинг1. Nannelli G., Ziche M., Donnini S., Morbidelli L. Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing. Biomedicines 2020;8(1):4. DOI: 10.3390/biomedicines8010004.Nannelli G., Ziche M., Donnini S., Morbidelli L. Endothelial Aldehyde Dehydrogenase 2 as a Target to Maintain Vascular Wellness and Function in Ageing. Biomedicines 2020;8(1):4. DOI: 10.3390/biomedicines8010004.2. Wagner D.D., Frenette P.S. The vessel wall and its interactions. Blood 2008;111(11):5271–81. DOI: 10.1182/blood-2008-01-078204.Wagner D.D., Frenette P.S. The vessel wall and its interactions. Blood 2008;111(11):5271–81. DOI: 10.1182/blood-2008-01-078204.3. Rajendran P., Rengarajan T., Thangavel J. et al. The vascular endothelium and human diseases. Int J Biol Sci 2013;9(10):1057–69. DOI: 10.7150/ijbs.7502.Rajendran P., Rengarajan T., Thangavel J. et al. The vascular endothelium and human diseases. Int J Biol Sci 2013;9(10):1057–69. DOI: 10.7150/ijbs.7502.4. Calder P.C., Bosco N., Bourdet-Sicard R. et al. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev 2017;40:95–119. DOI: 10.1016/j.arr.2017.09.001.Calder P.C., Bosco N., Bourdet-Sicard R. et al. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev 2017;40:95–119. DOI: 10.1016/j.arr.2017.09.001.5. 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.Ferrucci L., Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018;15(9):505–22. DOI: 10.1038/s41569-018-0064-2.6. Sebastian-Valverde М., Pasinetti G.M. The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process. Cells 2020;9(6):1552. DOI: 10.3390/cells9061552.Sebastian-Valverde М., Pasinetti G.M. The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process. Cells 2020;9(6):1552. DOI: 10.3390/cells9061552.7. Bonilla F.A., Oettgen H.C. Adaptive immunity. J Allergy Clin Immunol 2010;125(2 Suppl 2):S33–40. DOI: 10.1016/j.jaci.2009.09.017.Bonilla F.A., Oettgen H.C. Adaptive immunity. J Allergy Clin Immunol 2010;125(2 Suppl 2):S33–40. DOI: 10.1016/j.jaci.2009.09.017.8. Weiskopf D., Weinberger B., GrubeckLoebenstein B. The aging of the immune system. Transpl Int 2009;22(11):1041–50. DOI: 10.1111/j.1432-2277.2009.00927.x.Weiskopf D., Weinberger B., GrubeckLoebenstein B. The aging of the immune system. Transpl Int 2009;22(11):1041–50. DOI: 10.1111/j.1432-2277.2009.00927.x.9. Ferrando-Martínez S., Ruiz-Mateos E., Hernandez A. et al. Age-related deregulation of naive T cell homeostasis in elderly humans. Age 2010;33(2):197–207. DOI: 10.1007/s11357-010-9170-8.Ferrando-Martínez S., Ruiz-Mateos E., Hernandez A. et al. Age-related deregulation of naive T cell homeostasis in elderly humans. Age 2010;33(2):197–207. DOI: 10.1007/s11357-010-9170-8.10. Weng N.-P. Aging of the Immune System: How Much Can the Adaptive Immune System Adapt? Immunity 2006;24(5):495–9. DOI: 10.1016/j.immuni.2006.05.001.Weng N.-P. Aging of the Immune System: How Much Can the Adaptive Immune System Adapt? Immunity 2006;24(5):495–9. DOI: 10.1016/j.immuni.2006.05.001.11. Medzhitov R., Janeway C. Innate Immunity. N Engl J Med 2000;343(5):338–44. DOI: 10.1056/NEJM200008033430506.Medzhitov R., Janeway C. Innate Immunity. N Engl J Med 2000;343(5):338–44. DOI: 10.1056/NEJM200008033430506.12. de Almeida A.J.P.O., de Almeida Rezende M.S., Dantas S.H. et al. Unveiling the Role of Inflammation and Oxidative Stress on Age-Related Cardiovascular Diseases. Oxid Med Cell Longev 2020;2020:1954398. DOI: 10.1155/2020/1954398.de Almeida A.J.P.O., de Almeida Rezende M.S., Dantas S.H. et al. Unveiling the Role of Inflammation and Oxidative Stress on Age-Related Cardiovascular Diseases. Oxid Med Cell Longev 2020;2020:1954398. DOI: 10.1155/2020/1954398.13. Zuccolo E., Badi I., Scavello F. et al. The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification. Int J Mol Sci 2020;21(12):4454. DOI: 10.3390/ijms21124454.Zuccolo E., Badi I., Scavello F. et al. The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification. Int J Mol Sci 2020;21(12):4454. DOI: 10.3390/ijms21124454.14. Rea I.M., Gibson D.S., McGilligan V. et al. Age and Age-Related Diseases: Role of inflammation Triggers and Cytokines. Front Immunol 2018;9:586. DOI: 10.3389/fimmu.2018.00586.Rea I.M., Gibson D.S., McGilligan V. et al. Age and Age-Related Diseases: Role of inflammation Triggers and Cytokines. Front Immunol 2018;9:586. DOI: 10.3389/fimmu.2018.00586.15. Mortensen R.F. C-Reactive Protein, Inflammation, and Innate Immunity. Immunol Res 2001;24(2):163–76. DOI: 10.1385/IR:24:2:163.Mortensen R.F. C-Reactive Protein, Inflammation, and Innate Immunity. Immunol Res 2001;24(2):163–76. DOI: 10.1385/IR:24:2:163.16. Daiber A., Oelze M., Wenzel P. et al. Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress. Pharmacol Rep 2009;61(1):33–48. DOI: 10.1016/S1734-1140(09)70005-2.Daiber A., Oelze M., Wenzel P. et al. Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress. Pharmacol Rep 2009;61(1):33–48. DOI: 10.1016/S1734-1140(09)70005-2.17. Monti M., Donnini S., Giachetti A. et al. DeltaPKC inhibition or varepsilonPKC activation repairs endothelial vascular dysfunction by regulating eNOS post-translational modification. J Mol Cell Cardiol 2010;48(4):746–56. DOI: 10.1016/j.yjmcc.2009.11.002.Monti M., Donnini S., Giachetti A. et al. DeltaPKC inhibition or varepsilonPKC activation repairs endothelial vascular dysfunction by regulating eNOS post-translational modification. J Mol Cell Cardiol 2010;48(4):746–56. DOI: 10.1016/j.yjmcc.2009.11.002.18. Summers C., Rankin S.M., Condlie A.M. et al. Neutrophil kinetics in health and disease. Trends Immunol 2010;31(8):318–24. DOI: 10.1016/j.it.2010.05.006.Summers C., Rankin S.M., Condlie A.M. et al. Neutrophil kinetics in health and disease. Trends Immunol 2010;31(8):318–24. DOI: 10.1016/j.it.2010.05.006.19. Haybar H., Shahrabi S., Rezaeeyan H. et al. Endothelial Cells: From Dysfunction Mechanism to Pharmacological Effect in Cardiovascular Disease. Cardiovasc Toxicol 2019;19(1):13–22. DOI: 10.1007/s12012-018-9493-8.Haybar H., Shahrabi S., Rezaeeyan H. et al. Endothelial Cells: From Dysfunction Mechanism to Pharmacological Effect in Cardiovascular Disease. Cardiovasc Toxicol 2019;19(1):13–22. DOI: 10.1007/s12012-018-9493-8.20. Donnini S., Cantara S., Morbidelli L. et al. FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium. Cell Death Differ 2006;13(7): 1088–96. DOI: 10.1038/sj.cdd.4401803.Donnini S., Cantara S., Morbidelli L. et al. FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium. Cell Death Differ 2006;13(7): 1088–96. DOI: 10.1038/sj.cdd.4401803.21. Morbidelli L., Donnini S., Ziche M. Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents. Cardiooncology 2016;2(1):3. DOI: 10.1186/s40959-016-0010-6.Morbidelli L., Donnini S., Ziche M. Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents. Cardiooncology 2016;2(1):3. DOI: 10.1186/s40959-016-0010-6.22. Ungvari Z., Tarantini S., Kiss T. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol 2018;15(9):555–65. DOI: 10.1038/s41569-018-0030-z.Ungvari Z., Tarantini S., Kiss T. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol 2018;15(9):555–65. DOI: 10.1038/s41569-018-0030-z.23. Li B., Li W., Li X., Zhou H. Inflammation: A Novel Therapeutic Target/ Direction in Atherosclerosis. Curr Pharm Des 2017;23(8):1216–27. DOI: 10.2174/1381612822666161230142931.Li B., Li W., Li X., Zhou H. Inflammation: A Novel Therapeutic Target/ Direction in Atherosclerosis. Curr Pharm Des 2017;23(8):1216–27. DOI: 10.2174/1381612822666161230142931.24. Trott D.W., Fadel P.J. Inflammation as a mediator of arterial ageing. Exp Physiol 2019;104(10):1455–71. DOI: 10.1113/EP087499.Trott D.W., Fadel P.J. Inflammation as a mediator of arterial ageing. Exp Physiol 2019;104(10):1455–71. DOI: 10.1113/EP087499.25. Caruso P., Signori R., Moretti R. Small vessel disease to subcortical dementia: a dynamic model, which interfaces ageing, cholinergic dysregulation and the neurovascular unit. Vasc Health Risk Manag 2019;15:259–81. DOI: 10.2147/VHRM.S190470.Caruso P., Signori R., Moretti R. Small vessel disease to subcortical dementia: a dynamic model, which interfaces ageing, cholinergic dysregulation and the neurovascular unit. Vasc Health Risk Manag 2019;15:259–81. DOI: 10.2147/VHRM.S190470.26. Kroemer G., Zitvogel L. CD4+ T Cells at the Center of Inflammaging. Cell Metab 2020;32(1):4–5. DOI: 10.1016/j.cmet.2020.04.016.Kroemer G., Zitvogel L. CD4+ T Cells at the Center of Inflammaging. Cell Metab 2020;32(1):4–5. DOI: 10.1016/j.cmet.2020.04.016.27. Nguyen G.T., Green E.R., Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front Cell Infect Microbiol 2017;7:373. DOI: 10.3389/fcimb.2017.00373.Nguyen G.T., Green E.R., Mecsas J. Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance. Front Cell Infect Microbiol 2017;7:373. DOI: 10.3389/fcimb.2017.00373.28. Peng Z., Zhan H., Shao Y. et al. 13-Methylberberine improves endothelial dysfunction by inhibiting NLRP3 inflammasome activation via autophagy induction in human umbilical vein endothelial cells. Chin Med 2020;15:8. DOI: 10.1186/s13020-020-0286-1.Peng Z., Zhan H., Shao Y. et al. 13-Methylberberine improves endothelial dysfunction by inhibiting NLRP3 inflammasome activation via autophagy induction in human umbilical vein endothelial cells. Chin Med 2020;15:8. DOI: 10.1186/s13020-020-0286-1.29. Tortorella C., Piazzolla G., Spaccavento F. et al. Age-related effects of oxidative metabolism and cyclic AMP signaling on neutrophil apoptosis. Mech Ageing Dev 1999;110(3):195–205. DOI: 10.1016/S0047-6374(99)00055-x.Tortorella C., Piazzolla G., Spaccavento F. et al. Age-related effects of oxidative metabolism and cyclic AMP signaling on neutrophil apoptosis. Mech Ageing Dev 1999;110(3):195–205. DOI: 10.1016/S0047-6374(99)00055-x.30. Bäck M., Yurdagul A.Jr., Tabas I. et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 2019;16(7):389–406. DOI: 10.1038/s41569-019-0169-2.Bäck M., Yurdagul A.Jr., Tabas I. et al. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 2019;16(7):389–406. DOI: 10.1038/s41569-019-0169-2.31. Fülöp T., Larbi A., Douziech N. et al. Signal transduction and functional changes in neutrophils with aging. Aging Cell 2004;3(4):217–26. DOI: 10.1111/j.1474-9728.2004.00110.x.Fülöp T., Larbi A., Douziech N. et al. Signal transduction and functional changes in neutrophils with aging. Aging Cell 2004;3(4):217–26. DOI: 10.1111/j.1474-9728.2004.00110.x.32. Ito Y., Kajkenova O., Feuers R.J. et al. Impaired glutathione peroxidase activity accounts for the age-related accumulation of hydrogen peroxide in activated human neutrophils. J Gerontol A Biol Sci Med Sci 1998;53(3):M169–75. DOI: 10.1093/gerona/53a.3.m169.Ito Y., Kajkenova O., Feuers R.J. et al. Impaired glutathione peroxidase activity accounts for the age-related accumulation of hydrogen peroxide in activated human neutrophils. J Gerontol A Biol Sci Med Sci 1998;53(3):M169–75. DOI: 10.1093/gerona/53a.3.m169.