Age-dependent disregulation of the immune response in humans

The review article analyzes literature data on the issues of immune response dysregulation during aging. It has been shown that impairment of innate and adaptive immune response in elderly and senile people under the conditions of spreading the new coronavirus infection is an aggravating factor in the course of the disease and recovery. Neuro-immuno-endocrine changes occurring in the organs of immune system, immunocompetent cells, molecules and receptor formations involved into the arising immune response have been traced. The imbalance of the brain-intestine-microbiota axis is considered in sufficient details, where a significant role is attributed to the changes occurring in hypothalamic-adrenal system under participation of biogenic neurotransmitters and neuromodulators. It is shown that intestinal microbiota may be involved into the neurodegeneration events, due to toxic effects on the brain via the neuro-immuno-endocrine and metabolic pathways. The data are presented, which show that adrenaline, norepinephrine, dopamine and serotonin are involved in the immune response dysregulation, thus making this process similar to the changes that occur during the general adaptation syndrome and stress response of the body. On the other hand, the review notes that chronic stress during aging not only alters the activity of macrophages, lymphocytes and dendritic cells, but also increases the level of proinflammatory cytokines in blood, thereby affecting permeability of the blood-brain barrier. The article emphasizes that with body aging, a neuroendocrine sensory pathway of immune response dysregulation is gradually formed. In this regard, it is noted that the afferent nerve endings and neurons of the vagus, adrenergic and peptidergic nerves are involved into dysfunction of immune system by affecting the processes occurring not only in thymus, but also in the brain. However, it is obvious that the pathodynamic “dysadapting circuit” formed in the higher compartments of nervous system is also involved in dysregulatory immune responses during aging. Hence, the work concludes that the signaling networks of the body's regulatory systems (nervous, immune and endocrine) are closely interconnected throughout the lifetime, but with aging and penetration of antigens into the body, this interaction is easily disrupted at different levels of organization of living matter, thus leading to dysregulation.

1. Artemenkov A.A. Maladaptive dysregulation of functions during aging. Uspekhi gerontologii = Advances in Gerontology, 2018, Vol. 31, no. 5, pp. 696-706. (In Russ.)

2. Artemenkov A.A. Maladaptive neuropathological syndrome of aging of blood vessels. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology, 2019, no. 24 (9), pp. 33-40. (In Russ.)

3. Artemieva O.V., Gankovskaya L.V. Inflammatory aging as the basis of age-associated pathology. Meditsinskaya immunologiya = Medical Immunology (Russia), 2020, Vol. 22, no. 3, pp. 419-432. (In Russ.) doi: 10.15789/1563-0625-IAT-1938.

4. Korneva E.A. Ways of interaction of the nervous and immune systems: history and modernity, clinical application. Meditsinskaya immunologiya = Medical Immunology (Russia), 2020, Vol. 22, no. 3, pp. 405-418. (In Russ.) doi: 10.15789/1563-0625-PON-1974.

5. Kuznik B.I., Chalisova N.I., Tsybikov N.N., Linkova N.S., Davydov S.O. Stress, aging and a unified humoral defense system. Epigenetic mechanisms of regulation. Uspekhi fiziologicheskikh nauk = Advances in Physiological Sciences, 2020, Vol. 51, no. 3, pp. 51-68. (In Russ.)

6. Mechnikov I.I. Notes of an old biologist. How to live and when to die. Moscow: Rodina, 2020. 512 p.

7. Nizhegorodova D.B., Levkovskaya A.N., Zafranskaya M.M. Immunological mechanisms of neuroinflammation and neurodegeneration. Immunologiya, allergologiya, infektologiya = Immunology, Allergology, Infectology, 2018, no. 4, pp. 27-42. (In Russ.)

8. Proshkina E.N., Soloviev I.A., Shaposhnikov M.V., Moskalev A.A. Key molecular mechanisms of aging, biomarkers and potential interventions. Molekuljarnaya biologiya = Molecular Biology, 2020, Vol. 54, no. 6, pp. 883-921. (In Russ.)

9. Pukhalsky A.L., Shmarina G.V., Alyoshkin V.A. Immunological impairments and cognitive deficits during stress and physiological aging. Part I: pathogenesis and risk factors. Vestnik RAMN = Bulletin of the Russian Academy of Medical Sciences, 2014, no. 5-6, pp. 14-22. (In Russ.)

10. Romanchuk N.P. Healthy microbiota and natural functional nutrition: humoral and cellular immunity. Byulleten nauki i praktiki = Bulletin of Science and Practice, 2020, Vol. 6, no. 9, pp. 127-166. (In Russ.)

11. Sladkova E.A., Shamrai E.A., Tishchenko A.Yu., Skorkina M.Yu. Functional characteristics of peripheral blood of people of mature age upon activation of the purinergic signaling system. Zhurnal mediko-biologicheskikh issledovaniy = Journal of Biomedical Research, 2019, Vol. 7, no. 3, pp. 272-279. (In Russ.)

12. Sobol K.V. The role of microbiota in neurodegenerative diseases. Ontogenez = Ontogenesis, 2018, Vol. 49, no. 6, pp. 333-352. (In Russ.)

13. Tikhovskaya T.I., Belova O.V., Zimina I.V., Kryuchkova A.V., Moskvina S.N., Bystrova O.V., Arion V.Ya., Sergienko V.I. Neuropeptides, cytokines and thymotic peptides as effectors of interaction between the thymus and the neuroendocrine system. Vestnik RAMN = Bulletin of the Russian Academy of Medical Sciences, 2015, Vol. 70, no. 6, pp. 727-733. (In Russ.)

14. Shirinsky V.S., Shirinsky I.S. Polymorbidity, aging of the immune system and systemic sluggish inflammation - a challenge to modern medicine. Meditsinskaya immunologiya = Medical Immunology (Russia), 2020, Vol. 22, no. 4, pp. 609-624. (In Russ.) doi: 10.15789/1563-0625-PAO-2042.

15. Yuzhaninova S.V., Saidakova E.V. The phenomenon of immune exhaustion. Uspekhi sovremennoj biologii = Advances in Modern Biology, 2017, Vol. 137, no. 1, pp. 70-83. (In Russ.)

16. Akha A.A.S. Aging and the immune system: An overview. J. Immunol. Methods, 2018, Vol. 463, pp. 21-26.

17. Alonso-Fernandez P., de la Fuente M. Role of the immune system in aging and longevity. Curr. Aging Sci., 2011, Vol. 4, no. 2, pp. 78-100.

18. Becher B., Spath S., Goverman J. Cytokine networks in neuroinflammation. Nat. Rev. Immunol., 2017, Vol. 17, no. 1, pp. 49-59.

19. Bowen L., Nath A., Smith B. CNS immune reconstitution inflammatory syndrome. Handb. Clin. Neurol., 2018, Vol. 152, pp. 167-176.

20. Cao W., Zheng H. Peripheral immune system in aging and Alzheimer's disease. Mol. Neurodegener., 2018, Vol. 13, no. 1, 51. doi: 10.1186/s13024-018-0284-2.

21. Castelo-Branco C., Soveral I. The immune system and aging: a review. Gynecol. Endocrinol., 2014, Vol. 30, no. 1, pp. 16-22. doi: 10.3109/09513590.2013.852531.

22. Cruces J., Venero C., Pereda-Perez I., de la Fuente M. The effect of psychological stress and social isolation on neuroimmunoendocrine communication. Curr. Pharm. Des., 2014, Vol. 20, no. 29, pp. 4608-4628.

23. Csaba G. Immunity and longevity. Acta Microbiol. Immunol. Hung., 2019, Vol. 66, no. 1, pp. 1-17.

24. Damiot A., Pinto A.J., Turner J.E., Gualano B. Immunological implications of physical inactivity among older adults during the COVID-19 pandemic. Gerontology, 2020, Vol. 66, no. 5, pp. 431-438.

25. de Miranda A.S., Zhang C.-J., Katsumoto A., Teixeira A.L. Hippocampal adult neurogenesis: does the immune system matter? J. Neurol. Sci., 2017, Vol. 372, pp. 482-495.

26. di Benedetto S., Muller L., Wenger E., Duzel S., Pawelec G. Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci. Biobehav. Rev., 2017, Vol., 75, pp. 114-128.

27. Fali T., Vallet H., Sauce D. Impact of stress on aged immune system compartments: overview from fundamental to clinical data. Exp, Gerontol., 2018, Vol. 105, pp. 19-26.

28. Farzi A., Frohlich E.E., Holzer P Gut microbiota and the neuroendocrine system. Neurotherapeutics, 2018, Vol. 15, no. 1, pp. 5-22.

29. Franceschi C., Bonafe M., Valensin S., Olivieri F., de Luca M., Ottaviani E., Benedictis G. De Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci., 2000, Vol. 908, pp. 244-254.

30. Fuentes E., Fuentes M., Alarcon M., Palomo I. Immune system dysfunction in the elderly. An. Acad. Bras. Cienc, 2017, Vol. 89, no. 1, pp. 285-299.

31. Haase S., Haghikia A., Wilck N., Muller D.N., Linker R.A. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology., 2018, Vol. 154, no. 2, pp. 230-238.

32. Hang S., Huh J. The immune-mind connection. Cell., 2019, Vol. 179, no. 4, pp. 803-805.

33. Kowalski K., Mulak A. Brain-gut-microbiota axis in alzheimer's disease. J. Neurogastroenterol. Motil., 2019, Vol. 25, no. 1, pp. 48-60.

34. Liang Z., Zhao Y., Ruan L., Zhu L., Jin K., Zhuge Q., Su D.-M., Zhao Y. Impact of aging immune system on neurodegeneration and potential immunotherapies. Prog. Neurobiol., 2017, Vol. 157, pp. 2-28.

35. Mittal R., Debs L.H., Patel A.P., Nguyen D., Patel K., O'Connor G., Grati M., Mittal J., Yan D., Eshraghi A.A., Deo S.K., Daunert S., Liu X.Z. Neurotransmitters: the critical modulators regulating gut-brain axis. J. Cell. Physiol., 2017, Vol. 232, no. 9, pp. 2359-2372.

36. Montecino-Rodriguez E., Berent-Maoz B., Dorshkind K. Causes, consequences, and reversal of immune system aging. J. Clin. Invest., 2013, Vol. 123, no. 3, pp. 958-965.

37. Muller L., di Benedetto S., Pawelec G. The immune system and its dysregulation with Aging. Subcell. Biochem., 2019, Vol. 91, pp. 21-43.

38. Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol., 2018, Vol. 19, no. 1, pp. 10-19.

39. Oglodek E., Szota A., Just M., Mos D., Araszkiewicz A. The role of the neuroendocrine and immune systems in the pathogenesis of depression. Pharmacol. Rep., 2014, Vol. 66, no. 5, pp. 776-781.

40. Pangrazzi L., Meryk A., Naismith E., Koziel R., Lair J., Krismer M., Trieb K., Grubeck-Loebenstein B. “Inflamm-aging” influences immune cell survival factors in human bone marrow. Eur. J. Immunol., 2017, Vol. 47, no. 3, pp. 481-492.

41. Patterson S. L Immune dysregulation and cognitive vulnerability in the aging brain: interactions of microglia, IL-1 в, BDNF and synaptic plasticity. Neuropharmacology. 2015, Vol. 96, (Pt A), pp. 11-18.

42. Pavlov V.A., Chavan S.S., Tracey K.J. Molecular and functional neuroscience in immunity. Annu. Rev. Immunol., 2018, Vol. 36, pp. 783-812.

43. Pedersen B.K., Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev., 2000, Vol. 80, no. 3, pp. 1055-1081.

44. Petra A.I., Panagiotidou S., Hatziagelaki E., Stewart J.M., Conti P., Theoharides T.C. Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther., 2015, Vol. 37, no. 5, pp. 984-995.

45. Ramirez K., Fornaguera-Tnas J., Sheridan J.F. Stress-induced microglia activation and monocyte trafficking to the brain underlie the development of anxiety and depression. Curr. Top. Behav. Neurosci., 2017, Vol. 31, pp. 155-172.

46. Ransohoff R.M., Schafer D., Vincent A., Blachere N.E., Bar-Or A. Neuroinflammation: ways in which the immune system affects the brain. Neurotherapeutics, 2015, Vol. 12, no. 4, pp. 896-909.

47. Shaw A.C., Joshi S., Greenwood H., Panda A., Lord J. M Aging of the innate immune system. Curr. Opin. Immunol., 2010, Vol. 22, no. 4, pp. 507-513.

48. Simpson R.J., Lowder T.W., Spielmann G., Bigley A.B., La Voy E.C., Kunz H. Exercise and the aging immune system. Ageing Res. Rev., 2012, Vol. 11, no. 3, pp. 404-420.

49. Spath S., Komuczki J., Hermann M., Pelczar P., Mair F., Schreiner B., Becher B. Invasion and immunopathology in the central nervous system. Immunity, 2017, Vol. 46, no. 2, pp. 245-260.

50. Straub R.H., Cutolo M. Psychoneuroimmunology-developments in stress research. Wien. Med. Wochenschr., 2018, Vol. 168, no. 3-4, pp. 76-84.

51. Thapa P., Farber D.L. The role of the thymus in the immune response. Thorac. Surg. Clin., 2019, Vol. 29, no. 2, pp. 123-131.

52. Vallet H., Fali T., Sauce D. Aging of the immune system: from fundamental to clinical data. Rev. Med. Interne, 2019, Vol. 40, no. 2, pp. 105-111.

53. Wilson D., Jackson T., Sapey E., Lord J.M. Frailty and sarcopenia: the potential role of an aged immune system. Ageing Res. Rev., 2017, Vol. 36, pp. 1-10.

54. Yirmiya K., Djalovski A., Motsan S., Zagoory-Sharon O., Feldman R. Stress and immune biomarkers interact with parenting behavior to shape anxiety symptoms in trauma-exposed youth. Psychoneuroendocrinology, 2018, Vol. 98, pp. 153-160.

55. Zapatera B., Prados A., Gomez-Martmez S., Marcos A. Immunonutrition: methodology and applications. Nutr. Hosp., 2015, Vol. 31, Suppl. 3, pp. 145-154.