Abstract
Introduction. Proinflammatory cytokines produced in elevated concentrations in the elderly significantly impair neurogenesis in the dentate gyrus of the hippocampus, long-term potentiality, alter neuronal morphology and function, and increase apoptosis. This leads to impaired episodic memory, executive function, and spatial learning, as well as neurodegeneration. Half of the elderly suffer from sleep disorders. Insomnia causes activation of microglia and increases 24-hour expression of proinflammatory cytokines, which enhances pre-existing inflammation, which in turn exacerbates insomnia.
Objective: to systematize scientific data on the role of sleep disorders in the development of neuroinflammation in the elderly, other causes and consequences of this condition, as well as on methods of insomnia correction in the elderly.
Material and methods: an analysis of the main foreign and domestic sources from PubMed/Medline, elibrary.ru databases was performed.
Conclusion. Aging is associated with the inevitable accumulation of cellular damage and depletion of endogenous mechanisms to eliminate DAMPs. Their excessive amount excessively activates NLRP3 inflammasome expressing proinflammatory cytokines. Chronic sleep deprivation in aging occurs because of disturbances in the interaction between sleep homeostatic mechanisms and circadian clock parameters, resulting in increased levels of proinflammatory cytokines. Increased levels of neuroinflammation impair the survival and proliferation of new neurons and their proper integration into pre-existing hippocampal neural networks encoding spatial information. Increased apoptosis, impaired gliogenesis, dendritic atrophy, and loss of synapses also contribute to the decreased size of the hippocampus in sleep disorders.
The use of behavioral strategies to improve sleep quality in the elderly (sleep hygiene, moderate exercise, and social activity) has been discussed to correct the negative effects of chronic neuroinflammation.
Authors and affiliations
K.E. Nazarova, R.A. Kostromina, N.A. Malinovskaya, E.D. Khilazheva, Y.K. Komleva
Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Departament of Biochemistry, Medical,
Pharmaceutical & Toxicological Chemistry, Partizana Zheleznyaka str., 1Z, Krasnoyarsk, 660022, Russian Federation
References
Rudnicka E., Napierała P., Podfigurna A., Męczekalski B., Smolarczyk R., Grymowicz M. The World Health Organization (WHO) approach to healthy ageing. Maturitas. 2020; 139: 6–11. DOI: https://doi.org/10.1016/j.maturitas.2020.05.018
Komleva Y., Chernykh A., Lopatina O., Gorina Y., Lokteva I., Salmina A., Gollasch M. Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration. Front Neurosci. 2020; 14: 618395. DOI: https://doi.org/10.3389/fnins.2020.618395
Harada C.N., Natelson Love M.C., Triebel K.L. Normal Cognitive Aging. Clin Geriatr Med. 2013; 29 (4): 737–52. DOI: https://doi.org/10.1016/j.cger.2013.07.002
Simen A.A., Bordner K.A., Martin M.P., Moy L.A., Barry L.C. Cognitive Dysfunction with Aging and the Role of Inflammation. Ther Adv Chronic Dis. 2011; 2 (3): 175–95. DOI: https://doi.org/10.1177/2040622311399145
Reid K.J., Baron K.G., Lu B., Naylor E., Wolfe L., Zee P.C. Aerobic exercise improves self-reported sleep and quality of life in older adults with insomnia. Sleep Med. 2010; 11 (9): 934–40. DOI: https://doi.org/10.1016/j.sleep.2010.04.014
Foley D.J., Monjan A.A., Brown S.L., Simonsick E.M., Wallace R.B., Blazer D.G. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995; 18 (6): 425–32. DOI: https://doi.org/10.1093/sleep/18.6.425
Ingiosi A.M., Opp M.R., Krueger J.M. Sleep and immune function: glial contributions and consequences of aging. Curr Opin Neurobiol. 2013; 23 (5): 806–11. DOI: https://doi.org/10.1016/j.conb.2013.02.003
Choudhury M.E., Miyanishi K., Takeda H., Tanaka J. Microglia and the Aging Brain: Are Geriatric Microglia Linked to Poor Sleep Quality? Int J. Mol. Sci. 2021; 22 (15): 7824. DOI: https://doi.org/10.3390/ijms22157824
Hurtado-Alvarado G., Pavón L., Castillo-Garcia S.A., Hernández M.E., Dominguez-Salazar E., Velázquez-Moctezuma J., Gómez-González B. Sleep Loss as a Factor to Induce Cellular and Molecular Inflammatory Variations. Clin Dev Immunol. 2013; 2013: 801341. DOI: https://doi.org/10.1155/2013/801341
Кувачева Н.В., Моргун А.В., Хилажева Е.Д., Малиновская Н.А., Горина Я.В., Пожиленкова Е.А., Фролова О.В., Труфанова Л.В., Мартынова Г.П., Салмина А.Б. Формирование инфламмасом: новые механизмы регуляции межклеточных взаимодействий и секреторной активности клеток. Сибирское Медицинское Обозрение. 2013; 5: 3–10. [Kuvacheva N.V., Morgun A.V., Hilazheva E.D., Malinovskaja N.A., Gorina Ja.V., Pozhilenkova E.A., Frolova O.V., Trufanova L.V., Martynova G.P., Salmina A.B. Inflammasomes forming: new mechanisms of intercellular interactions regulation and secretory activity of the cells. Sibirskoe Medicinskoe Obozrenie. 2013; 5: 3–10 (in Russian)]
Kelley N., Jeltema D., Duan Y., He Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J. Mol. Sci. 2019; 20 (13): 3328. DOI: https://doi.org/10.3390/ijms20133328
Zielinski M.R, Gibbons A.J. Neuroinflammation, Sleep, and Circadian Rhythms. Front Cell Infect Microbiol. 2022; 12: 853096. DOI: https://doi.org/10.3389/fcimb.2022.853096
Guo H., Callaway J.B., Ting J.P. Inflammasomes: Mechanism of Action, Role in Disease, and Therapeutics. Nat Med. 2015; 21 (7): 677–87. DOI: https://doi.org/10.1038/nm.3893
Ransohoff R.M, Brown M.A. Innate immunity in the central nervous system. J Clin Invest. 2012; 122 (4): 1164–71. DOI: https://doi.org/10.1172/JCI58644
Goldberg E.L., Dixit V.D. Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev. 2015; 265 (1): 63–74. DOI: https://doi.org/10.1111/imr.12295
Deleidi M., Jäggle M., Rubino G. Immune aging, dysmetabolism, and inflammation in neurological diseases. Front Neurosci. 2015; 9: 172. DOI: https://doi.org/10.3389/fnins.2015.00172
Di Benedetto S., Müller L., Wenger E., Düzel S., Pawelec G. Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions. Neurosci Biobehav Rev. 2017; 75: 114–28. DOI: https://doi.org/10.1016/j.neubiorev.2017.01.044
Игрункова А.В., Валиева Я.М., Калиниченко А.М., Курков А.В., Попова К.Ю., Шестаков Д.Ю., Заборова В.А. Клеточное старение: молекулярный и морфологический аспекты. Молекулярная медицина. 2022; 20 (4): 16–21. DOI: https://doi.org/10.29296/24999490-2022-04-03 [Igrunkova A.V., Valieva Ja.M., Kalinichenko A.M., Kurkov A.V., Popova K.Ju., Shestakov D.Ju., Zaborova V.A. Cellular senescence: molecular biology and morphology. Molekulyarnaya meditsina. 2022; 20 (4): 16–21 (in Russian). DOI: https://doi.org/10.29296/24999490-2022-04-03]
Youm Y.H., Grant R.W., McCabe L.R., Albarado D.C., Nguyen K.Y., Ravussin A., Pistell P., Newman S., Carter R., Laque A., Münzberg H., Rosen C.J., Ingram D.K., Salbaum J.M., Dixit V.D. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 2013; 18 (4): 519–32. DOI: https://doi.org/10.1016/j.cmet.2013.09.010
Brunt V.E., LaRocca T.J., Bazzoni A.E., Sapinsley Z.J., Miyamoto-Ditmon J., Gioscia-Ryan R.A., Neilson A.P., Link C.D., Seals D.R. The gut microbiome–derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging. GeroScience. 2020; 43 (1): 377–94. DOI: https://doi.org/10.1007/s11357-020-00257-2
Norden D.M., Muccigrosso M.M., Godbout J.P. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology. 2015; 96 (Pt A): 29–41. DOI: https://doi.org/10.1016/j.neuropharm.2014.10.028
Imeri L., Opp M.R. How (and why) the immune system makes us sleep. Nat Rev Neurosci. 2009; 10 (3): 199–210. DOI: https://doi.org/10.1038/nrn2576
Irwin M.R., Opp M.R. Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity. Neuropsychopharmacology. 2017; 42 (1): 129–55. DOI: https://doi.org/10.1038/npp.2016.148
Lee H.G., Won S.M., Gwag B.J., Lee Y.B. Microglial P2X7 receptor expression is accompanied by neuronal damage in the cerebral cortex of the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Exp Mol. Med. 2011; 43 (1): 7–14. DOI: https://doi.org/10.3858/emm.2011.43.1.001
Mander B.A., Winer J.R., Walker M.P. Sleep and Human Aging. Neuron. 2017; 94 (1): 19–36. DOI: https://doi.org/10.1016/j.neuron.2017.02.004
Leise T.L., Harrington M.E., Molyneux P.C., Song I., Queenan H., Zimmerman E., Lall G.S., Biello S.M. Voluntary exercise can strengthen the circadian system in aged mice. Age (Dordr). 2013; 35 (6): 2137–52. DOI: https://doi.org/10.1007/s11357-012-9502-y
Krueger J.M., Nguyen J.T., Dykstra-Aiello C.J., Taishi P. Local sleep. Sleep Med Rev. 2019; 43: 14–21. DOI: https://doi.org/10.1016/j.smrv.2018.10.001
Fonken L.K., Kitt M.M., Gaudet A.D., Barrientos R.M., Watkins L.R., Maier S.F. Diminished circadian rhythms in hippocampal microglia may contribute to age-related neuroinflammatory sensitization. Neurobiol Aging. 2016; 47: 102–12. DOI: https://doi.org/10.1016/j.neurobiolaging.2016.07.019
Zamore Z., Veasey S.C. Neural consequences of chronic sleep disruption. Trends Neurosci. 2022; 45 (9): 678–91. DOI: https://doi.org/10.1016/j.tins.2022.05.007
Cardinali D.P., Brown G.M., Pandi-Perumal S.R. Melatonin’s Benefits and Risks as a Therapy for Sleep Disturbances in the Elderly: Current Insights. Nat Sci Sleep. 2022; 14: 1843–55. DOI: https://doi.org/10.2147/NSS.S380465
Faraut B., Boudjeltia K.Z., Vanhamme L., Kerkhofs M. Immune, inflammatory and cardiovascular consequences of sleep restriction and recovery. Sleep Med Rev. 2012; 16 (2): 137–49. DOI: https://doi.org/10.1016/j.smrv.2011.05.001
Jewett K.A., Krueger J.M. Humoral sleep regulation; interleukin-1 and tumor necrosis factor. Vitam Horm. 2012; 89: 241–57. DOI: https://doi.org/10.1016/B978-0-12-394623-2.00013-5
Kapsimalis F., Basta M., Varouchakis G., Gourgoulianis K., Vgontzas A., Kryger M. Cytokines and pathological sleep. Sleep Med. 2008; 9 (6): 603–14. DOI: https://doi.org/10.1016/j.sleep.2007.08.019
Friedman E.M., Hayney M.S., Love G.D., Urry H.L., Rosenkranz M.A., Davidson R.J., Singer B.H., Ryff C.D. Social relationships, sleep quality, and interleukin-6 in aging women. Proc Natl Acad Sci USA. 2005; 102 (51): 18757–62. DOI: https://doi.org/10.1073/pnas.0509281102
Zhu B., Dong Y., Xu Z., Gompf H.S., Ward S.A., Xue Z., Miao C., Zhang Y., Chamberlin N.L., Xie Z. Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis. 2012; 48 (3): 348–55. DOI: https://doi.org/10.1016/j.nbd.2012.06.022
Rockstrom M., Chen L., Taishi P., Nguyen J.T., Gibbons C.M., Veasey S., Krueger J.M. Tumor Necrosis Factor Alpha in Sleep Regulation. Sleep Med Rev. 2018; 40: 69–78. DOI: https://doi.org/10.1016/j.smrv.2017.10.005
Garofalo S., Picard K., Limatola C., Nadjar A., Pascual O., Tremblay MÈ. Role of Glia in the Regulation of Sleep in Health and Disease. Compr Physiol. 2020; 10 (2): 687–712. DOI: https://doi.org/10.1002/cphy.c190022
Obal F., Krueger J.M. Biochemical regulation of non-rapid-eye-movement sleep. Front Biosci. 2003; 8: 520–50. DOI: https://doi.org/10.2741/1033
Xia M., Li X., Yang L., Ren J., Sun G., Qi S., Verkhratsky A., Li B. The ameliorative effect of fluoxetine on neuroinflammation induced by sleep deprivation. J. Neurochem. 2017; 146: 63–75. DOI: https://doi.org/10.1111/jnc.14272
Bellesi M., de Vivo L., Chini M., Gilli F., Tononi G., Cirelli C. Sleep Loss Promotes Astrocytic Phagocytosis and Microglial Activation in Mouse Cerebral Cortex. J. Neurosci. 2017; 37 (21): 5263–73. DOI: https://doi.org/10.1523/JNEUROSCI.3981-16.2017
Marshall L., Born J. Brain-immune interactions in sleep. Int Rev Neurobiol. 2002; 52: 93–131. DOI: https://doi.org/10.1016/s0074-7742(02)52007-9
Mullington J.M., Simpson N.S., Meier-Ewert H.K., Haack M. Sleep Loss and Inflammation. Best Pract Res Clin Endocrinol Metab. 2010; 24 (5): 775–84. DOI: https://doi.org/10.1016/j.beem.2010.08.014
Reutrakul S., Van Cauter E. Sleep influences on obesity, insulin resistance, and risk of type 2 diabetes. Metabolism. 2018; 84: 56–66. DOI: https://doi.org/10.1016/j.metabol.2018.02.010
Drapeau E., Nora Abrous D. Stem Cell Review Series: Role of neurogenesis in age-related memory disorders. Aging Cell. 2008; 7 (4): 569–89. DOI: https://doi.org/10.1111/j.1474-9726.2008.00369.x
Isaev N.K., Stelmashook E.V., Genrikhs E.E. Neurogenesis and brain aging. Reviews in the Neurosciences. 2019; 30 (6): 573–80. DOI: https://doi.org/10.1515/revneuro-2018-0084
Leeman D.S., Hebestreit K., Ruetz T., Webb A.E., McKay A., Pollina E.A., Dulken B.W., Zhao X., Yeo R.W., Ho T.T., Mahmoudi S., Devarajan K., Passegué E., Rando T.A., Frydman J., Brunet A. Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science. 2018; 359 (6381): 1277–83. DOI: https://doi.org/10.1126/science.aag3048
Calabrese F., Rossetti A.C., Racagni G., Gass P., Riva M.A., Molteni R. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci. 2014; 8: 430. DOI: https://doi.org/10.3389/fncel.2014.00430
Gonçalves J.T., Schafer S.T., Gage F.H. Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. Cell. 2016; 167 (4): 897–914. DOI: https://doi.org/10.1016/j.cell.2016.10.021
Kreutzmann J.C., Havekes R., Abel T., Meerlo P. Sleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function. Neuroscience. 2015; 309: 173–90. DOI: https://doi.org/10.1016/j.neuroscience.2015.04.053
Bah T.M., Goodman J., Iliff J.J. Sleep as a Therapeutic Target in the Aging Brain. Neurotherapeutics. 2019; 16 (3): 554–68. DOI: https://doi.org/10.1007/s13311-019-00769-6