Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions

Neuroscience and Biobehavioral Reviews

Volumn 75, Issue , 2017, Pages 114-128

  Di Benedetto, Svetlana ^a,b   Müller, Ludmila ^a   Wenger, Elisabeth ^a   Düzel, Sandra ^a   Pawelec, Graham ^b  

^a MAX PLANCK INSTITUTE FOR HUMAN DEVELOPMENT   (Germany)

^b UNIVERSITY OF TÜBINGEN   (Germany)

Author keywords

Aging; Brain; Cognition; Cognitive intervention; Cytokines; Immunosenescence; Inflammaging; Microglia; Neuroinflammation; Neuroplasticity; Neurotrophic factors; Physical exercise; T cells

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; INTERLEUKIN 1; INTERLEUKIN 10; INTERLEUKIN 4; SOMATOMEDIN C; TRANSFORMING GROWTH FACTOR BETA;

ASTROCYTE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; HELPER CELL; HUMAN; IMMUNE SYSTEM; IMMUNITY; IMMUNOMODULATION; IMMUNOSENESCENCE; MENTAL PERFORMANCE; MICROGLIA; NERVE CELL PLASTICITY; NERVOUS SYSTEM INFLAMMATION; NEUROIMMUNOLOGY; NONHUMAN; PHYSICAL ACTIVITY; REVIEW; TH1 CELL; TH2 CELL; AGING; BRAIN; COGNITION; INFLAMMATION;

AGING; BRAIN; COGNITION; HUMANS; IMMUNE SYSTEM; INFLAMMATION;

EID: 85011545486     PISSN: 01497634     EISSN: 18737528     Source Type: Journal    
DOI: 10.1016/j.neubiorev.2017.01.044     Document Type: Review

References (196)

1. Ahlskog, J.E., Geda, Y.E., Graff-Radford, N.R., Petersen, R.C., Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin. Proc. 86 (2011), 876–884.
2. Aid, T., Kazantseva, A., Piirsoo, M., Palm, K., Timmusk, T., Mouse and rat BDNF gene structure and expression revisited. J. Neurosci. Res. 85 (2007), 525–535.
3. Aimone, J.B., Li, Y., Lee, S.W., Clemenson, G.D., Deng, W., Gage, F.H., Regulation and function of adult neurogenesis: from genes to cognition. Physiol. Rev. 94 (2014), 991–1026.
4. Alboni, S., Maggi, L., Editorial: cytokines as players of neuronal plasticity and sensitivity to environment in healthy and pathological brain. Front. Cell. Neurosci., 9, 2015, 508.
5. Aloisi, F., Ria, F., Adorini, L., Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. Immunol. Today 21 (2000), 141–147.
6. Anthony, D.C., Bolton, S.J., Fearn, S., Perry, V.H., Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats. Brain 120:Pt 3 (1997), 435–444.
7. Arnold, C.R., Wolf, J., Brunner, S., Herndler-Brandstetter, D., Grubeck-Loebenstein, B., Gain and loss of T cell subsets in old age–age-related reshaping of the T cell repertoire. J. Clin. Immunol. 31 (2011), 137–146.
8. Au, A., Feher, A., McPhee, L., Jessa, A., Oh, S., Einstein, G., Estrogens, inflammation and cognition. Front. Neuroendocrinol. 40 (2016), 87–100.
9. Auffray, C., Fogg, D., Garfa, M., Elain, G., Join-Lambert, O., Kayal, S., Sarnacki, S., Cumano, A., Lauvau, G., Geissmann, F., Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317 (2007), 666–670.
10. Auffray, C., Fogg, D.K., Narni-Mancinelli, E., Senechal, B., Trouillet, C., Saederup, N., Leemput, J., Bigot, K., Campisi, L., Abitbol, M., Molina, T., Charo, I., Hume, D.A., Cumano, A., Lauvau, G., Geissmann, F., CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J. Exp. Med. 206 (2009), 595–606.
11. Bains, J.S., Oliet, S.H., Glia: they make your memories stick!. Trends Neurosci. 30 (2007), 417–424.
12. Bamidis, P.D., Vivas, A.B., Styliadis, C., Frantzidis, C., Klados, M., Schlee, W., Siountas, A., Papageorgiou, S.G., A review of physical and cognitive interventions in aging. Neurosci. Biobehav. Rev. 44 (2014), 206–220.
13. Banks, W.A., The blood-brain barrier in neuroimmunology: tales of separation and assimilation. Brain Behav. Immun. 44 (2015), 1–8.
14. Barrientos, R.M., Frank, M.G., Crysdale, N.Y., Chapman, T.R., Ahrendsen, J.T., Day, H.E., Campeau, S., Watkins, L.R., Patterson, S.L., Maier, S.F., Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J. Neurosci. 31 (2011), 11578–11586.
15. Barrientos, R.M., Frank, M.G., Watkins, L.R., Maier, S.F., Aging-related changes in neuroimmune-endocrine function: implications for hippocampal-dependent cognition. Horm. Behav. 62 (2012), 219–227.
16. Barrientos, R.M., Kitt, M.M., Watkins, L.R., Maier, S.F., Neuroinflammation in the normal aging hippocampus. Neuroscience 309 (2015), 84–99.
17. Baruch, K., Schwartz, M., CNS-specific T cells shape brain function via the choroid plexus. Brain Behav. Immun. 34 (2013), 11–16.
18. Baune, B.T., Ponath, G., Rothermundt, M., Riess, O., Funke, H., Berger, K., Association between genetic variants of IL-1beta, IL-6 and TNF-alpha cytokines and cognitive performance in the elderly general population of the MEMO-study. Psychoneuroendocrinology 33 (2008), 68–76.
19. Beattie, E.C., Stellwagen, D., Morishita, W., Bresnahan, J.C., Ha, B.K., Von Zastrow, M., Beattie, M.S., Malenka, R.C., Control of synaptic strength by glial TNFalpha. Science 295 (2002), 2282–2285.
20. Beery, A.K., Zucker, I., Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35 (2011), 565–572.
21. Ben-Smith, A., Gorak-Stolinska, P., Floyd, S., Weir, R.E., Lalor, M.K., Mvula, H., Crampin, A.C., Wallace, D., Beverley, P.C., Fine, P.E., Dockrell, H.M., Differences between naive and memory T cell phenotype in Malawian and UK adolescents: a role for Cytomegalovirus?. BMC Infect. Dis., 8, 2008, 139.
22. Bennett, J.M., Glaser, R., Malarkey, W.B., Beversdorf, D.Q., Peng, J., Kiecolt-Glaser, J.K., Inflammation and reactivation of latent herpesviruses in older adults. Brain Behav. Immun. 26 (2012), 739–746.
23. Berry, A., Carnevale, D., Giorgio, M., Pelicci, P.G., de Kloet, E.R., Alleva, E., Minghetti, L., Cirulli, F., Greater resistance to inflammation at adulthood could contribute to extended life span of p66(Shc-/-) mice. Exp. Gerontol. 45 (2010), 343–350.
24. Berry, A., Panetta, P., Luoni, A., Bellisario, V., Capoccia, S., Riva, M.A., Cirulli, F., Decreased Bdnf expression and reduced social behavior in periadolescent rats following prenatal stress. Dev. Psychobiol. 57 (2015), 365–373.
25. Beurel, E., Harrington, L.E., Buchser, W., Lemmon, V., Jope, R.S., Astrocytes modulate the polarization of CD4+ T cells to Th1 cells. PLoS One, 9, 2014, e86257.
26. Bherer, L., Cognitive plasticity in older adults: effects of cognitive training and physical exercise. Ann. N. Y. Acad. Sci. 1337 (2015), 1–6.
27. Bisht, K., Sharma, K.P., Lecours, C., Sanchez, M.G., El Hajj, H., Milior, G., Olmos-Alonso, A., Gomez-Nicola, D., Luheshi, G., Vallieres, L., Branchi, I., Maggi, L., Limatola, C., Butovsky, O., Tremblay, M.E., Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64 (2016), 826–839.
28. Bramham, C.R., Messaoudi, E., BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog. Neurobiol. 76 (2005), 99–125.
29. Brynskikh, A., Warren, T., Zhu, J., Kipnis, J., Adaptive immunity affects learning behavior in mice. Brain Behav. Immun. 22 (2008), 861–869.
30. Burch, D., What could computerized brain training learn from evidence-based medicine?. PLoS Med., 11, 2014, e1001758.
31. Burdette, J.H., Laurienti, P.J., Espeland, M.A., Morgan, A., Telesford, Q., Vechlekar, C.D., Hayasaka, S., Jennings, J.M., Katula, J.A., Kraft, R.A., Rejeski, W.J., Using network science to evaluate exercise-associated brain changes in older adults. Front Aging Neurosci., 2, 2010, 23.
32. 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., 8, 2014, 430.
33. Campbell, A., Inflammation, neurodegenerative diseases, and environmental exposures. Ann. N. Y. Acad. Sci. 1035 (2004), 117–132.
34. Capoccia, S., Berry, A., Bellisario, V., Vacirca, D., Ortona, E., Alleva, E., Cirulli, F., Quality and timing of stressors differentially impact on brain plasticity and neuroendocrine-immune function in mice. Neural Plast., 2013, 2013, 971817.
35. Carvalho, A., Rea, I.M., Parimon, T., Cusack, B.J., Physical activity and cognitive function in individuals over 60 years of age: a systematic review. Clin. Interv. Aging 9 (2014), 661–682.
36. Chapman, T.R., Barrientos, R.M., Ahrendsen, J.T., Hoover, J.M., Maier, S.F., Patterson, S.L., Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol. Aging 33:83 (2012), e831–814.
37. Chen, W.W., Zhang, X., Huang, W.J., Role of neuroinflammation in neurodegenerative diseases (Review). Mol. Med. Rep. 13 (2016), 3391–3396.
38. Cheng, Y., Wu, W., Feng, W., Wang, J., Chen, Y., Shen, Y., Li, Q., Zhang, X., Li, C., The effects of multi-domain versus single-domain cognitive training in non-demented older people: a randomized controlled trial. BMC Med., 10, 2012, 30.
39. Chennaoui, M., Gomez-Merino, D., Drogou, C., Geoffroy, H., Dispersyn, G., Langrume, C., Ciret, S., Gallopin, T., Sauvet, F., Effects of exercise on brain and peripheral inflammatory biomarkers induced by total sleep deprivation in rats. J. Inflamm. (Lond.), 12, 2015, 56.
40. Colcombe, S., Kramer, A.F., Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol. Sci. 14 (2003), 125–130.
41. Colcombe, S.J., Erickson, K.I., Scalf, P.E., Kim, J.S., Prakash, R., McAuley, E., Elavsky, S., Marquez, D.X., Hu, L., Kramer, A.F., Aerobic exercise training increases brain volume in aging humans. J. Gerontol. A: Biol. Sci. Med. Sci. 61 (2006), 1166–1170.
42. Cotman, C.W., Berchtold, N.C., Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25 (2002), 295–301.
43. Düzel, E., van Praag, H., Sendtner, M., Can physical exercise in old age improve memory and hippocampal function?. Brain 139 (2016), 662–673.
44. Da Mesquita, S., Ferreira, A.C., Sousa, J.C., Correia-Neves, M., Sousa, N., Marques, F., Insights on the pathophysiology of Alzheimer's disease: the crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci. Biobehav. Rev. 68 (2016), 547–562.
45. Deak, F., Sonntag, W.E., Aging, synaptic dysfunction, and insulin-like growth factor (IGF)-1. J. Gerontol. A. Biol. Sci. Med. Sci. 67 (2012), 611–625.
46. Deleidi, M., Jaggle, M., Rubino, G., Immune aging, dysmetabolism, and inflammation in neurological diseases. Front. Neurosci., 9, 2015, 172.
47. Derecki, N.C., Cardani, A.N., Yang, C.H., Quinnies, K.M., Crihfield, A., Lynch, K.R., Kipnis, J., Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207 (2010), 1067–1080.
48. Di Benedetto, S., Derhovanessian, E., Steinhagen-Thiessen, E., Goldeck, D., Muller, L., Pawelec, G., Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. Biogerontology 16 (2015), 631–643.
49. Di Filippo, M., Chiasserini, D., Gardoni, F., Viviani, B., Tozzi, A., Giampa, C., Costa, C., Tantucci, M., Zianni, E., Boraso, M., Siliquini, S., de Iure, A., Ghiglieri, V., Colcelli, E., Baker, D., Sarchielli, P., Fusco, F.R., Di Luca, M., Calabresi, P., Effects of central and peripheral inflammation on hippocampal synaptic plasticity. Neurobiol. Dis. 52 (2013), 229–236.
50. Dik, M., Deeg, D.J., Visser, M., Jonker, C., Early life physical activity and cognition at old age. J. Clin. Exp. Neuropsychol. 25 (2003), 643–653.
51. Dishman, R.K., Berthoud, H.R., Booth, F.W., Cotman, C.W., Edgerton, V.R., Fleshner, M.R., Gandevia, S.C., Gomez-Pinilla, F., Greenwood, B.N., Hillman, C.H., Kramer, A.F., Levin, B.E., Moran, T.H., Russo-Neustadt, A.A., Salamone, J.D., Van Hoomissen, J.D., Wade, C.E., York, D.A., Zigmond, M.J., Neurobiology of exercise. Obesity 14 (2006), 345–356.
52. Doty, K.R., Guillot-Sestier, M.V., Town, T., The role of the immune system in neurodegenerative disorders: adaptive or maladaptive?. Brain Res. 1617 (2015), 155–173.
53. Dunn, A.J., Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism: comparison with interleukin-1. J. Pharmacol. Exp. Ther. 261 (1992), 964–969.
54. Elenkov, I.J., Iezzoni, D.G., Daly, A., Harris, A.G., Chrousos, G.P., Cytokine dysregulation, inflammation and well-being. Neuroimmunomodulation 12 (2005), 255–269.
55. Ellwardt, E., Walsh, J.T., Kipnis, J., Zipp, F., Understanding the role of T cells in CNS homeostasis. Trends Immunol. 37 (2016), 154–165.
56. Engelhardt, B., Carare, R.O., Bechmann, I., Flugel, A., Laman, J.D., Weller, R.O., Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132 (2016), 317–338.
57. Engvig, A., Fjell, A.M., Westlye, L.T., Moberget, T., Sundseth, O., Larsen, V.A., Walhovd, K.B., Effects of memory training on cortical thickness in the elderly. Neuroimage 52 (2010), 1667–1676.
58. Erickson, K.I., Voss, M.W., Prakash, R.S., Basak, C., Szabo, A., Chaddock, L., Kim, J.S., Heo, S., Alves, H., White, S.M., Wojcicki, T.R., Mailey, E., Vieira, V.J., Martin, S.A., Pence, B.D., Woods, J.A., McAuley, E., Kramer, A.F., Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U. S. A. 108 (2011), 3017–3022.
59. Erickson, K.I., Leckie, R.L., Weinstein, A.M., Physical activity, fitness, and gray matter volume. Neurobiol. Aging 35:Suppl. (2) (2014), S20–28.
60. Eskes, G.A., Longman, S., Brown, A.D., McMorris, C.A., Langdon, K.D., Hogan, D.B., Poulin, M., Contribution of physical fitness, cerebrovascular reserve and cognitive stimulation to cognitive function in post-menopausal women. Front Aging Neurosci., 2, 2010, 137.
61. Eyre, H., Baune, B.T., Neuroimmunological effects of physical exercise in depression. Brain Behav. Immun. 26 (2012), 251–266.
62. Fabre, C., Chamari, K., Mucci, P., Masse-Biron, J., Prefaut, C., Improvement of cognitive function by mental and/or individualized aerobic training in healthy elderly subjects. Int. J. Sports Med. 23 (2002), 415–421.
63. Feigenson, K.A., Kusnecov, A.W., Silverstein, S.M., Inflammation and the two-hit hypothesis of schizophrenia. Neurosci. Biobehav. Rev. 38 (2014), 72–93.
64. Ferencz, B., Laukka, E.J., Welmer, A.K., Kalpouzos, G., Angleman, S., Keller, L., Graff, C., Lovden, M., Backman, L., The benefits of staying active in old age: physical activity counteracts the negative influence of PICALM, BIN1, and CLU risk alleles on episodic memory functioning. Psychol. Aging 29 (2014), 440–449.
65. Fiatarone Singh, M.A., Gates, N., Saigal, N., Wilson, G.C., Meiklejohn, J., Brodaty, H., Wen, W., Singh, N., Baune, B.T., Suo, C., Baker, M.K., Foroughi, N., Wang, Y., Sachdev, P.S., Valenzuela, M., The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double-blind, double-sham controlled trial. J. Am. Med. Dir. Assoc. 15 (2014), 873–880.
66. Fissler, P., Kuster, O., Schlee, W., Kolassa, I.T., Novelty interventions to enhance broad cognitive abilities and prevent dementia: synergistic approaches for the facilitation of positive plastic change. Prog. Brain Res. 207 (2013), 403–434.
67. Franceschi, C., Campisi, J., Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A. Biol. Sci. Med. Sci. 69:Suppl. (1) (2014), S4–S9.
68. Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De Benedictis, G., Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908 (2000), 244–254.
69. Franceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panourgia, M.P., Invidia, L., Celani, L., Scurti, M., Cevenini, E., Castellani, G.C., Salvioli, S., Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128 (2007), 92–105.
70. Geda, Y.E., Silber, T.C., Roberts, R.O., Knopman, D.S., Christianson, T.J., Pankratz, V.S., Boeve, B.F., Tangalos, E.G., Petersen, R.C., Computer activities physical exercise, aging, and mild cognitive impairment: a population-based study. Mayo Clin. Proc. 87 (2012), 437–442.
71. Gemechu, J.M., Bentivoglio, M., T cell recruitment in the brain during normal aging. Front. Cell. Neurosci., 6, 2012, 38.
72. Giunta, B., Fernandez, F., Nikolic, W.V., Obregon, D., Rrapo, E., Town, T., Tan, J., Inflammaging as a prodrome to Alzheimer's disease. J. Neuroinflammation, 5, 2008, 51.
73. Goldeck, D., Witkowski, J.M., Fulop, T., Pawelec, G., Peripheral immune signatures in alzheimer disease. Curr. Alzheimer Res. 13 (2016), 739–749.
74. Goshen, I., Yirmiya, R., Interleukin-1 (IL-1): a central regulator of stress responses. Front. Neuroendocrinol. 30 (2009), 30–45.
75. Goshen, I., Kreisel, T., Ben-Menachem-Zidon, O., Licht, T., Weidenfeld, J., Ben-Hur, T., Yirmiya, R., Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol. Psychiatry 13 (2008), 717–728.
76. Guan, Z., Fang, J., Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav. Immun. 20 (2006), 64–71.
77. Gutierrez, E.G., Banks, W.A., Kastin, A.J., Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J. Neuroimmunol. 47 (1993), 169–176.
78. Gutierrez, E.G., Banks, W.A., Kastin, A.J., Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. J. Neuroimmunol. 55 (1994), 153–160.
79. Hansel, A., Hong, S., Camara, R.J., von Kanel, R., Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neurosci. Biobehav. Rev. 35 (2010), 115–121.
80. Hansen, M.K., Taishi, P., Chen, Z., Krueger, J.M., Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta. J. Neurosci. 18 (1998), 2247–2253.
81. Hansen, M.K., Nguyen, K.T., Goehler, L.E., Gaykema, R.P., Fleshner, M., Maier, S.F., Watkins, L.R., Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1beta protein in rats. Auton. Neurosci. 85 (2000), 119–126.
82. Hanson, M.A., Gluckman, P.D., Early developmental conditioning of later health and disease: physiology or pathophysiology?. Physiol. Rev. 94 (2014), 1027–1076.
83. Harrison, N.A., Brain structures implicated in inflammation-associated depression. Curr. Top. Behav. Neurosci., 2016.
84. Hasegawa-Ishii, S., Inaba, M., Umegaki, H., Unno, K., Wakabayashi, K., Shimada, A., Endotoxemia-induced cytokine-mediated responses of hippocampal astrocytes transmitted by cells of the brain-immune interface. Sci. Rep., 6, 2016, 25457.
85. Hearps, A.C., Martin, G.E., Angelovich, T.A., Cheng, W.J., Maisa, A., Landay, A.L., Jaworowski, A., Crowe, S.M., Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11 (2012), 867–875.
86. Hefendehl, J.K., Neher, J.J., Suhs, R.B., Kohsaka, S., Skodras, A., Jucker, M., Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13 (2014), 60–69.
87. Hickey, W.F., P selectin, pioneer cells and the path to inflammation. Brain 123:Pt 6 (2000), 1073–1074.
88. Holvoet, P., Stress in obesity and associated metabolic and cardiovascular disorders. Scientifica (Cairo), 2012, 2012, 205027.
89. Hotting, K., Roder, B., Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci. Biobehav. Rev. 37 (2013), 2243–2257.
90. Iozzo, P., Holmes, M., Schmidt, M.V., Cirulli, F., Guzzardi, M.A., Berry, A., Balsevich, G., Andreassi, M.G., Wesselink, J.J., Liistro, T., Gomez-Puertas, P., Eriksson, J.G., Seckl, J., Developmental ORIgins of Healthy and Unhealthy AgeiNg: the role of maternal obesity—introduction to DORIAN. Obes Facts 7 (2014), 130–151.
91. Johnson, P.L., Goronzy, J.J., Antia, R., A population biological approach to understanding the maintenance and loss of the T-cell repertoire during aging. Immunology 142 (2014), 167–175.
92. Jones, R.S., Lynch, M.A., How dependent is synaptic plasticity on microglial phenotype?. Neuropharmacology 96 (2015), 3–10.
93. Kempermann, G., Gast, D., Gage, F.H., Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52 (2002), 135–143.
94. Kempermann, G., Fabel, K., Ehninger, D., Babu, H., Leal-Galicia, P., Garthe, A., Wolf, S.A., Why and how physical activity promotes experience-induced brain plasticity. Front. Neurosci., 4, 2010, 189.
95. Khairova, R.A., Machado-Vieira, R., Du, J., Manji, H.K., A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int. J. Neuropsychopharmacol. 12 (2009), 561–578.
96. Kim, S.E., Ko, I.G., Kim, B.K., Shin, M.S., Cho, S., Kim, C.J., Kim, S.H., Baek, S.S., Lee, E.K., Jee, Y.S., Treadmill exercise prevents aging-induced failure of memory through an increase in neurogenesis and suppression of apoptosis in rat hippocampus. Exp. Gerontol. 45 (2010), 357–365.
97. Kipnis, J., Cohen, H., Cardon, M., Ziv, Y., Schwartz, M., T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc. Natl. Acad. Sci. U. S. A. 101 (2004), 8180–8185.
98. Kipnis, J., Gadani, S., Derecki, N.C., Pro-cognitive properties of T cells. Nat. Rev. Immunol. 12 (2012), 663–669.
99. Kirk-Sanchez, N.J., McGough, E.L., Physical exercise and cognitive performance in the elderly: current perspectives. Clin. Interv. Aging 9 (2014), 51–62.
100. Kohman, R.A., DeYoung, E.K., Bhattacharya, T.K., Peterson, L.N., Rhodes, J.S., Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain Behav. Immun. 26 (2012), 803–810.
101. Kraft, E., Cognitive function, physical activity, and aging: possible biological links and implications for multimodal interventions. Neuropsychol. Dev. Cogn. Sect. B: Aging Neuropsychol. Cogn. 19 (2012), 248–263.
102. Kumar, A., Rani, A., Tchigranova, O., Lee, W.H., Foster, T.C., Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology. Neurobiol. Aging 33 (2012), e1–17.
103. Lövdén, M., Wenger, E., Martensson, J., Lindenberger, U., Backman, L., Structural brain plasticity in adult learning and development. Neurosci. Biobehav. Rev. 37 (2013), 2296–2310.
104. Laws, K.R., Irvine, K., Gale, T.M., Sex differences in cognitive impairment in Alzheimer's disease. World J. Psychiatry 6 (2016), 54–65.
105. Leckie, R.L., Oberlin, L.E., Voss, M.W., Prakash, R.S., Szabo-Reed, A., Chaddock-Heyman, L., Phillips, S.M., Gothe, N.P., Mailey, E., Vieira-Potter, V.J., Martin, S.A., Pence, B.D., Lin, M., Parasuraman, R., Greenwood, P.M., Fryxell, K.J., Woods, J.A., McAuley, E., Kramer, A.F., Erickson, K.I., BDNF mediates improvements in executive function following a 1-year exercise intervention. Front. Hum. Neurosci., 8, 2014, 985.
106. Leiter, O., Kempermann, G., Walker, T.L., A common language: how neuroimmunological cross talk regulates adult hippocampal neurogenesis. Stem Cells Int., 2016, 2016, 1681590.
107. Leza, J.C., Garcia-Bueno, B., Bioque, M., Arango, C., Parellada, M., Do, K., O'Donnell, P., Bernardo, M., Inflammation in schizophrenia: a question of balance. Neurosci. Biobehav. Rev. 55 (2015), 612–626.
108. Lindenberger, U., Human cognitive aging: corriger la fortune?. Science 346 (2014), 572–578.
109. Litteljohn, D., Nelson, E., Hayley, S., IFN-gamma differentially modulates memory-related processes under basal and chronic stressor conditions. Front. Cell. Neurosci., 8, 2014, 391.
110. Louveau, A., Harris, T.H., Kipnis, J., Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 36 (2015), 569–577.
111. Lu, B., Pang, P.T., Woo, N.H., The yin and yang of neurotrophin action. Nat. Rev. Neurosci. 6 (2005), 603–614.
112. Lustig, C., Shah, P., Seidler, R., Reuter-Lorenz, P.A., Aging, training, and the brain: a review and future directions. Neuropsychol. Rev. 19 (2009), 504–522.
113. Müller, L., Pawelec, G., Aging and immunity—impact of behavioral intervention. Brain Behav. Immun. 39 (2014), 8–22.
114. Müller, L., Pawelec, G., As we age: does slippage of quality control in the immune system lead to collateral damage?. Ageing Res. Rev. 23 (2015), 116–123.
115. Müller, L., Fulop, T., Pawelec, G., Immunosenescence in vertebrates and invertebrates. Immun. Ageing: I & A, 10, 2013, 12.
116. Maass, A., Duzel, S., Goerke, M., Becke, A., Sobieray, U., Neumann, K., Lovden, M., Lindenberger, U., Backman, L., Braun-Dullaeus, R., Ahrens, D., Heinze, H.J., Muller, N.G., Duzel, E., Vascular hippocampal plasticity after aerobic exercise in older adults. Mol. Psychiatry 20 (2015), 585–593.
117. Maier, S.F., Goehler, L.E., Fleshner, M., Watkins, L.R., The role of the vagus nerve in cytokine-to-brain communication. Ann. N. Y. Acad. Sci. 840 (1998), 289–300.
118. Majka, D.S., Chang, R.W., Vu, T.H., Palmas, W., Geffken, D.F., Ouyang, P., Ni, H., Liu, K., Physical activity and high-sensitivity C-reactive protein: the multi-ethnic study of atherosclerosis. Am. J. Prev. Med. 36 (2009), 56–62.
119. Malaguarnera, L., Cristaldi, E., Malaguarnera, M., The role of immunity in elderly cancer. Crit. Rev. Oncol. Hematol. 74 (2010), 40–60.
120. Minter, M.R., Moore, Z., Zhang, M., Brody, K.M., Jones, N.C., Shultz, S.R., Taylor, J.M., Crack, P.J., Deletion of the type-1 interferon receptor in APPSWE/PS1DeltaE9 mice preserves cognitive function and alters glial phenotype. Acta Neuropathol. Commun., 4, 2016, 72.
121. Moylan, S., Eyre, H.A., Maes, M., Baune, B.T., Jacka, F.N., Berk, M., Exercising the worry away: how inflammation, oxidative and nitrogen stress mediates the beneficial effect of physical activity on anxiety disorder symptoms and behaviours. Neurosci. Biobehav. Rev. 37 (2013), 573–584.
122. Na, K.S., Jung, H.Y., Kim, Y.K., The role of pro-inflammatory cytokines in the neuroinflammation and neurogenesis of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry. 48 (2014), 277–286.
123. Naylor, K., Li, G., Vallejo, A.N., Lee, W.W., Koetz, K., Bryl, E., Witkowski, J., Fulbright, J., Weyand, C.M., Goronzy, J.J., The influence of age on T cell generation and TCR diversity. J. Immunol. 174 (2005), 7446–7452.
124. Ngandu, T., Lehtisalo, J., Solomon, A., Levalahti, E., Ahtiluoto, S., Antikainen, R., Backman, L., Hanninen, T., Jula, A., Laatikainen, T., Lindstrom, J., Mangialasche, F., Paajanen, T., Pajala, S., Peltonen, M., Rauramaa, R., Stigsdotter-Neely, A., Strandberg, T., Tuomilehto, J., Soininen, H., Kivipelto, M., A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385 (2015), 2255–2263.
125. Nimmerjahn, A., Kirchhoff, F., Helmchen, F., Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308 (2005), 1314–1318.
126. 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 96 (2015), 29–41.
127. Norton, S., Matthews, F.E., Barnes, D.E., Yaffe, K., Brayne, C., Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 13 (2014), 788–794.
128. Nunes, S.O., Vargas, H.O., Prado, E., Barbosa, D.S., de Melo, L.P., Moylan, S., Dodd, S., Berk, M., The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependence. Neurosci. Biobehav. Rev. 37 (2013), 1336–1345.
129. Oswald, W.D.G., Rupprecht, T., Hagen, R., Differential effects of single versus combined cognitive and physical training with older adults: the SimA study in a 5-year perspective. Eur. J. Ageing, 3, 2006.
130. Ownby, R.L., Neuroinflammation and cognitive aging. Curr. Psychiatry Rep. 12 (2010), 39–45.
131. Papenberg, G., Ferencz, B., Mangialasche, F., Mecocci, P., Cecchetti, R., Kalpouzos, G., Fratiglioni, L., Backman, L., Physical activity and inflammation: effects on gray-matter volume and cognitive decline in aging. Hum. Brain Mapp., 2016.
132. Patterson, S.L., Immune dysregulation and cognitive vulnerability in the aging brain: interactions of microglia, IL-1beta, BDNF and synaptic plasticity. Neuropharmacology 96 (2015), 11–18.
133. Pawelec, G., Derhovanessian, E., Role of CMV in immune senescence. Virus Res. 157 (2011), 175–179.
134. Pawelec, G., Larbi, A., Derhovanessian, E., Senescence of the human immune system. J. Comp. Pathol. 142:Suppl. (1) (2010), S39–44.
135. Pedersen, B.K., Hoffman-Goetz, L., Exercise and the immune system: regulation, integration, and adaptation. Physiol. Rev. 80 (2000), 1055–1081.
136. Pedersen, B.K., Exercise-induced myokines and their role in chronic diseases. Brain Behav. Immun. 25 (2011), 811–816.
137. Petersen, A.M., Pedersen, B.K., The anti-inflammatory effect of exercise. J. Appl. Physiol. 98 (2005), 1154–1162 1985.
138. Phillips, C., Baktir, M.A., Srivatsan, M., Salehi, A., Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front. Cell. Neurosci., 8, 2014, 170.
139. Pizza, V., Agresta, A., D'Acunto, C.W., Festa, M., Capasso, A., Neuroinflammation and ageing: current theories and an overview of the data. Rev. Recent Clin. Trials 6 (2011), 189–203.
140. Plata-Salaman, C.R., Immunoregulators in the nervous system. Neurosci. Biobehav. Rev. 15 (1991), 185–215.
141. Podewils, L.J., Guallar, E., Kuller, L.H., Fried, L.P., Lopez, O.L., Carlson, M., Lyketsos, C.G., Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am. J. Epidemiol. 161 (2005), 639–651.
142. Prakash, R.S., Voss, M.W., Erickson, K.I., Kramer, A.F., Physical activity and cognitive vitality. Annu. Rev. Psychol. 66 (2015), 769–797.
143. Prinz, M., Priller, J., Sisodia, S.S., Ransohoff, R.M., Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14 (2011), 1227–1235.
144. Qi, Q., Liu, Y., Cheng, Y., Glanville, J., Zhang, D., Lee, J.Y., Olshen, R.A., Weyand, C.M., Boyd, S.D., Goronzy, J.J., Diversity and clonal selection in the human T-cell repertoire. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 13139–13144.
145. Qi, Q., Zhang, D.W., Weyand, C.M., Goronzy, J.J., Mechanisms shaping the naive T cell repertoire in the elderly—thymic involution or peripheral homeostatic proliferation?. Exp. Gerontol. 54 (2014), 71–74.
146. Quan, N., Banks, W.A., Brain-immune communication pathways. Brain Behav. Immun. 21 (2007), 727–735.
147. Raper, D., Louveau, A., Kipnis, J., How do meningeal lymphatic vessels drain the CNS?. Trends Neurosci. 39 (2016), 581–586.
148. Ritzel, R.M., Crapser, J., Patel, A.R., Verma, R., Grenier, J.M., Chauhan, A., Jellison, E.R., McCullough, L.D., Age-associated resident memory CD8 T cells in the central nervous system are primed to potentiate inflammation after ischemic brain injury. J. Immunol. 196 (2016), 3318–3330.
149. Ron-Harel, N., Cardon, M., Schwartz, M., Brain homeostasis is maintained by danger signals stimulating a supportive immune response within the brain's borders. Brain Behav. Immun. 25 (2011), 1036–1043.
150. Salam, N., Rane, S., Das, R., Faulkner, M., Gund, R., Kandpal, U., Lewis, V., Mattoo, H., Prabhu, S., Ranganathan, V., Durdik, J., George, A., Rath, S., Bal, V., T cell ageing: effects of age on development, survival & function. Indian J. Med. Res. 138 (2013), 595–608.
151. Scheinert, R.B., Asokan, A., Rani, A., Kumar, A., Foster, T.C., Ormerod, B.K., Some hormone, cytokine and chemokine levels that change across lifespan vary by cognitive status in male Fischer 344 rats. Brain Behav. Immun. 49 (2015), 216–232.
152. Schmiedek, F., Lövdén, M., Lindenberger, U., Hundred days of cognitive training enhance broad cognitive abilities in adulthood: findings from the COGITO study. Front. Aging Neurosci., 2, 2010.
153. Schnydrig, S., Korner, L., Landweer, S., Ernst, B., Walker, G., Otten, U., Kunz, D., Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain. Neurosci. Lett. 429 (2007), 69–73.
154. Shechter, R., London, A., Varol, C., Raposo, C., Cusimano, M., Yovel, G., Rolls, A., Mack, M., Pluchino, S., Martino, G., Jung, S., Schwartz, M., Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med., 6, 2009, e1000113.
155. Shechter, R., London, A., Schwartz, M., Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13 (2013), 206–218.
156. Silverman, M.N., Deuster, P.A., Biological mechanisms underlying the role of physical fitness in health and resilience. Interface Focus, 4, 2014, 20140040.
157. Simpson, R.J., Aging and inflammation: directing traffic through physical activity. Brain Behav. Immun. 56 (2016), 10–11.
158. Singhal, G., Jaehne, E.J., Corrigan, F., Baune, B.T., Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment. Front. Cell. Neurosci., 8, 2014, 97.
159. Snigdha, S., de Rivera, C., Milgram, N.W., Cotman, C.W., Exercise enhances memory consolidation in the aging brain. Front. Aging Neurosci., 6, 2014, 3.
160. Sparkman, N.L., Johnson, R.W., Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress. Neuroimmunomodulation 15 (2008), 323–330.
161. Speisman, R.B., Kumar, A., Rani, A., Foster, T.C., Ormerod, B.K., Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats. Brain Behav. Immun. 28 (2013), 25–43.
162. Speisman, R.B., Kumar, A., Rani, A., Pastoriza, J.M., Severance, J.E., Foster, T.C., Ormerod, B.K., Environmental enrichment restores neurogenesis and rapid acquisition in aged rats. Neurobiol. Aging 34 (2013), 263–274.
163. Stellwagen, D., Malenka, R.C., Synaptic scaling mediated by glial TNF-alpha. Nature 440 (2006), 1054–1059.
164. Stolp, H.B., Liddelow, S.A., Sa-Pereira, I., Dziegielewska, K.M., Saunders, N.R., Immune responses at brain barriers and implications for brain development and neurological function in later life. Front. Integr. Neurosci., 7, 2013, 61.
165. Swardfager, W., Rosenblat, J.D., Benlamri, M., McIntyre, R.S., Mapping inflammation onto mood: inflammatory mediators of anhedonia. Neurosci. Biobehav. Rev. 64 (2016), 148–166.
166. Szuhany, K.L., Bugatti, M., Otto, M.W., A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor. J. Psychiatr. Res. 60 (2015), 56–64.
167. Tansey, M.G., Goldberg, M.S., Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 37 (2010), 510–518.
168. Tansey, M.G., Inflammation in neuropsychiatric disease. Neurobiol. Dis. 37 (2010), 491–492.
169. Tay, T.L., Savage, J., Hui, C.W., Bisht, K., Tremblay, M.E., Microglia across the lifespan: from origin to function in brain development, plasticity and cognition. J. Physiol., 2016.
170. Timmerman, K.L., Flynn, M.G., Coen, P.M., Markofski, M.M., Pence, B.D., Exercise training-induced lowering of inflammatory (CD14 + CD16 + ) monocytes: a role in the anti-inflammatory influence of exercise. J. Leukoc. Biol. 84 (2008), 1271–1278.
171. Tolppanen, A.M., Solomon, A., Kulmala, J., Kareholt, I., Ngandu, T., Rusanen, M., Laatikainen, T., Soininen, H., Kivipelto, M., Leisure-time physical activity from mid- to late life, body mass index, and risk of dementia. Alzheimer's Demen. 11 (2015), 434–443 e436.
172. Tumati, S., Burger, H., Martens, S., van der Schouw, Y.T., Aleman, A., Association between cognition and serum insulin-like growth factor-1 in middle-aged & older men: an 8 year follow-up study. PLoS One, 11, 2016, e0154450.
173. Turner, J.E., Is immunosenescence influenced by our lifetime dose of exercise?. Biogerontology 17 (2016), 581–602.
174. Varma, V.R., Chuang, Y.F., Harris, G.C., Tan, E.J., Carlson, M.C., Low-intensity daily walking activity is associated with hippocampal volume in older adults. Hippocampus 25 (2015), 605–615.
175. Vaupel, J.W., Carey, J.R., Christensen, K., Aging. It's never too late Science 301 (2003), 1679–1681.
176. Vegeto, E., Benedusi, V., Maggi, A., Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Front. Neuroendocrinol. 29 (2008), 507–519.
177. Veiga-Fernandes, H., Mucida, D., Neuro-immune interactions at barrier surfaces. Cell 165 (2016), 801–811.
178. Vescovini, R., Fagnoni, F.F., Telera, A.R., Bucci, L., Pedrazzoni, M., Magalini, F., Stella, A., Pasin, F., Medici, M.C., Calderaro, A., Volpi, R., Monti, D., Franceschi, C., Nikolich-Zugich, J., Sansoni, P., Naive and memory CD8 T cell pool homeostasis in advanced aging: impact of age and of antigen-specific responses to cytomegalovirus. Age (Dordr) 36 (2014), 625–640.
179. Villeda, S.A., Luo, J., Mosher, K.I., Zou, B., Britschgi, M., Bieri, G., Stan, T.M., Fainberg, N., Ding, Z., Eggel, A., Lucin, K.M., Czirr, E., Park, J.S., Couillard-Despres, S., Aigner, L., Li, G., Peskind, E.R., Kaye, J.A., Quinn, J.F., Galasko, D.R., Xie, X.S., Rando, T.A., Wyss-Coray, T., The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477 (2011), 90–94.
180. Wekerle, H., Breaking ignorance: the case of the brain. Curr. Top. Microbiol. Immunol. 305 (2006), 25–50.
181. Willis, S.L., Tennstedt, S.L., Marsiske, M., Ball, K., Elias, J., Koepke, K.M., Morris, J.N., Rebok, G.W., Unverzagt, F.W., Stoddard, A.M., Wright, E., Group, A.S., Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA 296 (2006), 2805–2814.
182. Wilson, C.J., Finch, C.E., Cohen, H.J., Cytokines and cognition?the case for a head-to-toe inflammatory paradigm. J. Am. Geriatr. Soc. 50 (2002), 2041–2056.
183. Wirth, M., Haase, C.M., Villeneuve, S., Vogel, J., Jagust, W.J., Neuroprotective pathways: lifestyle activity, brain pathology, and cognition in cognitively normal older adults. Neurobiol. Aging 35 (2014), 1873–1882.
184. Wistuba-Hamprecht, K., Haehnel, K., Janssen, N., Demuth, I., Pawelec, G., Peripheral blood T-cell signatures from high-resolution immune phenotyping of gammadelta and alphabeta T-cells in younger and older subjects in the Berlin Aging Study II. Immun. Ageing: I & A, 12, 2015, 25.
185. Wohleb, E.S., Delpech, J.C., Dynamic cross-talk between microglia and peripheral monocytes underlies stress-induced neuroinflammation and behavioral consequences. Prog. Neuropsychopharmacol. Biol. Psychiatry, 2016.
186. Wolf, S.A., Steiner, B., Akpinarli, A., Kammertoens, T., Nassenstein, C., Braun, A., Blankenstein, T., Kempermann, G., CD4-positive T lymphocytes provide a neuroimmunological link in the control of adult hippocampal neurogenesis. J. Immunol. 182 (2009), 3979–3984.
187. Xie, L., Choudhury, G.R., Winters, A., Yang, S.H., Jin, K., Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur. J. Immunol. 45 (2015), 180–191.
188. Yaffe, K., Barnes, D., Nevitt, M., Lui, L.Y., Covinsky, K., A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch. Intern. Med. 161 (2001), 1703–1708.
189. Yau, S.Y., Lau, B.W., So, K.F., Adult hippocampal neurogenesis: a possible way how physical exercise counteracts stress. Cell Transplant. 20 (2011), 99–111.
190. Yau, S.Y., Li, A., So, K.F., Involvement of adult hippocampal neurogenesis in learning and forgetting. Neural Plast., 2015, 2015, 717958.
191. Ye, S.M., Johnson, R.W., Increased interleukin-6 expression by microglia from brain of aged mice. J. Neuroimmunol. 93 (1999), 139–148.
192. Yirmiya, R., Goshen, I., Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav. Immun. 25 (2011), 181–213.
193. Zagni, E., Simoni, L., Colombo, D., Sex and gender differences in central nervous system-related disorders. Neurosci. J., 2016, 2016, 2827090.
194. Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., Cohen, H., Kipnis, J., Schwartz, M., Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9 (2006), 268–275.
195. de Pablo-Bernal, R.S., Canizares, J., Rosado, I., Galva, M.I., Alvarez-Rios, A.I., Carrillo-Vico, A., Ferrando-Martinez, S., Munoz-Fernandez, M.A., Rafii-El-Idrissi Benhnia, M., Pacheco, Y.M., Ramos, R., Leal, M., Ruiz-Mateos, E., Monocyte phenotype and polyfunctionality are associated with elevated soluble inflammatory markers, cytomegalovirus infection, and functional and cognitive decline in elderly adults. J. Gerontol. A. Biol. Sci. Med. Sci. 71 (2016), 610–618.
196. von Bernhardi, R., Tichauer, J.E., Eugenin, J., Aging-dependent changes of microglial cells and their relevance for neurodegenerative disorders. J. Neurochem. 112 (2010), 1099–1114.