Peripheral Immunosenescence and Central Neuroinflammation: A Dangerous Liaison - A Dietary Approach

Thea       Magrone; Manrico       Magrone; Matteo    A.   Russo; Emilio       Jirillo
doi:10.2174/1871530320666200406123734
Abstract

Background & Objectives: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS).
Aims: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases.
Discussion: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer’s disease, Parkinson’s disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics.
Conclusion: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.
Keywords: Ageing, cellular and molecular rehabilitation, immunity, inflamm-ageing, neuroinflammation, nutraceuticals.
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Graphical Abstract

[1] 
Kumar, H.; Kawai, T.; Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol.,  2011, 30(1), 16-34.
[http://dx.doi.org/10.3109/08830185.2010.529976 ] [PMID:  21235323] 
[2] 
Barry, M.; Bleackley, R.C. Cytotoxic T lymphocytes: all roads lead to death. Nat. Rev. Immunol.,  2002, 2(6), 401-409.
[http://dx.doi.org/10.1038/nri819 ] [PMID:  12093006] 
[3] 
Wagner, M.; Koyasu, S. Cancer Immunoediting by Innate Lymphoid Cells. Trends Immunol.,  2019, 40(5), 415-430.
[http://dx.doi.org/10.1016/j.it.2019.03.004 ] [PMID:  30992189] 
[4] 
Magrone, T.; Jirillo, E. The Tolerant Immune System: Biological Significance and Clinical Implications of T Cell Tolerance. Endocr. Metab. Immune Disord. Drug Targets,  2019, 19(5), 580-593.
[http://dx.doi.org/10.2174/1871530319666181211161721 ] [PMID:  30539706] 
[5] 
Sugimoto, M.A.; Vago, J.P.; Perretti, M.; Teixeira, M.M. Mediators of the resolution of the inflammatory response. Trends Immunol.,  2019, 40(3), 212-227.
[http://dx.doi.org/10.1016/j.it.2019.01.007 ] [PMID:  30772190] 
[6] 
Hatami, M.; Abdolahi, M.; Soveyd, N.; Djalali, M.; Togha, M.; Honarvar, N.M. Molecular mechanisms of curcumin in neuroinflammatory disorders: a mini review of current evidences. Endocr. Metab. Immune Disord. Drug Targets,  2019, 19(3), 247-258.
[http://dx.doi.org/10.2174/1871530319666181129103056 ] [PMID:  30488803] 
[7] 
Magrone, T.; Jirillo, E. Childhood obesity: immune response and nutritional approaches. Front. Immunol.,  2015, 6, 76.
[http://dx.doi.org/10.3389/fimmu.2015.00076 ] [PMID:  25759691] 
[8] 
Borges, M.D.; Franca, E.L.; Fujimori, M.; Silva, S.M.C.; de Marchi, P.G.F.; Deluque, A.L.; Honorio-Franca, A.C.; de Abreu, L.C. Relationship between proinflammatory cytokines/chemokines and adipokines in serum of young adults with obesity. Endocr. Metab. Immune Disord. Drug Targets,  2018, 18(3), 260-267.
[http://dx.doi.org/10.2174/1871530318666180131094733 ] [PMID:  29384066] 
[9] 
Kopp, W. How western diet and lifestyle drive the pandemic of obesity and civilization diseases. Diabetes Metab. Syndr. Obes.,  2019, 12, 2221-2236.
[http://dx.doi.org/10.2147/DMSO.S216791 ] [PMID:  31695465] 
[10] 
Zamboni, M.; Rossi, A.P.; Fantin, F.; Zamboni, G.; Chirumbolo, S.; Zoico, E.; Mazzali, G. Adipose tissue, diet and aging. Mech. Ageing Dev.,  2014, 136-137, 129-137.
[http://dx.doi.org/10.1016/j.mad.2013.11.008 ] [PMID:  24321378] 
[11] 
Caballero, S.; Pamer, E.G. Microbiota-mediated inflammation and antimicrobial defense in the intestine. Annu. Rev. Immunol.,  2015, 33, 227-256.
[http://dx.doi.org/10.1146/annurev-immunol-032713-120238 ] [PMID:  25581310] 
[12] 
Shreiner, A.B.; Kao, J.Y.; Young, V.B. The gut microbiome in health and in disease. Curr. Opin. Gastroenterol.,  2015, 31(1), 69-75.
[http://dx.doi.org/10.1097/MOG.0000000000000139 ] [PMID:  25394236] 
[13] 
Magrone, T.; Jirillo, E. The interplay between the gut immune system and microbiota in health and disease: nutraceutical intervention for restoring intestinal homeostasis. Curr. Pharm. Des.,  2013, 19(7), 1329-1342.
[http://dx.doi.org/10.2174/138161213804805793 ] [PMID:  23151182] 
[14] 
Brestoff, J.R.; Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol.,  2013, 14(7), 676-684.
[http://dx.doi.org/10.1038/ni.2640 ] [PMID:  23778795] 
[15] 
Rapozo, D.C.; Bernardazzi, C.; de Souza, H.S. Diet and microbiota in inflammatory bowel disease: The gut in disharmony. World J. Gastroenterol.,  2017, 23(12), 2124-2140.
[http://dx.doi.org/10.3748/wjg.v23.i12.2124 ] [PMID:  28405140] 
[16] 
Magrone, T.; Jirillo, E. The interaction between gut microbiota and age-related changes in immune function and inflammation. Immun. Ageing,  2013, 10(1), 31.
[http://dx.doi.org/10.1186/1742-4933-10-31 ] [PMID:  23915308] 
[17] 
Cerovic, M.; Forloni, G.; Balducci, C. Neuroinflammation and the gut microbiota: possible alternative therapeutic targets to counteract Alzheimer’s disease? Front. Aging Neurosci.,  2019, 11, 284.
[http://dx.doi.org/10.3389/fnagi.2019.00284 ] [PMID:  31680937] 
[18] 
Thevaranjan, N.; Puchta, A.; Schulz, C.; Naidoo, A.; Szamosi, J.C.; Verschoor, C.P.; Loukov, D.; Schenck, L.P.; Jury, J.; Foley, K.P.; Schertzer, J.D.; Larché, M.J.; Davidson, D.J.; Verdú, E.F.; Surette, M.G.; Bowdish, D.M.E. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe,  2018, 23(4), 570.
[http://dx.doi.org/10.1016/j.chom.2018.03.006 ] [PMID:  29649447] 
[19] 
Victorelli, S.; Passos, J.F. Telomeres and cell senescence - size matters not. EBioMedicine,  2017, 21, 14-20.
[http://dx.doi.org/10.1016/j.ebiom.2017.03.027 ] [PMID:  28347656] 
[20] 
Chuprin, A.; Gal, H.; Biron-Shental, T.; Biran, A.; Amiel, A.; Rozenblatt, S.; Krizhanovsky, V. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev.,  2013, 27(21), 2356-2366.
[http://dx.doi.org/10.1101/gad.227512.113 ] [PMID:  24186980] 
[21] 
Di Micco, R.; Fumagalli, M.; Cicalese, A.; Piccinin, S.; Gasparini, P.; Luise, C.; Schurra, C.; Garre’, M.; Nuciforo, P.G.; Bensimon, A.; Maestro, R.; Pelicci, P.G.; d’Adda di Fagagna, F. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature,  2006, 444(7119), 638-642.
[http://dx.doi.org/10.1038/nature05327 ] [PMID:  17136094] 
[22] 
Ewald, J.A.; Desotelle, J.A.; Wilding, G.; Jarrard, D.F. Therapy-induced senescence in cancer. J. Natl. Cancer Inst.,  2010, 102(20), 1536-1546.
[http://dx.doi.org/10.1093/jnci/djq364 ] [PMID:  20858887] 
[23] 
Burton, D.G.A.; Stolzing, A. Cellular senescence: immunosurveillance and future immunotherapy. Ageing Res. Rev.,  2018, 43, 17-25.
[http://dx.doi.org/10.1016/j.arr.2018.02.001 ] [PMID:  29427795] 
[24] 
Ritschka, B.; Storer, M.; Mas, A.; Heinzmann, F.; Ortells, M.C.; Morton, J.P.; Sansom, O.J.; Zender, L.; Keyes, W.M. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev.,  2017, 31(2), 172-183.
[http://dx.doi.org/10.1101/gad.290635.116 ] [PMID:  28143833] 
[25] 
Mosteiro, L.; Pantoja, C.; Alcazar, N.; Marión, R.M.; Chondronasiou, D.; Rovira, M.; Fernandez-Marcos, P.J.; Muñoz-Martin, M.; Blanco-Aparicio, C.; Pastor, J.; Gómez-López, G.; De Martino, A.; Blasco, M.A.; Abad, M.; Serrano, M. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science,  2016, 354(6315)
[http://dx.doi.org/10.1126/science.aaf4445 ] [PMID:  27884981] 
[26] 
Demaria, M.; Ohtani, N.; Youssef, S.A.; Rodier, F.; Toussaint, W.; Mitchell, J.R.; Laberge, R.M.; Vijg, J.; Van Steeg, H.; Dollé, M.E.; Hoeijmakers, J.H.; de Bruin, A.; Hara, E.; Campisi, J. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell,  2014, 31(6), 722-733.
[http://dx.doi.org/10.1016/j.devcel.2014.11.012 ] [PMID:  25499914] 
[27] 
Sagiv, A.; Burton, D.G.; Moshayev, Z.; Vadai, E.; Wensveen, F.; Ben-Dor, S.; Golani, O.; Polic, B.; Krizhanovsky, V. NKG2D ligands mediate immunosurveillance of senescent cells. Aging (Albany NY),  2016, 8(2), 328-344.
[http://dx.doi.org/10.18632/aging.100897 ] [PMID:  26878797] 
[28] 
Dou, Z.; Ghosh, K.; Vizioli, M.G.; Zhu, J.; Sen, P.; Wangensteen, K.J.; Simithy, J.; Lan, Y.; Lin, Y.; Zhou, Z.; Capell, B.C.; Xu, C.; Xu, M.; Kieckhaefer, J.E.; Jiang, T.; Shoshkes-Carmel, M.; Tanim, K.M.A.A.; Barber, G.N.; Seykora, J.T.; Millar, S.E.; Kaestner, K.H.; Garcia, B.A.; Adams, P.D.; Berger, S.L. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature,  2017, 550(7676), 402-406.
[http://dx.doi.org/10.1038/nature24050 ] [PMID:  28976970] 
[29] 
Mackenzie, K.J.; Carroll, P.; Martin, C.A.; Murina, O.; Fluteau, A.; Simpson, D.J.; Olova, N.; Sutcliffe, H.; Rainger, J.K.; Leitch, A.; Osborn, R.T.; Wheeler, A.P.; Nowotny, M.; Gilbert, N.; Chandra, T.; Reijns, M.A.M.; Jackson, A.P. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature,  2017, 548(7668), 461-465.
[http://dx.doi.org/10.1038/nature23449 ] [PMID:  28738408] 
[30] 
Xue, W.; Zender, L.; Miething, C.; Dickins, R.A.; Hernando, E.; Krizhanovsky, V.; Cordon-Cardo, C.; Lowe, S.W. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature,  2007, 445(7128), 656-660.
[http://dx.doi.org/10.1038/nature05529 ] [PMID:  17251933] 
[31] 
Di Mitri, D.; Toso, A.; Chen, J.J.; Sarti, M.; Pinton, S.; Jost, T.R.; D’Antuono, R.; Montani, E.; Garcia-Escudero, R.; Guccini, I.; Da Silva-Alvarez, S.; Collado, M.; Eisenberger, M.; Zhang, Z.; Catapano, C.; Grassi, F.; Alimonti, A. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature,  2014, 515(7525), 134-137.
[http://dx.doi.org/10.1038/nature13638 ] [PMID:  25156255] 
[32] 
Ruhland, M.K.; Loza, A.J.; Capietto, A.H.; Luo, X.; Knolhoff, B.L.; Flanagan, K.C.; Belt, B.A.; Alspach, E.; Leahy, K.; Luo, J.; Schaffer, A.; Edwards, J.R.; Longmore, G.; Faccio, R.; DeNardo, D.G.; Stewart, S.A. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun.,  2016, 7, 11762.
[http://dx.doi.org/10.1038/ncomms11762 ] [PMID:  27272654] 
[33] 
Eggert, T.; Wolter, K.; Ji, J.; Ma, C.; Yevsa, T.; Klotz, S.; Medina-Echeverz, J.; Longerich, T.; Forgues, M.; Reisinger, F.; Heikenwalder, M.; Wang, X.W.; Zender, L.; Greten, T.F. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell,  2016, 30(4), 533-547.
[http://dx.doi.org/10.1016/j.ccell.2016.09.003 ] [PMID:  27728804] 
[34] 
Biswas, S.K. Metabolic reprogramming of immune cells in cancer progression. Immunity,  2015, 43(3), 435-449.
[http://dx.doi.org/10.1016/j.immuni.2015.09.001 ] [PMID:  26377897] 
[35] 
Aspinall, R.; Andrew, D. Thymic involution in aging. J. Clin. Immunol.,  2000, 20(4), 250-256.
[http://dx.doi.org/10.1023/A:1006611518223 ] [PMID:  10939712] 
[36] 
Magrone, T.; Jirillo, E. Prebiotics and probiotics in aging population: effects on the immune-gut microbiota axis.,  Molecular Basis of
	Nutrition and Aging: A Volume in the Molecular Nutrition Series;
	Ed. Elsevier, 2016, pp. 681-692.978-0-12-801816-3.. 
[http://dx.doi.org/10.1016/B978-0-12-801816-3.00049-2] 
[37] 
Magrone, T.; Jirillo, E. Disorders of innate immunity in human ageing and effects of nutraceutical administration. Endocr. Metab. Immune Disord. Drug Targets,  2014, 14(4), 272-282.
[http://dx.doi.org/10.2174/1871530314666141010105540 ] [PMID:  25307109] 
[38] 
Di Lorenzo, G.; Balistreri, C.R.; Candore, G.; Cigna, D.; Colombo, A.; Romano, G.C.; Colucci, A.T.; Gervasi, F.; Listì, F.; Potestio, M.; Caruso, C. Granulocyte and natural killer activity in the elderly. Mech. Ageing Dev.,  1999, 108(1), 25-38.
[http://dx.doi.org/10.1016/S0047-6374(98)00156-0 ] [PMID:  10366037] 
[39] 
Butcher, S.K.; Chahal, H.; Nayak, L.; Sinclair, A.; Henriquez, N.V.; Sapey, E.; O’Mahony, D.; Lord, J.M. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J. Leukoc. Biol.,  2001, 70(6), 881-886.
[PMID:  11739550] 
[40] 
Hazeldine, J.; Harris, P.; Chapple, I.L.; Grant, M.; Greenwood, H.; Livesey, A.; Sapey, E.; Lord, J.M. Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. Aging Cell,  2014, 13(4), 690-698.
[http://dx.doi.org/10.1111/acel.12222 ] [PMID:  24779584] 
[41] 
Qian, F.; Guo, X.; Wang, X.; Yuan, X.; Chen, S.; Malawista, S.E.; Bockenstedt, L.K.; Allore, H.G.; Montgomery, R.R. Reduced bioenergetics and toll-like receptor 1 function in human polymorphonuclear leukocytes in aging. Aging (Albany NY),  2014, 6(2), 131-139.
[http://dx.doi.org/10.18632/aging.100642 ] [PMID:  24595889] 
[42] 
Yarbro, J.R.; Pence, B.D. Classical monocytes from older adults maintain capacity for metabolic compensation during glucose deprivation and lipopolysaccharide stimulation. Mech. Ageing Dev., 2019. 183111146
[http://dx.doi.org/10.1016/j.mad.2019.111146 ] [PMID:  31493436] 
[43] 
Nyugen, J.; Agrawal, S.; Gollapudi, S.; Gupta, S. Impaired functions of peripheral blood monocyte subpopulations in aged humans. J. Clin. Immunol.,  2010, 30(6), 806-813.
[http://dx.doi.org/10.1007/s10875-010-9448-8 ] [PMID:  20703784] 
[44] 
van Royen, N.; Hoefer, I.; Böttinger, M.; Hua, J.; Grundmann, S.; Voskuil, M.; Bode, C.; Schaper, W.; Buschmann, I.; Piek, J.J. Local monocyte chemoattractant protein-1 therapy increases collateral artery formation in apolipoprotein E-deficient mice but induces systemic monocytic CD11b expression, neointimal formation, and plaque progression. Circ. Res.,  2003, 92(2), 218-225.
[http://dx.doi.org/10.1161/01.RES.0000052313.23087.3F ] [PMID:  12574150] 
[45] 
De Martinis, M.; Modesti, M.; Ginaldi, L. Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol. Cell Biol.,  2004, 82(4), 415-420.
[http://dx.doi.org/10.1111/j.0818-9641.2004.01242.x ] [PMID:  15283852] 
[46] 
Albright, J.M.; Dunn, R.C.; Shults, J.A.; Boe, D.M.; Afshar, M.; Kovacs, E.J. Advanced age alters monocyte and macrophage responses. Antioxid. Redox Signal.,  2016, 25(15), 805-815.
[http://dx.doi.org/10.1089/ars.2016.6691 ] [PMID:  27357201] 
[47] 
Arai, Y.; Martin-Ruiz, C.M.; Takayama, M.; Abe, Y.; Takebayashi, T.; Koyasu, S.; Suematsu, M.; Hirose, N.; von Zglinicki, T. Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians. EBioMedicine,  2015, 2(10), 1549-1558.
[http://dx.doi.org/10.1016/j.ebiom.2015.07.029 ] [PMID:  26629551] 
[48] 
van Duin, D.; Shaw, A.C. Toll-like receptors in older adults. J. Am. Geriatr. Soc.,  2007, 55(9), 1438-1444.
[http://dx.doi.org/10.1111/j.1532-5415.2007.01300.x ] [PMID:  17767688] 
[49] 
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,  2012, 11(5), 867-875.
[http://dx.doi.org/10.1111/j.1474-9726.2012.00851.x ] [PMID:  22708967] 
[50] 
Izgüt-Uysal, V.N.; Agaç, A.; Karadogan, I.; Derin, N. Peritoneal macrophages function modulation by L-carnitine in aging rats. Aging Clin. Exp. Res.,  2004, 16(5), 337-341.
[http://dx.doi.org/10.1007/BF03324561 ] [PMID:  15636457] 
[51] 
Linehan, E.; Dombrowski, Y.; Snoddy, R.; Fallon, P.G.; Kissenpfennig, A.; Fitzgerald, D.C. Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. Aging Cell,  2014, 13(4), 699-708.
[http://dx.doi.org/10.1111/acel.12223 ] [PMID:  24813244] 
[52] 
Mancuso, P.; McNish, R.W.; Peters-Golden, M.; Brock, T.G. Evaluation of phagocytosis and arachidonate metabolism by alveolar macrophages and recruited neutrophils from F344xBN rats of different ages. Mech. Ageing Dev.,  2001, 122(15), 1899-1913.
[http://dx.doi.org/10.1016/S0047-6374(01)00322-0 ] [PMID:  11557288] 
[53] 
Guilliams, M.; De Kleer, I.; Henri, S.; Post, S.; Vanhoutte, L.; De Prijck, S.; Deswarte, K.; Malissen, B.; Hammad, H.; Lambrecht, B.N. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J. Exp. Med.,  2013, 210(10), 1977-1992.
[http://dx.doi.org/10.1084/jem.20131199 ] [PMID:  24043763] 
[54] 
Jackaman, C.; Nelson, D.J. Are macrophages, myeloid derived suppressor cells and neutrophils mediators of local suppression in healthy and cancerous tissues in aging hosts? Exp. Gerontol.,  2014, 54, 53-57.
[http://dx.doi.org/10.1016/j.exger.2013.11.009 ] [PMID:  24291067] 
[55] 
Thomas, D.R. Age-related changes in wound healing. Drugs Aging,  2001, 18(8), 607-620.
[http://dx.doi.org/10.2165/00002512-200118080-00005 ] [PMID:  11587247] 
[56] 
Swift, M.E.; Kleinman, H.K.; DiPietro, L.A. Impaired wound repair and delayed angiogenesis in aged mice. Lab. Invest.,  1999, 79(12), 1479-1487.
[PMID:  10616199] 
[57] 
Della Bella, S.; Bierti, L.; Presicce, P.; Arienti, R.; Valenti, M.; Saresella, M.; Vergani, C.; Villa, M.L. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin. Immunol.,  2007, 122(2), 220-228.
[http://dx.doi.org/10.1016/j.clim.2006.09.012 ] [PMID:  17101294] 
[58] 
Jing, Y.; Shaheen, E.; Drake, R.R.; Chen, N.; Gravenstein, S.; Deng, Y. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum. Immunol.,  2009, 70(10), 777-784.
[http://dx.doi.org/10.1016/j.humimm.2009.07.005 ] [PMID:  19596035] 
[59] 
Pérez-Cabezas, B.; Naranjo-Gómez, M.; Fernández, M.A.; Grífols, J.R.; Pujol-Borrell, R.; Borràs, F.E. Reduced numbers of plasmacytoid dendritic cells in aged blood donors. Exp. Gerontol.,  2007, 42(10), 1033-1038.
[http://dx.doi.org/10.1016/j.exger.2007.05.010 ] [PMID:  17606348] 
[60] 
Kapetanovic, R.; Bokil, N.J.; Sweet, M.J. Innate immune perturbations, accumulating DAMPs and inflammasome dysregulation: A ticking time bomb in ageing., Ageing Res. Rev, 2015, 24(Pt A), 40-
53.. 
[http://dx.doi.org/10.1016/j.arr.2015.02.005] 
[61] 
Le Garff-Tavernier, M.; Béziat, V.; Decocq, J.; Siguret, V.; Gandjbakhch, F.; Pautas, E.; Debré, P.; Merle-Beral, H.; Vieillard, V. Human NK cells display major phenotypic and functional changes over the life span. Aging Cell,  2010, 9(4), 527-535.
[http://dx.doi.org/10.1111/j.1474-9726.2010.00584.x ] [PMID:  20477761] 
[62] 
Campos, C.; Pera, A.; Lopez-Fernandez, I.; Alonso, C.; Tarazona, R.; Solana, R. Proinflammatory status influences NK cells subsets in the elderly. Immunol. Lett.,  2014, 162(1 Pt B), 298-302.
[http://dx.doi.org/10.1016/j.imlet.2014.06.015 ] [PMID:  24998470] 
[63] 
Rukavina, D.; Laskarin, G.; Rubesa, G.; Strbo, N.; Bedenicki, I.; Manestar, D.; Glavas, M.; Christmas, S.E.; Podack, E.R. Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells. Blood,  1998, 92(7), 2410-2420.
[http://dx.doi.org/10.1182/blood.V92.7.2410 ] [PMID:  9746781] 
[64] 
Chan, A.; Hong, D.L.; Atzberger, A.; Kollnberger, S.; Filer, A.D.; Buckley, C.D.; McMichael, A.; Enver, T.; Bowness, P. CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts. J. Immunol.,  2007, 179(1), 89-94.
[http://dx.doi.org/10.4049/jimmunol.179.1.89 ] [PMID:  17579025] 
[65] 
Kempuraj, D.; Mentor, S.; Thangavel, R.; Ahmed, M.E.; Selvakumar, G.P.; Raikwar, S.P.; Dubova, I.; Zaheer, S.; Iyer, S.S.; Zaheer, A. Mast Cells in Stress, Pain, Blood-Brain Barrier, Neuroinflammation and Alzheimer’s Disease. Front. Cell. Neurosci.,  2019, 13, 54.
[http://dx.doi.org/10.3389/fncel.2019.00054 ] [PMID:  30837843] 
[66] 
Magrone, T.; Jirillo, E. Sepsis: From Historical Aspects to Novel Vistas. Pathogenic and Therapeutic Considerations. Endocr. Metab. Immune Disord. Drug Targets,  2019, 19(4), 490-502.
[http://dx.doi.org/10.2174/1871530319666181129112708 ] [PMID:  30857516] 
[67] 
Goronzy, J.J.; Fang, F.; Cavanagh, M.M.; Qi, Q.; Weyand, C.M. Naive T cell maintenance and function in human aging. J. Immunol.,  2015, 194(9), 4073-4080.
[http://dx.doi.org/10.4049/jimmunol.1500046 ] [PMID:  25888703] 
[68] 
Weng, N.P.; Akbar, A.N.; Goronzy, J. CD28(-) T cells: their role in the age-associated decline of immune function. Trends Immunol.,  2009, 30(7), 306-312.
[http://dx.doi.org/10.1016/j.it.2009.03.013 ] [PMID:  19540809] 
[69] 
Zanni, F.; Vescovini, R.; Biasini, C.; Fagnoni, F.; Zanlari, L.; Telera, A.; Di Pede, P.; Passeri, G.; Pedrazzoni, M.; Passeri, M.; Franceschi, C.; Sansoni, P. Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence. Exp. Gerontol.,  2003, 38(9), 981-987.
[http://dx.doi.org/10.1016/S0531-5565(03)00160-8 ] [PMID:  12954485] 
[70] 
Ponnappan, S.; Ponnappan, U. Aging and immune function: molecular mechanisms to interventions. Antioxid. Redox Signal.,  2011, 14(8), 1551-1585.
[http://dx.doi.org/10.1089/ars.2010.3228 ] [PMID:  20812785] 
[71] 
Witkowski, J.M.; Mikosik, A.; Bryl, E.; Fulop, T. Proteodynamics in aging human T cells - The need for its comprehensive study to understand the fine regulation of T lymphocyte functions. Exp. Gerontol.,  2018, 107, 161-168.
[http://dx.doi.org/10.1016/j.exger.2017.10.009 ] [PMID:  29038026] 
[72] 
Rink, L.; Cakman, I.; Kirchner, H. Altered cytokine production in the elderly. Mech. Ageing Dev.,  1998, 102(2-3), 199-209.
[http://dx.doi.org/10.1016/S0047-6374(97)00153-X ] [PMID:  9720652] 
[73] 
Schmitt, V.; Rink, L.; Uciechowski, P. The Th17/Treg balance is disturbed during aging. Exp. Gerontol.,  2013, 48(12), 1379-1386.
[http://dx.doi.org/10.1016/j.exger.2013.09.003 ] [PMID:  24055797] 
[74] 
Raynor, J.; Lages, C.S.; Shehata, H.; Hildeman, D.A.; Chougnet, C.A. Homeostasis and function of regulatory T cells in aging. Curr. Opin. Immunol.,  2012, 24(4), 482-487.
[http://dx.doi.org/10.1016/j.coi.2012.04.005 ] [PMID:  22560294] 
[75] 
Hwang, K.A.; Kim, H.R.; Kang, I. Aging and human CD4(+) regulatory T cells. Mech. Ageing Dev.,  2009, 130(8), 509-517.
[http://dx.doi.org/10.1016/j.mad.2009.06.003 ] [PMID:  19540259] 
[76] 
Magrone, T.; Jirillo, E. Development and Organization of the Secondary and Tertiary Lymphoid Organs: Influence of Microbial and Food Antigens. Endocr. Metab. Immune Disord. Drug Targets,  2019, 19(2), 128-135.
[http://dx.doi.org/10.2174/1871530319666181128160411 ] [PMID:  30488802] 
[77] 
Linterman, M.A. How T follicular helper cells and the germinal centre response change with age. Immunol. Cell Biol.,  2014, 92(1), 72-79.
[http://dx.doi.org/10.1038/icb.2013.77 ] [PMID:  24217812] 
[78] 
Ratliff, M.; Alter, S.; McAvoy, K.; Frasca, D.; Wright, J.A.; Zinkel, S.S.; Khan, W.N.; Blomberg, B.B.; Riley, R.L. In aged mice, low surrogate light chain promotes pro-B-cell apoptotic resistance, compromises the PreBCR checkpoint, and favors generation of autoreactive, phosphorylcholine-specific B cells. Aging Cell,  2015, 14(3), 382-390.
[http://dx.doi.org/10.1111/acel.12302 ] [PMID:  25727904] 
[79] 
Miller, J.P.; Allman, D. The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J. Immunol.,  2003, 171(5), 2326-2330.
[http://dx.doi.org/10.4049/jimmunol.171.5.2326 ] [PMID:  12928378] 
[80] 
Kennedy, D.E.; Knight, K.L. Inhibition of B Lymphopoiesis by Adipocytes and IL-1-Producing Myeloid-Derived Suppressor Cells. J. Immunol.,  2015, 195(6), 2666-2674.
[http://dx.doi.org/10.4049/jimmunol.1500957 ] [PMID:  26268654] 
[81] 
Bulati, M.; Caruso, C.; Colonna-Romano, G. From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”. Ageing Res. Rev.,  2017, 36, 125-136.
[http://dx.doi.org/10.1016/j.arr.2017.04.001 ] [PMID:  28396185] 
[82] 
Russell Knode, L.M.; Naradikian, M.S.; Myles, A.; Scholz, J.L.; Hao, Y.; Liu, D.; Ford, M.L.; Tobias, J.W.; Cancro, M.P.; Gearhart, P.J.; Age-Associated, B.; Age-Associated, B. Cells Express a Diverse Repertoire of VH and Vκ Genes with Somatic Hypermutation. J. Immunol.,  2017, 198(5), 1921-1927.
[http://dx.doi.org/10.4049/jimmunol.1601106 ] [PMID:  28093524] 
[83] 
Gibson, K.L.; Wu, Y.C.; Barnett, Y.; Duggan, O.; Vaughan, R.; Kondeatis, E.; Nilsson, B.O.; Wikby, A.; Kipling, D.; Dunn-Walters, D.K. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell,  2009, 8(1), 18-25.
[http://dx.doi.org/10.1111/j.1474-9726.2008.00443.x ] [PMID:  18986373] 
[84] 
Miller, J.P.; Cancro, M.P. B cells and aging: balancing the homeostatic equation. Exp. Gerontol.,  2007, 42(5), 396-399.
[http://dx.doi.org/10.1016/j.exger.2007.01.010 ] [PMID:  17344004] 
[85] 
Harris, T.B.; Ferrucci, L.; Tracy, R.P.; Corti, M.C.; Wacholder, S.; Ettinger, W.H., Jr; Heimovitz, H.; Cohen, H.J.; Wallace, R. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am. J. Med.,  1999, 106(5), 506-512.
[http://dx.doi.org/10.1016/S0002-9343(99)00066-2 ] [PMID:  10335721] 
[86] 
Bruunsgaard, H.; Andersen-Ranberg, K.; Hjelmborg, Jv.; Pedersen, B.K.; Jeune, B. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am. J. Med.,  2003, 115(4), 278-283.
[http://dx.doi.org/10.1016/S0002-9343(03)00329-2 ] [PMID:  12967692] 
[87] 
Cappola, A.R.; Xue, Q.L.; Ferrucci, L.; Guralnik, J.M.; Volpato, S.; Fried, L.P. Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women. J. Clin. Endocrinol. Metab.,  2003, 88(5), 2019-2025.
[http://dx.doi.org/10.1210/jc.2002-021694 ] [PMID:  12727948] 
[88] 
Licastro, F.; Pedrini, S.; Caputo, L.; Annoni, G.; Davis, L.J.; Ferri, C.; Casadei, V.; Grimaldi, L.M. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J. Neuroimmunol.,  2000, 103(1), 97-102.
[http://dx.doi.org/10.1016/S0165-5728(99)00226-X ] [PMID:  10674995] 
[89] 
Cape, E.; Hall, R.J.; van Munster, B.C.; de Vries, A.; Howie, S.E.; Pearson, A.; Middleton, S.D.; Gillies, F.; Armstrong, I.R.; White, T.O.; Cunningham, C.; de Rooij, S.E.; MacLullich, A.M. Cerebrospinal fluid markers of neuroinflammation in delirium: a role for interleukin-1β in delirium after hip fracture. J. Psychosom. Res.,  2014, 77(3), 219-225.
[http://dx.doi.org/10.1016/j.jpsychores.2014.06.014 ] [PMID:  25124807] 
[90] 
Driver, T.H.; Katz, R.; Ix, J.H.; Magnani, J.W.; Peralta, C.A.; Parikh, C.R.; Fried, L.; Newman, A.B.; Kritchevsky, S.B.; Sarnak, M.J.; Shlipak, M.G.; Health, A.B.C. Health ABC Study. Urinary kidney injury molecule 1 (KIM-1) and interleukin 18 (IL-18) as risk markers for heart failure in older adults: the Health, Aging, and Body Composition (Health ABC) Study. Am. J. Kidney Dis.,  2014, 64(1), 49-56.
[http://dx.doi.org/10.1053/j.ajkd.2014.01.432 ] [PMID:  24656453] 
[91] 
Franceschi, C.; Bonafè, 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.,  2000, 908, 244-254.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb06651.x ] [PMID:  10911963] 
[92] 
Smale, S.T. Hierarchies of NF-κB target-gene regulation. Nat. Immunol.,  2011, 12(8), 689-694.
[http://dx.doi.org/10.1038/ni.2070 ] [PMID:  21772277] 
[93] 
Salvioli, S.; Monti, D.; Lanzarini, C.; Conte, M.; Pirazzini, C.; Bacalini, M.G.; Garagnani, P.; Giuliani, C.; Fontanesi, E.; Ostan, R.; Bucci, L.; Sevini, F.; Yani, S.L.; Barbieri, A.; Lomartire, L.; Borelli, V.; Vianello, D.; Bellavista, E.; Martucci, M.; Cevenini, E.; Pini, E.; Scurti, M.; Biondi, F.; Santoro, A.; Capri, M.; Franceschi, C. Immune system, cell senescence, aging and longevity--inflamm-aging reappraised. Curr. Pharm. Des.,  2013, 19(9), 1675-1679.
[PMID:  23589904] 
[94] 
Jirillo, E.; Candore, G.; Magrone, T.; Caruso, C. A scientific approach to anti-ageing therapies: state of the art. Curr. Pharm. Des.,  2008, 14(26), 2637-2642.
[http://dx.doi.org/10.2174/138161208786264070 ] [PMID:  18991682] 
[95] 
Humphries, F.; Fitzgerald, K.A. Assembling the Inflammasome, Piece by Piece. J. Immunol.,  2019, 203(5), 1093-1094.
[http://dx.doi.org/10.4049/jimmunol.1900764 ] [PMID:  31427397] 
[96] 
Kuzuya, M.; Ando, F.; Iguchi, A.; Shimokata, H. Effect of aging on serum uric acid levels: longitudinal changes in a large Japanese population group. J. Gerontol. A Biol. Sci. Med. Sci.,  2002, 57(10), M660-M664.
[http://dx.doi.org/10.1093/gerona/57.10.M660 ] [PMID:  12242321] 
[97] 
Luo, M.; Li, Z.Z.; Li, Y.Y.; Chen, L.Z.; Yan, S.P.; Chen, P.; Hu, Y.Y. Relationship between red cell distribution width and serum uric acid in patients with untreated essential hypertension. Sci. Rep.,  2014, 4, 7291.
[http://dx.doi.org/10.1038/srep07291 ] [PMID:  25464864] 
[98] 
Nagahama, K.; Inoue, T.; Kohagura, K.; Ishihara, A.; Kinjo, K.; Ohya, Y. Hyperuricemia predicts future metabolic syndrome: a 4-year follow-up study of a large screened cohort in Okinawa, Japan. Hypertens. Res.,  2014, 37(3), 232-238.
[http://dx.doi.org/10.1038/hr.2013.137 ] [PMID:  24173358] 
[99] 
Moriyama, T.; Itabashi, M.; Takei, T.; Kataoka, H.; Sato, M.; Shimizu, A.; Iwabuchi, Y.; Nishida, M.; Uchida, K.; Nitta, K. High uric acid level is a risk factor for progression of IgA nephropathy with chronic kidney disease stage G3a. J. Nephrol.,  2015, 28(4), 451-456.
[http://dx.doi.org/10.1007/s40620-014-0154-0 ] [PMID:  25355499] 
[100] 
Shimada, K.; Crother, T.R.; Karlin, J.; Dagvadorj, J.; Chiba, N.; Chen, S.; Ramanujan, V.K.; Wolf, A.J.; Vergnes, L.; Ojcius, D.M.; Rentsendorj, A.; Vargas, M.; Guerrero, C.; Wang, Y.; Fitzgerald, K.A.; Underhill, D.M.; Town, T.; Arditi, M. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity,  2012, 36(3), 401-414.
[http://dx.doi.org/10.1016/j.immuni.2012.01.009 ] [PMID:  22342844] 
[101] 
Zhou, R.; Yazdi, A.S.; Menu, P.; Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature,  2011, 469(7329), 221-225.
[http://dx.doi.org/10.1038/nature09663 ] [PMID:  21124315] 
[102] 
Heid, M.E.; Keyel, P.A.; Kamga, C.; Shiva, S.; Watkins, S.C.; Salter, R.D. Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J. Immunol.,  2013, 191(10), 5230-5238.
[http://dx.doi.org/10.4049/jimmunol.1301490 ] [PMID:  24089192] 
[103] 
Griendling, K.K.; Alexander, R.W. Oxidative stress and cardiovascular disease. Circulation,  1997, 96(10), 3264-3265.
[PMID:  9396412] 
[104] 
Kaneto, H.; Matsuoka, T.A.; Katakami, N.; Kawamori, D.; Miyatsuka, T.; Yoshiuchi, K.; Yasuda, T.; Sakamoto, K.; Yamasaki, Y.; Matsuhisa, M. Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes. Curr. Mol. Med.,  2007, 7(7), 674-686.
[http://dx.doi.org/10.2174/156652407782564408 ] [PMID:  18045145] 
[105] 
Barnham, K.J.; Masters, C.L.; Bush, A.I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov.,  2004, 3(3), 205-214.
[http://dx.doi.org/10.1038/nrd1330 ] [PMID:  15031734] 
[106] 
Benz, C.C.; Yau, C. Ageing, oxidative stress and cancer: paradigms in parallax. Nat. Rev. Cancer,  2008, 8(11), 875-879.
[http://dx.doi.org/10.1038/nrc2522 ] [PMID:  18948997] 
[107] 
Cordero, M.D.; Williams, M.R.; Ryffel, B. AMP-Activated Protein Kinase Regulation of the NLRP3 Inflammasome during Aging. Trends Endocrinol. Metab.,  2018, 29(1), 8-17.
[http://dx.doi.org/10.1016/j.tem.2017.10.009 ] [PMID:  29150317] 
[108] 
Garrido-Maraver, J.; Paz, M.V.; Cordero, M.D.; Bautista-Lorite, J.; Oropesa-Ávila, M.; de la Mata, M.; Pavón, A.D.; de Lavera, I.; Alcocer-Gómez, E.; Galán, F.; Ybot González, P.; Cotán, D.; Jackson, S.; Sánchez-Alcázar, J.A. Critical role of AMP-activated protein kinase in the balance between mitophagy and mitochondrial biogenesis in MELAS disease. Biochim. Biophys. Acta,  2015, 1852(11), 2535-2553.
[http://dx.doi.org/10.1016/j.bbadis.2015.08.027 ] [PMID:  26341273] 
[109] 
Menu, P.; Mayor, A.; Zhou, R.; Tardivel, A.; Ichijo, H.; Mori, K.; Tschopp, J.  ER stress activates the NLRP3 inflammasome via an
	UPR-independent pathway. Cell Death Dis., 2012, 3e261. 
[http://dx.doi.org/10.1038/cddis.2011.132] [PMID:  22278288] 
[110] 
Bae, H.R.; Kim, D.H.; Park, M.H.; Lee, B.; Kim, M.J.; Lee, E.K.; Chung, K.W.; Kim, S.M. Im, D.S.; Chung, H.Y. β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation. Oncotarget,  2016, 7(41), 66444-66454.
[http://dx.doi.org/10.18632/oncotarget.12119 ] [PMID:  27661104] 
[111] 
Price, N.L.; Gomes, A.P.; Ling, A.J.; Duarte, F.V.; Martin-Montalvo, A.; North, B.J.; Agarwal, B.; Ye, L.; Ramadori, G.; Teodoro, J.S.; Hubbard, B.P.; Varela, A.T.; Davis, J.G.; Varamini, B.; Hafner, A.; Moaddel, R.; Rolo, A.P.; Coppari, R.; Palmeira, C.M.; de Cabo, R.; Baur, J.A.; Sinclair, D.A. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab.,  2012, 15(5), 675-690.
[http://dx.doi.org/10.1016/j.cmet.2012.04.003 ] [PMID:  22560220] 
[112] 
de Kreutzenberg, S.V.; Ceolotto, G.; Cattelan, A.; Pagnin, E.; Mazzucato, M.; Garagnani, P.; Borelli, V.; Bacalini, M.G.; Franceschi, C.; Fadini, G.P.; Avogaro, A. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutr. Metab. Cardiovasc. Dis.,  2015, 25(7), 686-693.
[http://dx.doi.org/10.1016/j.numecd.2015.03.007 ] [PMID:  25921843] 
[113] 
Guarda, G.; Braun, M.; Staehli, F.; Tardivel, A.; Mattmann, C.; Förster, I.; Farlik, M.; Decker, T.; Du Pasquier, R.A.; Romero, P.; Tschopp, J. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity,  2011, 34(2), 213-223.
[http://dx.doi.org/10.1016/j.immuni.2011.02.006 ] [PMID:  21349431] 
[114] 
Qian, F.; Wang, X.; Zhang, L.; Lin, A.; Zhao, H.; Fikrig, E.; Montgomery, R.R. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J. Infect. Dis.,  2011, 203(10), 1415-1424.
[http://dx.doi.org/10.1093/infdis/jir048 ] [PMID:  21398396] 
[115] 
Shaw, A.C.; Panda, A.; Joshi, S.R.; Qian, F.; Allore, H.G.; Montgomery, R.R. Dysregulation of human Toll-like receptor function in aging. Ageing Res. Rev.,  2011, 10(3), 346-353.
[http://dx.doi.org/10.1016/j.arr.2010.10.007 ] [PMID:  21074638] 
[116] 
Sridharan, A.; Esposo, M.; Kaushal, K.; Tay, J.; Osann, K.; Agrawal, S.; Gupta, S.; Agrawal, A. Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age (Dordr.),  2011, 33(3), 363-376.
[http://dx.doi.org/10.1007/s11357-010-9191-3 ] [PMID:  20953722] 
[117] 
Harris, J.; Hartman, M.; Roche, C.; Zeng, S.G.; O’Shea, A.; Sharp, F.A.; Lambe, E.M.; Creagh, E.M.; Golenbock, D.T.; Tschopp, J.; Kornfeld, H.; Fitzgerald, K.A.; Lavelle, E.C. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J. Biol. Chem.,  2011, 286(11), 9587-9597.
[http://dx.doi.org/10.1074/jbc.M110.202911 ] [PMID:  21228274] 
[118] 
Shi, C.S.; Shenderov, K.; Huang, N.N.; Kabat, J.; Abu-Asab, M.; Fitzgerald, K.A.; Sher, A.; Kehrl, J.H. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol.,  2012, 13(3), 255-263.
[http://dx.doi.org/10.1038/ni.2215 ] [PMID:  22286270] 
[119] 
Cruz, C.M.; Rinna, A.; Forman, H.J.; Ventura, A.L.; Persechini, P.M.; Ojcius, D.M. ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J. Biol. Chem.,  2007, 282(5), 2871-2879.
[http://dx.doi.org/10.1074/jbc.M608083200 ] [PMID:  17132626] 
[120] 
Lipinski, M.M.; Zheng, B.; Lu, T.; Yan, Z.; Py, B.F.; Ng, A.; Xavier, R.J.; Li, C.; Yankner, B.A.; Scherzer, C.R.; Yuan, J. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA,  2010, 107(32), 14164-14169.
[http://dx.doi.org/10.1073/pnas.1009485107 ] [PMID:  20660724] 
[121] 
Godbout, J.P.; Johnson, R.W. Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Immunol. Allergy Clin. North Am.,  2009, 29(2), 321-337.
[http://dx.doi.org/10.1016/j.iac.2009.02.007 ] [PMID:  19389585] 
[122] 
Apelt, J.; Schliebs, R. Beta-amyloid-induced glial expression of both pro- and anti-inflammatory cytokines in cerebral cortex of aged transgenic Tg2576 mice with Alzheimer plaque pathology. Brain Res.,  2001, 894(1), 21-30.
[http://dx.doi.org/10.1016/S0006-8993(00)03176-0 ] [PMID:  11245811] 
[123] 
Lue, L.F.; Rydel, R.; Brigham, E.F.; Yang, L.B.; Hampel, H.; Murphy, G.M., Jr; Brachova, L.; Yan, S.D.; Walker, D.G.; Shen, Y.; Rogers, J. Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia,  2001, 35(1), 72-79.
[http://dx.doi.org/10.1002/glia.1072 ] [PMID:  11424194] 
[124] 
Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol.,  2008, 9(8), 857-865.
[http://dx.doi.org/10.1038/ni.1636 ] [PMID:  18604209] 
[125] 
Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.C.; Gelpi, E.; Halle, A.; Korte, M.; Latz, E.; Golenbock, D.T. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature,  2013, 493(7434), 674-678.
[http://dx.doi.org/10.1038/nature11729] [PMID: 23254930] 
[126] 
Tan, M.S.; Tan, L.; Jiang, T.; Zhu, X.C.; Wang, H.F.; Jia, C.D.; Yu, J.T. Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease.,  Cell Death Dis., 2014, 5e1382. 
[http://dx.doi.org/10.1038/cddis.2014.348] [PMID:  25144717] 
[127] 
Fann, D.Y.; Lee, S.Y.; Manzanero, S.; Tang, S.C.; Gelderblom, M.; Chunduri, P.; Bernreuther, C.; Glatzel, M.; Cheng, Y.L.; Thundyil, J.; Widiapradja, A.; Lok, K.Z.; Foo, S.L.; Wang, Y.C.; Li, Y.I.; Drummond, G.R.; Basta, M.; Magnus, T.; Jo, D.G.; Mattson, M.P.; Sobey, C.G.; Arumugam, T.V. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke., Cell Death Dis., 2013, 4e790. 
[http://dx.doi.org/10.1038/cddis.2013.326] [PMID:  24008734] 
[128] 
Fang, P.; Schachner, M.; Shen, Y.Q. HMGB1 in development and diseases of the central nervous system. Mol. Neurobiol.,  2012, 45(3), 499-506.
[http://dx.doi.org/10.1007/s12035-012-8264-y ] [PMID:  22580958] 
[129] 
Mazarati, A.; Maroso, M.; Iori, V.; Vezzani, A.; Carli, M. High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products. Exp. Neurol.,  2011, 232(2), 143-148.
[http://dx.doi.org/10.1016/j.expneurol.2011.08.012 ] [PMID:  21884699] 
[130] 
Takata, K.; Kitamura, Y.; Tsuchiya, D.; Kawasaki, T.; Taniguchi, T.; Shimohama, S. High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity. J. Neurosci. Res.,  2004, 78(6), 880-891.
[http://dx.doi.org/10.1002/jnr.20340 ] [PMID:  15499593] 
[131] 
Song, J.X.; Lu, J.H.; Liu, L.F.; Chen, L.L.; Durairajan, S.S.; Yue, Z.; Zhang, H.Q.; Li, M. HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression: a process modulated by the natural autophagy inducer corynoxine B. Autophagy,  2014, 10(1), 144-154.
[http://dx.doi.org/10.4161/auto.26751 ] [PMID:  24178442] 
[132] 
Chaves, M.L.; Camozzato, A.L.; Ferreira, E.D.; Piazenski, I.; Kochhann, R.; Dall’Igna, O.; Mazzini, G.S.; Souza, D.O.; Portela, L.V. Serum levels of S100B and NSE proteins in Alzheimer’s disease patients. J. Neuroinflammation,  2010, 7, 6.
[http://dx.doi.org/10.1186/1742-2094-7-6 ] [PMID:  20105309] 
[133] 
Sathe, K.; Maetzler, W.; Lang, J.D.; Mounsey, R.B.; Fleckenstein, C.; Martin, H.L.; Schulte, C.; Mustafa, S.; Synofzik, M.; Vukovic, Z.; Itohara, S.; Berg, D.; Teismann, P. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-α pathway. Brain,  2012, 135(Pt 11), 3336-3347.
[http://dx.doi.org/10.1093/brain/aws250 ] [PMID:  23169921] 
[134] 
Stetler, R.A.; Gan, Y.; Zhang, W.; Liou, A.K.; Gao, Y.; Cao, G.; Chen, J. Heat shock proteins: cellular and molecular mechanisms in the central nervous system. Prog. Neurobiol.,  2010, 92(2), 184-211.
[http://dx.doi.org/10.1016/j.pneurobio.2010.05.002 ] [PMID:  20685377] 
[135] 
Broere, F.; van der Zee, R.; van Eden, W. Heat shock proteins are no DAMPs, rather ‘DAMPERs’. Nat. Rev. Immunol.,  2011, 11(8), 565.
[http://dx.doi.org/10.1038/nri2873-c1 ] [PMID:  21785457] 
[136] 
Ganter, M.T.; Ware, L.B.; Howard, M.; Roux, J.; Gartland, B.; Matthay, M.A.; Fleshner, M.; Pittet, J.F. Extracellular heat shock protein 72 is a marker of the stress protein response in acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2006, 291(3), L354-L361.
[http://dx.doi.org/10.1152/ajplung.00405.2005 ] [PMID:  16679378] 
[137] 
LoCicero, J., III; Xu, X.; Zhang, L. Heat shock protein suppresses the senescent lung cytokine response to acute endotoxemia. Ann. Thorac. Surg.,  1999, 68(4), 1150-1153.
[http://dx.doi.org/10.1016/S0003-4975(99)00919-4 ] [PMID:  10543471] 
[138] 
Zhang, Q.; Raoof, M.; Chen, Y.; Sumi, Y.; Sursal, T.; Junger, W.; Brohi, K.; Itagaki, K.; Hauser, C.J. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature,  2010, 464(7285), 104-107.
[http://dx.doi.org/10.1038/nature08780 ] [PMID:  20203610] 
[139] 
Pinti, M.; Cevenini, E.; Nasi, M.; De Biasi, S.; Salvioli, S.; Monti, D.; Benatti, S.; Gibellini, L.; Cotichini, R.; Stazi, M.A.; Trenti, T.; Franceschi, C.; Cossarizza, A. Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for “inflamm-aging”. Eur. J. Immunol.,  2014, 44(5), 1552-1562.
[http://dx.doi.org/10.1002/eji.201343921 ] [PMID:  24470107] 
[140] 
Magrone, T.; Marzulli, G.; Jirillo, E. Immunopathogenesis of neurodegenerative diseases: current therapeutic models of neuroprotection with special reference to natural products. Curr. Pharm. Des.,  2012, 18(1), 34-42.
[http://dx.doi.org/10.2174/138161212798919057 ] [PMID:  22211682] 
[141] 
Papadopoulos, D.; Scheiner-Bobis, G. Dehydroepiandrosterone sulfate augments blood-brain barrier and tight junction protein expression in brain endothelial cells. Biochim. Biophys. Acta Mol. Cell Res.,  2017, 1864(8), 1382-1392.
[http://dx.doi.org/10.1016/j.bbamcr.2017.05.006 ] [PMID:  28495656] 
[142] 
Ito, S.; Yanai, M.; Yamaguchi, S.; Couraud, P.O.; Ohtsuki, S. Regulation of Tight-Junction Integrity by Insulin in an In vitro Model of Human Blood-Brain Barrier. J. Pharm. Sci.,  2017, 106(9), 2599-2605.
[http://dx.doi.org/10.1016/j.xphs.2017.04.036 ] [PMID:  28456720] 
[143] 
Chen, R.L. Is it appropriate to use albumin CSF/plasma ratio to assess blood brain barrier permeability? Neurobiol. Aging,  2011, 32(7), 1338-1339.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.08.024 ] [PMID:  19709781] 
[144] 
Montagne, A.; Barnes, S.R.; Sweeney, M.D.; Halliday, M.R.; Sagare, A.P.; Zhao, Z.; Toga, A.W.; Jacobs, R.E.; Liu, C.Y.; Amezcua, L.; Harrington, M.G.; Chui, H.C.; Law, M.; Zlokovic, B.V. Blood-brain barrier breakdown in the aging human hippocampus. Neuron,  2015, 85(2), 296-302.
[http://dx.doi.org/10.1016/j.neuron.2014.12.032 ] [PMID:  25611508] 
[145] 
Stamatovic, S.M.; Martinez-Revollar, G.; Hu, A.; Choi, J.; Keep, R.F.; Andjelkovic, A.V. Decline in Sirtuin-1 expression and activity plays a critical role in blood-brain barrier permeability in aging. Neurobiol. Dis.,  2019, 126, 105-116.
[http://dx.doi.org/10.1016/j.nbd.2018.09.006 ] [PMID:  30196051] 
[146] 
Ramanathan, A.; Nelson, A.R.; Sagare, A.P.; Zlokovic, B.V. Impaired vascular-mediated clearance of brain amyloid beta in Alzheimer’s disease: the role, regulation and restoration of LRP1. Front. Aging Neurosci.,  2015, 7, 136.
[http://dx.doi.org/10.3389/fnagi.2015.00136 ] [PMID:  26236233] 
[147] 
Hartz, A.M.; Miller, D.S.; Bauer, B. Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer’s disease. Mol. Pharmacol.,  2010, 77(5), 715-723.
[http://dx.doi.org/10.1124/mol.109.061754 ] [PMID:  20101004] 
[148] 
Chiu, C.; Miller, M.C.; Monahan, R.; Osgood, D.P.; Stopa, E.G.; Silverberg, G.D. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer’s disease: preliminary observations. Neurobiol. Aging,  2015, 36(9), 2475-2482.
[http://dx.doi.org/10.1016/j.neurobiolaging.2015.05.020 ] [PMID:  26159621] 
[149] 
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.,  2016, 196(8), 3318-3330.
[http://dx.doi.org/10.4049/jimmunol.1502021 ] [PMID:  26962232] 
[150] 
Jaeger, L.B.; Dohgu, S.; Sultana, R.; Lynch, J.L.; Owen, J.B.; Erickson, M.A.; Shah, G.N.; Price, T.O.; Fleegal-Demotta, M.A.; Butterfield, D.A.; Banks, W.A. Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav. Immun.,  2009, 23(4), 507-517.
[http://dx.doi.org/10.1016/j.bbi.2009.01.017 ] [PMID:  19486646] 
[151] 
Erickson, M.A.; Liang, W.S.; Fernandez, E.G.; Bullock, K.M.; Thysell, J.A.; Banks, W.A. Genetics and sex influence peripheral and central innate immune responses and blood-brain barrier integrity. PLoS One,  2018, 13(10) e0205769
[http://dx.doi.org/10.1371/journal.pone.0205769 ] [PMID:  30325961] 
[152] 
Banks, W.A.; Gray, A.M.; Erickson, M.A.; Salameh, T.S.; Damodarasamy, M.; Sheibani, N.; Meabon, J.S.; Wing, E.E.; Morofuji, Y.; Cook, D.G.; Reed, M.J. Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J. Neuroinflammation,  2015, 12, 223.
[http://dx.doi.org/10.1186/s12974-015-0434-1 ] [PMID:  26608623] 
[153] 
Erickson, M.A.; Banks, W.A. Age-Associated Changes in the Immune System and Blood−Brain Barrier Functions. Int. J. Mol. Sci.,  2019, 20(7) E1632
[http://dx.doi.org/10.3390/ijms20071632 ] [PMID:  30986918] 
[154] 
Sumbria, R.K.; Grigoryan, M.M.; Vasilevko, V.; Paganini-Hill, A.; Kilday, K.; Kim, R.; Cribbs, D.H.; Fisher, M.J. Aging exacerbates development of cerebral microbleeds in a mouse model. J. Neuroinflammation,  2018, 15(1), 69.
[http://dx.doi.org/10.1186/s12974-018-1092-x ] [PMID:  29510725] 
[155] 
Frasca, D.; Blomberg, B.B.; Paganelli, R. Aging, Obesity, and Inflammatory Age-Related Diseases. Front. Immunol.,  2017, 8, 1745.
[http://dx.doi.org/10.3389/fimmu.2017.01745 ] [PMID:  29270179] 
[156] 
Rhea, E.M.; Salameh, T.S.; Logsdon, A.F.; Hanson, A.J.; Erickson, M.A.; Banks, W.A. Blood-Brain Barriers in Obesity. AAPS J.,  2017, 19(4), 921-930.
[http://dx.doi.org/10.1208/s12248-017-0079-3 ] [PMID:  28397097] 
[157] 
Stranahan, A.M.; Hao, S.; Dey, A.; Yu, X.; Baban, B. Blood-brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice. J. Cereb. Blood Flow Metab.,  2016, 36(12), 2108-2121.
[http://dx.doi.org/10.1177/0271678X16642233 ] [PMID:  27034250] 
[158] 
Xu, Z.; Zeng, W.; Sun, J.; Chen, W.; Zhang, R.; Yang, Z.; Yao, Z.; Wang, L.; Song, L.; Chen, Y.; Zhang, Y.; Wang, C.; Gong, L.; Wu, B.; Wang, T.; Zheng, J.; Gao, F. The quantification of blood-brain barrier disruption using dynamic contrast-enhanced magnetic resonance imaging in aging rhesus monkeys with spontaneous type 2 diabetes mellitus. Neuroimage,  2017, 158, 480-487.
[http://dx.doi.org/10.1016/j.neuroimage.2016.07.017 ] [PMID:  27402601] 
[159] 
Salameh, T.S.; Mortell, W.G.; Logsdon, A.F.; Butterfield, D.A.; Banks, W.A. Disruption of the hippocampal and hypothalamic blood-brain barrier in a diet-induced obese model of type II diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate. Fluids Barriers CNS,  2019, 16(1), 1.
[http://dx.doi.org/10.1186/s12987-018-0121-6 ] [PMID:  30616618] 
[160] 
Arnold, S.E.; Arvanitakis, Z.; Macauley-Rambach, S.L.; Koenig, A.M.; Wang, H.Y.; Ahima, R.S.; Craft, S.; Gandy, S.; Buettner, C.; Stoeckel, L.E.; Holtzman, D.M.; Nathan, D.M. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat. Rev. Neurol.,  2018, 14(3), 168-181.
[http://dx.doi.org/10.1038/nrneurol.2017.185 ] [PMID:  29377010] 
[161] 
Chen, F.; Dong, R.R.; Zhong, K.L.; Ghosh, A.; Tang, S.S.; Long, Y.; Hu, M.; Miao, M.X.; Liao, J.M.; Sun, H.B.; Kong, L.Y.; Hong, H. Antidiabetic drugs restore abnormal transport of amyloid-β across the blood-brain barrier and memory impairment in db/db mice. Neuropharmacology,  2016, 101, 123-136.
[http://dx.doi.org/10.1016/j.neuropharm.2015.07.023 ] [PMID:  26211973] 
[162] 
Hippe, B.; Zwielehner, J.; Liszt, K.; Lassl, C.; Unger, F.; Haslberger, A.G. Quantification of butyryl CoA:acetate CoA-transferase genes reveals different butyrate production capacity in individuals according to diet and age. FEMS Microbiol. Lett.,  2011, 316(2), 130-135.
[http://dx.doi.org/10.1111/j.1574-6968.2010.02197.x ] [PMID:  21204931] 
[163] 
Scott, K.A.; Ida, M.; Peterson, V.L.; Prenderville, J.A.; Moloney, G.M.; Izumo, T.; Murphy, K.; Murphy, A.; Ross, R.P.; Stanton, C.; Dinan, T.G.; Cryan, J.F. Revisiting Metchnikoff: Age-related alterations in microbiota-gut-brain axis in the mouse. Brain Behav. Immun.,  2017, 65, 20-32.
[http://dx.doi.org/10.1016/j.bbi.2017.02.004 ] [PMID:  28179108] 
[164] 
Bateman, R.J.; Aisen, P.S.; De Strooper, B.; Fox, N.C.; Lemere, C.A.; Ringman, J.M.; Salloway, S.; Sperling, R.A.; Windisch, M.; Xiong, C. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res. Ther.,  2011, 3(1), 1.
[http://dx.doi.org/10.1186/alzrt59 ] [PMID:  21211070] 
[165] 
Karch, C.M.; Goate, A.M. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry,  2015, 77(1), 43-51.
[http://dx.doi.org/10.1016/j.biopsych.2014.05.006 ] [PMID:  24951455] 
[166] 
Xu, W.; Tan, L.; Wang, H.F.; Jiang, T.; Tan, M.S.; Tan, L.; Zhao, Q.F.; Li, J.Q.; Wang, J.; Yu, J.T. Meta-analysis of modifiable risk factors for Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry,  2015, 86(12), 1299-1306.
[http://dx.doi.org/10.1136/jnnp-2015-310548 ] [PMID:  26294005] 
[167] 
Qizilbash, N.; Gregson, J.; Johnson, M.E.; Pearce, N.; Douglas, I.; Wing, K.; Evans, S.J.W.; Pocock, S.J. BMI and risk of dementia in two million people over two decades: a retrospective cohort study. Lancet Diabetes Endocrinol.,  2015, 3(6), 431-436.
[http://dx.doi.org/10.1016/S2213-8587(15)00033-9 ] [PMID:  25866264] 
[168] 
Lane, C.A.; Hardy, J.; Schott, J.M. Alzheimer’s disease. Eur. J. Neurol.,  2018, 25(1), 59-70.
[http://dx.doi.org/10.1111/ene.13439 ] [PMID:  28872215] 
[169] 
Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med.,  2016, 8(6), 595-608.
[http://dx.doi.org/10.15252/emmm.201606210 ] [PMID:  27025652] 
[170] 
Hamelin, L.; Lagarde, J.; Dorothée, G.; Leroy, C.; Labit, M.; Comley, R.A.; de Souza, L.C.; Corne, H.; Dauphinot, L.; Bertoux, M.; Dubois, B.; Gervais, P.; Colliot, O.; Potier, M.C.; Bottlaender, M.; Sarazin, M. Clinical IMABio3 team. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain,  2016, 139(Pt 4), 1252-1264.
[http://dx.doi.org/10.1093/brain/aww017 ] [PMID:  26984188] 
[171] 
Blaylock, R.L. Parkinson’s disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration. Surg. Neurol. Int.,  2017, 8, 65.
[http://dx.doi.org/10.4103/sni.sni_441_16 ] [PMID:  28540131] 
[172] 
Ascherio, A.; Schwarzschild, M.A. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol.,  2016, 15(12), 1257-1272.
[http://dx.doi.org/10.1016/S1474-4422(16)30230-7 ] [PMID:  27751556] 
[173] 
Leverenz, J.B.; Quinn, J.F.; Zabetian, C.; Zhang, J.; Montine, K.S.; Montine, T.J. Cognitive impairment and dementia in patients with Parkinson disease. Curr. Top. Med. Chem.,  2009, 9(10), 903-912.
[PMID:  19754405] 
[174] 
Calabrese, V.; Santoro, A.; Monti, D.; Crupi, R.; Di Paola, R.; Latteri, S.; Cuzzocrea, S.; Zappia, M.; Giordano, J.; Calabrese, E.J.; Franceschi, C. Aging and Parkinson’s Disease: Inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radic. Biol. Med.,  2018, 115, 80-91.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.10.379 ] [PMID:  29080843] 
[175] 
Dodiya, H.B.; Forsyth, C.B.; Voigt, R.M.; Engen, P.A.; Patel, J.; Shaikh, M.; Green, S.J.; Naqib, A.; Roy, A.; Kordower, J.H.; Pahan, K.; Shannon, K.M.; Keshavarzian, A. Chronic stress-induced gut dysfunction exacerbates Parkinson’s disease phenotype and pathology in a rotenone-induced mouse model of Parkinson’s disease. Neurobiol. Dis., 2020. 135104352
[http://dx.doi.org/10.1016/j.nbd.2018.12.012 ] [PMID:  30579705] 
[176] 
Dias, V.; Junn, E.; Mouradian, M.M. The role of oxidative stress in Parkinson’s disease. J. Parkinsons Dis.,  2013, 3(4), 461-491.
[http://dx.doi.org/10.3233/JPD-130230 ] [PMID:  24252804] 
[177] 
Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, D.A.; Stella, A.M. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat. Rev. Neurosci.,  2007, 8(10), 766-775.
[http://dx.doi.org/10.1038/nrn2214 ] [PMID:  17882254] 
[178] 
Devi, L.; Raghavendran, V.; Prabhu, B.M.; Avadhani, N.G.; Anandatheerthavarada, H.K. Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J. Biol. Chem.,  2008, 283(14), 9089-9100.
[http://dx.doi.org/10.1074/jbc.M710012200 ] [PMID:  18245082] 
[179] 
Prodinger, C.; Bunse, J.; Krüger, M.; Schiefenhövel, F.; Brandt, C.; Laman, J.D.; Greter, M.; Immig, K.; Heppner, F.; Becher, B.; Bechmann, I. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol.,  2011, 121(4), 445-458.
[http://dx.doi.org/10.1007/s00401-010-0774-y ] [PMID:  21076838] 
[180] 
Phani, S.; Loike, J.D.; Przedborski, S. Neurodegeneration and inflammation in Parkinson’s disease. Parkinsonism Relat. Disord.,  2012, 18(Suppl. 1), S207-S209.
[http://dx.doi.org/10.1016/S1353-8020(11)70064-5 ] [PMID:  22166436] 
[181] 
Calopa, M.; Bas, J.; Callén, A.; Mestre, M. Apoptosis of peripheral blood lymphocytes in Parkinson patients. Neurobiol. Dis.,  2010, 38(1), 1-7.
[http://dx.doi.org/10.1016/j.nbd.2009.12.017 ] [PMID:  20044003] 
[182] 
Saunders, J.A.; Estes, K.A.; Kosloski, L.M.; Allen, H.E.; Dempsey, K.M.; Torres-Russotto, D.R.; Meza, J.L.; Santamaria, P.M.; Bertoni, J.M.; Murman, D.L.; Ali, H.H.; Standaert, D.G.; Mosley, R.L.; Gendelman, H.E. CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J. Neuroimmune Pharmacol.,  2012, 7(4), 927-938.
[http://dx.doi.org/10.1007/s11481-012-9402-z ] [PMID:  23054369] 
[183] 
Chen, H.; O’Reilly, E.J.; Schwarzschild, M.A.; Ascherio, A. Peripheral inflammatory biomarkers and risk of Parkinson’s disease. Am. J. Epidemiol.,  2008, 167(1), 90-95.
[http://dx.doi.org/10.1093/aje/kwm260 ] [PMID:  17890755] 
[184] 
Rentzos, M.; Nikolaou, C.; Andreadou, E.; Paraskevas, G.P.; Rombos, A.; Zoga, M.; Tsoutsou, A.; Boufidou, F.; Kapaki, E.; Vassilopoulos, D. Circulating interleukin-10 and interleukin-12 in Parkinson’s disease. Acta Neurol. Scand.,  2009, 119(5), 332-337.
[http://dx.doi.org/10.1111/j.1600-0404.2008.01103.x ] [PMID:  18976327] 
[185] 
Liu, J.Q.; Chu, S.F.; Zhou, X.; Zhang, D.Y.; Chen, N.H. Role of chemokines in Parkinson’s disease. Brain Res. Bull.,  2019, 152, 11-18.
[http://dx.doi.org/10.1016/j.brainresbull.2019.05.020 ] [PMID:  31136787] 
[186] 
Dendrou, C.A.; Fugger, L.; Friese, M.A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol.,  2015, 15(9), 545-558.
[http://dx.doi.org/10.1038/nri3871 ] [PMID:  26250739] 
[187] 
Nylander, A.; Hafler, D.A. Multiple sclerosis. J. Clin. Invest.,  2012, 122(4), 1180-1188.
[http://dx.doi.org/10.1172/JCI58649 ] [PMID:  22466660] 
[188] 
Hollenbach, J.A.; Oksenberg, J.R. The immunogenetics of multiple sclerosis: A comprehensive review. J. Autoimmun.,  2015, 64, 13-25.
[http://dx.doi.org/10.1016/j.jaut.2015.06.010 ] [PMID:  26142251] 
[189] 
Zuvich, R.L.; McCauley, J.L.; Pericak-Vance, M.A.; Haines, J.L. Genetics and pathogenesis of multiple sclerosis. Semin. Immunol.,  2009, 21(6), 328-333.
[http://dx.doi.org/10.1016/j.smim.2009.08.003 ] [PMID:  19775910] 
[190] 
Hussman, J.P.; Beecham, A.H.; Schmidt, M.; Martin, E.R.; McCauley, J.L.; Vance, J.M.; Haines, J.L.; Pericak-Vance, M.A. GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis. Genes Immun.,  2016, 17(5), 305-312.
[http://dx.doi.org/10.1038/gene.2016.23 ] [PMID:  27278126] 
[191] 
Cao, Y.; Goods, B.A.; Raddassi, K.; Nepom, G.T.; Kwok, W.W.; Love, J.C.; Hafler, D.A. Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci. Transl. Med.,  2015, 7(287) 287ra74
[http://dx.doi.org/10.1126/scitranslmed.aaa8038 ] [PMID:  25972006] 
[192] 
Markovic-Plese, S. Degenerate T-cell receptor recognition, autoreactive cells, and the autoimmune response in multiple sclerosis. Neuroscientist,  2009, 15(3), 225-231.
[http://dx.doi.org/10.1177/1073858409332404 ] [PMID:  19297658] 
[193] 
Geginat, J.; Paroni, M.; Pagani, M.; Galimberti, D.; De Francesco, R.; Scarpini, E.; Abrignani, S. The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance? Trends Immunol.,  2017, 38(7), 498-512.
[http://dx.doi.org/10.1016/j.it.2017.04.006 ] [PMID:  28549714] 
[194] 
Sospedra, M.; Martin, R. Molecular mimicry in multiple sclerosis. Autoimmunity,  2006, 39(1), 3-8.
[http://dx.doi.org/10.1080/08916930500484922 ] [PMID:  16455577] 
[195] 
Zhang, X.; Tao, Y.; Chopra, M.; Dujmovic-Basuroski, I.; Jin, J.; Tang, Y.; Drulovic, J.; Markovic-Plese, S. IL-11 Induces Th17 Cell Responses in Patients with Early Relapsing-Remitting Multiple Sclerosis. J. Immunol.,  2015, 194(11), 5139-5149.
[http://dx.doi.org/10.4049/jimmunol.1401680 ] [PMID:  25895532] 
[196] 
Nyirenda, M.H.; Morandi, E.; Vinkemeier, U.; Constantin-Teodosiu, D.; Drinkwater, S.; Mee, M.; King, L.; Podda, G.; Zhang, G.X.; Ghaemmaghami, A.; Constantinescu, C.S.; Bar-Or, A.; Gran, B. TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis. J. Immunol.,  2015, 194(12), 5761-5774.
[http://dx.doi.org/10.4049/jimmunol.1400472 ] [PMID:  25980006] 
[197] 
Molnarfi, N.; Schulze-Topphoff, U.; Weber, M.S.; Patarroyo, J.C.; Prod’homme, T.; Varrin-Doyer, M.; Shetty, A.; Linington, C.; Slavin, A.J.; Hidalgo, J.; Jenne, D.E.; Wekerle, H.; Sobel, R.A.; Bernard, C.C.; Shlomchik, M.J.; Zamvil, S.S. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J. Exp. Med.,  2013, 210(13), 2921-2937.
[http://dx.doi.org/10.1084/jem.20130699 ] [PMID:  24323356] 
[198] 
Salzer, J.; Svenningsson, R.; Alping, P.; Novakova, L.; Björck, A.; Fink, K.; Islam-Jakobsson, P.; Malmeström, C.; Axelsson, M.; Vågberg, M.; Sundström, P.; Lycke, J.; Piehl, F.; Svenningsson, A. Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy. Neurology,  2016, 87(20), 2074-2081.
[http://dx.doi.org/10.1212/WNL.0000000000003331 ] [PMID:  27760868] 
[199] 
Kebir, H.; Ifergan, I.; Alvarez, J.I.; Bernard, M.; Poirier, J.; Arbour, N.; Duquette, P.; Prat, A. Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis. Ann. Neurol.,  2009, 66(3), 390-402.
[http://dx.doi.org/10.1002/ana.21748 ] [PMID:  19810097] 
[200] 
Kebir, H.; Kreymborg, K.; Ifergan, I.; Dodelet-Devillers, A.; Cayrol, R.; Bernard, M.; Giuliani, F.; Arbour, N.; Becher, B.; Prat, A. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat. Med.,  2007, 13(10), 1173-1175.
[http://dx.doi.org/10.1038/nm1651 ] [PMID:  17828272] 
[201] 
Zhang, X.; Kiapour, N.; Kapoor, S.; Khan, T.; Thamilarasan, M.; Tao, Y.; Cohen, S.; Miller, R.; Sobel, R.A.; Markovic-Plese, S. IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis. J. Immunol.,  2019, 203(5), 1142-1150.
[http://dx.doi.org/10.4049/jimmunol.1900311 ] [PMID:  31341075] 
[202] 
Duffy, S.S.; Keating, B.A.; Moalem-Taylor, G. Adoptive Transfer of Regulatory T Cells as a Promising Immunotherapy for the Treatment of Multiple Sclerosis. Front. Neurosci.,  2019, 13, 1107.
[http://dx.doi.org/10.3389/fnins.2019.01107 ] [PMID:  31680840] 
[203] 
Rosenblum, M.D.; Remedios, K.A.; Abbas, A.K. Mechanisms of human autoimmunity. J. Clin. Invest.,  2015, 125(6), 2228-2233.
[http://dx.doi.org/10.1172/JCI78088 ] [PMID:  25893595] 
[204] 
Candore, G.; Caruso, C.; Jirillo, E.; Magrone, T.; Vasto, S. Low grade inflammation as a common pathogenetic denominator in age-related diseases: novel drug targets for anti-ageing strategies and successful ageing achievement. Curr. Pharm. Des.,  2010, 16(6), 584-596.
[http://dx.doi.org/10.2174/138161210790883868 ] [PMID:  20388068] 
[205] 
Pansarasa, O.; Pistono, C.; Davin, A.; Bordoni, M.; Mimmi, M.C.; Guaita, A.; Cereda, C. Altered immune system in frailty: Genetics and diet may influence inflammation. Ageing Res. Rev., 2019. c54100935
[http://dx.doi.org/10.1016/j.arr.2019.100935 ] [PMID:  31326616] 
[206] 
Hernández Morante, J.J.; Gómez Martínez, C.; Morillas-Ruiz, J.M. Dietary Factors Associated with Frailty in Old Adults: A Review of Nutritional Interventions to Prevent Frailty Development. Nutrients,  2019, 11(1) E102
[http://dx.doi.org/10.3390/nu11010102 ] [PMID:  30621313] 
[207] 
Tabung, F.K.; Steck, S.E.; Zhang, J.; Ma, Y.; Liese, A.D.; Agalliu, I.; Hingle, M.; Hou, L.; Hurley, T.G.; Jiao, L.; Martin, L.W.; Millen, A.E.; Park, H.L.; Rosal, M.C.; Shikany, J.M.; Shivappa, N.; Ockene, J.K.; Hebert, J.R. Construct validation of the dietary inflammatory index among postmenopausal women. Ann. Epidemiol.,  2015, 25(6), 398-405.
[http://dx.doi.org/10.1016/j.annepidem.2015.03.009 ] [PMID:  25900255] 
[208] 
Shivappa, N.; Stubbs, B.; Hébert, J.R.; Cesari, M.; Schofield, P.; Soysal, P.; Maggi, S.; Veronese, N. The Relationship Between the Dietary Inflammatory Index and Incident Frailty: A Longitudinal Cohort Study. J. Am. Med. Dir. Assoc.,  2018, 19(1), 77-82.
[http://dx.doi.org/10.1016/j.jamda.2017.08.006 ] [PMID:  28943182] 
[209] 
Bonaccio, M.; Cerletti, C.; Iacoviello, L.; de Gaetano, G. Mediterranean diet and low-grade subclinical inflammation: the Moli-sani study. Endocr. Metab. Immune Disord. Drug Targets,  2015, 15(1), 18-24.
[http://dx.doi.org/10.2174/1871530314666141020112146 ] [PMID:  25329200] 
[210] 
Kunisawa, J.; Kiyono, H. Vitamins mediate immunological homeostasis and diseases at the surface of the body. Endocr. Metab. Immune Disord. Drug Targets,  2015, 15(1), 25-30.
[http://dx.doi.org/10.2174/1871530314666141021114651 ] [PMID:  25335990] 
[211] 
Casas, R.; Sacanella, E.; Estruch, R. The immune protective effect of the Mediterranean diet against chronic low-grade inflammatory diseases. Endocr. Metab. Immune Disord. Drug Targets,  2014, 14(4), 245-254.
[http://dx.doi.org/10.2174/1871530314666140922153350 ] [PMID:  25244229] 
[212] 
Aiello, A.; Farzaneh, F.; Candore, G.; Caruso, C.; Davinelli, S.; Gambino, C.M.; Ligotti, M.E.; Zareian, N.; Accardi, G. Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front. Immunol.,  2019, 10, 2247.
[http://dx.doi.org/10.3389/fimmu.2019.02247 ] [PMID:  31608061] 
[213] 
Martinez-Gonzalez, M.A.; Bes-Rastrollo, M.; Serra-Majem, L.; Lairon, D.; Estruch, R.; Trichopoulou, A. Mediterranean food pattern and the primary prevention of chronic disease: recent developments. Nutr. Rev.,  2009, 67(Suppl. 1), S111-S116.
[http://dx.doi.org/10.1111/j.1753-4887.2009.00172.x ] [PMID:  19453663] 
[214] 
Gopinath, B.; Buyken, A.E.; Flood, V.M.; Empson, M.; Rochtchina, E.; Mitchell, P. Consumption of polyunsaturated fatty acids, fish, and nuts and risk of inflammatory disease mortality. Am. J. Clin. Nutr.,  2011, 93(5), 1073-1079.
[http://dx.doi.org/10.3945/ajcn.110.009977 ] [PMID:  21411616] 
[215] 
He, K.; Liu, K.; Daviglus, M.L.; Jenny, N.S.; Mayer-Davis, E.; Jiang, R.; Steffen, L.; Siscovick, D.; Tsai, M.; Herrington, D. Associations of dietary long-chain n-3 polyunsaturated fatty acids and fish with biomarkers of inflammation and endothelial activation (from the Multi-Ethnic Study of Atherosclerosis [MESA]). Am. J. Cardiol.,  2009, 103(9), 1238-1243.
[http://dx.doi.org/10.1016/j.amjcard.2009.01.016 ] [PMID:  19406265] 
[216] 
Muka, T.; Kiefte-de Jong, J.C.; Hofman, A.; Dehghan, A.; Rivadeneira, F.; Franco, O.H. Polyunsaturated fatty acids and serum C-reactive protein: the Rotterdam study. Am. J. Epidemiol.,  2015, 181(11), 846-856.
[http://dx.doi.org/10.1093/aje/kwv021 ] [PMID:  25899092] 
[217] 
León-Muñoz, L.M.; García-Esquinas, E.; López-García, E.; Banegas, J.R.; Rodríguez-Artalejo, F. Major dietary patterns and risk of frailty in older adults: a prospective cohort study. BMC Med.,  2015, 13, 11.
[http://dx.doi.org/10.1186/s12916-014-0255-6 ] [PMID:  25601152] 
[218] 
Lo, Y.L.; Hsieh, Y.T.; Hsu, L.L.; Chuang, S.Y.; Chang, H.Y.; Hsu, C.C.; Chen, C.Y.; Pan, W.H. Dietary Pattern Associated with Frailty: Results from Nutrition and Health Survey in Taiwan. J. Am. Geriatr. Soc.,  2017, 65(9), 2009-2015.
[http://dx.doi.org/10.1111/jgs.14972 ] [PMID:  28603896] 
[219] 
Polyphenols in Human Health and Disease Polyphenols in Human Health and Disease. In, Watson, R.R.;
	Preedy, V.; Zibaldi, S. Publisher: Elsevier, United Kingdom, 2014,
	1, ISBN: 978-0-12-398471-5.. 
[220] 
Polyphenols in Human Health and Disease. Watson, R.R.; Preedy, V.; Zibaldi, S, 2nd ed Publisher; Elsevier: United Kingdom, UK, 2014, Vol. 2, .  ISBN 978-0-12-398472-2.
[221] 
Magrone, T.; Panaro, M.A.; Jirillo, E.; Covelli, V. Molecular effects elicited in vitro by red wine on human healthy peripheral blood mononuclear cells: potential therapeutical application of polyphenols to diet-related chronic diseases. Curr. Pharm. Des.,  2008, 14(26), 2758-2766.
[http://dx.doi.org/10.2174/138161208786264179 ] [PMID:  18991694] 
[222] 
Magrone, T.; Jirillo, E. Polyphenols from red wine are potent modulators of innate and adaptive immune responsiveness. Proc. Nutr. Soc.,  2010, 69(3), 279-285.
[http://dx.doi.org/10.1017/S0029665110000121 ] [PMID:  20522276] 
[223] 
Marzulli, G.; Magrone, T.; Kawaguchi, K.; Kumazawa, Y.; Jirillo, E. Fermented grape marc (FGM): immunomodulating properties and its potential exploitation in the treatment of neurodegenerative diseases. Curr. Pharm. Des.,  2012, 18(1), 43-50.
[http://dx.doi.org/10.2174/138161212798919011 ] [PMID:  22211687] 
[224] 
Magrone, T.; Salvatore, R.; Spagnoletta, A.; Magrone, M.; Russo, M.A.; Jirillo, E. In vitro Effects of Nickel on Healthy Non-Allergic Peripheral Blood Mononuclear Cells. The Role of Red Grape Polyphenols. Endocr. Metab. Immune Disord. Drug Targets,  2017, 17(2), 166-173.
[http://dx.doi.org/10.2174/1871530317666170713145350 ] [PMID:  28707594] 
[225] 
Magrone, T.; Romita, P.; Verni, P.; Salvatore, R.; Spagnoletta, A.; Magrone, M.; Russo, M.A.; Jirillo, E.; Foti, C. In vitro Effects of Polyphenols on the Peripheral Immune Responses in Nickel-sensitized Patients. Endocr. Metab. Immune Disord. Drug Targets,  2017, 17(4), 324-331.
[http://dx.doi.org/10.2174/1871530317666171003161314 ] [PMID:  28982342] 
[226] 
Magrone, T.; Jirillo, E.; Magrone, M.; Russo, M.A.; Romita, P.; Massari, F.; Foti, C. Red Grape Polyphenol Oral Administration Improves Immune Response in Women Affected by Nickel-Mediated Allergic Contact Dermatitis. Endocr. Metab. Immune Disord. Drug Targets, 2020. Epub ahead of print.
[http://dx.doi.org/10.2174/1871530320666200313152648] [PMID: 32167433] 
[227] 
Magrone, T.; Russo, M.A.; Jirillo, E. Impact of heavy metals on host cells: Special focus on nickel-mediated pathologies and novel interventional approaches. Endocr. Metab. Immune Disord. Drug Targets, 2019. Epub ahead of print
[http://dx.doi.org/10.2174/1871530319666191129120253 ] [PMID:  31782370] 
[228] 
Magrone, T.; Jirillo, E.; Spagnoletta, A.; Magrone, M.; Russo, M.A.; Fontana, S.; Laforgia, F.; Donvito, I.; Campanella, A.; Silvestris, F.; De Pergola, G. Immune Profile of Obese People and In vitro Effects of Red Grape Polyphenols on Peripheral Blood Mononuclear Cells. Oxid. Med. Cell. Longev.,  2017, 2017 9210862 PMID: 28243360
[229] 
Marzulli, G.; Magrone, T.; Vonghia, L.; Kaneko, M.; Takimoto, H.; Kumazawa, Y.; Jirillo, E. Immunomodulating and anti-allergic effects of Negroamaro and Koshu Vitis vinifera fermented grape marc (FGM). Curr. Pharm. Des.,  2014, 20(6), 864-868.
[http://dx.doi.org/10.2174/138161282006140220120640 ] [PMID:  23701568] 
[230] 
Magrone, T.; Pugliese, V.; Fontana, S.; Jirillo, E. Human use of Leucoselect® Phytosome® with special reference to inflammatory-allergic pathologies in frail elderly patients. Curr. Pharm. Des.,  2014, 20(6), 1011-1019.
[http://dx.doi.org/10.2174/138161282006140220144411 ] [PMID:  23701566] 
[231] 
Magrone, T.; Spagnoletta, A.; Salvatore, R.; Magrone, M.; Dentamaro, F.; Russo, M.A.; Difonzo, G.; Summo, C.; Caponio, F.; Jirillo, E. Olive Leaf Extracts Act as Modulators of the Human Immune Response. Endocr. Metab. Immune Disord. Drug Targets,  2018, 18(1), 85-93.
[http://dx.doi.org/10.2174/1871530317666171116110537] [PMID:  29149822] 
[232] 
Savino, W.; Dardenne, M. Neuroendocrine control of thymus physiology. Endocr. Rev.,  2000, 21(4), 412-443.
[PMID:  10950159] 
[233] 
Mocchegiani, E.; Giacconi, R.; Costarelli, L.; Muti, E.; Cipriano, C.; Tesei, S.; Pierpaoli, S.; Giuli, C.; Papa, R.; Marcellini, F.; Gasparini, N.; Pierandrei, R.; Piacenza, F.; Mariani, E.; Monti, D.; Dedoussis, G.; Kanoni, S.; Herbein, G.; Fulop, T.; Rink, L.; Jajte, J.; Malavolta, M. Zinc deficiency and IL-6 -174G/C polymorphism in old people from different European countries: effect of zinc supplementation. ZINCAGE study. Exp. Gerontol.,  2008, 43(5), 433-444.
[http://dx.doi.org/10.1016/j.exger.2008.01.001 ] [PMID:  18267353] 
[234] 
Mocchegiani, E.; Costarelli, L.; Giacconi, R.; Malavolta, M.; Basso, A.; Piacenza, F.; Ostan, R.; Cevenini, E.; Gonos, E.S.; Monti, D. Micronutrient-gene interactions related to inflammatory/immune response and antioxidant activity in ageing and inflammation. A systematic review. Mech. Ageing Dev.,  2014, 136-137, 29-49.
[http://dx.doi.org/10.1016/j.mad.2013.12.007 ] [PMID:  24388876] 
[235] 
Pawelec, G.; Larbi, A.; Derhovanessian, E. Senescence of the human immune system. J. Comp. Pathol.,  2010, 142(Suppl. 1), S39-S44.
[http://dx.doi.org/10.1016/j.jcpa.2009.09.005 ] [PMID:  19897208] 
[236] 
Prasad, A.S. Clinical, immunological, anti-inflammatory and antioxidant roles of zinc. Exp. Gerontol.,  2008, 43(5), 370-377.
[http://dx.doi.org/10.1016/j.exger.2007.10.013 ] [PMID:  18054190] 
[237] 
Prasad, A.S. Zinc in human health: effect of zinc on immune cells. Mol. Med.,  2008, 14(5-6), 353-357.
[http://dx.doi.org/10.2119/2008-00033.Prasad ] [PMID:  18385818] 
[238] 
Fortes, C.; Forastiere, F.; Agabiti, N.; Fano, V.; Pacifici, R.; Virgili, F.; Piras, G.; Guidi, L.; Bartoloni, C.; Tricerri, A.; Zuccaro, P.; Ebrahim, S.; Perucci, C.A. The effect of zinc and vitamin A supplementation on immune response in an older population. J. Am. Geriatr. Soc.,  1998, 46(1), 19-26.
[http://dx.doi.org/10.1111/j.1532-5415.1998.tb01008.x ] [PMID:  9434661] 
[239] 
Huijskens, M.J.; Walczak, M.; Sarkar, S.; Atrafi, F.; Senden-Gijsbers, B.L.; Tilanus, M.G.; Bos, G.M.; Wieten, L.; Germeraad, W.T. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Cytotherapy,  2015, 17(5), 613-620.
[http://dx.doi.org/10.1016/j.jcyt.2015.01.004 ] [PMID:  25747742] 
[240] 
Maggini, S.; Pierre, A.; Calder, P.C. Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients,  2018, 10(10) E1531
[http://dx.doi.org/10.3390/nu10101531 ] [PMID:  30336639] 
[241] 
De la Fuente, M.; Hernanz, A.; Guayerbas, N.; Victor, V.M.; Arnalich, F. Vitamin E ingestion improves several immune functions in elderly men and women. Free Radic. Res.,  2008, 42(3), 272-280.
[http://dx.doi.org/10.1080/10715760801898838 ] [PMID:  18344122] 
[242] 
de Jongh, R.T.; van Schoor, N.M.; Lips, P. Changes in vitamin D endocrinology during aging in adults. Mol. Cell. Endocrinol.,  2017, 453, 144-150.
[http://dx.doi.org/10.1016/j.mce.2017.06.005 ] [PMID:  28602863] 
[243] 
De Vita, F.; Lauretani, F.; Bauer, J.; Bautmans, I.; Shardell, M.; Cherubini, A.; Bondi, G.; Zuliani, G.; Bandinelli, S.; Pedrazzoni, M.; Dall’Aglio, E.; Ceda, G.P.; Maggio, M. Relationship between vitamin D and inflammatory markers in older individuals. Age (Dordr.),  2014, 36(4), 9694.
[http://dx.doi.org/10.1007/s11357-014-9694-4 ] [PMID:  25086618] 
[244] 
Laird, E.; McNulty, H.; Ward, M.; Hoey, L.; McSorley, E.; Wallace, J.M.; Carson, E.; Molloy, A.M.; Healy, M.; Casey, M.C.; Cunningham, C.; Strain, J.J. Vitamin D deficiency is associated with inflammation in older Irish adults. J. Clin. Endocrinol. Metab.,  2014, 99(5), 1807-1815.
[http://dx.doi.org/10.1210/jc.2013-3507 ] [PMID:  24606079] 
[245] 
Cuervo, A.; Salazar, N.; Ruas-Madiedo, P.; Gueimonde, M.; González, S. Fiber from a regular diet is directly associated with fecal short-chain fatty acid concentrations in the elderly. Nutr. Res.,  2013, 33(10), 811-816.
[http://dx.doi.org/10.1016/j.nutres.2013.05.016 ] [PMID:  24074739] 
[246] 
Rahmani, S.; Sadeghi, O.; Sadeghian, M.; Sadeghi, N.; Larijani, B.; Esmaillzadeh, A. The Effect of Whole-Grain Intake on Biomarkers of Subclinical Inflammation: A Comprehensive Meta-analysis of Randomized Controlled Trials. Adv. Nutr.,  2020, 11(1), 52-65. PMID: 10950159
[247] 
Bouter, K.E.; van Raalte, D.H.; Groen, A.K.; Nieuwdorp, M. Role of the Gut Microbiome in the Pathogenesis of Obesity and Obesity-Related Metabolic Dysfunction. Gastroenterology,  2017, 152(7), 1671-1678.
[http://dx.doi.org/10.1053/j.gastro.2016.12.048 ] [PMID:  28192102] 
[248] 
Tenorio-Jiménez, C.; Martínez-Ramírez, M.J.; Gil, Á.; Gómez-Llorente, C. Effects of Probiotics on Metabolic Syndrome: A Systematic Review of Randomized Clinical Trials. Nutrients,  2020, 12(1) E124
[http://dx.doi.org/10.3390/nu12010124 ] [PMID:  31906372] 
[249] 
Gill, H.S.; Rutherfurd, K.J.; Cross, M.L.; Gopal, P.K. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am. J. Clin. Nutr.,  2001, 74(6), 833-839.
[http://dx.doi.org/10.1093/ajcn/74.6.833 ] [PMID:  11722966] 
[250] 
Landete, J.M.; Gaya, P.; Rodríguez, E.; Langa, S.; Peirotén, Á.; Medina, M.; Arqués, J.L. Probiotic Bacteria for Healthier Aging: Immunomodulation and Metabolism of Phytoestrogens. BioMed Res. Int.,  2017, 2017 5939818
[http://dx.doi.org/10.1155/2017/5939818 ] [PMID:  29109959] 
[251] 
Suez, J.; Zmora, N.; Segal, E.; Elinav, E. The pros, cons, and many unknowns of probiotics. Nat. Med.,  2019, 25(5), 716-729.
[http://dx.doi.org/10.1038/s41591-019-0439-x ] [PMID:  31061539] 
[252] 
Jirillo, E.; Jirillo, F.; Magrone, T. Healthy effects exerted by prebiotics, probiotics, and symbiotics with special reference to their impact on the immune system. Int. J. Vitam. Nutr. Res.,  2012, 82(3), 200-208.
[http://dx.doi.org/10.1024/0300-9831/a000112 ] [PMID:  23258401] 
[253] 
Bartosch, S.; Woodmansey, E.J.; Paterson, J.C.; McMurdo, M.E.; Macfarlane, G.T. Microbiological effects of consuming a synbiotic containing Bifidobacterium bifidum, Bifidobacterium lactis, and oligofructose in elderly persons, determined by real-time polymerase chain reaction and counting of viable bacteria. Clin. Infect. Dis.,  2005, 40(1), 28-37.
[http://dx.doi.org/10.1086/426027 ] [PMID:  15614689] 
[254] 
Macfarlane, S.; Cleary, S.; Bahrami, B.; Reynolds, N.; Macfarlane, G.T. Synbiotic consumption changes the metabolism and composition of the gut microbiota in older people and modifies inflammatory processes: a randomised, double-blind, placebo-controlled crossover study. Aliment. Pharmacol. Ther.,  2013, 38(7), 804-816.
[http://dx.doi.org/10.1111/apt.12453 ] [PMID:  23957631] 
[255] 
Amati, L.; Marzulli, G.; Martulli, M.; Pugliese, V.; Caruso, C.; Candore, G.; Vasto, S.; Jirillo, E. Administration of a synbiotic to free-living elderly and evaluation of serum cytokines. A pilot study. Curr. Pharm. Des.,  2010, 16(7), 854-858.
[http://dx.doi.org/10.2174/138161210790883633 ] [PMID:  20388097] 
[256] 
Jirillo, F.; Magrone, T. Anti-inflammatory and anti-allergic properties of donkey’s and goat’s milk. Endocr. Metab. Immune Disord. Drug Targets,  2014, 14(1), 27-37.
[http://dx.doi.org/10.2174/1871530314666140121143747 ] [PMID:  24450455] 
[257] 
Canhada, S.; Castro, K.; Perry, I.S.; Luft, V.C. Omega-3 fatty acids’ supplementation in Alzheimer’s disease: A systematic review. Nutr. Neurosci.,  2018, 21(8), 529-538.
[http://dx.doi.org/10.1080/1028415X.2017.1321813 ] [PMID:  28466678] 
[258] 
Shinto, L.; Quinn, J.; Montine, T.; Dodge, H.H.; Woodward, W.; Baldauf-Wagner, S.; Waichunas, D.; Bumgarner, L.; Bourdette, D.; Silbert, L.; Kaye, J. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J. Alzheimers Dis.,  2014, 38(1), 111-120.
[http://dx.doi.org/10.3233/JAD-130722 ] [PMID:  24077434] 
[259] 
Freund-Levi, Y.; Eriksdotter-Jönhagen, M.; Cederholm, T.; Basun, H.; Faxén-Irving, G.; Garlind, A.; Vedin, I.; Vessby, B.; Wahlund, L.O.; Palmblad, J. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol.,  2006, 63(10), 1402-1408.
[http://dx.doi.org/10.1001/archneur.63.10.1402 ] [PMID:  17030655] 
[260] 
Panza, F.; Frisardi, V.; Seripa, D.; Imbimbo, B.P.; Pilotto, A.; Solfrizzi, V. Dietary unsaturated fatty acids and risk of mild cognitive impairment. J. Alzheimers Dis.,  2010, 21(3), 867-870.
[http://dx.doi.org/10.3233/JAD-2010-100777 ] [PMID:  20693628] 
[261] 
Valls-Pedret, C.; Lamuela-Raventós, R.M.; Medina-Remón, A.; Quintana, M.; Corella, D.; Pintó, X.; Martínez-González, M.Á.; Estruch, R.; Ros, E. Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J. Alzheimers Dis.,  2012, 29(4), 773-782.
[http://dx.doi.org/10.3233/JAD-2012-111799 ] [PMID:  22349682] 
[262] 
Campolongo, P.; Roozendaal, B.; Trezza, V.; Cuomo, V.; Astarita, G.; Fu, J.; McGaugh, J.L.; Piomelli, D. Fat-induced satiety factor oleoylethanolamide enhances memory consolidation. Proc. Natl. Acad. Sci. USA,  2009, 106(19), 8027-8031.
[http://dx.doi.org/10.1073/pnas.0903038106 ] [PMID:  19416833] 
[263] 
Colizzi, C. The protective effects of polyphenols on Alzheimer’s disease: A systematic review. Alzheimers Dement. (N. Y.),  2018, 5, 184-196.
[http://dx.doi.org/10.1016/j.trci.2018.09.002 ] [PMID:  31194101] 
[264] 
Magrone, T.; Russo, M.A.; Jirillo, E. Cocoa and Dark Chocolate Polyphenols: From Biology to Clinical Applications. Front. Immunol.,  2017, 8, 677.
[http://dx.doi.org/10.3389/fimmu.2017.00677 ] [PMID:  28649251] 
[265] 
Mischley, L.K.; Lau, R.C.; Bennett, R.D. Role of Diet and Nutritional Supplements in Parkinson’s Disease Progression. Oxid. Med. Cell. Longev., 2017. 20176405278
[http://dx.doi.org/10.1155/2017/6405278 ] [PMID:  29081890] 
[266] 
da Silva, T.M.; Munhoz, R.P.; Alvarez, C.; Naliwaiko, K.; Kiss, A.; Andreatini, R.; Ferraz, A.C. Depression in Parkinson’s disease: a double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J. Affect. Disord.,  2008, 111(2-3), 351-359.
[http://dx.doi.org/10.1016/j.jad.2008.03.008 ] [PMID:  18485485] 
[267] 
Clegg, A.; Young, J.; Iliffe, S.; Rikkert, M.O.; Rockwood, K. Frailty in elderly people. Lancet,  2013, 381(9868), 752-762.
[http://dx.doi.org/10.1016/S0140-6736(12)62167-9 ] [PMID:  23395245] 
[268] 
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.,  2007, 128(1), 92-105.
[http://dx.doi.org/10.1016/j.mad.2006.11.016 ] [PMID:  17116321] 
[269] 
Leonardi, G.C.; Accardi, G.; Monastero, R.; Nicoletti, F.; Libra, M. Ageing: from inflammation to cancer. Immun. Ageing,  2018, 15, 1.
[http://dx.doi.org/10.1186/s12979-017-0112-5 ] [PMID:  29387133] 
[270] 
De la Fuente, M.; Miquel, J. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr. Pharm. Des.,  2009, 15(26), 3003-3026.
[http://dx.doi.org/10.2174/138161209789058110 ] [PMID:  19754376] 
[271] 
Vaiserman, A.M.; Koliada, A.K.; Marotta, F. Gut microbiota: A player in aging and a target for anti-aging intervention. Ageing Res. Rev.,  2017, 35, 36-45.
[http://dx.doi.org/10.1016/j.arr.2017.01.001 ] [PMID:  28109835] 
[272] 
Accardi, G.; Shivappa, N.; Di Maso, M.; Hébert, J.R.; Fratino, L.; Montella, M.; La Vecchia, C.; Caruso, C.; Serraino, D.; Libra, M.; Polesel, J. Dietary inflammatory index and cancer risk in the elderly: A pooled-analysis of Italian case-control studies. Nutrition,  2019, 63-64, 205-210.
[http://dx.doi.org/10.1016/j.nut.2019.02.008 ] [PMID:  31029049] 
[273] 
Picocci, S.; Bizzoca, A.; Corsi, P.; Magrone, T.; Jirillo, E.; Gennarini, G. Modulation of Nerve Cell Differentiation: Role of Polyphenols and of Contactin Family Components. Front. Cell Dev. Biol.,  2019, 7, 119.
[http://dx.doi.org/10.3389/fcell.2019.00119 ] [PMID:  31380366] 
[274] 
Magrone, T.; Spagnoletta, A.; Bizzoca, A.; Russo, M.A.; Jirillo, E.; Gennarini, G. Polyphenol Effects on Splenic Cytokine Response in Post-Weaning Contactin 1-Overexpressing Transgenic Mice. Molecules,  2019, 24(12) E2205
[http://dx.doi.org/10.3390/molecules24122205 ] [PMID:  31212848] 
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DOI https://dx.doi.org/10.2174/1871530320666200406123734	Print ISSN 1871-5303
Publisher Name Bentham Science Publisher	Online ISSN 2212-3873
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