{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:44:17Z","timestamp":1792907057325,"version":"4.5.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Physiology and Pharmacology at University of Georgia","award":["Startup funds"],"award-info":[{"award-number":["Startup funds"]}]},{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["Target Advancement Grant"],"award-info":[{"award-number":["Target Advancement Grant"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Immun Ageing"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL\/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8\u2009+\u2009T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson\u2019s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-\u03b3 production, and impairment of \u03b1-synuclein endocytosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine\/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson\u2019s disease, where immune dysfunction is implicated in their etiology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12979-021-00214-3","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T04:10:48Z","timestamp":1610079048000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":79,"title":["Sex- and age\u2010dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL\/6J mice"],"prefix":"10.1186","volume":"18","author":[{"given":"Kelly B.","family":"Menees","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael H.","family":"Earls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaegwon","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janna","family":"Jernigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolay M.","family":"Filipov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Carpenter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Kyung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"issue":"6","key":"214_CR1","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","volume":"153","author":"C Lopez-Otin","year":"2013","unstructured":"Lopez-Otin C, et al. The hallmarks of aging. Cell. 2013;153(6):1194\u2013217.","journal-title":"Cell"},{"key":"214_CR2","volume-title":"Population Division World Population Prospects 2019: Ten Key Findings","author":"United, Nations. D.o.E.a.S.A.","year":"2019","unstructured":"United, Nations. D.o.E.a.S.A. Population Division World Population Prospects 2019: Ten Key Findings. 2019."},{"issue":"3","key":"214_CR3","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s00439-019-02082-w","volume":"139","author":"NK Sampathkumar","year":"2020","unstructured":"Sampathkumar NK, et al. Widespread sex dimorphism in aging and age-related diseases. Hum Genet. 2020;139(3):333\u201356.","journal-title":"Hum Genet"},{"issue":"2","key":"214_CR4","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.cellimm.2015.02.002","volume":"294","author":"MR Gubbels Bupp","year":"2015","unstructured":"Gubbels Bupp MR. Sex, the aging immune system, and chronic disease. Cell Immunol. 2015;294(2):102\u201310.","journal-title":"Cell Immunol"},{"issue":"2","key":"214_CR5","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1007\/s00281-018-0723-8","volume":"41","author":"SM Gold","year":"2019","unstructured":"Gold SM, et al. Sex differences in autoimmune disorders of the central nervous system. Semin Immunopathol. 2019;41(2):177\u201388.","journal-title":"Semin Immunopathol"},{"key":"214_CR6","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.yfrne.2017.09.002","volume":"50","author":"JC Jurado-Coronel","year":"2018","unstructured":"Jurado-Coronel JC, et al. Sex differences in Parkinson\u2019s disease: features on clinical symptoms, treatment outcome, sexual hormones and genetics. Front Neuroendocrinol. 2018;50:18\u201330.","journal-title":"Front Neuroendocrinol"},{"issue":"2","key":"214_CR7","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1097\/YCO.0000000000000401","volume":"31","author":"KR Laws","year":"2018","unstructured":"Laws KR, Irvine K, Gale TM. Sex differences in Alzheimer\u2019s disease. Curr Opin Psychiatry. 2018;31(2):133\u20139.","journal-title":"Curr Opin Psychiatry"},{"key":"214_CR8","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.jsbmb.2015.09.039","volume":"160","author":"R Hanamsagar","year":"2016","unstructured":"Hanamsagar R, Bilbo SD. Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development. J Steroid Biochem Mol Biol. 2016;160:127\u201333.","journal-title":"J Steroid Biochem Mol Biol"},{"key":"214_CR9","doi-asserted-by":"publisher","first-page":"586","DOI":"10.3389\/fimmu.2018.00586","volume":"9","author":"IM Rea","year":"2018","unstructured":"Rea IM, et al. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. 2018;9:586.","journal-title":"Front Immunol"},{"issue":"2","key":"214_CR10","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/ni1033","volume":"5","author":"PJ Linton","year":"2004","unstructured":"Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004;5(2):133\u20139.","journal-title":"Nat Immunol"},{"key":"214_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1742-4933-5-1","volume":"5","author":"LM Pinchuk","year":"2008","unstructured":"Pinchuk LM, Filipov NM. Differential effects of age on circulating and splenic leukocyte populations in C57BL\/6 and BALB\/c male mice. Immun Ageing. 2008;5:1.","journal-title":"Immun Ageing"},{"issue":"5","key":"214_CR12","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/ni.2588","volume":"14","author":"JJ Goronzy","year":"2013","unstructured":"Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013;14(5):428\u201336.","journal-title":"Nat Immunol"},{"key":"214_CR13","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.jim.2018.08.005","volume":"463","author":"AA Sadighi Akha","year":"2018","unstructured":"Sadighi Akha AA. Aging and the immune system: an overview. J Immunol Methods. 2018;463:21\u20136.","journal-title":"J Immunol Methods"},{"key":"214_CR14","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s12979-016-0079-7","volume":"13","author":"Y Lin","year":"2016","unstructured":"Lin Y, et al. Changes in blood lymphocyte numbers with age in vivo and their association with the levels of cytokines\/cytokine receptors. Immun Ageing. 2016;13:24.","journal-title":"Immun Ageing"},{"issue":"8","key":"214_CR15","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1089\/ars.2010.3228","volume":"14","author":"S Ponnappan","year":"2011","unstructured":"Ponnappan S, Ponnappan U. Aging and immune function: molecular mechanisms to interventions. Antioxid Redox Signal. 2011;14(8):1551\u201385.","journal-title":"Antioxid Redox Signal"},{"key":"214_CR16","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1111\/j.0105-2896.2005.00273.x","volume":"205","author":"DM Murasko","year":"2005","unstructured":"Murasko DM, Jiang J. Response of aged mice to primary virus infections. Immunol Rev. 2005;205:285\u201396.","journal-title":"Immunol Rev"},{"key":"214_CR17","doi-asserted-by":"publisher","first-page":"103998","DOI":"10.1016\/j.cellimm.2019.103998","volume":"348","author":"HL Dugan","year":"2019","unstructured":"Dugan HL, Henry C, Wilson PC. Aging and influenza vaccine-induced immunity. Cell Immunol. 2019;348:103998.","journal-title":"Cell Immunol."},{"key":"214_CR18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.mad.2013.11.007","volume":"135","author":"E Beli","year":"2014","unstructured":"Beli E, et al. Natural killer cell development and maturation in aged mice. Mech Ageing Dev. 2014;135:33\u201340.","journal-title":"Mech Ageing Dev"},{"issue":"3","key":"214_CR19","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/S0531-5565(99)00008-X","volume":"34","author":"R Solana","year":"1999","unstructured":"Solana R, Alonso MC, Pena J. Natural killer cells in healthy aging. Exp Gerontol. 1999;34(3):435\u201343.","journal-title":"Exp Gerontol"},{"key":"214_CR20","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.3389\/fimmu.2018.01269","volume":"9","author":"MR Gubbels Bupp","year":"2018","unstructured":"Gubbels Bupp MR, et al. The confluence of sex hormones and aging on immunity. Front Immunol. 2018;9:1269.","journal-title":"Front Immunol"},{"issue":"5","key":"214_CR21","doi-asserted-by":"publisher","first-page":"283","DOI":"10.3322\/caac.21153","volume":"62","author":"R Siegel","year":"2012","unstructured":"Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics\/Latinos, 2012. CA Cancer J Clin. 2012;62(5):283\u201398.","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"214_CR22","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/s41467-020-14396-9","volume":"11","author":"EJ Marquez","year":"2020","unstructured":"Marquez EJ, et al. Sexual-dimorphism in human immune system aging. Nat Commun. 2020;11(1):751.","journal-title":"Nat Commun"},{"issue":"2","key":"214_CR23","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.immuni.2006.06.013","volume":"25","author":"N Anfossi","year":"2006","unstructured":"Anfossi N, et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;25(2):331\u201342.","journal-title":"Immunity"},{"issue":"9","key":"214_CR24","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1172\/JCI129338","volume":"129","author":"JJ Hodgins","year":"2019","unstructured":"Hodgins JJ, et al. Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Invest. 2019;129(9):3499\u2013510.","journal-title":"J Clin Invest"},{"issue":"9","key":"214_CR25","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1084\/jem.20092749","volume":"207","author":"J Hao","year":"2010","unstructured":"Hao J, et al. Central nervous system (CNS)-resident natural killer cells suppress Th17 responses and CNS autoimmune pathology. J Exp Med. 2010;207(9):1907\u201321.","journal-title":"J Exp Med"},{"issue":"8","key":"214_CR26","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1007\/s10072-017-2988-4","volume":"38","author":"S Jiang","year":"2017","unstructured":"Jiang S, et al. The correlation of lymphocyte subsets, natural killer cell, and Parkinson\u2019s disease: a meta-analysis. Neurol Sci. 2017;38(8):1373\u201380.","journal-title":"Neurol Sci"},{"issue":"4","key":"214_CR27","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.4049\/jimmunol.1102002","volume":"188","author":"FB Thoren","year":"2012","unstructured":"Thoren FB, et al. Human NK Cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. J Immunol. 2012;188(4):1668\u201374.","journal-title":"J Immunol"},{"issue":"5","key":"214_CR28","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1111\/j.1474-9726.2012.00839.x","volume":"11","author":"J Hazeldine","year":"2012","unstructured":"Hazeldine J, Hampson P, Lord JM. Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell. 2012;11(5):751\u20139.","journal-title":"Aging Cell"},{"issue":"4","key":"214_CR29","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.humimm.2011.01.009","volume":"72","author":"A Almeida-Oliveira","year":"2011","unstructured":"Almeida-Oliveira A, et al. Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol. 2011;72(4):319\u201329.","journal-title":"Hum Immunol"},{"issue":"4","key":"214_CR30","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/j.arr.2013.04.003","volume":"12","author":"J Hazeldine","year":"2013","unstructured":"Hazeldine J, Lord JM. The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev. 2013;12(4):1069\u201378.","journal-title":"Ageing Res Rev"},{"issue":"7","key":"214_CR31","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.1182\/blood.V92.7.2410","volume":"92","author":"D Rukavina","year":"1998","unstructured":"Rukavina D, et al. Age-related decline of perforin expression in human cytotoxic T lymphocytes and natural killer cells. Blood. 1998;92(7):2410\u201320.","journal-title":"Blood"},{"issue":"5","key":"214_CR32","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1007\/s10522-015-9581-0","volume":"16","author":"C Campos","year":"2015","unstructured":"Campos C, et al. Expression of NKp30, NKp46 and DNAM-1 activating receptors on resting and IL-2 activated NK cells from healthy donors according to CMV-serostatus and age. Biogerontology. 2015;16(5):671\u201383.","journal-title":"Biogerontology"},{"issue":"6\u20137","key":"214_CR33","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.mad.2005.01.004","volume":"126","author":"CT Lutz","year":"2005","unstructured":"Lutz CT, et al. Reciprocal age related change in natural killer cell receptors for MHC class I. Mech Ageing Dev. 2005;126(6\u20137):722\u201331.","journal-title":"Mech Ageing Dev"},{"key":"214_CR34","first-page":"3128758","volume":"2018","author":"C Solana","year":"2018","unstructured":"Solana C, Tarazona R, Solana R. Immunosenescence of natural killer cells, inflammation, and Alzheimer\u2019s disease. Int J Alzheimers Dis. 2018;2018:3128758.","journal-title":"Int J Alzheimers Dis"},{"issue":"2","key":"214_CR35","first-page":"369","volume":"29","author":"MP Scola","year":"2002","unstructured":"Scola MP, et al. Interferon-gamma:interleukin 4 ratios and associated type 1 cytokine expression in juvenile rheumatoid arthritis synovial tissue. J Rheumatol. 2002;29(2):369\u201378.","journal-title":"J Rheumatol"},{"issue":"4","key":"214_CR36","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1080\/09629350123387","volume":"10","author":"GV Shmarina","year":"2001","unstructured":"Shmarina GV, et al. Tumor necrosis factor-alpha\/interleukin-10 balance in normal and cystic fibrosis children. Mediators Inflamm. 2001;10(4):191\u20137.","journal-title":"Mediators Inflamm"},{"issue":"1","key":"214_CR37","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1186\/s12974-019-1636-8","volume":"16","author":"RH Earls","year":"2019","unstructured":"Earls RH, et al. Intrastriatal injection of preformed alpha-synuclein fibrils alters central and peripheral immune cell profiles in non-transgenic mice. J Neuroinflammation. 2019;16(1):250.","journal-title":"J Neuroinflammation"},{"key":"214_CR38","doi-asserted-by":"publisher","first-page":"1762","DOI":"10.1073\/pnas.1909110117","volume":"117","author":"RH Earls","year":"2020","unstructured":"Earls RH, et al. NK cells clear alpha-synuclein and the depletion of NK cells exacerbates synuclein pathology in a mouse model of alpha-synucleinopathy. Proc Natl Acad Sci USA. 2020;117:1762\u201371.","journal-title":"Proc Natl Acad Sci USA."},{"key":"214_CR39","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0065-2776(07)96002-2","volume":"96","author":"JR Schoenborn","year":"2007","unstructured":"Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41\u2013101.","journal-title":"Adv Immunol"},{"issue":"2","key":"214_CR40","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1080\/13548506.2014.936884","volume":"20","author":"TL Rochelle","year":"2015","unstructured":"Rochelle TL, et al. Predictors of the gender gap in life expectancy across 54 nations. Psychol Health Med. 2015;20(2):129\u201338.","journal-title":"Psychol Health Med"},{"key":"214_CR41","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.exger.2015.01.003","volume":"63","author":"M Lessard-Beaudoin","year":"2015","unstructured":"Lessard-Beaudoin M, et al. Characterization of age-associated changes in peripheral organ and brain region weights in C57BL\/6 mice. Exp Gerontol. 2015;63:27\u201334.","journal-title":"Exp Gerontol"},{"issue":"5","key":"214_CR42","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1007\/s10522-017-9707-7","volume":"18","author":"VM Turner","year":"2017","unstructured":"Turner VM, Mabbott NA. Influence of ageing on the microarchitecture of the spleen and lymph nodes. Biogerontology. 2017;18(5):723\u201338.","journal-title":"Biogerontology"},{"issue":"11","key":"214_CR43","doi-asserted-by":"publisher","first-page":"5356","DOI":"10.4049\/jimmunol.1201867","volume":"189","author":"MJ Smithey","year":"2012","unstructured":"Smithey MJ, et al. Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life. J Immunol. 2012;189(11):5356\u201366.","journal-title":"J Immunol"},{"issue":"5","key":"214_CR44","doi-asserted-by":"publisher","first-page":"2143","DOI":"10.4049\/jimmunol.1301721","volume":"192","author":"AM Wertheimer","year":"2014","unstructured":"Wertheimer AM, et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J Immunol. 2014;192(5):2143\u201355.","journal-title":"J Immunol"},{"issue":"2","key":"214_CR45","first-page":"81","volume":"19","author":"G Bruno","year":"2017","unstructured":"Bruno G, et al. The revival of an \u201cOld\u201d Marker: CD4\/CD8 ratio. AIDS Rev. 2017;19(2):81\u20138.","journal-title":"AIDS Rev"},{"issue":"2","key":"214_CR46","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.cellimm.2015.05.006","volume":"296","author":"GC Muller","year":"2015","unstructured":"Muller GC, et al. The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging. Cell Immunol. 2015;296(2):149\u201354.","journal-title":"Cell Immunol"},{"issue":"11","key":"214_CR47","doi-asserted-by":"publisher","first-page":"e1006624","DOI":"10.1371\/journal.ppat.1006624","volume":"13","author":"JA McBride","year":"2017","unstructured":"McBride JA, Striker R. Imbalance in the game of T cells: What can the CD4\/CD8 T-cell ratio tell us about HIV and health? PLoS Pathog. 2017;13(11):e1006624.","journal-title":"PLoS Pathog"},{"issue":"3","key":"214_CR48","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1007\/s11357-012-9400-3","volume":"35","author":"J Strindhall","year":"2013","unstructured":"Strindhall J, et al. The inverted CD4\/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age (Dordr). 2013;35(3):985\u201391.","journal-title":"Age (Dordr)"},{"issue":"5","key":"214_CR49","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1111\/j.1474-9726.2012.00849.x","volume":"11","author":"DB Bartlett","year":"2012","unstructured":"Bartlett DB, et al. The age-related increase in low-grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection. Aging Cell. 2012;11(5):912\u20135.","journal-title":"Aging Cell"},{"issue":"3","key":"214_CR50","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/0167-5699(96)80606-2","volume":"17","author":"TR Mosmann","year":"1996","unstructured":"Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17(3):138\u201346.","journal-title":"Immunol Today"},{"issue":"7","key":"214_CR51","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1097\/WNR.0b013e32832aa95b","volume":"20","author":"NM Filipov","year":"2009","unstructured":"Filipov NM, Norwood AB, Sistrunk SC. Strain-specific sensitivity to MPTP of C57BL\/6 and BALB\/c mice is age dependent. Neuroreport. 2009;20(7):713\u20137.","journal-title":"Neuroreport"},{"issue":"5","key":"214_CR52","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1007\/s12026-017-8940-0","volume":"65","author":"DH Lee","year":"2017","unstructured":"Lee DH, et al. Age-dependent alterations in serum cytokines, peripheral blood mononuclear cell cytokine production, natural killer cell activity, and prostaglandin F2alpha. Immunol Res. 2017;65(5):1009\u201316.","journal-title":"Immunol Res"},{"issue":"3","key":"214_CR53","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1111\/acel.12320","volume":"14","author":"TU Metcalf","year":"2015","unstructured":"Metcalf TU, et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell. 2015;14(3):421\u201332.","journal-title":"Aging Cell"},{"issue":"8","key":"214_CR54","doi-asserted-by":"publisher","first-page":"4590","DOI":"10.4049\/jimmunol.1002732","volume":"186","author":"CT Lutz","year":"2011","unstructured":"Lutz CT, et al. Human NK cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults. J Immunol. 2011;186(8):4590\u20138.","journal-title":"J Immunol"},{"issue":"11","key":"214_CR55","doi-asserted-by":"publisher","first-page":"e1002368","DOI":"10.1371\/journal.ppat.1002368","volume":"7","author":"RL Schmidt","year":"2011","unstructured":"Schmidt RL, et al. A LysM and SH3-domain containing region of the Listeria monocytogenes p60 protein stimulates accessory cells to promote activation of host NK cells. PLoS Pathog. 2011;7(11):e1002368.","journal-title":"PLoS Pathog"},{"issue":"8","key":"214_CR56","doi-asserted-by":"publisher","first-page":"5558","DOI":"10.4049\/jimmunol.180.8.5558","volume":"180","author":"CL Small","year":"2008","unstructured":"Small CL, et al. NK cells play a critical protective role in host defense against acute extracellular Staphylococcus aureus bacterial infection in the lung. J Immunol. 2008;180(8):5558\u201368.","journal-title":"J Immunol"},{"issue":"15","key":"214_CR57","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1038\/onc.2012.206","volume":"32","author":"A Sagiv","year":"2013","unstructured":"Sagiv A, et al. Granule exocytosis mediates immune surveillance of senescent cells. Oncogene. 2013;32(15):1971\u20137.","journal-title":"Oncogene"},{"issue":"12","key":"214_CR58","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1038\/ni1138","volume":"5","author":"A Martin-Fontecha","year":"2004","unstructured":"Martin-Fontecha A, et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol. 2004;5(12):1260\u20135.","journal-title":"Nat Immunol"},{"issue":"2","key":"214_CR59","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1182\/blood-2004-10-4035","volume":"106","author":"M Vitale","year":"2005","unstructured":"Vitale M, et al. NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood. 2005;106(2):566\u201371.","journal-title":"Blood"},{"key":"214_CR60","doi-asserted-by":"publisher","first-page":"377","DOI":"10.3389\/fimmu.2012.00377","volume":"3","author":"SN Waggoner","year":"2012","unstructured":"Waggoner SN, Kumar V. Evolving role of 2B4\/CD244 in T and NK cell responses during virus infection. Front Immunol. 2012;3:377.","journal-title":"Front Immunol"},{"issue":"1\u20132","key":"214_CR61","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.jim.2004.08.008","volume":"294","author":"G Alter","year":"2004","unstructured":"Alter G, Malenfant JM, Altfeld M. CD107a as a functional marker for the identification of natural killer cell activity. J Immunol Methods. 2004;294(1\u20132):15\u201322.","journal-title":"J Immunol Methods"},{"issue":"1-2","key":"214_CR62","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0165-2478(96)02519-9","volume":"50","author":"R Krishnaraj","year":"1996","unstructured":"Krishnaraj R, Bhooma T. Cytokine sensitivity of human NK cells during immunosenescence. 2. IL2-induced interferon gamma secretion. Immunol Lett. 1996;50(1-2):59\u201363.","journal-title":"Immunol Lett"},{"key":"214_CR63","doi-asserted-by":"publisher","first-page":"441","DOI":"10.3389\/fimmu.2018.00441","volume":"9","author":"FM Wensveen","year":"2018","unstructured":"Wensveen FM, Jelencic V, Polic B. NKG2D: a master regulator of immune cell responsiveness. Front Immunol. 2018;9:441.","journal-title":"Front Immunol"},{"issue":"2","key":"214_CR64","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1615\/CritRevImmunol.2016017387","volume":"36","author":"AY Mah","year":"2016","unstructured":"Mah AY, Cooper MA. Metabolic regulation of natural killer cell IFN-gamma production. Crit Rev Immunol. 2016;36(2):131\u201347.","journal-title":"Crit Rev Immunol"},{"issue":"12","key":"214_CR65","doi-asserted-by":"publisher","first-page":"3328","DOI":"10.1523\/JNEUROSCI.5321-06.2007","volume":"27","author":"MP Mount","year":"2007","unstructured":"Mount MP, et al. Involvement of interferon-gamma in microglial-mediated loss of dopaminergic neurons. J Neurosci. 2007;27(12):3328\u201337.","journal-title":"J Neurosci"}],"container-title":["Immunity &amp; Ageing"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12979-021-00214-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12979-021-00214-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12979-021-00214-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T07:08:48Z","timestamp":1610089728000},"score":1,"resource":{"primary":{"URL":"https:\/\/immunityageing.biomedcentral.com\/articles\/10.1186\/s12979-021-00214-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,8]]},"references-count":65,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["214"],"URL":"https:\/\/doi.org\/10.1186\/s12979-021-00214-3","relation":{},"ISSN":["1742-4933"],"issn-type":[{"value":"1742-4933","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,8]]},"assertion":[{"value":"23 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}