{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T06:00:43Z","timestamp":1792044043082,"version":"4.4.0"},"reference-count":123,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2004,6,25]],"date-time":"2004-06-25T00:00:00Z","timestamp":1088121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2004,8]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Evolutionary pressure has selected individuals with traits that allow them to survive to reproduction, without consideration of the consequences for the post\u2010child rearing years and old age. In the 21st century, society is populated increasingly by the elderly and with the falling birth rate and improved health care this trend is set to continue for the foreseeable future. To minimize the potential burden on health services one would hope that \u2018growing old gracefully\u2019 should also mean \u2018growing old healthily\u2019. However, for too many the aging process is accompanied by increasing physical and mental frailty producing an elevated risk of physical and psychological stress in old age. Stress is a potent modulator of immune function, which in youth can be compensated for by the presence of an optimal immune response. In the elderly the immune response is blunted as a result of the decline in several components of the immune system (immune senescence) and a shifting to a chronic pro\u2010inflammatory status (the so\u2010called \u2018inflamm\u2010aging\u2019 effect). We discuss here what is known of the effects of both stress and aging upon the innate immune system, focusing in particular upon the age\u2010related alterations in the hypopituitary\u2013adrenal axis. We propose a double hit model for age and stress in which the age\u2010related increase in the cortisol\/sulphated dehydroepiandrosterone ratio synergizes with elevated cortisol during stress to reduce immunity in the elderly significantly.<\/jats:p>","DOI":"10.1111\/j.1474-9728.2004.00103.x","type":"journal-article","created":{"date-parts":[[2004,7,21]],"date-time":"2004-07-21T11:45:59Z","timestamp":1090410359000},"page":"151-160","source":"Crossref","is-referenced-by-count":113,"title":["Stress responses and innate immunity: aging as a contributory factor"],"prefix":"10.1111","volume":"3","author":[{"given":"Stephen K.","family":"Butcher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet M.","family":"Lord","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,7,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/428116a"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/35021228"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/brbi.2001.0630"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200115040-00009"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199602000-00001"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.153.1.8542141"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.8.4279"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc1530"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.1890380302"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1099\/00222615-48-5-425"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1491"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1159\/000289082"},{"key":"e_1_2_10_14_1","first-page":"512","article-title":"Nosocomial infections in elderly trauma patients: incidence and microbiology","volume":"19","author":"Bochicchio GV","year":"2002","journal-title":"Infections Med."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0803389"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1532-5415.50.7s.4.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(03)00329-2"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0531-5565(01)00162-0"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005373-200110000-00033"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.70.6.881"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1042\/bst0310449"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1385\/IR:27:2-3:141"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(85)90194-9"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(93)90431-H"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/cyto.1998.0458"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/152.4_Pt_2.S53"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006842-199903000-00009"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0889-1591(03)00110-7"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02895111"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006842-200203000-00014"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199108293250903"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.10.2275"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.82.9.2911"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005373-199106000-00001"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1532-5415.1997.tb01482.x"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1089\/jir.1998.18.125"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(98)00156-0"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-472X(00)00544-0"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-003-2111-6"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-4453(03)00068-9"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1159\/000212809"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3109\/08820139609059301"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(96)00095-3"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1086\/515218"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0173(01)00133-3"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1042\/bst0310457"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(02)00437-1"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1781(03)00255-5"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0020-1383(02)00416-3"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02786468"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.24.2268"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1997.00327.x"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(02)80017-7"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.bmb.a011638"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-972864"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006842-199307000-00004"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2003.08.001"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M208140200"},{"key":"e_1_2_10_59_1","first-page":"101","article-title":"Sympathetic nervous system mediates central corticotropin\u2010releasing factor induced suppression of natural killer cytotoxicity","volume":"255","author":"Irwin M","year":"1990","journal-title":"J. Pharmacol. Exp. Therapeutics"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-3999(96)00123-7"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(01)01917-7"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.135.4.416"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.10.5014"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/52A.1.M1"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1998.00433.x"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2001.90.2.678"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1103538"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1033"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200491200"},{"key":"e_1_2_10_70_1","first-page":"140","article-title":"Dehydroepiandrosterone activates MAP\u2010 and Akt kinase signaling pathways through a Gi protein\u2010mediated process and inhibits serum deprivation\u2010induced cell death in vascular endothelial cells","volume":"23","author":"Liu DM","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"e_1_2_10_71_1","first-page":"S209","article-title":"Regulation of the immune response by dehydroepiandrosterone and its metabolites","volume":"150","author":"Loria RM","year":"1996","journal-title":"J. Endocrinol."},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.1.318"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/geronj\/45.2.M55"},{"key":"e_1_2_10_74_1","first-page":"4864","article-title":"Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor alpha","volume":"59","author":"Maggiolini M","year":"1999","journal-title":"Cancer Res."},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0031-9384(02)00923-X"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/1469-8986.3960865"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1997.00440360129015"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1003-1011"},{"key":"e_1_2_10_79_1","doi-asserted-by":"crossref","first-page":"328","DOI":"10.4049\/jimmunol.156.1.328","article-title":"Dehydroepiandrosterone modulation of lipopolysaccharide\u2010stimulated monocyte cytotoxicity","volume":"156","author":"McLachlan JA","year":"1996","journal-title":"J. Immunol."},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(88)80054-X"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5271.70"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0039-6109(16)46587-4"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/0960-0760(91)90282-A"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198410253111701"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199906243402502"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200210000-00007"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4906(03)00173-X"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.12.7231"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005373-199911000-00018"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfg583"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-5699(97)01145-6"},{"key":"e_1_2_10_92_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.64.6.703"},{"key":"e_1_2_10_93_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.163.6.720"},{"key":"e_1_2_10_94_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199703063361007"},{"key":"e_1_2_10_95_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.7168"},{"key":"e_1_2_10_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3999(01)00234-3"},{"key":"e_1_2_10_97_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.123.1.174"},{"key":"e_1_2_10_98_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.9.4697"},{"key":"e_1_2_10_99_1","first-page":"48","article-title":"Neutrophil oxidative burst activation and the pattern of respiratory physiological abnormalities in the fulminant posttraumatic adult respiratory distress syndrome","volume":"33","author":"Rivkind AI","year":"1991","journal-title":"Circulatory Shock"},{"key":"e_1_2_10_100_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-200013020-00002"},{"key":"e_1_2_10_101_1","doi-asserted-by":"publisher","DOI":"10.1006\/brbi.1994.1023"},{"key":"e_1_2_10_102_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2003.08.002"},{"key":"e_1_2_10_103_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(01)14130-5"},{"key":"e_1_2_10_104_1","first-page":"271","article-title":"The effects of lithotripsy on adrenocortical hormones","volume":"80","author":"Saydam S","year":"1995","journal-title":"Int. Surg."},{"key":"e_1_2_10_105_1","doi-asserted-by":"publisher","DOI":"10.1097\/00024382-199701000-00007"},{"key":"e_1_2_10_106_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112190200"},{"key":"e_1_2_10_107_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.5.2502"},{"key":"e_1_2_10_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0264-410X(99)00495-8"},{"key":"e_1_2_10_109_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.84.9.3260"},{"key":"e_1_2_10_110_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-200105000-00015"},{"key":"e_1_2_10_111_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.134.11.1222"},{"key":"e_1_2_10_112_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(03)00857-0"},{"key":"e_1_2_10_113_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.WCB.0000080701.47016.24"},{"key":"e_1_2_10_114_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/57.5.M326"},{"key":"e_1_2_10_115_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.6206"},{"key":"e_1_2_10_116_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009601220552"},{"key":"e_1_2_10_117_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.67.1.40"},{"key":"e_1_2_10_118_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-305X(98)00027-5"},{"key":"e_1_2_10_119_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000073620.42047.D7"},{"key":"e_1_2_10_120_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1995.tb17377.x"},{"key":"e_1_2_10_121_1","doi-asserted-by":"publisher","DOI":"10.1086\/516547"},{"key":"e_1_2_10_122_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(01)00315-1"},{"key":"e_1_2_10_123_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(01)01437-6"},{"key":"e_1_2_10_124_1","first-page":"51","article-title":"Age\u2010related decrease in accessory cell function of human alveolar macrophages","volume":"47","author":"Zissel G","year":"1999","journal-title":"J. Invest. Med."}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1474-9728.2004.00103.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1474-9728.2004.00103.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T14:43:58Z","timestamp":1697208238000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1474-9728.2004.00103.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,7,9]]},"references-count":123,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2004,8]]}},"alternative-id":["10.1111\/j.1474-9728.2004.00103.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1474-9728.2004.00103.x","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,7,9]]}}}