{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:06:26Z","timestamp":1782281186486,"version":"3.54.5"},"reference-count":128,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Neuroendocrinology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cushing's syndrome (CS), characterized by chronic endogenous hypercortisolism and disruption of the normal circadian cortisol rhythm, represents a unique human model for investigating the interplay between stress endocrinology and biological aging. Glucocorticoid excess drives multiple convergent aging pathways: it suppresses telomerase activity and may accelerate telomere attrition, induces durable epigenetic remodeling, including hypomethylation of stress\u2010responsive genes such as\n                    <jats:italic>FKBP5<\/jats:italic>\n                    , TET\u2010mediated DNA hydroxymethylation changes, and broad dysregulation of circadian clock\n                    <jats:italic>loci<\/jats:italic>\n                    , and promotes telomere\u2010independent senescence through mitochondrial dysfunction, oxidative stress, and cytokine\u2010driven inflammation. These observations underpin a proposed dual\u2010pathway model of glucocorticoid\u2010accelerated aging, in which direct telomerase suppression and indirect epigenomic remodeling converge on common hallmarks of cellular senescence. However, clinical evidence remains heterogeneous and inconclusive: studies of leukocyte telomere length in CS report discrepant results attributable to assay platform differences, failure to correct for glucocorticoid\u2010induced lymphopenia, small sample sizes, and predominant reliance on cross\u2010sectional designs. Epigenetic clocks capable of quantifying biological age acceleration, particularly second\u2010generation tools such as GrimAge and DunedinPACE, have not yet been applied to CS cohorts, representing a critical evidence gap. Furthermore, virtually all molecular aging measurements in CS have been performed in peripheral blood, leaving the causal chain from glucocorticoid excess to organ\u2010level aging and excess mortality empirically unproven. Rather than a definitive null result, this paradox reveals that CS is an underexplored natural experiment: the syndrome's defined onset, quantifiable cortisol exposure, and surgically curable course offer a unique before\u2010after design for testing whether stress\u2010induced endocrine disruption genuinely accelerates biological aging through telomere and epigenetic mechanisms.\n                  <\/jats:p>","DOI":"10.1111\/jne.70213","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T13:08:06Z","timestamp":1781183286000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The aging paradox of Cushing's syndrome: Stress without clear senescence?"],"prefix":"10.1111","volume":"38","author":[{"given":"Israel Nunes","family":"Silveira","sequence":"first","affiliation":[{"name":"Department of Genetics Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo \u2013 USP  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8323-1477","authenticated-orcid":false,"given":"Alexandro","family":"Guterres","sequence":"additional","affiliation":[{"name":"Department of Genetics Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo \u2013 USP  S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20108587(23)00150\u2010X"},{"key":"e_1_2_11_3_1","article-title":"Pituitary adenomas: from diagnosis to therapeutics","volume":"9","author":"Banskota S","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvae194"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-001-0032-5"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018\u201002524"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-025-04234-7"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvac045"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12020\u2010016\u20101083\u20106"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2018.00697"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2018.09.002"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.630186"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14174"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsbl.2017.0164"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2006.8.4\/ssmith"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1816847116"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2014.22"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20679-y"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes11121425"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201061241\u20106"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2007.38"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/35040500"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad3267"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/82586"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2007.00340.x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000251281.00845.18"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2009.09.070"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/895185"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djv074"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.167049"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1656"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-016-0324-x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi266"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/czoolo\/56.6.714"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0026-0495(00)80077-3"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2011.10.445"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1104\/pp.106.077073"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3181a9eafb"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1080\/15216540701225958"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1297.047"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.090043"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/icb\/icw044"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsbl.2015.0211"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2013.03.010"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.35946\/arcr.v34.4.11"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1080\/10253890802305075"},{"key":"e_1_2_11_47_1","first-page":"447","article-title":"A meta\u2010analysis of glucocorticoids as modulators of oxidative stress in vertebrates","volume":"181","author":"Costantini D","year":"2011","journal-title":"J Comp Physiol B"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2007.12.004"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2002.00948.x"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-022-02678-9"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101507"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/NNR.0000000000000037"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0257370"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2020.110836"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-3035"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE\u201014\u20100098"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvaa067"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0120185"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab519"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1530\/EC-18-0362"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0245582"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-49007-4"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4269"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.01.013"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2016.5662"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2015.06.020"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2023.13070"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.29272"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-01174-9"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1080\/09168451.2016.1210502"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-02552"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.4161\/jkst.25763"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01502-8"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-203146"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13193"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11121966"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2014.11.012"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.04.013"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060301"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2012.00818.x"},{"key":"e_1_2_11_81_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64098"},{"key":"e_1_2_11_82_1","doi-asserted-by":"publisher","DOI":"10.37349\/eemd.2024.00016"},{"key":"e_1_2_11_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105462"},{"key":"e_1_2_11_84_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-59541-y"},{"key":"e_1_2_11_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2020.101474"},{"key":"e_1_2_11_86_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13974"},{"key":"e_1_2_11_87_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-57-3-529"},{"key":"e_1_2_11_88_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds383"},{"key":"e_1_2_11_89_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2008.01.004"},{"key":"e_1_2_11_90_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.16.2395"},{"key":"e_1_2_11_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2719"},{"key":"e_1_2_11_92_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.112"},{"key":"e_1_2_11_93_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08514"},{"key":"e_1_2_11_94_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0510310103"},{"key":"e_1_2_11_95_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3230"},{"key":"e_1_2_11_96_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg.2017.80"},{"key":"e_1_2_11_97_1","doi-asserted-by":"publisher","DOI":"10.1177\/1947601910393957"},{"key":"e_1_2_11_98_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.235"},{"key":"e_1_2_11_99_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-019-0682-5"},{"key":"e_1_2_11_100_1","doi-asserted-by":"publisher","DOI":"10.3389\/freae.2024.1435634"},{"key":"e_1_2_11_101_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep44445"},{"key":"e_1_2_11_102_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.159"},{"key":"e_1_2_11_103_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae151"},{"key":"e_1_2_11_104_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107137"},{"key":"e_1_2_11_105_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102552"},{"key":"e_1_2_11_106_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2022.101743"},{"key":"e_1_2_11_107_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.204434"},{"key":"e_1_2_11_108_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glaa286"},{"key":"e_1_2_11_109_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-019-0656-7"},{"key":"e_1_2_11_110_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-024-01795-8"},{"key":"e_1_2_11_111_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.102173"},{"key":"e_1_2_11_112_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.203126"},{"key":"e_1_2_11_113_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgac265"},{"key":"e_1_2_11_114_1","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2024.1493406"},{"key":"e_1_2_11_115_1","doi-asserted-by":"publisher","DOI":"10.1080\/15592294.2025.2530618"},{"key":"e_1_2_11_116_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glt121"},{"key":"e_1_2_11_117_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0113747"},{"key":"e_1_2_11_118_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2018.10.005"},{"key":"e_1_2_11_119_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2013.12.004"},{"key":"e_1_2_11_120_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psyneuen.2021.105270"},{"key":"e_1_2_11_121_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz6876"},{"key":"e_1_2_11_122_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsos.180744"},{"key":"e_1_2_11_123_1","article-title":"Telomeres and age\u2010related diseases","volume":"9","author":"Gruber H\u2010J","year":"2021","journal-title":"Biomedicine"},{"key":"e_1_2_11_124_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14138"},{"key":"e_1_2_11_125_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.203849"},{"key":"e_1_2_11_126_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00171"},{"key":"e_1_2_11_127_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14451"},{"key":"e_1_2_11_128_1","doi-asserted-by":"publisher","DOI":"10.1080\/17501911.2025.2603880"},{"key":"e_1_2_11_129_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-022-00248-2"}],"container-title":["Journal of Neuroendocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jne.70213","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/jne.70213","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jne.70213","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:34:38Z","timestamp":1782279278000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jne.70213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":128,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1111\/jne.70213"],"URL":"https:\/\/doi.org\/10.1111\/jne.70213","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/JNE.70213\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNE.70213\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/JNE.70213\/v1\/review1","asserted-by":"object"}]},"ISSN":["0953-8194","1365-2826"],"issn-type":[{"value":"0953-8194","type":"print"},{"value":"1365-2826","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"2025-10-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70213"}}