{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T14:38:57Z","timestamp":1775486337321,"version":"3.50.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T00:00:00Z","timestamp":1710460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 AG066518"],"award-info":[{"award-number":["P30 AG066518"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P51 OD011092"],"award-info":[{"award-number":["P51 OD011092"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RF1 AG062220"],"award-info":[{"award-number":["RF1 AG062220"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The hippocampus is especially susceptible to age-associated neuronal pathologies, and there is concern that the age-associated rise in cortisol secretion from the adrenal gland may contribute to their etiology. Furthermore, because 11\u03b2-hydroxysteroid dehydrogenase type 1 (HSD11B1) catalyzes the reduction of cortisone to the active hormone cortisol, it is plausible that an increase in the expression of this enzyme enhances the deleterious impact of cortisol in the hippocampus and contributes to the neuronal pathologies that underlie cognitive decline in the elderly.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rhesus macaques were used as a translational animal model of human aging, to examine age-related changes in gene and protein expressions of (<jats:italic>HSD11B1<\/jats:italic>\/HSD11B1) in the hippocampus, a region of the brain that plays a crucial role in learning and memory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Older animals showed significantly (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01) higher base-line cortisol levels in the circulation. In addition, they showed significantly (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.05) higher hippocampal expression of <jats:italic>HSD11B1<\/jats:italic> but not <jats:italic>NR3C1<\/jats:italic> and <jats:italic>NR3C2<\/jats:italic> (i.e., two receptor-encoding genes through which cortisol exerts its physiological actions). A similar age-related significant (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.05) increase in the expression of the HSD11B1 was revealed at the protein level by western blot analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The data suggest that an age-related increase in the expression of hippocampal <jats:italic>HSD11B1<\/jats:italic> is likely to raise cortisol concentrations in this cognitive brain area, and thereby contribute to the etiology of neuropathologies that ultimately lead to neuronal loss and dementia. Targeting this enzyme pharmacologically may help to reduce the negative impact of elevated cortisol concentrations within glucocorticoid-sensitive brain areas and thereby afford neuronal protection.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2024.1328543","type":"journal-article","created":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T04:26:15Z","timestamp":1710476775000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Age-related increase in the expression of 11\u03b2-hydroxysteroid dehydrogenase type 1 in the hippocampus of male rhesus macaques"],"prefix":"10.3389","volume":"16","author":[{"given":"Alejandro","family":"Lomniczi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Selva L.","family":"Luna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Cervera-Juanes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria-Luisa","family":"Appleman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven G.","family":"Kohama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henryk F.","family":"Urbanski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.neurobiolaging.2017.03.032","article-title":"Effect of caloric restriction on plasma melatonin levels in aged rhesus macaques","volume":"55","author":"Aghazadeh-Sanai","year":"2017","journal-title":"Neurobiol. 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Neurosci."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/s11357-021-00453-8","article-title":"Effects of estradiol supplementation on the brain transcriptome of old rhesus macaques maintained on an obesogenic diet","volume":"44","author":"Cervera-Juanes","year":"2022","journal-title":"Geroscience"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1152\/physrev.00020.2012","article-title":"11\u03b2-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action","volume":"93","author":"Chapman","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.12688\/f1000research.8987.2","article-title":"From reads to genes to pathways: differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline","volume":"5","author":"Chen","year":"2016","journal-title":"F1000Res."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1016\/j.neurobiolaging.2007.03.011","article-title":"Effect of age and caloric restriction on circadian adrenal steroid rhythms in rhesus macaques","volume":"29","author":"Downs","year":"2008","journal-title":"Neurobiol. 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Sci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/271","article-title":"Cortisol levels during human aging predict hippocampal atrophy and memory deficits","volume":"1","author":"Lupien","year":"1998","journal-title":"Nat. Neurosci."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"207.e1","DOI":"10.1016\/j.neurobiolaging.2010.09.010","article-title":"11\u03b2-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline","volume":"33","author":"MacLullich","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/s0197-4580(02)00027-1","article-title":"Sex, stress and the hippocampus: allostasis, allostatic load and the aging process","volume":"23","author":"McEwen","year":"2002","journal-title":"Neurobiol. 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Pharmacol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1081\/erc-120016990","article-title":"11\u03b2-hydroxysteroid dehydrogenases: a novel control of glucocorticoid action in the brain","volume":"28","author":"Seckl","year":"2002","journal-title":"Endocr. Res."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"4592","DOI":"10.1210\/en.2015-1395","article-title":"Cognitive and disease-modifying effects of 11\u03b2-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer\u2019s disease","volume":"156","author":"Sooy","year":"2015","journal-title":"Endocrinology"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1487.e1","DOI":"10.1016\/j.neurobiolaging.2011.05.004","article-title":"Perimenopausal regulation of steroidogenesis in the nonhuman primate","volume":"33","author":"Sorwell","year":"2012","journal-title":"Neurobiol. 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Biol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1007\/s00125-014-3228-6","article-title":"Tissue-specific dysregulation of cortisol regeneration by 11\u03b2HSD1 in obesity: has it promised too much?","volume":"57","author":"Stomby","year":"2014","journal-title":"Diabetologia"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"734173","DOI":"10.3389\/fnagi.2021.734173","article-title":"The rhesus macaque as a translational model for neurodegeneration and Alzheimer\u2019s disease","volume":"13","author":"Stonebarger","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1210\/er.2003-0031","article-title":"11\u03b2-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response","volume":"25","author":"Tomlinson","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/0197-4580(93)90067-l","article-title":"The incidence of senile plaques and multiple infarction in aged macaque brain","volume":"14","author":"Uno","year":"1993","journal-title":"Neurobiol. Aging"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-1-60761-883-6_9","article-title":"Circadian variation in the physiology and behavior of humans and nonhuman primates","volume-title":"Animal models of behavioral analysis","author":"Urbanski","year":"2011"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.neurobiolaging.2017.02.020","article-title":"Effect of androgen supplementation on 24-hour activity-rest patterns of aged male rhesus macaques","volume":"54","author":"Urbanski","year":"2017","journal-title":"Neurobiol. 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