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This study aimed to elucidate the physiological mechanisms contributing to this age\u2010related decrease in plasma OXT and the possible use of OXT supplementation on improving age\u2010related decline of neural function. Comparing young (9\u2009weeks) and aged (&gt;\u200945\u2009weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs\u2010CRP, and decreased OXT\u2010positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten\u2010eleven translocation (TET) family mRNA expression, decreased 5\u2010hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10\u2009\u03bcg\/day) for 10\u2009days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT\u2010positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age\u2010matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.<\/jats:p>","DOI":"10.1111\/acel.70198","type":"journal-article","created":{"date-parts":[[2025,8,11]],"date-time":"2025-08-11T16:40:36Z","timestamp":1754930436000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oxytocin Enhances Demethylation Through <scp>TET<\/scp> Enzyme Expression in Neurons of Aged Mice: Oxytocin as a Potential Antiaging Peptide"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5370-5758","authenticated-orcid":false,"given":"Yuko","family":"Maejima","sequence":"first","affiliation":[{"name":"Department of Bioregulation and Pharmacological Medicine Fukushima Medical University School of Medicine  Fukushima Japan"},{"name":"Departments of Obesity and Inflammation Research Fukushima Medical University School of Medicine  Fukushima Japan"},{"name":"Department of Physiology, Anatomy and Genetics, Sherrington Building University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Yokota","sequence":"additional","affiliation":[{"name":"Department of Bioregulation and Pharmacological Medicine Fukushima Medical University School of Medicine  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Yamachi","sequence":"additional","affiliation":[{"name":"Department of Bioregulation and Pharmacological Medicine Fukushima Medical University School of Medicine  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizu","family":"Hidema","sequence":"additional","affiliation":[{"name":"Department of Bioregulation and Pharmacological Medicine Fukushima Medical University School of Medicine  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Bioregulation and Pharmacological Medicine Fukushima Medical University School of Medicine  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Taira","sequence":"additional","affiliation":[{"name":"Faculty of Food and Agricultural Sciences Fukushima University  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuhiko","family":"Nishimori","sequence":"additional","affiliation":[{"name":"Departments of Obesity and Inflammation Research Fukushima Medical University School of Medicine  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9871-6909","authenticated-orcid":false,"given":"Heidi","family":"de Wet","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, Sherrington Building University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenju","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Department of Bioregulation and Pharmacological Medicine Fukushima Medical University School of Medicine  Fukushima Japan"},{"name":"Departments of Obesity and Inflammation Research Fukushima Medical University School of Medicine  Fukushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,11]]},"reference":[{"issue":"3","key":"e_1_2_10_2_1","first-page":"169","article-title":"Role of Oxytocin in Deceleration of Early Atherosclerotic Inflammatory Processes in Adult Male Rats","volume":"4","author":"Ahmed M. 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