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However, the long-term impact of abnormal circadian rhythms on the immune-related functions of the spleen are poorly understood. Hence, we aimed to investigate the immune-related functions of spleen in Per1\/Per2 double-knockout (DKO) and wild-type (WT) mice aged 4, 9, and 14 months. Compared to the WT mice, the DKO mice had smaller spleen white pulp (WP) and lymphocyte germinal area, as well as fewer immune cells with age\u2014these differences were especially clear. The spleen lymphocyte mortality, malondialdehyde (MDA) levels, reactive oxygen species (ROS) levels, and ferritin-binding receptor (TFR1) levels were significantly higher in the 14-month-old DKO mice than in WT mice of the same age. Transcriptome analysis showed that most of the differentially expressed mRNAs were enriched in DNA damage repair-related pathways. In DKO mice, spleen cells showed up-regulation of pro-ferroptosis genes, such as Cd36,Atm, and Acsl4, and down-regulation of anti-ferroptosis genes, such as GPX4. We found that long-term abnormalities in the circadian rhythm can induce DNA damage and ferroptosis in mouse spleen.<\/jats:p>","DOI":"10.3390\/ijms232112962","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T09:59:37Z","timestamp":1666778377000},"page":"12962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Per1\/Per2 knockout Affects Spleen Immune Function in Elderly Mice via Inducing Spleen Lymphocyte Ferroptosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-9781","authenticated-orcid":false,"given":"Ruyi","family":"He","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojie","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangyi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7325-6478","authenticated-orcid":false,"given":"Zhiguo","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1126\/science.1195027","article-title":"Circadian integration of metabolism and energetics","volume":"330","author":"Bass","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1093\/nar\/gkq1335","article-title":"Retinoic acid-related orphan receptor gamma directly regulates neuronal PAS domain protein 2 transcription in vivo","volume":"39","author":"Takeda","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1111\/ejn.14066","article-title":"The circadian gene Nr1d1 in the mouse nucleus accumbens modulates sociability and anxiety-related behaviour","volume":"48","author":"Zhao","year":"2018","journal-title":"Eur. 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