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However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro\u2010longevity gene in mice. Cisd2\u00a0mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial functioning. Intriguingly, the protein level of Cisd2 is significantly decreased by about 50% in the livers of old male mice. This down\u2010regulation of Cisd2\u00a0may result in the aging liver exhibiting non\u2010alcoholic fatty liver disease (NAFLD) phenotype. Here, we use Cisd2 transgenic mice to investigate whether maintaining Cisd2 protein at a persistently high level is able to slow down liver aging. Our study identifies four major discoveries. Firstly, that Cisd2 expression attenuates age\u2010related dysregulation of lipid metabolism and other pathological abnormalities. Secondly, revealed by RNA sequencing analysis, the livers of old male mice undergo extensive transcriptomic alterations, and these are associated with steatosis, hepatitis, fibrosis, and xenobiotic detoxification. Intriguingly, a youthful transcriptomic profile, like that of young 3\u2010month\u2010old mice, was found in old Cisd2 transgenic male mice at 26\u00a0months old. Thirdly, Cisd2\u00a0suppresses the age\u2010associated dysregulation of various transcription regulators (Nrf2, IL\u20106, and Hnf4a), which keeps the transcriptional network in a normal pattern. Finally, a high level of Cisd2 protein protects the liver from oxidative stress, and this is associated with a reduction in mitochondrial DNA deletions. These findings demonstrate that Cisd2 is a promising target for the development of therapeutic agents that, by bringing about an effective enhancement of Cisd2 expression, will slow down liver aging.<\/jats:p>","DOI":"10.1111\/acel.13523","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T07:00:47Z","timestamp":1637650847000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Cisd2 slows down liver aging and attenuates age\u2010related metabolic dysfunction in male mice"],"prefix":"10.1111","volume":"20","author":[{"given":"Yi\u2010Long","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"},{"name":"Aging and Health Research Center National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao\u2010Qing","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen\u2010Hua","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao\u2010Hsiung","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"},{"name":"Aging and Health Research Center National Yang Ming Chiao Tung University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3239-4430","authenticated-orcid":false,"given":"Ting\u2010Fen","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung University  Taipei Taiwan"},{"name":"Aging and Health Research Center National Yang Ming Chiao Tung University  Taipei Taiwan"},{"name":"Institute of Molecular and Genomic Medicine National Health Research Institutes  Zhunan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,22]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0145-7"},{"issue":"1","key":"e_1_2_10_3_1","first-page":"1","article-title":"Molecular aging of human liver: An epigenetic\/transcriptomic signature","volume":"74","author":"Bacalini M. 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