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By 2050, the global population of those who are aged 65\u2009years and older will have tripled. In this context, delaying age-associated diseases and increasing the healthy lifespan of the aged population has become an important issue for geriatric medicine. CDGSH iron-sulfur domain 2 (CISD2), the causative gene for Wolfram syndrome 2 (WFS2; MIM 604928), plays a pivotal role in mediating lifespan and healthspan by maintaining mitochondrial function, endoplasmic reticulum integrity, intracellular Ca2+ homeostasis, and redox status. Here, we summarize the most up-to-date publications on CISD2 and discuss the crucial role that this gene plays in aging and age-associated diseases. This review mainly focuses on the following topics: (1) CISD2 is one of the few pro-longevity genes identified in mammals. Genetic evidence from loss-of-function (knockout mice) and gain-of-function (transgenic mice) studies have demonstrated that CISD2 is essential to lifespan control. (2) CISD2 alleviates age-associated disorders. A higher level of CISD2 during natural aging, when achieved by transgenic overexpression, improves Alzheimer\u2019s disease, ameliorates non-alcoholic fatty liver disease and steatohepatitis, and maintains corneal epithelial homeostasis. (3) CISD2, the expression of which otherwise decreases during natural aging, can be pharmaceutically activated at a late-life stage of aged mice. As a proof-of-concept, we have provided evidence that hesperetin is a promising CISD2 activator that is able to enhance CISD2 expression, thus slowing down aging and promoting longevity. (4) The anti-aging effect of hesperetin is mainly dependent on CISD2 because transcriptomic analysis of the skeletal muscle reveals that most of the differentially expressed genes linked to hesperetin are regulated by hesperetin in a CISD2-dependent manner. Furthermore, three major metabolic pathways that are affected by hesperetin have been identified in skeletal muscle, namely lipid metabolism, protein homeostasis, and nitrogen and amino acid metabolism. This review highlights the urgent need for CISD2-based pharmaceutical development to be used as a potential therapeutic strategy for aging and age-associated diseases.<\/jats:p>","DOI":"10.3390\/ijms232214014","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:29:32Z","timestamp":1668392972000},"page":"14014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Rejuvenation: Turning Back Time by Enhancing CISD2"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8850-4144","authenticated-orcid":false,"given":"Chi-Hsiao","family":"Yeh","sequence":"first","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou 333, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9126-0219","authenticated-orcid":false,"given":"Zhao-Qing","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Cheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Kuang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Fen","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"},{"name":"Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350, Taiwan"},{"name":"Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,13]]},"reference":[{"key":"ref_1","unstructured":"United Nations DoEaSA, Population Division (2022, September 14). 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