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Rejuvenation: Turning Back Time by Enhancing CISD2

The aging human population with age-associated diseases has become a problem worldwide. By 2050, the global population of those who are aged 65 years and older will have tripled. In this context, delaying age-associated diseases and increasing the healthy lifespan of the aged population has become a...

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Autores principales: Yeh, Chi-Hsiao, Shen, Zhao-Qing, Lin, Ching-Cheng, Lu, Chung-Kuang, Tsai, Ting-Fen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695557/
https://www.ncbi.nlm.nih.gov/pubmed/36430496
http://dx.doi.org/10.3390/ijms232214014
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author Yeh, Chi-Hsiao
Shen, Zhao-Qing
Lin, Ching-Cheng
Lu, Chung-Kuang
Tsai, Ting-Fen
author_facet Yeh, Chi-Hsiao
Shen, Zhao-Qing
Lin, Ching-Cheng
Lu, Chung-Kuang
Tsai, Ting-Fen
author_sort Yeh, Chi-Hsiao
collection PubMed
description The aging human population with age-associated diseases has become a problem worldwide. By 2050, the global population of those who are aged 65 years 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 Ca(2+) 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’s 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.
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spelling pubmed-96955572022-11-26 Rejuvenation: Turning Back Time by Enhancing CISD2 Yeh, Chi-Hsiao Shen, Zhao-Qing Lin, Ching-Cheng Lu, Chung-Kuang Tsai, Ting-Fen Int J Mol Sci Review The aging human population with age-associated diseases has become a problem worldwide. By 2050, the global population of those who are aged 65 years 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 Ca(2+) 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’s 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. MDPI 2022-11-13 /pmc/articles/PMC9695557/ /pubmed/36430496 http://dx.doi.org/10.3390/ijms232214014 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Yeh, Chi-Hsiao
Shen, Zhao-Qing
Lin, Ching-Cheng
Lu, Chung-Kuang
Tsai, Ting-Fen
Rejuvenation: Turning Back Time by Enhancing CISD2
title Rejuvenation: Turning Back Time by Enhancing CISD2
title_full Rejuvenation: Turning Back Time by Enhancing CISD2
title_fullStr Rejuvenation: Turning Back Time by Enhancing CISD2
title_full_unstemmed Rejuvenation: Turning Back Time by Enhancing CISD2
title_short Rejuvenation: Turning Back Time by Enhancing CISD2
title_sort rejuvenation: turning back time by enhancing cisd2
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9695557/
https://www.ncbi.nlm.nih.gov/pubmed/36430496
http://dx.doi.org/10.3390/ijms232214014
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