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Review
. 2022 Nov 13;23(22):14014.
doi: 10.3390/ijms232214014.

Rejuvenation: Turning Back Time by Enhancing CISD2

Chi-Hsiao Yeh  1   2 , Zhao-Qing Shen  3 , Ching-Cheng Lin  3 , Chung-Kuang Lu  3   4 , Ting-Fen Tsai  3   5   6
Affiliations
Review

Rejuvenation: Turning Back Time by Enhancing CISD2

Chi-Hsiao Yeh et al. Int J Mol Sci. .

Abstract

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 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'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.

Keywords: CISD2; aging; calcium homeostasis; hesperetin; longevity; mitochondria; rejuvenation.

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Conflict of interest statement

The authors declare no conflict of interest. T.-F.T. and C.-K.L. are inventors on the Taiwan patent TW109120312.

Figures

Figure 1
Figure 1
CISD2 attenuates heart and skeletal muscle aging. (A) An age-dependent decrease in CISD2 correlates with cardiac dysfunctions and molecular pathological alterations. Whole-body CISD2 overexpression (CISD2 TG) delays age-associated cardiac damage. In addition, the CISD2 activator, hesperetin (Hes), reverses age-associated cardiac damage via the activation of CISD2. (B) Age-dependent CISD2 reduction leads to sarcopenia and pathological alterations. Maintaining a high level of CISD2 by transgenic overexpression, or by hesperetin treatment, is able to protect skeletal muscle from age-related pathological and molecular damage. The figure was created with BioRender.com.
Figure 2
Figure 2
The chemical structures of the plant bio-activators of CISD2. The metabolism and bioavailability of hesperidin and its occurrence in foods. (A–F) The chemical structures of (A) hesperidin, (B) curcumin, (C) α-eleostearic acid, (D) sophoricoside, (E) genistein, (F) formononetin. (G) The chemical structures and metabolic processing of hesperidin and its derivatives in vivo. (H) Hesperidin, a bioflavonoid compound, is mostly found in citrus fruits, including oranges, grapefruits, tangerines, and lemons. In the colon, hesperidin is converted into hesperetin by the microflora, and then hesperetin can be absorbed into systematic circulation by colonocytes. In the liver, hesperetin can be conjugated with a glucuronide or sulfate, which results in two other major metabolites, namely hesperetin-7-O-sulfate (H7S) and hesperetin-7-O-β-D-glucuronide (H7G), respectively. The figure was created with BioRender.com.
Figure 3
Figure 3
Beneficial effects of hesperetin on natural aging and age-related diseases in rodents and humans. (A) Hesperetin delays aging and promotes healthy longevity in rodents. There are many beneficial effects of hesperetin on the aging process in old mice, including improvements in healthy lifespan, whole-body metabolism, and glucose homeostasis. The beneficial effects of hesperetin on multiple tissues in aged rodents have been investigated and these include the brain, heart, skeletal muscle, liver, and kidneys. In the brain, hesperetin improves emotional memory functioning, hippocampal synaptic plasticity, and reduces oxidative stress in aged rats. In the hearts of older mice, hesperetin slows down heart aging, including an enhancement of mechanical and electrical cardiac functioning, reductions in fibrosis and ultrastructural damage, and change toward a younger transcriptome pattern. In the skeletal muscle of older mice, hesperetin slows down muscle aging, including improvements in muscle functioning; reductions in fibrosis, and levels of muscle fiber degeneration, and ultrastructural damage; and a change toward a younger transcriptome pattern. In the liver of aged rats, hesperetin reduces oxidative stress, enhances antioxidant enzyme activity, and improves the phospholipid composition of cell membranes. In the kidney of aged rats, hesperetin exerts anti-inflammation and antioxidant effects via the modulation of nuclear factor-κB (NF-κB) pathway. (B) Hesperetin exerts a range of biological effects that improve several age-related diseases in rodents, such as neurodegenerative diseases (Alzheimer’s and Parkinson’s disease), eye disease (cataracts), cardiovascular disease (atherosclerosis, hypertrophic cardiomyopathy, and ischemic heart disease), and metabolic syndrome, specifically diabetes. These phenotypic improvements are associated with the anti-inflammatory and antioxidant efficacies of hesperetin. (C) The mechanisms underlying the beneficial effects of hesperetin regarding age-related diseases in rodents were deciphered using different cell lines, such as neuronal cells (SH-SY5Y and HT22), immune cells (THP-1), cardiac myoblast cells (H9c2), β-cells (e.g., INS-1), and myoblast cells (L6). (D) In clinical studies, the efficacy and safety of hesperetin had been evaluated in overweight and obese human subjects. The biological efficacy of hesperetin in human subjects includes improved glucose homeostasis and vascular function and reduced inflammation. The figure was created with BioRender.com.
Figure 4
Figure 4
The CISD2-dependent and CISD2-independent metabolic pathways identified in the skeletal muscle of 3-month-old WT and CISD2 mcKO mice who undergo hesperetin treatment for 4 months. A schematic illustration of metabolism in the hesperetin-treated and vehicle-treated CISD2 mcKO mice that carry a CISD2 knockout background specifically affecting the skeletal and cardiac muscles. In aged skeletal muscle (gastrocnemius), hesperetin brings about improvements in various dysregulated pathways, namely (A) lipid metabolism, (B) proteostasis and (C) nitrogen, protein, and amino acid metabolism. Red indicates upregulation and blue indicates downregulation of the identified proteins. The presence of (*) emphasizes that these proteins were affected by hesperetin in a CISD2-independent manner. The figure was created with BioRender.com.
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