Reviewing Work on CISD2, a Mammalian Longevity Gene

Few genes have been shown to robustly alter mammalian longevity as a result of altered expression, with data obtained primarily in mice. Klotho is perhaps the most well known and well studied of that small but steadily growing portfolio. The topic of today's open access paper is another of these longevity genes, CISD2. Loss of CISD2 shortens lifespan, while increased expression extends life span in mice. CISD2 is upregulated after exercise, and may act through autophagy, a common factor in many approaches shown to modestly slow aging in laboratory species. Like other approaches to upregulation of autophagy, increased CISD2 expression improves liver function in mice. Recently researchers have extended mouse life span by a small degree via pharmacological approaches to upregulation of CISD2.

The authors of the this paper overstate, I think, the level of interest we should have in CISD2 upregulation as a basis for therapy. Any form of upregulation of autophagy might be described as a calorie restriction mimetic strategy, given that increased autophagy appears to be the primary means by which calorie restriction produces benefits to health and longevity. While calorie restriction improves health in humans, it certainly does not move the needle on life span in long-lived mammals the same way it does in short-lived mammals. The underlying reasons for this difference have yet to be established in any detail, but this is why we should be skeptical of most of the methods of slowing aging demonstrated in mice to date. They largely function through stress response pathways that converge on increased autophagy.

Rejuvenation: Turning Back Time by Enhancing CISD2

Currently, only eight genes (BUB1B, CISD2, KLOTHO, PAWR, PPARG, PTEN, SIRT1, and SIRT6) are listed as pro-longevity genes by the Human Aging Genomic Resources, which means that they have been experimentally demonstrated to mediate lifespan in mammals. 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), 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 highlights the urgent need for CISD2-based pharmaceutical development to be used as a potential therapeutic strategy for 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.

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