From Longevity Wiki

CISD2 (CDGSH Iron Sulfur Domain 2) is an evolutionarily conserved pro-longevity gene (also known as: ERIS (endoplasmic reticulum intermembrane small protein), Miner1, NAF-1 (nutrient-deprivation autophagy factor-1), WFS2, and ZCD2) that is located at position 24 on the long arm of human chromosome 4 (4q24) – the region significantly contributing to life-span control as has been revealed by a genome-wide linkage scan of long-lived families. [1][2] CISD2 localizes onto the endoplasmic reticulum (ER), the outer mitochondrial membrane and the mitochondria-associated membrane. It plays a crucial role in the regulation of cytosolic Ca2+ homeostasis, ER integrity and in preventing mitochondrial dysfunction, and also in the activation of autophagy and apoptosis in different cells. [3] [4][5][6] By functioning as a transport conduit across intracellular membranes for labile iron and calcium, CISD2 protects cells from overaccumulation of iron and calcium excitotoxicity.[7]

A disruption in CISD2 cluster transfer activity (via inducible expression of a point mutant of CISD2 (H114C) with a significantly higher stability of the CISD2 [2Fe-2S] cluster) results in the activation of oxidative stress that triggers a ferroptosis-like process of cell death. [8][9]

Elevated expression of NAF-1 is associated with the progression of multiple cancer types since CISD2 promotes rapid cell proliferation by preventing unstable mitochondrial labile iron (mLI) and reactive oxygen species (mROS) overloads.[10] NAF-1 protein are critical for inducing oxidative stress tolerance in cancer cells, leading to rapid tumor growth, and drugs that stabilize the NAF-1 cluster could be used as part of a treatment strategy for cancers that display high NAF-1 expression.[11][12]

The pre-mRNA of CISD2 has two splice sites, creating 3 exons and 2 introns. [13] CISD2 was identified as the carrier of a mutations that causes neurodegenerative diseases such as Wolfram Syndrome 2 (WFS2) and partly Alzheimer’s Disease due to alterations in the ER and mitochondrial Ca2+ homeostasis, mitochondrial dysfunction and increased ROS (Reactive oxygen species, chemically reactive molecules containing oxygen) production.[14] [15] CISD2, loss-of-function mutations in humans characterized by diabetes mellitus, optic atrophy, deafness peptic ulcer bleeding and defective platelet aggregation. [16][10] CISD2 knockout mice also show accelerated aging, blindness, an abnormal skeleton, and muscle atrophy, effects that are very similar to those described in the WFS2 patients.[10] [17]

Cisd2 level is a key determinant of lifespan and healthspan

Mouse Cisd2 deficiency shortens lifespan and accelerates aging that results in premature aging.[18]

Beneficial effects of exercise and Cisd2 overexpression delay aging in skeletal muscle.[19]

Cisd2 is essential to delaying cardiac aging and to maintaining heart functions. Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Cisd2 deficiency also disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes.[20]

Conversely, a persistently high level of Cisd2 promotes longevity.[21] CISD2 protects cardiomyocytes from overaccumulation of iron, which is common in aging hearts and can contribute to the pathogenesis of heart failure.[22] Cisd2 overexpression modulates a number of aging-related pathways, namely the sirtuins signaling, autophagy, and senescence pathways, to bring about rejuvenation of the heart as it enters old age.[23] Cisd2 ameliorates age-associated degeneration of the skin, skeletal muscles and neurons. [21] Moreover, Cisd2 protects mitochondria from age-associated damage and functional decline as well as attenuating the age-associated reduction in whole-body energy metabolism. [21] It was shown that a persistent level of Cisd2 achieved by transgenic expression in mice extends their median and maximum lifespan without any apparent deleterious side effects.[7] According to Teng et al., exercise and Cisd2 activation are two very promising strategies as an individual ages to build a healthy lifespan.[19]

Natural compounds that can upregulate CISD2 expression

CISD2, the expression of which otherwise decreases during natural aging, can be pharmaceutically activated at a late-life stage of aged mice.[24] Treatment with dietary hesperetin, starting at 19–21 month old, has shown to enhance CISD2 gene expression and extend the lifespan and healthspan of mice. In addition, hesperidin and its aglycone, hesperetin treatment appears to attenuate whole-body metabolic decline, reducing fat and improving glucose homeostasis, as well as slowing down heart and skeletal muscle aging.[25][24] Hesperetin has various beneficial biological properties, which confer cardioprotective[26], anticancer,[27][28] antidiabetic effects,[29][30] protective effect against bone loss,[31] skin aging[32] and also against neurodegeneration triggered by aging.[30][33]

The beneficial anti-aging effects of hesperidin and its aglycone, hesperetin are largely dependent on CISD2 as revealed from transcriptomic analysis - most (79%) of the genes influenced by hesperetin lost their differential expression patterns in the absence of CISD2.[25][24] It would be interesting to check in the same way if the anti-aging effects of naringenin also depend on CISD2.[34]

Hesperetin is a well-known bioflavonoid that is found in dried peppermint leaves (60-200 mg/100 g),[35] as well as in numerous types of citrus fruits including- oranges, grapefruit, and tangerines upon ingestion, also in small amounts in sauerkraut.[36][37][30]

Inclusion complexes of hesperidin or hesperetin with hydroxypropyl β-cyclodextrin[38] or Soluplus®, alginate sodium, and hydroxypropylmethylcellulose in a 1:5 w/w ratio,[39] increase solubility and antioxidant potential. Such solid dispersions are promising delivery systems of hesperidin, and they can pose a more effective approach to treating civilization diseases.

The principal bright yellow compound obtained from the root of turmeric (Curcuma longa) named curcumin also was found to increase the CISD2 protein level in the astrocytes of the spinal cords of old mice.[40][41]


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