This open access paper provides an overview of Cisd2, one of many genes for which upregulation extends life and improves health in mice. This is potentially mediated by its effects on the cellular maintenance processes of autophagy and on mitochondrial function. It reduces the loss of mitochondrial function that occurs in aging, perhaps through improved removal of damaged mitochondria via mitophagy, but perhaps through other mechanisms. The researchers show that Cisd2 expression is upregulated as a result of exercise, making it plausibly a part of the regulatory system by which the response to exercise can improve health and slow the progression of aging.
Cisd2 (CDGSH Iron Sulfur Domain 2) is an oxidative stress-sensitive gene, the expression of which is able to prolong the lifespan in mice. Cisd2 loss-of-function mice exhibit premature aging phenotypes and have a shortened lifespan. Conversely, Cisd2 transgenic mice not only are longer lived (both males and females), they also have a healthier physical condition, such as better fur function, increased muscle strength and improved cardiac function. The Cisd2 protein has been localized to mitochondria, mitochondria-associated membrane (MAM) and the endoplasmic reticulum (ER), and is involved in calcium homeostasis. We have demonstrated using aged mice that maintenance of the expression level of Cisd2 sustains metabolic activity, ameliorates aging-associated mitochondrial dysregulation, reduces DNA damages and improves the calcium imbalance within skeletal muscles, liver, and heart. Taken together, Cisd2 is a lifespan regulator and its expression level seems to be a critical factor in relation to prolong healthspan.
Cisd2 and exercise have both been reported to contribute to an extended lifespan and to improve healthspan. A recent report has shown that the protein levels of Cisd1 and Cisd2 in skeletal muscle and white adipose tissue are increased approximately 1.5-fold and 1.2-fold after 4 weeks of voluntary excise in mice. The authors also observed that there were significant increases in the levels of multiple mitochondrial proteins, which agrees with our previous discovery of increased mitochondrial number in the muscle of Cisd2 transgenic mice compared to their wild type cohorts. To examine the transcription of Cisd2 in real-time, here we have generated a Cisd2 reporter transgenic mouse that carries luciferase as the reporter. The Cisd2-Luciferase reporter mice were trained on a treadmill for 56 days. It was found that a drastic enhancement in Cisd2 transcription was able to be observed. The most intense signal was observed at the abdomen, with the thymus showing the next largest increase in signal. A moderately increase in signal was also observed in forelimbs and hindlimbs.