Misha Batin
- December 5, 2021
- 5:11 pm
Why it was important to add the CISD2 gene to the Open Genes database
There was such a belief that if cancer was defeated, then life would last only 2-3 years. It’s not like that at all! If you defeat cancer, then consider it – this is defeating aging. You can then water the body with growth factors, Yamanaka factors, cytoprotectors without stopping. Cancer has been defeated, now nothing is scary (it is possible oncology that is the main obstacle to rejuvenation of the body). But let’s take an example, pay attention, one gene from our Open Genes database is CISD2.
Genetics
So, the CISD2 gene , and why it was important to add it to our Open Genes database.
It’s a cytoprotector. In 2001, T. Perls and colleagues identified a locus on chromosome 41, associated with exceptional human lifespan. One of the genes located in this region turned out to be the CISD2 gene .
Its active study began in 2007, when it was found that a mutation in CISD2 leads to the development of a genetic disease – Wolfram syndrome type 2. When a gene did not work well, neurodegeneration and metabolic disorders occurred.
In 2009, Y. Chen and colleagues were the first to show the relationship between CISD2 and aging: mice with CISD2 knockout (turned off) accelerated aging2. Vision worsened (degeneration of the optic nerve occurred), hair lost its normal color and density along with the death of hair follicles, subcutaneous fat and muscles decreased in volume. It also decreased bone density and impaired lung function. Such mice lived on average a third less than their wild relatives.
As the results of the study showed, the negative effects of CISD2 knockout were mainly associated with mitochondrial dysfunction and cell death.
Then we learned that with age itself there is a decrease in the level of the CISD2 protein in a number of tissues, including the brain, heart, muscles and liver.
Studies show that age-related regulation3 CISD2 expression depends on other genes associated with aging. Such as Sirt7 and NRF2 , which are also in the Open Genes database.
Normally , CISD2 regulates autophagy, calcium and iron homeostasis, ROS levels, oxidative phosphorylation, and lipid metabolism. And increased expression of CISD2 in animal models was associated with a 19% increase in life expectancy. Plus there were a number of positive effects: the heart, liver, brain, muscles and eyes worked better.
In an animal model of Alzheimer’s disease, overexpression of CISD2 promoted survival and reduced pathological defects. The decrease in CISD2 levels accelerated the pathogenesis of Alzheimer’s. At the same time, overexpression of CISD2 protected against β-amyloid-mediated mitochondrial damage and reduced the loss of neurons and neuronal progenitor cells.
A number of genes associated with the functions of neurons and mitochondria, the expression of which was changed in the Alzheimer model, under the influence of CISD2 overexpression, changed their activity to a similar one that was present in healthy wild-type mice. That is, their activity returned to normal.
More recently, scientists have shown that overexpression of CISD2 in aged mice promoted normal heart function, preventing fibrosis, electromechanical dysfunction of the heart, and changing the cardiac transcriptome profile characteristic of aged mice to a younger one4.
In addition, studies have shown a protective role for CISD2 overexpression : it prevented age-related and unhealthy diet-induced negative changes in the liver in an animal model5.
By the way, exercise stimulates the expression of CISD26.
And now about oncogenesis
The bad news is that elevated CISD2 activity may be involved in tumorigenesis. 7 Acting in its main function as a cytoprotector, CISD2 protects all cells indiscriminately from death, including cancer cells.
Thus, CISD2 activates the AKT/FOXO signaling pathway through AKT phosphorylation at Thr308 and Ser473.
AKT is known to be an important cell cycle mediator in oncogenesis, promoting proliferation and migration of cancer cells and resistance to apoptosis.
Also , CISD2 maintains normal mitochondrial function in degenerate cells, preventing elevated levels of iron and ROS (reactive oxygen species) from killing such a cell.
Therefore, manipulation of CISD2 , as with many similar genes, requires some kind of strong idea related to the suppression of tumorigenesis.
Maybe turn off telomerase or use some kind of cancer vaccine. For example, oncolytic viral immunotherapy, which acts exclusively on mutated cells, without affecting normal ones. Soon there will be material about this.
However…
The good news is that unlike, for example, epigenetic reprogramming, overexpression of CISD2 in animal models did not lead to negative effects associated with tissue transformation.
On the other hand, CISD2 may also act as a tumor-suppressing protein, depending on the stage or cell type involved in tumor development. So, in hepatocellular carcinoma, it has a protective effect, and its deficiency accelerates the pathological transformation of the tissue. Moreover, this has been described both in animal models and in humans.
Tellingly , the long-lived rodent Spalax , which is resistant to tissue degeneration, has a much higher expression of CISD2 in the liver compared to mice3.
A similar dual role situation has been described with another cytoprotective protein, the heat shock protein Hsp90 .
The family of heat shock proteins performs the function of chaperones in the body, participating in folding (folding into the correct structure), degradation and stabilization of the protein, correcting errors in the protein structure. And, as is often the case, Hsp90 has a dual role in the body: useful and not very useful.
In addition to protecting vital proteins, Hsp90 supports proteins involved in carcinogenesis: it stabilizes several unstable oncogenic factors at once, such as mutant EGFR , BRAF and HER2 , as well as some anti-apoptotic factors, preventing the removal of degenerated cells.
That is, it turns out that going to the sauna is very useful, but only if you do not have cancer.
James Kickrland found senolytic properties in inhibitors of the Hsp90 protein (geldanamycin, tanespymycin, 17-DMAG, etc.)7. The mechanism by which Hsp90 inhibitors removed aged cells involved targeting an activated form of the protein kinase AKT. And it, in turn, suppresses apoptosis by affecting MTOR, NF-kB, Foxo3a and other signaling pathways in cancerous and old cells.
Introduction to transgenic mice with accelerated aging of one of the Hsp90 inhibitors, 17-DMAG, alleviated and delayed the onset of several age-related symptoms at once.
Note that the AKT signaling pathway appears in both cases: with Hsp90 and CISD2 proteins. Therefore, in order to combat age-related changes, it seems reasonable, along with CISD2 overexpression, to test in a laboratory experiment the effect of some senolytics that block the ACT pathway.
Or maybe the HSP90 also needs to be alternately activated and blocked.
In general, we suggest overexpressing and inhibiting the same thing in turn to try to add up the positive effects. It would be interesting to see what happens.
When creating Open Genes, we are pursuing the task so that any person with a natural science education can understand the genetics of aging and even be able to put forward their own hypothesis of what complex aging therapy might look like.
We want to systematize more information, so we are waiting for suggestions on how to improve everything. Come in and see how things are set up there.
