The Isg15 Axis: A Central Mediator And Therapeutic Target In Vascular Inflammaging
As we age, our blood vessels undergo changes that can lead to serious cardiovascular problems. Two key processes contributing to this decline are “inflammaging,” a state of chronic low-grade inflammation, and cellular senescence, where cells stop dividing and can release harmful substances. For a long time, the exact molecular connections between these two phenomena in vascular aging were not fully understood.
Recent research highlights a protein called Interferon-stimulated gene 15 (ISG15) as a central player in this intricate process. While ISG15 is well-known for its role in fighting off viruses, it appears to be repurposed in aging to drive the deterioration of blood vessels.
This protein operates through a dual mechanism. Outside the cell, ISG15 acts as a signal that promotes and spreads inflammation. Inside the cell, it can attach itself to other proteins, a process known as ISGylation. This attachment can disrupt the normal functioning of these proteins and interfere with essential cellular processes that maintain health.
When activated by certain triggers, the ISG15 system contributes to several issues in blood vessels, including endothelial dysfunction (where the inner lining of blood vessels doesn’t work properly), changes in vascular smooth muscle cells, an increase in harmful oxidative stress, and the induction of cellular senescence. It also disrupts proteostasis, the delicate balance of protein production and degradation within cells.
These findings suggest that targeting the ISG15 pathway could be a promising new strategy for developing treatments to preserve vascular health as we get older. Potential therapeutic approaches could involve directly blocking ISGylation, neutralizing the ISG15 protein outside cells, or even repurposing existing medications that influence the interferon pathway, which is upstream of ISG15 activation.
Source: link to paper