RNASEK Overexpression to Remove Circular RNAs Slows Aging in Nematodes
In recent years, researchers have noted that circular RNAs accumulate in cells in old age. It has been unclear as to whether this is only a marker of dysfunction or a change that in and of itself causes further downstream issues. The fastest way to obtain an answer to this sort of question is to repair the problem and see what happens. Researchers here identify that levels of RNASEK, a protein responsible for breaking down circular RNA, decline with age, allowing circular RNA levels to rise. Forcing increased expression of RNASEK slows aging and extends life, which strongly suggests that circular RNAs are harmful in some way. The researchers suggest that harms result from circular RNA aggregation in the cell, but further research is needed on this topic.
Until now, circular RNA has been regarded mainly as an aging marker because of its stability, which allows it to accumulate over time. However, the molecular mechanism for removing this RNA and its direct link to aging had not been clearly identified. Using Caenorhabditis elegans, a short-lived roundworm widely used in aging research, researchers first confirmed that the circular RNA-degrading enzyme RNASEK is essential for longevity. They also discovered that as aging progresses, the amount of RNASEK decreases, resulting in an abnormal accumulation of circular RNA within cells.
Conversely, artificially increasing the levels of RNASEK (overexpression) extended the lifespan and allowed the organisms to survive longer in a healthy state. This implies that the process of appropriately removing cellular circular RNA is critical for maintaining health and longevity.
The research team also found that RNASEK prevents the toxic aggregation of circular RNAs in aged organisms. When RNASEK is deficient and circular RNA accumulates, "stress granules" form abnormally inside the cell, which can impair cellular functions and accelerate aging. RNASEK works alongside the chaperone protein HSP90 (which helps proteins avoid misfolding or clumping) to inhibit the formation of these stress granules and help cells maintain a normal state. Notably, this phenomenon was observed not only in C. elegans but also in human cells. In mammals, RNASEK also functions to directly degrade circular RNA; a deficiency of RNASEK in human cells and mouse models led to premature aging.
Link: https://news.kaist.ac.kr/newsen/html/news/?mode=V&mng_no=59490
Should this be a new category within damage within Hallmarks of Aging?