Cells in our bodies produce RNA based on genetic information stored in DNA, and RNA serves as a blueprint for making proteins. Researchers at our university have discovered a new phenomenon: removing 'circular RNA' that accumulates in cells as we age can slow down aging and extend lifespan. This study provides crucial clues for uncovering the principles of aging and developing treatment strategies for related diseases.
Professor Seung-Jae V. Lee’s research team (RNA-Mediated Healthspan and Longevity Research Center) from the Department of Biological Sciences, in collaboration with research teams led by Professors Yoon Ki Kim and Gwangrog Lee, announced on the 18th that they discovered the RNASEK protein—an enzyme that degrades circular RNA—plays a vital role in slowing aging and extending lifespan.
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. The research team conducted this study to determine how the accumulation of circular RNA affects aging and whether an intracellular management system exists to regulate it.
Using Caenorhabditis elegans (C. elegans), a short-lived roundworm widely used in aging research, the team 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.
The researchers explained that this study is significant as it identifies a mechanism for regulating aging at the RNA level. They suggested that research using RNASEK to control circular RNA could lead to the development of treatment strategies for human aging and degenerative diseases.
Professor Seung-Jae V. Lee of KAIST, who led the study, explained, "Until now, circular RNA was merely regarded as a marker of aging that accumulates over time due to its stability. This study proves that circular RNA accumulated during aging actually induces aging, and that RNASEK, which removes it, is a key regulator that slows aging and induces healthy longevity."
Drs. Sieun S. Kim, Seokjin Ham, Sung Ho Boo, and Donghun Lee from the KAIST Department of Biological Sciences participated as joint first authors. The research results were published on February 24 in the world-renowned scientific journal Molecular Cell.
This research was conducted with support from the Leader Researcher Program of the National Research Foundation of Korea.