Circular RNAs-Stress Granule Interplay Drives Aging-Related Proteostasis Loss

Aging involves a gradual loss of cellular balance, leading to reduced function and increased disease risk. While impaired proteostasis is a key hallmark of aging, more evidence shows the importance of RNA homeostasis (ribostasis), particularly the regulation of circular RNAs (circRNAs). CircRNAs are stable RNA molecules that build up over time and are linked to age-related cellular dysfunctions. In this regard, Kim et al. 2026 provide new insights into the impact of circRNA turnover on aging and lifespan. Their findings indicate that the accumulation of circRNAs is partly due to a decline in ribonuclease K (RNASEK), an enzyme that breaks down circRNAs. Using models such as worms, mice, and human cells, they show that RNASEK is crucial for healthy aging and longevity, suggesting its role is conserved across species. The research also shows that circRNAs gather in stress granules (SGs), which are ribonucleoprotein complexes formed during cell stress. RNASEK collaborates with heat shock protein 90 to prevent harmful RNA-rich aggregates, maintaining cellular dynamics in balance. These findings suggest a link between ribostasis and proteostasis, identifying circRNA clearance as a potential factor in longevity. The study also points to RNASEK as a promising target for treating age-related diseases. However, key questions remain, such as how RNASEK specifically degrades circRNAs, whether specific circRNAs or overall circRNA levels drive aging traits, and whether circRNA buildup is a cause or result of cell aging. Further research is needed to evaluate the conservation, safety, and therapeutic potential of this proteostasis-ribostasis axis in human biology.