Ribonuclease ? promotes longevity by preventing age-associated accumulation of circular RNA in stress granules [rnk-1rnk-2]
Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging remains elusive. In this study, we reveal a mechanism by which ribonuclease ? (RNASEK) prevents age-dependent circRNA accumulation by promoting its degradation. Through a genetic screen targeting ribonucleases, we identified RNASEK as a specific circRNA-cleaving ribonuclease. RNASEK is downregulated during aging, causing the age-dependent increase in circRNA levels. RNASEK is necessary and sufficient for lifespan extension and healthspan maintenance in Caenorhabditis elegans. Mammalian RNASEK also directly degrades circRNAs, and is required for preventing premature aging in cultured human cells and mice, indicating its evolutionarily conserved role. Notably, we demonstrate that circRNAs localize within stress granules, where RNASEK, in collaboration with HSP90, prevents toxic aggregation of circRNAs in aged organisms. Our study establishes RNASEK as a conserved regulator of aging and offers a framework for targeting circRNAs to mitigate age-associated diseases and to extend organismal healthspan. Overall design: RNA-seq profiling of wild-type N2 under control or rnk-1 rnk-2 RNAi conditions