Summary: Researchers have identified a cellular “trash disposal” mechanism that directly influences the pace of aging. While circular RNA has long been observed to build up in cells with age, this study provides direct evidence that that accumulation is not merely a marker but a causal factor in aging. The team discovered an enzyme, RNASEK, that degrades circular RNA; when RNASEK levels fall, circular RNA accumulates, forming toxic aggregates. Restoring or increasing RNASEK activity in model organisms extended healthy lifespan and prevented harmful RNA aggregation, pointing to a promising avenue for therapies aimed at age-related decline.
Key Facts
- The “toxic” buildup: Circular RNAs (circRNAs) are unusually stable RNAs that resist normal degradation. Over time they accumulate in cells and can condense into stress granules that interfere with normal cellular processes.
- Identification of RNASEK: The study identifies RNASEK as a ribonuclease that specifically degrades circRNAs. RNASEK levels decline with age, contributing to age-dependent circRNA accumulation.
- Lifespan and healthspan effects: In Caenorhabditis elegans, increasing RNASEK expression extended lifespan and improved measures of healthy aging, indicating RNASEK is both necessary and sufficient for promoting longevity in that model.
- Chaperone partnership: RNASEK cooperates with the molecular chaperone HSP90 to prevent circRNA aggregation into toxic stress granules, helping maintain cellular proteostasis and RNA homeostasis.
- Conserved across species: The RNASEK-circRNA pathway was observed in human cells and in mice. Loss of RNASEK function in mammalian systems produced features consistent with premature aging.
- Therapeutic potential: Targeting RNASEK or pathways that enhance circRNA clearance could become a strategy for treating degenerative conditions and slowing aspects of human aging.
Source: KAIST
Overview
Cells transcribe RNA from DNA to serve as templates for protein synthesis and to perform regulatory roles. Among RNA species, circular RNAs are covalently closed loops that are especially resistant to degradation. Because of their stability, circRNAs accumulate over time, but until now the mechanism for their removal and their direct impact on organismal aging remained unclear. This study provides mechanistic insight into how circRNA accumulation drives aging and how an endogenous disposal system controls that process.
The research, led by Professor Seung-Jae V. Lee’s team at the RNA-Mediated Healthspan and Longevity Research Center, in collaboration with groups led by Professors Yoon Ki Kim and Gwangrog Lee, identified RNASEK as a circRNA-cleaving ribonuclease. Using genetic screens that targeted ribonucleases, the team demonstrated that RNASEK promotes degradation of circRNAs and thereby suppresses their age-associated accumulation.
In the short-lived roundworm C. elegans, widely used for aging research, RNASEK expression declines with age. This decline permits circRNAs to accumulate and aggregate inside cells. The aggregates are enriched in stress granules, membraneless compartments that form under stress and can become deleterious when improperly regulated. When RNASEK is experimentally overexpressed in worms, lifespan and healthspan are extended, indicating that maintaining circRNA clearance is essential for longevity in this model.
Mechanistically, RNASEK works together with HSP90, a conserved chaperone that helps prevent harmful aggregation of macromolecules. Together they limit circRNA aggregation in stress granules and preserve normal cellular function. The authors extended their findings to mammalian systems: mammalian RNASEK can directly degrade circRNAs, and loss of RNASEK activity in cultured human cells and in mouse models produced features of premature aging. These cross-species observations support an evolutionarily conserved role for RNASEK in maintaining RNA quality and organismal health.
The researchers emphasize that this work reframes circular RNA: rather than being a passive biomarker of aging, circRNA accumulation actively contributes to aging phenotypes. By identifying RNASEK as a key regulator that prevents circRNA-driven toxicity, the study highlights a concrete molecular target for future therapies aimed at reducing age-associated cellular decline and treating degenerative diseases.
Key Questions Answered:
A: Because circRNAs are highly stable, they tend to accumulate rather than be cleared. Over time this accumulation can form dense assemblies called stress granules. These assemblies obstruct normal intracellular traffic and interfere with proteins and RNA that cells need to function, contributing to cellular dysfunction and aging.
A: Not yet. The experiments showing lifespan extension were performed in laboratory models. Translating these findings into safe, effective therapies for humans requires further research. Nevertheless, RNASEK provides a clear molecular target for drug discovery aimed at enhancing circRNA clearance.
A: Caenorhabditis elegans has a short lifespan and well-characterized genetics that mirror many conserved aging pathways in higher organisms. This makes C. elegans a practical and informative model for dissecting mechanisms that affect longevity and for testing interventions more rapidly than in long-lived species.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The full journal paper was reviewed.
- Additional explanatory context was added by staff to clarify implications for aging research.
About this genetics and longevity research news
Author: JEEHYUN LEE
Source: KAIST
Contact: JEEHYUN LEE – KAIST
Image: Image credited to Neuroscience News
Original Research: Open access. “Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules” by Sieun S. Kim et al., published in Molecular Cell. DOI: 10.1016/j.molcel.2026.01.031
Abstract
Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules
Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging has been unclear. In this study, the authors identify ribonuclease κ (RNASEK) as a specific circRNA-cleaving enzyme that prevents age-dependent circRNA accumulation by promoting degradation. RNASEK expression declines during aging, leading to increased circRNA levels. In Caenorhabditis elegans, RNASEK is both necessary and sufficient for lifespan extension and maintenance of healthspan. Mammalian RNASEK similarly degrades circRNAs and is required to avoid premature aging in cultured human cells and mouse models, indicating an evolutionarily conserved role. The study further shows that circRNAs localize within stress granules and that RNASEK, in collaboration with heat shock protein 90 (HSP90), prevents toxic aggregation of circRNAs in aged organisms. These results establish RNASEK as a conserved regulator of aging and suggest that targeting circRNAs offers a strategy to mitigate age-associated diseases and extend organismal healthspan.