Scientists Discover RNASEK Enzyme That Extends Lifespan by Clearing Toxic Circular RNA from Cells

In a groundbreaking discovery that could redefine anti-aging medicine, researchers at the Korea Advanced Institute of Science and Technology (KAIST) have identified a cellular mechanism that directly links the accumulation of circular RNA to the aging process—and a protein that, when activated, can significantly extend lifespan. Using the short-lived nematode Caenorhabditis elegans as a model organism, the KAIST team demonstrated that the enzyme RNASEK degrades toxic circular RNA buildup in cells, preventing harmful clumping that accelerates aging. The findings, published in the journal Molecular Cell , not only uncover a previously unknown driver of aging but also offer a promising therapeutic target for extending healthy lifespan in humans.

• RNASEK enzyme degrades toxic circular RNA that accumulates during aging
• Study conducted using C. elegans shows RNASEK overexpression extends lifespan by 20% and improves healthspan
• Toxic RNA clumps (stress granules) impair cellular function and accelerate aging
• RNASEK works with HSP90 to prevent RNA clumping; deficiency causes premature aging in mice and human cells
• Results suggest potential for RNA-based therapies targeting circular RNA accumulation in age-related diseases

How Circular RNA Became a Hidden Driver of Aging

For decades, circular RNA—so named because it forms a closed loop rather than a linear strand—was dismissed by scientists as a biological curiosity, a byproduct of gene expression with no clear function. That changed as research advanced in the last 10 years, revealing that circular RNA is not only abundant in cells but also remarkably stable. Unlike linear RNA, which degrades within hours, circular RNA can persist for years, making it a prime candidate to influence long-term cellular health. As organisms age, circular RNA accumulates to toxic levels, forming abnormal clusters known as stress granules that interfere with protein synthesis and cellular repair mechanisms.

The Biology Behind Stress Granules and Cellular Decline

Stress granules are temporary structures that cells form in response to stress—such as heat shock, oxidative damage, or metabolic strain—to protect essential proteins and RNA. However, when these granules fail to dissolve properly, as occurs with excess circular RNA, they become permanent and toxic. The KAIST team found that in aging C. elegans, circular RNA accumulation disrupts the normal function of stress granules, leading to impaired protein quality control and accelerated cellular aging. This phenomenon is not limited to worms: the researchers observed similar patterns in mouse models and human cell cultures, suggesting a universal mechanism across species.

To investigate this further, the team used RNA sequencing to analyze gene expression in young versus old C. elegans. They discovered that levels of RNASEK, the enzyme responsible for degrading circular RNA, decline sharply with age. By middle age in the worms (about 8–10 days), RNASEK activity drops by nearly 60%, allowing circular RNA to accumulate unchecked. This age-dependent decline in RNASEK mirrors the pattern seen in many age-related diseases in humans, including neurodegenerative disorders like Alzheimer’s and Parkinson’s, where toxic protein aggregates are a hallmark.

RNASEK: The Cellular Janitor That Extends Lifespan

The discovery of RNASEK as a key regulator of aging emerged from a targeted genetic screen in C. elegans. The KAIST researchers, led by Professor Seung-Jae V. Lee of the RNA-Mediated Healthspan and Longevity Research Center, found that worms genetically engineered to overexpress RNASEK not only lived 15–20% longer but also maintained better health in their later years, free from the typical decline in mobility and metabolic function seen in normal aging. Importantly, these long-lived worms did not exhibit the toxic stress granules that plagued their normal counterparts.

Further experiments revealed that RNASEK works in concert with HSP90, a chaperone protein that assists in proper protein folding. HSP90 normally helps prevent misfolded proteins from clumping together, but without RNASEK to clear circular RNA, even HSP90 becomes overwhelmed. The team’s data showed that in RNASEK-deficient worms, stress granules formed prematurely and persisted, leading to accelerated aging and reduced stress resistance. When RNASEK was reintroduced, these granules dissolved, and cellular function was restored.

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.

From Worms to Humans: A Universal Mechanism

While C. elegans is a powerful model for aging research due to its short 2–3 week lifespan and fully sequenced genome, the KAIST team sought to validate their findings in more complex organisms. In mouse models, RNASEK deficiency led to premature aging phenotypes, including reduced muscle mass, decreased cognitive function, and increased susceptibility to age-related diseases. Human cell cultures with suppressed RNASEK similarly showed signs of accelerated senescence, with cells entering a state of permanent growth arrest earlier than normal.

The conservation of this mechanism across species is a critical finding. It suggests that RNASEK’s role in degrading circular RNA is a fundamental process that has been preserved through evolution. Dr. Yoon Ki Kim, a co-lead author of the study and a professor in KAIST’s Department of Biological Sciences, noted that ‘the fact that we see this in worms, mice, and human cells implies that RNASEK is a linchpin in the aging process that could be targeted pharmacologically.’

Therapeutic Potential: Can Human Lifespan Be Extended?

The implications of this research extend far beyond academic curiosity. For the first time, scientists have identified a direct, actionable target for anti-aging interventions: the RNASEK enzyme. While the current study focuses on genetic overexpression of RNASEK, the team is already exploring pharmacological methods to boost RNASEK activity in humans. One approach under investigation involves small-molecule drugs that mimic the function of RNASEK or stabilize its interaction with circular RNA.

The potential applications are vast. Age-related diseases, including Alzheimer’s, cardiovascular disease, and type 2 diabetes, are all linked to cellular dysfunction driven by toxic protein and RNA aggregates. By clearing circular RNA, RNASEK-based therapies could delay the onset of these conditions, improving both lifespan and healthspan—the period of life free from chronic illness. Professor Gwangrog Lee, another co-author and collaborator on the study, emphasized the urgency of this line of research, stating, ‘If we can enhance RNASEK activity even modestly in humans, we may be able to significantly delay the aging process and reduce the burden of age-related diseases.’

Challenges and Ethical Considerations in Anti-Aging Research

Despite the promise of this discovery, significant challenges remain before RNASEK-based therapies can be brought to clinical trials. One major hurdle is delivering RNASEK or RNA-degrading enzymes directly to human cells without triggering immune responses or off-target effects. RNA molecules are notoriously difficult to target selectively, and any intervention would need to avoid degrading beneficial RNA species.

Ethical concerns also come into play. While extending lifespan is a noble goal, it raises questions about overpopulation, resource allocation, and the potential for increased age-related disparities. Additionally, the long-term effects of RNASEK overexpression are unknown—could it lead to unintended consequences, such as increased susceptibility to cancer by disrupting normal cellular surveillance mechanisms? The KAIST team acknowledges these concerns and is proceeding with caution, conducting rigorous safety studies in animal models before considering human applications.

The Broader Landscape of Anti-Aging Science

KAIST’s discovery joins a growing body of research exploring RNA-based interventions in aging. Other notable approaches include RNA interference (RNAi) therapies to silence harmful genes, senolytic drugs that clear senescent cells, and epigenetic reprogramming techniques like those pioneered by the Salk Institute. Unlike these methods, which focus on downstream effects of aging, RNASEK targets a root cause: the accumulation of toxic circular RNA. This positions it as a complementary strategy in the anti-aging toolkit.

The field of geroscience—interdisciplinary research aimed at understanding the biological mechanisms of aging—has gained significant momentum in recent years, fueled by breakthroughs in genomics, proteomics, and now RNA biology. Funding for anti-aging research has surged, with organizations like the National Institute on Aging (NIA) and private companies such as Altos Labs and Calico investing heavily in longevity science. KAIST’s findings add a critical piece to this puzzle, offering a new angle for intervention.

What’s Next: From Lab Bench to Clinic

The road from discovery to drug development is long, but the KAIST team is already laying the groundwork for translational research. Their next steps include identifying small molecules that can enhance RNASEK activity or mimic its function, as well as developing delivery systems such as lipid nanoparticles to transport RNASEK into cells. They are also expanding their studies to include other model organisms, such as zebrafish and non-human primates, to further validate the safety and efficacy of RNASEK-based interventions.

Collaborations with biotech firms and clinical researchers will be essential to bring this technology to market. Dr. Lee envisions a future where ‘simple, periodic treatments’—whether through gene therapy, RNA drugs, or enzyme supplements—could help individuals maintain youthful cellular function well into their later years. ‘We’re not talking about immortality,’ he clarifies. ‘But if we can add 10–15 healthy years to the average lifespan, that would be a revolution in public health.’

A Paradigm Shift in How We View Aging

For most of history, aging was seen as an inevitable decline, a process too complex to intervene in. But discoveries like KAIST’s are rapidly changing that narrative. Aging is now recognized as a malleable biological process, influenced by genetic, environmental, and molecular factors. The identification of RNASEK as a longevity regulator underscores the idea that aging can be targeted therapeutically—opening the door to a future where lifespan extension is not just possible but expected.