RNASEK, an enzyme that degrades circular RNAs, declines with age and allows circRNA accumulation in stress granules, disrupting both RNA and protein homeostasis. This mechanism, conserved across species, links impaired circRNA clearance directly to cellular dysfunction and shortened lifespan, identifying a previously underappreciated axis of aging.
Key Points
- RNASEK decline enables circRNA buildup in stress granules with age
- CircRNA accumulation disrupts both ribostasis and proteostasis simultaneously
- RNASEK activity is conserved across worms, mice, and human cells
Longevity Analysis
The aging process involves not just protein misfolding but also accumulation of stable RNA molecules that aggregate in cellular stress structures. When RNASEK activity falls—a hallmark of aging—these circular RNAs persist and interfere with the cell's ability to maintain proper protein function and energy metabolism. This reveals a specific molecular failure point: the body's capacity to clear a particular class of RNA directly controls whether stress responses remain functional or become dysregulated. Restoring or maintaining RNASEK activity, or preventing circRNA accumulation before dysfunction sets in, represents a tractable intervention target across multiple organ systems. Understanding whether this is a primary driver or a consequence of aging will determine whether therapeutic approaches should focus on enzyme replacement, circRNA degradation, or earlier prevention of the accumulation process itself.
Original published by Wiley Aging Cell, by José M. Izquierdo .