Aging associated RNA loss impairs the dynamics of RNA and protein condensates

Abstract

Altered biomolecular condensate dynamics are increasingly implicated in age-associated neurodegenerative disorders, yet the molecular principles governing these changes remain incompletely understood. Here, we demonstrate that aged cells across diverse cellular and organismal models harbor pre-formed, viscous, and persistent stress granules (SGs), which we term alt-SGs. These persistent condensates confer protection to senescent cells under fluctuating stress conditions. Comparative analyses reveal that alt-SGs exhibit elevated RNA-binding protein (RBP)-to-RNA ratios, underscoring a shift in condensate stoichiometry. By quantifying SG composition and dynamics in live cells and in vitro, we establish that RNA concentration is a key determinant of condensate material properties, molecular composition, and dissolution capacity. Importantly, aging cells display diminished absolute RNA concentrations due to reduced RNA metabolic activity. Reactivation of RNA metabolism restores RNA/RBP ratios within SGs and alleviates aging-associated phenotypes. Together, our findings highlight RNA metabolism as a central regulator of condensate stoichiometry and function, linking metabolic decline to altered phase behavior and cellular aging.