Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. While cytoplasmic DNA was shown to drive the inflammatory phenotype of senescent cells, an equivalent role for RNA has never been explored. Here, we show that cellular senescence correlates with reduced expression of RNA exosome subunits and coincident accumulation of promoter RNAs and immature RNA transcripts. Forced accumulation of these RNAs by inactivation of the Exosc3 exosome subunit induces expression of senescence markers and reduced mitochondrial gene expression. Reciprocally, mitochondrial suffering and oxidative stress results in reduced RNA decay, suggestive of a feedback loop between RNA decay and mitochondrial activity. As several of the accumulating RNAs are also produced during normal activation of immune cells and contain Alu sequences known to trigger an innate immune response, we propose that stabilizing immature and unstable RNAs participate in driving and maintaining the permanent inflammatory state characteristic of cellular senescence.

Reduced RNA turnover as a driver of cellular senescence