Accumulation of senescent cells is an important contributor to chronic inflammation upon aging. The inflammatory phenotype of senescent cells was previously shown to be driven by cytoplasmic DNA. Here, we propose that cytoplasmic double-stranded RNA has a similar effect. We find that several cell types driven into senescence by different routes share an accumulation of long promoter RNAs and 3′ gene extensions rich in retrotransposon sequences. Accordingly, these cells display increased expression of genes involved in response to double stranded RNA of viral origin downstream of the interferon pathway. The RNA accumulation is associated with evidence of reduced RNA turnover, including in some cases, reduced expression of RNA exosome subunits. Reciprocally, depletion of RNA exosome subunit EXOSC3 accelerated expression of multiple senescence markers. A senescence-like RNA accumulation was also observed in cells exposed to oxidative stress, an important trigger of cellular senescence. Altogether, we propose that in a subset of senescent cells, repeat-containing transcripts stabilized by oxidative stress or reduced RNA exosome activity participate in driving and maintaining the permanent inflammatory state characterizing cellular senescence.

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.