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 some senescent cells accumulate long promoter RNAs and 3prime gene extensions, rich in retrotransposon sequences. Accordingly, these cells display increased expression of genes involved in detecting double stranded RNA of viral origin downstream of the interferon pathway. The RNA accumulation is correlated with signs of reduced RNA turn-over, including in some cases, reduced expression of RNA exosome subunits. Reciprocally, engineered inactivation of RNA exosome subunit Exosc3 induces expression of multiple senescence markers. A senescence-like RNA accumulation is 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, possibly in combination with cytoplasmic DNA, in driving and maintaining the permanent inflammatory state characterizing cellular senescence.

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降低RNA转换作为细胞衰老的驱动力

衰老细胞的积累是衰老后慢性炎症的重要因素。尽管显示细胞质DNA可以驱动衰老细胞的炎症表型，但从未探索过RNA的等效作用。在这里，我们显示一些衰老细胞积累了长的启动子RNA和3prime基因扩展，富含逆转录转座子序列。因此，这些细胞显示出参与检测干扰素途径下游的病毒来源的双链RNA的基因的表达增加。RNA积累与RNA周转减少的迹象相关，包括在某些情况下RNA外泌体亚基的表达减少。相应地，RNA外泌体亚基Exosc3的工程失活诱导了多个衰老标记的表达。在暴露于氧化应激的细胞中也观察到了类似衰老的RNA积累，这是细胞衰老的重要诱因。总而言之，我们提出在衰老细胞的子集中，通过氧化应激或降低的RNA外泌体活性而稳定的含重复序列的转录本可能与细胞质DNA结合，参与驱动和维持表征细胞衰老的永久性炎症状态。