Long non-coding RNAs (lncRNAs) regulate diverse cellular processes and are associated with many age-associated diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we characterize the role of lncRNA H19 in senescence. We show that H19 levels decline as cells undergo senescence, and depletion of H19 results in premature senescence. We find that repression of H19 is triggered by the loss of CTCF and prolonged activation of p53 as part of the senescence pathway. Mechanistically, the loss of H19 drives senescence via increased let7b mediated targeting of EZH2. We further demonstrate that H19 is required for senescence inhibition by the mTOR inhibitor rapamycin, where it maintains lncRNA H19 levels throughout the cellular lifespan and thus prevents the reduction of EZH2 that would otherwise lead to cellular senescence. Therefore, lncRNA H19 is crucial in maintaining the balance between sustained cell growth and the onset of senescence.
