The state of cellular senescence is normally irreversible; a senescent cell ceases replication and generates pro-inflammatory signaling to attract the attention of the immune system. That the immune system becomes less efficient in clearing senescent cells is one of the reasons why a growing burden of senescent cells exists in later life, their signaling producing chronic inflammation, damage, and dysfunction. Researchers have found a number of ways to reverse the normally irreversible senescent state by adjusting levels of regulatory molecules, but the question of whether this is a good basis for therapy remains. Some senescent cells are senescent for good reasons, such as potentially cancerous DNA damage. It remains to be seen as to whether the positive can outweigh the negative for reversal of senescence as a way to alleviate the harms done by the senescent cell population in old individuals.
Cellular senescence is a fundamental driver of ageing and age-related diseases, characterized by irreversible growth arrest and profound epigenetic alterations. While long non-coding RNAs (lncRNAs) have emerged as key regulators of senescence, their potential for senescent cell rejuvenation remains unexplored. Here, we established lncRNA PURPL as a key regulator of cellular senescence, bridging the connection between epigenetic modifications and the transcriptional regulation of senescence-associated genes.
Our findings demonstrate that PURPL is significantly upregulated in both replicative senescence and doxorubicin-induced senescence models. Manipulation of PURPL profoundly impacts the senescence phenotype. These findings extend and are consistent with previous studies on ageing regulators such as EGR1, SERPINE1, and other lncRNAs, and provide novel mechanistic insights into how PURPL regulates ageing through epigenetic remodelling, highlighting its significant theoretical and clinical implications.
Although several studies have reported a strong correlation between increased PURPL expression and senescence at both the cellular and tissue levels, few have demonstrated causality. Recently, RNA interference was used to knock down PURPL expression in senescent cells, resulting in some morphological improvements. However, no changes in molecular markers such as p21 were observed. In this study, we employed a more persistent method of lentivirus-mediated CRISPR/Cas9 interference to knock down PURPL. Not only did we observe significant morphological changes, but we also detected decreased levels of CDKN1A/p21 (a tumour suppressor protein) at both the RNA and protein levels. Furthermore, we overexpressed PURPL in young cells to mimic the increased PURPL levels observed during cellular senescence. This overexpression accelerated cellular senescence, as evidenced by increased SA-β-gal activity, elevated p21 levels, and reduced LMNB1 levels. This study provides the first definitive evidence that PURPL acts as a driver of senescence.
Link: https://doi.org/10.1186/s12967-025-07208-5
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