Numerous demonstrations of rejuvenation via clearance of senescent cells in recent years have led to a newfound and considerable enthusiasm for the study of the mechanisms of cellular senescence. Ever more funding in flowing into this part of the life sciences. That any new discovery might lead to a company, valuable intellectual property, a means to treat aging, is a considerable incentive forthe various research and funding ecosystems. The open access research noted here is a representative example of numerous projects presently underway.
Cellular senescence is involved in modulating aging and aging-associated pathologies via the senescence-associated secretory phenotype (SASP). Growing evidence has implicated the accumulation of senescent cells are implicated in chronologic aging of organisms. Several lines of evidence have suggested that cellular senescence is closely associated with age-related diseases. Therefore, characterizing the regulatory mechanisms of cellular senescence may allow us to intervene in aging-related diseases.
Circular RNAs (CircRNA) generated by back-splicing are highly conserved and stable long non-coding RNAs abundant in eukaryotic transcriptomes. Currently, the functions of most CircRNAs remain largely unexplored; however, the known functions include (I) sequestration of microRNAs or proteins; (II) modulation of transcription and splicing; (III) peptide or protein encoding. CircRNAs are also involved in various pathological and physiological processes, including cancer development, cardiovascular disease, and aging. However, molecular mechanisms and functions of CircRNAs in cellular senescence and aging of organisms remain largely unknown.
The present study identified senescence-associated CircRNAs (SAC-RNAs) by the whole-transcriptome sequencing, and revealed that CircCCNB1 is dramatically downregulated in replicative senescence and prematurely senescent fibroblasts. Short hairpin RNA (shRNA)-induced knockdown of circular cyclin B1 (CircCCNB1) led to senescence in proliferating fibroblasts. Mechanistically, CircCCNB1 regulated cyclin E2 (CCNE2) by controlling microRNA 449a (miR-449a) activity. Our data implicated that CircCCNB1-miR-449a-CCNE2 axis in the regulation of cellular senescence. Modulating miRNA activity by targeting SAC-RNAs can influence target protein expression, which may represent a promising strategy for aging and age-related disease interventions.
Link: https://doi.org/10.18632/aging.102449
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