circHERC1-A telomerase activator.

Abstract

Telomerase, crucial for maintaining telomere integrity and genomic stability, is typically silenced in somatic cells with advancing age. In this study, we identify circHERC1 as a regulator of telomerase reverse transcriptase (TERT) transcription. Specifically, circHERC1 binds to the TERT promoter, facilitating the recruitment of RNA polymerase II and c-Fos, thereby activating TERT expression. Notably, circHERC1 expression exhibits a decline with age, which correlates with reduced telomerase activity. Restoration of circHERC1 expression enhances telomerase activity, promotes telomere elongation, and reverses aging-associated phenotypes. Furthermore, delivery of circHERC1 using adeno-associated virus vectors or extracellular vesicles effectively restores telomerase activity, preserves telomere integrity, and mitigates senescence. This intervention leads to improvements in cognitive function, physical performance, and a reduction in inflammation. These findings highlight the important role of circHERC1 in telomerase regulation and the aging process, positioning it as a potential therapeutic target for antiaging interventions.