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bioRxiv · 10.1101/2024.01.06.574476

A universal molecular mechanism driving aging

Jin, W.·Zheng, J.·Xiao, Y.·Ju, L.·Chen, F.·Fu, J.·Jiang, H.·Zhang, Y.
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Abstract

How cell replication ultimately results in aging and the Hayflick limit are not fully understood. Here we show that clock-like accumulation of DNA G-quadruplexes (G4s) throughout cell replication drives conserved aging mechanisms. G4 stimulates transcription-replication interactions to delay genome replication and impairs DNA re-methylation and histone modification recovery, leading to loss of heterochromatin. This creates a more permissive local environment for G4 formation in subsequent generations. As a result, G4s gradually accumulate on promoters throughout mitosis, driving clock-like DNA hypomethylation and chromatin opening. In patients and in vitro models, loss-of-function mutations in the G4-resolving enzymes WRN, BLM and ERCC8 accelerate the erosion of the epigenomic landscape around G4. G4-driven epigenomic aging is strongly correlated with biological age and is conserved in yeast, nematodes, insects, fish, rodents, and humans. Our results revealed a universal molecular mechanism of aging and provided mechanistic insight into how G-quadruplex processor mutations drive premature aging.

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Jin, W., Zheng, J., Xiao, Y., Ju, L., Chen, F., Fu, J., Jiang, H., Zhang, Y.. 2024-01-06. A universal molecular mechanism driving aging. https://doi.org/10.1101/2024.01.06.574476

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