{"version":2,"kind":"Article","sha256":"","slug":"217","location":"","dependencies":[],"frontmatter":{"title":"A universal molecular mechanism driving aging","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.","license":"CC BY","keywords":[],"authors":[{"name":"Wan Jin","affiliations":[],"corresponding":true},{"name":"Jing Zheng","affiliations":[],"corresponding":true},{"name":"Yu Xiao","affiliations":[],"corresponding":true},{"name":"Lingao Ju","affiliations":[],"corresponding":true},{"name":"Fangjin Chen","affiliations":[],"corresponding":true},{"name":"Jie Fu","affiliations":[],"corresponding":true},{"name":"Hui Jiang","affiliations":[],"corresponding":true},{"name":"Yi Zhang","orcid":"0000-0001-5388-1276","affiliations":[],"corresponding":true}],"date_submitted":"2024-06-24T14:36:48.000Z","external_publication_id":217,"revision_cids":["bafkreif2l2vqwzocmgmfyy2ejvrqd5uhhrzkqk45hthwcw4mt4oz7i4u7q","bafkreibyobujs3ljgpz6kidhgizhzh3tkwcts3s6526uliej7mu7k5ieei"]},"mdast":{"type":"root"},"references":{"cite":{"order":[]},"data":{}}}