A new molecular model of cellular aging based on Werner syndrome.
In the Hayflick model, a decrease in the number of cells capable of undergoing proliferation constitutes the main criterion of cellular aging and is closely linked to organismal aging. Evidence suggests that a reduction of DNA replication capacity or a failure in the regulation systems of DNA replication occurs in aging cells, which leads to cellular replicative senescence. DNA replication depends on two parameters: the number of active replicons and the rate of chain elongation. Epigenetic parameters, in particular methylation, would be able to, either directly or indirectly, regulate replication origin activity of normal mammalian cells, as well as subsequent DNA replication. Werner syndrome (WS) is an autosomal recessive disorder that results in premature aging and is considered to be a model system for the study of cellular senescence and aging. WRN could involve DNA replication initiation, replication foci establishment, and the resolution of stalled replication forks during replication. In this paper, a molecular model of in vitro cellular aging is presented in which changes in DNA methylation, in particular, global hypomethylation related to methyltransferase Dnmt1 downregulation, and specific hypermethylation related to methyltransferase Dnmt3b upregulation as seen during cellular aging, could be responsible for the inactivation of replication origins or foci and the subsequent documented reduction in DNA replication capacity and increased mutations that are observed in senescent cells. Thus, Werner syndrome cells could be mimicking what is observed in normal aging in an accelerated form.
Agrelo
Ruben
R
Coronel Brandzen 1961, Escritorio 501, CP 11200 Montevideo, Uruguay. ragrelo@adinet.com.uy <ragrelo@adinet.com.uy>
D000375:Aging; D000818:Animals; D016922:Cellular Senescence; D019175:DNA Methylation; D004261:DNA Replication; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D016296:Mutagenesis; D014898:Werner Syndrome / Q000175:diagnosis* / Q000473:pathology*
D008780:Methyltransferases