DNA Methylation, Genomic Stability andAging
2013 new Scholar Award in aging
Genome-wide hypomethylation of DNA is a near-universal feature of aging cells and has been proposed to be a major factor contributing to replicative senescence. However, a direct role for the gradual loss of methylation seen during an organism’s lifetime in the aging process has yet to be demonstrated. In support of a direct link, the upper limit on population doublings of primary cultured fibroblasts across several species correlates strongly with the rate at which they lose methylation. Furthermore, demethylation of normal human fibroblasts results in reduced in vitro lifespan and premature senescence. Consistent with dominant theories of aging that assume DNA damage is a central cause, hypomethylation-associated senescence occurs via activation of p21 and p53, suggesting that cell cycle arrest is triggered by DNA damage. Cells deficient in DNA methylation show persistent DNA damage, and increased chromosomal rearrangements, which are well known to drive replicative senescence. The mutations and rearrangements observed in hypomethylated cells are most pronounced at regions enriched in repetitive elements and require DNA synthesis to occur, indicating that impediments to DNA replication may play a role in the genomic instability observed in aging cells. The goal of Dr. Tahiliani’s research is to uncover the mechanism by which DNA methylation stabilizes the genome and thus protects against the aging process. Her research aims to definitively address how DNA methylation influences replication and repair of the genome. This work will define the role of DNA methylation in genomic stability and aging and may also form the foundation for novel strategies to counteract the deleterious effects of hypomethylation on the aging process.