DNA Methylation and Epigenetics in the Pathogenesis of Age-Related Diseases

Jean-Pierre Issa
Department of Leukemia; M.D. Anderson Cancer Center

Hypermethylation of DNA in promoter associated CpG islands is a mark of clonal and irreversible epigenetic silencing. Progressive increases in CpG island methylation were described in aging colonic tissues over a decade ago, and were proposed as an important molecular precursor to age-related diseases including cancer. In the past few years, age-related epigenetic mosaicism has been confirmed in multiple tissues, and is now a ubiquitous finding. Major features of the process include (i) involvement of stem cells, (ii) linear accumulation of epigenetic marks and (iii) individual variation in the rate of age-related changes. Known modulators of this rate of change, besides aging, include chronic inflammation as well as gene-specific factors such as promoter polymorphisms. The impact of other genetic or lifestyle factors on the process is unknown, but likely important. Acquired epigenetic changes provide an attractive model to account for the impact of environmental and lifestyle factors on disease, as will be illustrated for MGMT hypermethylation as a marker of the field defect in colon cancer, and ER-beta hypermethylation in atherosclerotic tissues. Above all, modulation of epigenetic changes may have a substantial role to play in the prevention and treatments of age related diseases.