Aging is a multifaceted process characterized by genetic and epigenetic changes in the genome. The genetic component of aging received initially all the attention. Telomere attrition and accumulation of mutations due to a progressive deficiency in the repair of DNA damage with age remain leading causes of genomic instability. However, epigenetic mechanisms have now emerged as key contributors to the alterations of genome structure and function that accompany aging.

The three pillars of epigenetic regulation are DNA methylation, histone modifications and non-coding RNA species. Alterations of these epigenetic mechanisms affect the vast majority of nuclear processes including gene transcription and silencing, DNA replication and repair, cell cycle progression, and telomere and centromere structure and function. DNA methylation patters are briefly introduced in this issue.

A large and growing body of literature demonstrates that epigenetic alterations accumulate over the life of the individual and are associated with a number of disorders acquired with age. DNA methylation patterns change with age in a complex fashion, including global hypomethylation but also gene-specific hypermethylation of some CpG islands. Global hypomethylation is generally reflective of decreased methylation of CpGs dispersed throughout repetitive sequences as well as of transcriptionally relevant regions of some genes. DNA hypomethylation promotes genomic instability, as well as overexpression of proto-oncogenes. In addition, hypomethylation of regions flanking the ITGAL promoter, encoding CD11a, a subunit of the adhesion molecule LFA-1 (CD11a/CD18), may increase LFA-1 expression in aging.

Since LFA-1 overexpression can induce anti-DNA antibodies, these changes may play a role in the development of autoimmunity in the elderly. While the mechanisms causing age- dependent changes in DNA methylation are unclear, DNMT1 decreases with age, which may contribute to the overall decrease in methylcytosine content. The mechanisms causing hypermethylation of CpG islands in aging cells are also unclear, but may be related to transcriptional up-regulation of the Dnmt3a and Dnmt3b452 genes. However, the changes can be important and have pathologic significance.

Toyota et al. cloned 26 CpG islands from a colorectal cancer cell line using methylated CpG island amplification (MCA) coupled with representational difference analysis (RDA), and 19 of the 26 (73%) were found to have age-dependent methylation in normal tissues. It was observed that promoter hypermethylation of ER (estrogen receptor), IGF2 (insulin-like growth factor 2), MYOD (Myogenic Differentiation Antigen), N33, and CSPG2 (chondroitin sulfate proteoglycan 2 (versican)) is associated with aging in normal colon mucosa. The embryonic RARbetal isoform and the adult RARbeta2 isoform are hypermethylated in aging colon mucosa as well as in colorectal cancers.

The age-related methylation may contribute to the hypermethylation observed in cancers. Gene-specific hypermethylation can be related to silencing of genes involved in the control of cell cycle, apoptosis, detoxification, and cholesterol metabolism.