Epigenetic alterations in aging

Abstract

Aging is a multifaceted process characterized by genetic and epigenetic changes in the genome. The genetic component of aging received initially all of 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 noncoding 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. Here, we summarize the lines of evidence indicating that these epigenetic defects might represent a major factor in the pathophysiology of aging and aging-related diseases, especially cancer.

Fig. 1.

Model of how genetic and epigenetic alterations contribute to aging and cancer. Genetic and epigenetic alterations contribute toward the pathogenesis of aging and aging-related diseases, especially cancer. Genetic alterations, such as chromosomal deletions, DNA rearrangements, gene amplifications, and mutations, can initiate aging and cancer phenotypes. Epigenetic alterations, including changes in DNA methylation, histone modifications, and levels of expression of noncoding RNAs, also contribute to these phenotypes. Epigenetic changes may directly trigger aging and cancer phenotypes, or prime cells to make them more susceptible to subsequent genetic or epigenetic alterations.

Fig. 2.

The nucleosome, chromatin, and specific marks. A: diagram of a nucleosome, formed by an octamer of histones wrapped around by DNA. Histone tails protruding from the nucleosome core are shown with a variety of posttranslational modifications. DNA methylation and binding of noncoding RNAs (ncRNAs) are also shown. B: the four histone tails are shown with the corresponding posttranslational modifications at specific residues. C: diagram illustrating the differences between euchromatin and heterochromatin domains. Euchromatin is characterized by hyperacetylation of histones and hypomethylation of histones and DNA. In contrast, heterochromatin shows hypoacetylation of histones and hypermethylation of histones and DNA.

Fig. 3.

DNA methylation in aging and cancer. The different proteins playing a role in DNA methylation are shown with their reported molecular activity and cellular function. A summary of the changes observed in DNA methylation patterns during cancer and aging by different studies are also shown. Both changes at a global level and at specific gene promoters are indicated. ER, estrogen receptor; BRCA1, breast cancer 1; APC, adenomatosis polyposis coli.

Fig. 4.

Histone-modifying activities in aging and cancer. Listing of the major classes of histone-modifying activities indicate their specific activities and reported cellular function. HDACs, histone deacetylases; HATs, histone acetyltransferases; HMTs, histone methyltransferases. In the case of HMTs, the specific lysine residues that are methylated and their function are indicated. A summary of the changes observed in histones modifications during aging and cancer is also shown. Note that the changes in SIRT1 expression and H4K20me3 levels during aging and cancer go in the opposite direction. See text for definition of histone acronyms.

Fig. 5.

Noncoding RNAs [micro-RNAs (miRNAs)] in aging and cancer. Summary is given of some of the functions reported for miRNAs and changes that could have an impact in cancer and aging phenotypes.