Epigenetic control of aging

Abstract

Organismal aging and longevity are influenced by many complex interacting factors. Epigenetics has recently emerged as another possible determinant of aging. Here, we review some of the epigenetic pathways that contribute to cellular senescence and age-associated phenotypes. Strategies aimed to reverse age-linked epigenetic alterations may lead to the development of new therapeutic interventions to delay or alleviate some of the most debilitating age-associated diseases.

FIG. 1.

The dynamic nature of chromatin. Chromatin is a highly dynamic structure able to transition from an uncondensed, loose form (top panel) to a condensed, tight one (bottom panel). The linker histone H1 and different histone-binding proteins (HBP) aid in the condensation of chromatin. Different modifications, including DNA methylation and various histone modifications, regulate the constant remodeling of chromatin.

FIG. 2.

Changes in DNA methylation during aging. Cells undergo a methlylation drift during aging resulting in a global DNA methylation decrease and aberrant hypermethylation of some promoters. Hypermethylated promoters cause reduced gene expression. Open hexagons denote unmethylated cytosines, whereas close hexagons represent methylated ones.

FIG. 3.

Histone modifications. This figure represents some of the potential modifications that histones can undergo. The aminoacid sequences of histone H2A, H2B, H3, and H4 are shown. These modifications include methylation (M), acetylation (A), phosphorylation (P), and ubiquitination (U).

FIG. 4.

Crosstalk between epigenetic pathways. DNA methyltransferases and histone-modifying enzymes work in concert with miRNA mechanisms to establish a specific chromatin structure that defines the transcriptional state of genes. Each of these mechanisms controls and is controlled by the others creating a complex regulatory machinery.

FIG. 5.

Cellular senescence in aging and cancer. Many different stresses, including telomere attrition, oncogenic stress, reactive oxygen species, and UV radiation, activate the cell cycle arrest proteins p16 and p21, which in turn leads to the activation of the tumor suppressors pRB and p53, respectively. Both of these pathways participate in establishing and maintaining cellular senescence. Senescent cells are growth-arrested and show changes in gene expression that affect tissue structure contributing to the aging phenotype.

FIG. 6.

Role of epigenetic modifications on aging. The accumulation of cell divisions and macromolecular damage contribute to the aging phenotype. Environmental and stochastic events can further modify this phenotype through epigenetic mechanisms such as DNA methylation, histone methylation, and histone acetylation. The potential reversibility of epigenetic modifications makes them attractive targets for treatment of age-related pathologies.