Epigenetic changes during aging and their reprogramming potential

Abstract

The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. Excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors. This review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes.

Keywords: Aging; DNA methylation; chromatin; clock; epigenetics; histones; reprogramming; sirtuins.

Figure 1.

Age-related changes to chromatin. With increasing age, there are both global and loci-specific changes to chromatin structure. Young chromatin is characterized by predominantly tightly packaged heterochromatin, with repressive histone marks and HP1 protein binding. Nucleosomes are made up of canonical histone proteins and there is an abundance of DNA cytosine methylation. Chromatin of cells from old individuals is characterized by globally reduced heterochromatin with specific areas of heterochromatin known as senescence-associated heterochromatin foci (SAHF). There is a decrease in repressive histone marks and an increase in active histone marks. Non-canonical histone variants are included in nucleosomes and there is general nucleo-some loss. Additionally, there is global DNA hypomethylation except in CpG islands where there is hypermethylation (see the color version of this figure at www.tandfonline.com/ibmg).

Figure 2.

Relocalization of chromatin modifying factors. In young cells, chromatin modifying factors such as SIRT1 (indicated by red circles) are usually located at canonical loci where they act to modulate transcription. When DNA is damaged these factors are recruited to the site of DNA damage to assist in repair. Relocalization results in altered gene expression or activation of retrotransposons. Usually these factors return to where they came from once the DNA is repaired. After repeated responses to DNA damage, however, not all factors return to their original sites, resulting in the relocalization of chromatin modifying factors (RCM), changes to gene expression, and a loss of cell identity during aging (see the color version of this figure at www.tandfon-line.com/ibmg).

Figure 3.

Interventions to prevent the stages of aging. Aging has four main stages: A0, when an organism/cell is young and healthy; A1, when the organism/cell begins to age; A2, when the organism/cell is aged; and A3, when the organism/cell is senescent. Interventions that delay or prevent aging can act at each of these stages such as calorie restriction, which prevents the aging process at A2. Rapamycin can increase lifespan even when started in later life and acts at A2 and senolytics/senomorphics that act to selectively remove or inhibit the deleterious effects of senescent cells act at stage A3. Reprogramming, the resetting of the epigenetic landscape using specific transcription factors, such as Yamanaka factors, can return cells from the A2 stage to the young A0 stage. Whether or not it is possible to safely reset cells to A1 without risking tumorigenesis is not yet known (see the color version of this figure at www.tandfonline.com/ibmg).