The Aging Epigenome

Abstract

During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs is unknown. Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline. These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging. We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging. Understanding age-dependent epigenomic changes will yield key insights into how aging begins and progresses and should lead to the development of new therapeutics that delay or even reverse aging and age-related diseases.

Figure 1. Transcription Factors and Chromatin Modifiers Act Together to Regulate Gene Expression

The remodeling and transcription activation of a gene occurs in a stepwise fashion that begins with the binding of a sequence-specific DNA-binding protein called a pioneer transcription factor. Following recruitment by a pioneer transcription factor, nucleosome remodeling complexes (e.g., SWI/SNF) displace or move nucleosomes and open chromatin. This increases DNA accessibility and allows binding of additional transcription factors, recruitment of chromatin modifiers that remove repressive marks (red hexagons) and add activating marks (green stars), and finally, transcription of the gene. Age-associated changes have been observed at every step of this process, and changes in one step (for example, the activity of pioneer transcription factor) can have downstream consequences for gene regulation.

Figure 2. Chromatin States Change during Aging

During aging and the emergence of cellular senescence, there is a general loss of heterochromatin that is characterized by a loss of repressive histone marks (H3K9me3), DNA methylation, nucleosome occupancy, and heterochromatin protein 1 (HP1) binding. These changes are associated with a loss of the nuclear lamina. In active regions of the genome (euchromatin), the patterning of histone marks changes (the active mark H3K4me3, the repressive mark H3K27me3, and the transcription elongation mark H3K36me3), DNA methylation increases at specific loci, and nucleosome remodeling occurs. Together, these changes can cause altered gene expression with age and contribute to the progression of aging.

Figure 3. Epigenomic Changes Are a Hub in the Progression of Aging

Epigenomic changes—changes in transcription factors, histone marks, nucleosome positioning, and DNA methylation—are connected with the other hallmarks of aging (Kennedy et al., 2014; López-Otín et al., 2013; Zhang et al., 2015a). Epigenomic changes can trigger the emergence of other hallmarks of aging and can also be affected by them.

Figure 4. The Aging Snowball Effect

Aging is the result of the accumulation of dysregulation and damage in a snowball effect that eventually ends in death. A small change or dysfunction of a cellular protective mechanism (for example, transcriptional networks or chromatin state) can begin the aging process by triggering the emergence of other age-associated changes. However, the aging snowball effect and the appearance of age-associated disease and dysfunction can be delayed or even reversed using aging therapeutics and interventions (reprogramming, parabiosis, epigenetic drugs, exercise, and diet). Eventually, the accumulation of age-associated changes may become so great that a “point of no return” is reached and interventions cannot extend lifespan or healthspan.