Epigenetic determinants of healthy and diseased brain aging and cognition

Abstract

A better understanding of normal and diseased brain aging and cognition will have a significant public health impact, given that the oldest-old persons older than 85 years of age represent the fastest-growing segment in the population in developed countries, with more than 30 million new cases of dementia predicted to occur worldwide each year by 2040. Dysregulation of gene expression and, more generally, genome organization and function are thought to contribute to age-related declines in cognition. Remarkably, nearly all neuronal nuclei that reside in an aged brain had permanently exited from the cell cycle during prenatal development, and DNA methylation and histone modifications and other molecular constituents of the epigenome are likely to play a critical role in the maintenance of neuronal health and function throughout the entire lifespan. Here, we provide an overview of age-related changes in the brain's chromatin structures, highlight potential epigenetic drug targets for cognitive decline and age-related neurodegenerative disease, and discuss opportunities and challenges when studying epigenetic biomarkers in aging research.

Figure 1. Epigenetic regulation of the genome

(top) chromosomes are organized into domains of loose (eu-) or highly condensed (hetero-) chromatin and other loosely defined higher order structures (‘globules’ etc), some of which could be tethered to the nuclear membrane. (bottom) shows 11 nm ‘beads-on-a-string’ chromatin fiber comprised of nucleosomal arrays connected by linker DNA and linker histone. The distribution of DNA cytosine methylation and hydroxymethylation markings, and of some of the posttranslational histone modifications differentiate show differential enrichment at actively expressed as opposed to repressed genes, with promoters, gene bodies including introns vs. exons, and enhancers each defined by a different set of epigenetic markings (see also text).

Figure 2. Epigenetic determinants of decreased neuronal gene expression in aging brain

Hypothetical, simplified scheme for age-related decline in neuronal gene expression, which is accompanied by a shift from open chromatin associated histone acetylation, including H3K27ac and H4K12ac, and methylation (H3-K36me3)) to repressive (H3K9me2/3, H3K27me3) chromatin-associated histone methylation and promoter-associated DNA methylation. These changes may result lead to an overall compaction of the surrounding chromatin and decreased presence of phospho-activated RNA II polymerase, thereby decreasing transcriptional activity (see text for further details).