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. In the top left, chromosomes are organized into domains of loose (eu-) or highly condensed (hetero-) chromatin and other loosely defined higher-order structures (eg, globules), some of which could be tethered to the nuclear membrane. The bottom shows 11-nm beads-on-a-string chromatin fiber consisting 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, show differential enrichment as 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. Ac indicates acetyl; H, histone; K, lysine; me1, monomethylated; me3, trimethylated; pol, polymerase.
Figure 2. Epigenetic determinants of decreased neuronal gene expression in the 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 histone (H) 3 lysine (K) 27 acetyl (ac) and H4K12ac, and methylation (trimethylated H3K36 [H3K36me3]) to repressive (H3K9me2/3 and H3K27me3) chromatin-associated histone methylation and promoter-associated DNA methylation. These changes may lead to an overall compaction of the surrounding chromatin and decreased presence of phosphoactivated RNA polymerase (pol) II, thereby decreasing transcriptional activity.
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