Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells.

Christopher J Harris,Joseph F Quinn,Nora E Gray,Brett A Davis,Jonathan A Zweig,Kimberly A Nevonen,Lucia Carbone

doi:10.3389/fgene.2020.00111

Abstract

As the population ages, interest in identifying biomarkers of healthy aging and developing antiaging interventions has increased. DNA methylation has emerged as a potentially powerful molecular marker of aging. Methylation changes at specific sites in the human genome that have been identified in peripheral blood have been used as robust estimators of chronological age. Similar age-related DNA methylation signatures are also seen in various tissue types in rodents. However, whether these peripheral alterations in methylation status reflect changes that also occur in the central nervous system remains unknown. This study begins to address this issue by identifying age-related methylation patterns in the hippocampus and blood of young and old mice. Reduced-representation bisulfite sequencing (RBSS) was used to identify differentially methylated regions (DMRs) in the blood and hippocampus of 2- and 20-month-old C57/Bl6 mice. Of the thousands of DMRs identified genome-wide only five were both found in gene promoters and significantly changed in the same direction with age in both tissues. We analyzed the hippocampal expression of these five hypermethylated genes and found that three were expressed at significantly lower levels in aged mice [suppressor of fused homolog (Sufu), nitric oxide synthase 1 (Nos1) and tripartite motif containing 2 (Trim2)]. We also identified several transcription factor binding motifs common to both hippocampus and blood that were enriched in the DMRs. Overall, our findings suggest that some age-related methylation changes that occur in the brain are also evident in the blood and could have significant translational relevance.

Highlights

As the population of older Americans continues to rise, with estimates that it will more than double in the coming decades (Populations Reference Bureau, 2015), there is a growing interest in understanding the underlying biology of aging in order to identify therapeutic interventions that can help improve the overall health of older people
There was a high correlation between methylation changes in the blood and hippocampus (Supplementary Figure 1), we found only three differentially methylated regions (DMRs) shared across tissues that were both hypomethylated with age (Figure 2A) and 20 that were hypermethylated with age (Figure 2B)
We identified 54 transcription factors (TF) binding motifs enriched in DMRs in the hippocampus and 111 in blood and 14 of these were common to both tissues (Table 1)

Summary

Introduction

As the population of older Americans continues to rise, with estimates that it will more than double in the coming decades (Populations Reference Bureau, 2015), there is a growing interest in understanding the underlying biology of aging in order to identify therapeutic interventions that can help improve the overall health of older people To this end, there has been an increased focused on epigenetic changes, which are chemical modification of the DNA that do not involve DNA sequence and might affect gene expression. Rodents display epigenetic alterations as they age (Stubbs et al, 2017; Meer et al, 2018) and many studies have reported that age-related methylation changes in the central nervous system (CNS) can likewise influence synaptic connectivity and cognitive function (Levenson et al, 2006; Miller and Sweatt, 2007; Lubin et al, 2008)

Methods

Results

Conclusion