# Dynamics of the brain epigenome with aging

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

Regulation of brain aging through epigenetic processes is currently one of the most provocative areas of aging
research. Epigenetic processes in the central nervous system may play a mechanistic role in susceptibility to
and progression of cognitive decline and age-related neurodegenerative disease such as Alzheimer’s disease
and other dementias. DNA modifications, principally methylation and hydroxymethylation of cytosines (mC and
hmC respectively), are fundamental regulators of DNA accessibility and gene regulation/expression with
differential effects on gene expression depending on the modification (mC/hmC), context CG/CH, and genomic
location. A barrier to progress in understanding the role of epigenetic mechanisms in brain aging, and DNA
modifications in particular, has been the lack of quantitatively accurate, genome-wide data. Without the
knowledge of the specific genomic locations of altered modifications with aging and it is impossible to design
well-rationalized, mechanistic studies that unravel the functional effects of epigenetic changes. Therefore, the
critical next step for the field is to generate this genome-wide data of mC and hmC in CG and CH contexts in
specific cell types and in both males and females. To address this barrier to progress we have developed
innovative methods to analyze mC and hmC levels across the genome with absolute quantitation in a base-
and strand-specific manner. Using these novel tools, we have found that there are significant changes with
aging in the patterns of hippocampal mC and hmC, that these changes are principally sex-specific, and they
correspond to altered gene expression. Intriguingly, we have also identified non-CpG methylation as the
primary form of altered methylation with aging and a male-specific increased inter-animal variance (methylation
entropy) across the genome with aging in the hippocampus. These findings raise significant questions that
must be addressed to move the field to mechanistic studies. Is the neuroepigenome altered in a similar or
dissimilar manner across CNS cell types and between sexes? Can age-related changes in the
neuroepigenome be prevented? What regions of the genome should be targeted by epigenome editing
approaches to test whether brain aging can be prevented or reversed by maintaining or restoring a ‘youthful’
DNA modification pattern? In Aim 1, cell type-specific changes in mC/hmC with aging in the CNS of male and
female mice will be examined by whole genome sequencing (WGoxBS). Microglia, astrocytes, and neurons
isolated from the hippocampus by both cell surface markers and NuTRAP technology will be examined. Young
(3M), Adult (12M), and Aged (24M) C57Bl6 male and female mice will be examined and mC/hmC data will be
concatenated with paired RNA-Seq data. Bioinformatic approaches will then be used to determine the role of
altered modification patterns in age-related changes in gene expression, enrichment of differential
modifications in regulatory regions of t...

## Key facts

- **NIH application ID:** 9898315
- **Project number:** 5I01BX003906-03
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** WILLARD M FREEMAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898315

## Citation

> US National Institutes of Health, RePORTER application 9898315, Dynamics of the brain epigenome with aging (5I01BX003906-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898315. Licensed CC0.

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