Sexually divergent DNA methylation patterns with hippocampal aging

Area of Science:

• Epigenetics
• Neuroscience
• Genomics

Background:

• DNA methylation regulates genome function and is linked to aging and mortality.
• Aging hippocampus exhibits sex-specific changes, affecting cognitive function and neurodegenerative disease vulnerability.
• The role of sex in age-related hippocampal epigenomic alterations remains largely unexplored.

Purpose of the Study:

• To investigate genome-wide DNA methylation changes in the aging mouse hippocampus, considering the factor of sex.
• To identify sex-specific age-related alterations in DNA methylation patterns within the hippocampus.
• To compare findings with human data to assess translational relevance.

Main Methods:

• High-depth, genome-wide bisulfite sequencing was performed on hippocampi from young (3-month) and old (24-month) male and female mice.
• Analysis focused on differential DNA methylation in both CG and non-CG (CH) contexts across the genome.
• Autosomal methylation patterns were analyzed for sex differences in both aging and lifelong contexts.

Main Results:

• Total genomic methylation levels did not change with age, but specific sites showed age-related increases or decreases.
• Age-related methylation changes were predominantly sexually divergent, affecting both CG and CH sites.
• Differential methylation was enriched in intergenic and intronic regions, while under-represented in promoters and CG islands.
• Lifelong sex differences in autosomal methylation were observed, consistent with findings in human data.

Conclusions:

• Sex is a critical, previously unrecognized factor in hippocampal epigenomic changes during aging.
• Aging-induced DNA methylation alterations in the hippocampus are intricate and influenced by sex, cytosine context, genomic location, and methylation level.
• These findings highlight the importance of considering sex in studies of brain aging and neurodegeneration.