High Intrinsic Aerobic Capacity Is Associated With a Distinct Epigenetic and Signaling Profile in the Aged Rat Brain

Area of Science:

• Neuroscience
• Molecular Biology
• Aging Research

Background:

• Exercise is vital for brain health during aging.
• The molecular basis of intrinsic exercise capacity's effect on the aged brain is not fully understood.
• Studies often focus on training interventions rather than inherent capacity.

Purpose of the Study:

• To investigate the hippocampal DNA methylation patterns associated with intrinsic exercise capacity in aged rats.
• To explore the relationship between DNA methylation and cortical protein signaling in relation to aerobic fitness.
• To identify a distinct molecular phenotype linked to high intrinsic aerobic capacity in the aging brain.

Main Methods:

• Reduced representation bisulfite sequencing (RRBS) for hippocampal DNA methylation profiling.
• Analysis of differentially methylated regions (DMRs) and functional enrichment.
• Assessment of spatial learning (Morris water maze), aerobic capacity (VO2max), and cortical protein signaling (Western blotting).

Main Results:

• Identified 6452 significant DMRs, with 82.4% hypermethylated in high-capacity runners (HCR).
• Hypermethylated DMRs were enriched in intronic/exonic regions, linked to MAPK, PI3K-Akt, TNF, calcium, and synaptic signaling pathways.
• HCR rats exhibited altered cortical protein phosphorylation (ERK1/2, AKT, mTOR, S6) and increased signaling molecules (JNK2, p38, NF-κB, TNF-α).

Conclusions:

• Intrinsic aerobic capacity in aged rats is associated with a distinct hippocampal DNA methylation profile.
• This methylation pattern correlates with specific cortical protein signaling pathways, including MAPK, AKT-mTOR-S6, synaptic, and inflammation-related signaling.
• Findings suggest a unique molecular phenotype tied to intrinsic exercise capacity in the aged brain, independent of training.