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

Abstract

Exercise is a powerful non-pharmacological strategy for preserving brain health during aging. However, whether intrinsic exercise capacity is associated with a distinct molecular phenotype in the aged brain, independent of training intervention, remains unclear. Aged selectively bred low-capacity runner (LCR) and high-capacity runner (HCR) rats were studied. Hippocampal DNA methylation was profiled by reduced representation bisulfite sequencing (RRBS), and differentially methylated regions (DMRs) were annotated and functionally enriched. Spatial learning, aerobic capacity, and cortical protein signaling were assessed by Morris water maze, VO₂max testing, and Western blotting. RRBS identified 6452 significant DMRs, most of which were hypermethylated in HCR rats (82.4%) and enriched in open-sea and gene-body regions. Genes linked to hypermethylated DMRs showed context-dependent enrichment, particularly in intronic and exonic regions, highlighting MAPK, PI3K-Akt, TNF, calcium, and synaptic signaling pathways. Core methylation-related enzymes TET1/2 and DNMT3A/B were unchanged. Cortical protein profiling showed higher phosphorylation of ERK1/2, AKT, mTOR, S6, and synapsin in HCR rats, together with higher JNK2, p38, NF-κB, TNF-α, and OGG1 abundance, whereas protein carbonylation and selected exercise-responsive neurotrophic and metabolic/mitochondrial markers were unchanged. Exploratory correlation analysis identified a subset of DMRs associated with individual VO₂max values. Morris water maze performance did not differ significantly between groups. High intrinsic exercise capacity in aged rats is associated with distinct hippocampal DNA methylation patterns that align with cortical protein profiles involving MAPK, AKT-mTOR-S6, synaptic, and inflammation-related signaling. These findings suggest a distinct molecular phenotype linked to intrinsic aerobic capacity in the aged brain.