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

Overview

1. Research Institute of Molecular Exercise Science, Hungarian University of Sports Science, Budapest, Hungary
2. Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan
3. Department of Physiology, Gdansk University of Physical Education and Sport, Gdansk, Poland
4. Faculty of Sport Science, Ningbo University, Ningbo, China
5. Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
6. Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE328395, at NCBI GEO; found in “Data Availability Statement”

Data Availability Statement

Raw and processed methylation data are publicly available in the Gene Expression Omnibus (GEO) under accession number GSE328395 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328395).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 7 keywords, 10 MeSH terms, 1 funder, 35 references.

Cite

This paper

Zhou, L., Mozaffaritabar, S., Koltai, E., Kawamura, T., Higuchi, M., Kujach, S., Gu, Y., Koch, L. G., Britton, S. L., & Radák, Z. (2026). High Intrinsic Aerobic Capacity Is Associated With a Distinct Epigenetic and Signaling Profile in the Aged Rat Brain. Aging cell, 25(7), e70622. https://doi.org/10.1111/acel.70622

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