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Organ Specificity and Commonality of Epigenetic Aging in Low- and High-Running Capacity Rats

Kawamura, Takuji ; Kerepesi, Csaba ; Sarkar, Juliet Polok ; Torma, Ferenc ; Bori, Zoltan ; Zhou, Lei ; Bakonyi, Peter ; Kolonics, Attila ; Balogh, Laszlo and Higuchi, Mitsuru , et al. (2025) In Aging Cell 24(8).
Abstract

Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we... (More)

Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ-specific differences in global mean DNA methylation and mean methylation entropy between LCR and HCR rats, and the direction of these differences was the opposite compared to the age-related changes in the rat blood. Notably, the soleus muscle exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. Our data suggest that CRF associates with epigenetic aging in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
epigenetic drift, global DNA methylation, intersection clock, maximal oxygen uptake, methylation entropy, rat epigenetic clock
in
Aging Cell
volume
24
issue
8
article number
e70110
publisher
Wiley-Blackwell
external identifiers
  • pmid:40485193
  • scopus:105007664663
ISSN
1474-9718
DOI
10.1111/acel.70110
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
id
f429a44b-3896-4188-829b-a845a5a791bb
date added to LUP
2025-12-02 13:04:14
date last changed
2025-12-16 14:45:55
@article{f429a44b-3896-4188-829b-a845a5a791bb,
  abstract     = {{<p>Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ-specific differences in global mean DNA methylation and mean methylation entropy between LCR and HCR rats, and the direction of these differences was the opposite compared to the age-related changes in the rat blood. Notably, the soleus muscle exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. Our data suggest that CRF associates with epigenetic aging in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.</p>}},
  author       = {{Kawamura, Takuji and Kerepesi, Csaba and Sarkar, Juliet Polok and Torma, Ferenc and Bori, Zoltan and Zhou, Lei and Bakonyi, Peter and Kolonics, Attila and Balogh, Laszlo and Higuchi, Mitsuru and Pillár, Vivien and Pircs, Karolina and Koch, Lauren Gerard and Britton, Steven Loyal and Koltai, Erika and Radak, Zsolt}},
  issn         = {{1474-9718}},
  keywords     = {{epigenetic drift; global DNA methylation; intersection clock; maximal oxygen uptake; methylation entropy; rat epigenetic clock}},
  language     = {{eng}},
  number       = {{8}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Aging Cell}},
  title        = {{Organ Specificity and Commonality of Epigenetic Aging in Low- and High-Running Capacity Rats}},
  url          = {{http://dx.doi.org/10.1111/acel.70110}},
  doi          = {{10.1111/acel.70110}},
  volume       = {{24}},
  year         = {{2025}},
}