DNA Methylation Ageing Atlas Across 17 Human Tissues

Jacques, M.; Seale, K.; Voisin, S.; Lysenko, A.; Grolaux, R.; Jones-Freeman, B.; Lamon, S.; Levinger, I.; Bauer, C.; Sharples, A. P.; Heikkinen, A.; Sillanpaa, E.; Ollikainen, M.; Smith, C.; Broatch, J. R.; Zarekookandeh, N.; Gillberg, L.; Blom, I.; Poganik, J. R.; Moqri, M.; Gladyshev, V.; Taper, M.; Malecki, C.; Lal, S.; Saurat, N.; Horvath, S.; Teschendorff, A.; EYNON, N.

doi:10.1101/2025.07.21.665830

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bioRxiv · 10.1101/2025.07.21.665830

DNA Methylation Ageing Atlas Across 17 Human Tissues

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Abstract

Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD{square} salvage metabolism supports therapeutic targeting of NAD{square} in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies.

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Jacques, M., Seale, K., Voisin, S., Lysenko, A., Grolaux, R., Jones-Freeman, B., Lamon, S., Levinger, I., Bauer, C., Sharples, A. P., Heikkinen, A., Sillanpaa, E., Ollikainen, M., Smith, C., Broatch, J. R., Zarekookandeh, N., Gillberg, L., Blom, I., Poganik, J. R., Moqri, M., Gladyshev, V., Taper, M., Malecki, C., Lal, S., Saurat, N., Horvath, S., Teschendorff, A., EYNON, N.. 2025-07-24. DNA Methylation Ageing Atlas Across 17 Human Tissues. https://doi.org/10.1101/2025.07.21.665830

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