Meta-analysis of DNA methylation aging signatures in 17 human tissues

Authors/Creators

• Macsue Jacques
• Kirsten Seale
• Sarah Voisin
• Anna Lysenko
• Robin Grolaux
• Bernadette Jones-Freeman
• Severine Lamon
• Mandhri Abeysooriya
• Itamar Levinger
• Carlie Bauer
• Adam P. Sharples
• Aino Heikkinen
• Elina Sillanpaa
• Miina Ollikainen
• Cassandra Smith, Edith Cowan UniversityFollow
• James R. Broatch
• Navabeh Zarekookandeh
• Linn Gillberg
• Ida Blom
• Jesse R. Poganik
• Mahdi Moqri
• Vadim N. Gladyshev
• Matthew Taper
• Cassandra Malecki
• Sean Lal
• Nathalie Saurat
• Steve Horvath
• Andrew Teschendorff
• Nir Eynon

Author Identifier (ORCID)

Cassandra Smith’s ORCID record

Abstract

Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular disorder across tissues. Network analysis revealed tightly connected gene clusters that are not modified by beneficial interventions, alongside a more modifiable cluster linked to NAD⁺ metabolism, supporting NAD⁺ as a potential therapeutic target in aging. A gene encoding a cell-adhesion protein, PCDHGA1, emerged as a conserved hub across tissues, implicating cell-to-cell communication pathways in aging across multiple organs. Our methylation atlas therefore provides a resource for dissecting the molecular basis of human aging and for identifying potential biomarkers and translational therapies.

Keywords

aging, DNA methylation, epigenetics, biomarkers, NAD metabolism, tissue-specific signatures

Document Type

Journal Article

Date of Publication

1-1-2026

Publication Title

Nature Aging

Publisher

Nature

School

Nutrition and Health Innovation Research Institute / School of Medical and Health Sciences

Funding Information

R.G. was supported by a WBI World Excellence Fellowship (2025). S. Lamon was supported by an Australian Research Council Future Fellowship (award no. FT210100278). A.P.S. was supported by the Research Council of Norway (grant no. 314157). E.S. was supported by the Research Council of Finland. C.S. was supported by a Heart Foundation Postdoctoral Fellowship (award no. 107194) from the National Heart Foundation of Australia. J.R.B. was supported by the Medical Research Future Fund Preventive and Public Health Grant Scheme (award no. MRF1200852). V.N.G. was supported by National Institute on Aging and Hevolution grants. A.T. was supported by a National Natural Science Foundation of China grant (grant no. W2431024). N.E. was supported by a National Health and Medical Research Council Investigator Grant (grant no. APP1194159), an Australian Research Council Discovery Project grant (grant no. DP240102155) and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research.

Funding received from the Australian Research Council (ARC)

FT210100278, DP240102155

Funding received from the National Health and Medical Research Council (NHMRC)

APP1194159

Funding received from the Medical Research Future Fund (MRFF)

MRF1200852

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Jacques, M., Seale, K., Voisin, S., Lysenko, A., Grolaux, R., Jones-Freeman, B., Lamon, S., Abeysooriya, M., Levinger, I., Bauer, C., Sharples, A. P., Heikkinen, A., Sillanpaa, E., Ollikainen, M., Smith, C., Broatch, J. R., Zarekookandeh, N., Gillberg, L., Blom, I., . . . Eynon, N. (2026). Meta-analysis of DNA methylation aging signatures in 17 human tissues. Nature Aging, 6, 1501–1515. https://doi.org/10.1038/s43587-026-01164-5