Abstract
Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.
| Original language | English |
|---|---|
| Pages (from-to) | 1144-1166 |
| Number of pages | 23 |
| Journal | Nature Aging |
| Volume | 3 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2023 |
Bibliographical note
Publisher Copyright:© 2023, The Author(s).
Funding
This work was mainly supported by the Paul G. Allen Frontiers Group (S.H.). Additional support was also provided by the Open Philanthropy–Silicon Valley Fund (S.H. and K.R.). J.E. was supported by UCLA Jonsson Comprehensive Cancer Center and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Ablon Scholars Program. J.A.M. and the NHP Core were supported by the Intramural Research Program, National Institute on Aging, NIH. Plains zebra sample collection was supported by National Geographic Society grant 8941-11. We acknowledge the Museum of Vertebrate Zoology and C.J. Conroy from the University of California, Berkeley. We acknowledge R. Miller and his laboratory ( http://www.richmillerlab.com/long-lived-mutants ) for providing dwarf mice and controls (Snell dwarf mouse, GHRKO experiments). Lemur sample collections were supported by Duke Lemur Center. N.C.B. was funded by a DST-NRF SARChI chair of Mammalian Behavioural Ecology and Physiology (GUN 64756). V.N.G., A.S. and V.G. were supported by NIA grants. V.G. was supported by the Milky Way Research Foundation. D.T.O. was supported by European Research Council (788937) and Cancer Research UK (20412). The FHS is funded by National Institutes of Health contracts N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute and the Center for Information Technology, National Institutes of Health. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. We thank the WHI investigators and staff for their dedication and the study participants for making the program possible. A full listing of WHI investigators can be found at https://www.whi.org/doc/WHI-Investigator-Long-List.pdf . The views expressed in this study are those of the authors and do not necessarily represent the views of funding bodies such as the National Heart, Lung, and Blood Institute, the National Institutes of Health or the U.S. Department of Health and Human Services.
| Funders | Funder number |
|---|---|
| Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research Ablon Scholars Program | |
| University of California Berkeley | |
| Jonsson Comprehensive Cancer Center | |
| Milky Way Research Foundation | |
| Division of Intramural Research, National Institute of Allergy and Infectious Diseases | |
| National Heart, Lung, and Blood Institute (NHLBI) | |
| H2020 European Research Council | |
| Duke Lemur Center | |
| National Institute on Aging | |
| Center for Information Technology | |
| Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre | 20412 |
| National Geographic Society | 8941-11 |
| U.S. Department of Health and Human Services | HHSN268201600002C, HHSN268201600003C, HHSN268201600001C, HHSN268201600018C, HHSN268201600004C |
| Horizon 2020 Framework Programme | 788937 |
| DST-NRF SARChI chair of Mammalian Behavioural Ecology and Physiology | GUN 64756 |
| National Institutes of Health (NIH) | N01-HC-25195, HHSN268201500001I |
| Natural Environment Research Council | NE/X001423/1 |
ASJC Scopus subject areas
- Neuroscience (miscellaneous)
- Aging
- Geriatrics and Gerontology
