@article{ad223827e8b946e6866061a6a8f6c468,
title = "DNA methylation-based estimator of telomere length",
abstract = "Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.",
keywords = "Aging, DNA methylation, Molecular biomarker, Telomere length",
author = "Lu, {Ake T.} and Anne Seeboth and Tsai, {Pei Chien} and Dianjianyi Sun and Austin Quach and Reiner, {Alex P.} and Charles Kooperberg and Luigi Ferrucci and Lifang Hou and Baccarelli, {Andrea A.} and Yun Li and Harris, {Sarah E.} and Janie Corley and Adele Taylor and Deary, {Ian J.} and Stewart, {James D.} and Whitsel, {Eric A.} and Assimes, {Themistocles L.} and Wei Chen and Shengxu Li and Massimo Mangino and Bell, {Jordana T.} and Wilson, {James G.} and Abraham Aviv and Marioni, {Riccardo E.} and Kenneth Raj and Steve Horvath",
note = "Funding Information: This study was mainly supported by 1U01AG060908-01 (Horvath, Lu). E.A. Whitsel, A. Baccarelli, and L. Hou were supported by NIH/NIEHS R01-ES020836. Dr. Wilson was supported by U54GM115428 from the National Institute of General Medical Sciences. The views expressed in this manuscript 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. The Women's Health Initiative 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. The authors 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: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. The Jackson Heart Study (JHS) is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. The Framingham Heart Study is funded by National Institutes of Health contract 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, Bethesda, MD. KR was funded by the National Institute for Health Research through the Health Protection Research Unit, Health Impact of Environmental Hazards in a partnership between King's College London with Public Health England. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or Public Health England. The LBC1921 is supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC), a Royal Society-Wolfson Research Merit Award to IJD, and the Chief Scientist Office (CSO) of the Scottish Government's Health Directorates. The LBC1936 is supported by Age UK (Disconnected Mind program) and the Medical Research Council (MR/M01311/1). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institu-tional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. The authors thank all LBC study participants and research team members who have contributed, and continue to contribute, to ongoing LBC studies. REM is supported by Alzheimer's Research UK (Grant ARUK-PG2017B-10). AS is supported by a Medical Research Council PhD Studentship in Precision Medicine with funding by the Medical Research Council Doctoral Training Programme and the University of Edinburgh College of Medicine and Veterinary Medicine. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013); National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. SNP genotyping was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/CIDR. The methylation study received support from ESRC UK (ES/N000404/1 to J.T.B).",
year = "2019",
doi = "10.18632/aging.102173",
language = "English (US)",
volume = "11",
pages = "5895--5923",
journal = "Aging",
issn = "1945-4589",
publisher = "US Administration on Aging",
number = "16",
}