DNA methylation-based estimator of telomere length.
Ake T. Lu,Anne Seeboth,Pei-Chien Tsai,Pei-Chien Tsai,Pei-Chien Tsai,Dianjianyi Sun,Dianjianyi Sun,Austin Quach,Alexander P. Reiner,Charles Kooperberg,Luigi Ferrucci,Lifang Hou,Andrea A. Baccarelli,Yun Li,Sarah E. Harris,Janie Corley,Adele M. Taylor,Ian J. Deary,James D. Stewart,Eric A. Whitsel,Themistocles L. Assimes,Themistocles L. Assimes,Wei Chen,Shengxu Li,Massimo Mangino,Jordana T. Bell,James G. Wilson,Abraham Aviv,Riccardo E. Marioni,Ken Raj,Steve Horvath +30 more
- 18 Aug 2019
- Vol. 11, Iss: 16, pp 5895-5923
TL;DR: Leukocyte 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 and is more strongly associated with age than measured leukocyte TL (LTL).
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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.
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Citations
DNA methylation aging clocks: challenges and recommendations
Christopher G. Bell,Robert Lowe,Peter D. Adams,Peter D. Adams,Andrea A. Baccarelli,Stephan Beck,Jordana T. Bell,Brock C. Christensen,Vadim N. Gladyshev,Bastiaan T. Heijmans,Steve Horvath,Trey Ideker,Jean Pierre J. Issa,Karl T. Kelsey,Riccardo E. Marioni,Wolf Reik,Wolf Reik,Caroline L Relton,Leonard C. Schalkwyk,Andrew E. Teschendorff,Andrew E. Teschendorff,Wolfgang Wagner,Kang Zhang,Vardhman K. Rakyan +23 more
TL;DR: Key challenges to understand clock mechanisms and biomarker utility are discussed, including dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models.
Identification of seven loci affecting mean telomere length and their association with disease
Veryan Codd,Christopher P. Nelson,Eva Albrecht,Massimo Mangino,Joris Deelen,Jessica L. Buxton,Jouke-Jan Hottenga,Krista Fischer,Tõnu Esko,Ida Surakka,Linda Broer,Dale R. Nyholt,Irene Mateo Leach,Perttu Salo,Sara Hägg,Mary K. Matthews,Jutta Palmen,Giuseppe Danilo Norata,Paul F. O'Reilly,Danish Saleheen,Najaf Amin,Anthony J. Balmforth,Marian Beekman,Rudolf A. de Boer,Stefan Böhringer,Peter S. Braund,Paul Burton,Anton J. M. de Craen,Matthew Denniff,Yanbin Dong,Konstantinos Douroudis,Elena Dubinina,Johan G. Eriksson,Katia Garlaschelli,Dehuang Guo,Anna-Liisa Hartikainen,Anjali K. Henders,Jeanine J. Houwing-Duistermaat,Laura Kananen,Lennart C. Karssen,Johannes Kettunen,Norman Klopp,Vasiliki Lagou,Elisabeth M. van Leeuwen,Pamela A. F. Madden,Reedik Maegi,Patrik K. E. Magnusson,Satu Männistö,Mark I. McCarthy,Sarah E. Medland,Evelin Mihailov,Grant W. Montgomery,Ben A. Oostra,Aarno Palotie,Annette Peters,Helen Pollard,Anneli Pouta,Inga Prokopenko,Samuli Ripatti,Veikko Salomaa,H. Eka D. Suchiman,Ana M. Valdes,Niek Verweij,Ana Viñuela,Xiaoling Wang,H-Erich Wichmann,Elisabeth Widen,Gonneke Willemsen,Margaret J. Wright,Kai Xia,Xiangjun Xiao,Dirk J. van Veldhuisen,Alberico L. Catapano,Martin D. Tobin,Alistair S. Hall,Alexandra I. F. Blakemore,Wiek H. van Gilst,Haidong Zhu,Jeanette Erdmann,Muredach P. Reilly,Sekar Kathiresan,Heribert Schunkert,Philippa J. Talmud,Nancy L. Pedersen,Markus Perola,Willem H. Ouwehand,Jaakko Kaprio,Nicholas G. Martin,Cornelia M. van Duijn,Iris Hovatta,Christian Gieger,Andres Metspalu,Dorret I. Boomsma,Marjo-Riitta Järvelin,P. Eline Slagboom,John R Thompson,Tim D. Spector,Pim van der Harst,Nilesh J. Samani +98 more
- 01 Jan 2013
TL;DR: In this article, a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals was carried out to identify seven loci, including five new loci associated with mean leukocyte telomere length (LTL).
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Measuring biological age using omics data
TL;DR: A new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution and can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.
290
Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives.
TL;DR: A review article as discussed by the authors describes the current state of the art in the field and discusses recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.
A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking
Albert T. Higgins-Chen,Jihao Liu +1 more
TL;DR: In this paper , the authors present a computational solution to bolster reliability, calculating principal components (PCs) from CpG-level data as input for biological age prediction, and retrained PC versions of six prominent epigenetic clocks show agreement between most replicates within 1.5 years.
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