Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Steve Horvath; Junko Oshima; George M. Martin; Ake T. Lu; Austin Quach; Howard Cohen; Sarah Felton; Mieko Matsuyama; Donna Lowe; Sylwia Kabacik; James G. Wilson; Alex P. Reiner; Anna Maierhofer; Julia Flunkert; Abraham Aviv; Lifang Hou; Andrea A. Baccarelli; Yun Li; James D. Stewart; Eric A. Whitsel; Luigi Ferrucci; Shigemi Matsuyama; Kenneth Raj

doi:10.18632/aging.101508

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Steve Horvath^*, Junko Oshima, George M. Martin, Ake T. Lu, Austin Quach, Howard Cohen, Sarah Felton, Mieko Matsuyama, Donna Lowe, Sylwia Kabacik, James G. Wilson, Alex P. Reiner, Anna Maierhofer, Julia Flunkert, Abraham Aviv, Lifang Hou, Andrea A. Baccarelli, Yun Li, James D. Stewart, Eric A. WhitselLuigi Ferrucci, Shigemi Matsuyama, Kenneth Raj

^*Corresponding author for this work

HP: Radiation Effects

Research output: Contribution to journal › Article › peer-review

215 Citations (Scopus)

Abstract

DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

Original language	English
Pages (from-to)	1758-1775
Number of pages	18
Journal	Aging
Volume	10
Issue number	7
DOIs	https://doi.org/10.18632/aging.101508
Publication status	Published - 1 Jul 2018

Bibliographical note

Funding Information:
We would like to acknowledge The Progeria Research Foundation Cell (Dr Leslie Gordon) and Tissue Bank for access to DNA samples and cell lines. 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: www.whi.org/researchers/Documents%20%20Write%20 a%20Paper/WHI%20Investigator%20Long%20List.pdf. We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The 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. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. This study was supported by NIH/NIA U34AG051425-01 (Horvath), NIH/NCI R01CA210916 (Martin/Oshima), and NIH/NIEHS R01-ES020836 (Whitsel; Baccarelli; Hou). The funding bodies played no role in the design, the collection, analysis, or interpretation of the data. The experimental research was funded by the National Institute for Health Research (NIHR) through Health Protection Research Unit (Health Impact of Environ mental Hazards with King's College London) in partnership with Public Health England (PHE). The views expressed are those of the authors and not necessarily those of the funding agencies or PHE

Publisher Copyright:
© Horvath et al.

Keywords

DNA methylation
Epigenetics
Fibroblasts
Hutchinson-Gilford
Progeria

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10.18632/aging.101508

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Horvath, S., Oshima, J., Martin, G. M., Lu, A. T., Quach, A., Cohen, H., Felton, S., Matsuyama, M., Lowe, D., Kabacik, S., Wilson, J. G., Reiner, A. P., Maierhofer, A., Flunkert, J., Aviv, A., Hou, L., Baccarelli, A. A., Li, Y., Stewart, J. D., ... Raj, K. (2018). Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging, 10(7), 1758-1775. https://doi.org/10.18632/aging.101508

@article{986a8251c6e3471b97df6cdbb90b694e,

title = "Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies",

abstract = "DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.",

keywords = "DNA methylation, Epigenetics, Fibroblasts, Hutchinson-Gilford, Progeria",

author = "Steve Horvath and Junko Oshima and Martin, {George M.} and Lu, {Ake T.} and Austin Quach and Howard Cohen and Sarah Felton and Mieko Matsuyama and Donna Lowe and Sylwia Kabacik and Wilson, {James G.} and Reiner, {Alex P.} and Anna Maierhofer and Julia Flunkert and Abraham Aviv and Lifang Hou and Baccarelli, {Andrea A.} and Yun Li and Stewart, {James D.} and Whitsel, {Eric A.} and Luigi Ferrucci and Shigemi Matsuyama and Kenneth Raj",

note = "Funding Information: We would like to acknowledge The Progeria Research Foundation Cell (Dr Leslie Gordon) and Tissue Bank for access to DNA samples and cell lines. 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: www.whi.org/researchers/Documents%20%20Write%20 a%20Paper/WHI%20Investigator%20Long%20List.pdf. We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The 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. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. This study was supported by NIH/NIA U34AG051425-01 (Horvath), NIH/NCI R01CA210916 (Martin/Oshima), and NIH/NIEHS R01-ES020836 (Whitsel; Baccarelli; Hou). The funding bodies played no role in the design, the collection, analysis, or interpretation of the data. The experimental research was funded by the National Institute for Health Research (NIHR) through Health Protection Research Unit (Health Impact of Environ mental Hazards with King's College London) in partnership with Public Health England (PHE). The views expressed are those of the authors and not necessarily those of the funding agencies or PHE Publisher Copyright: {\textcopyright} Horvath et al.",

year = "2018",

month = jul,

day = "1",

doi = "10.18632/aging.101508",

language = "English",

volume = "10",

pages = "1758--1775",

journal = "Aging",

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Horvath, S, Oshima, J, Martin, GM, Lu, AT, Quach, A, Cohen, H, Felton, S, Matsuyama, M, Lowe, D, Kabacik, S, Wilson, JG, Reiner, AP, Maierhofer, A, Flunkert, J, Aviv, A, Hou, L, Baccarelli, AA, Li, Y, Stewart, JD, Whitsel, EA, Ferrucci, L, Matsuyama, S & Raj, K 2018, 'Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies', Aging, vol. 10, no. 7, pp. 1758-1775. https://doi.org/10.18632/aging.101508

TY - JOUR

T1 - Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

AU - Horvath, Steve

AU - Oshima, Junko

AU - Martin, George M.

AU - Lu, Ake T.

AU - Quach, Austin

AU - Cohen, Howard

AU - Felton, Sarah

AU - Matsuyama, Mieko

AU - Lowe, Donna

AU - Kabacik, Sylwia

AU - Wilson, James G.

AU - Reiner, Alex P.

AU - Maierhofer, Anna

AU - Flunkert, Julia

AU - Aviv, Abraham

AU - Hou, Lifang

AU - Baccarelli, Andrea A.

AU - Li, Yun

AU - Stewart, James D.

AU - Whitsel, Eric A.

AU - Ferrucci, Luigi

AU - Matsuyama, Shigemi

AU - Raj, Kenneth

N1 - Funding Information: We would like to acknowledge The Progeria Research Foundation Cell (Dr Leslie Gordon) and Tissue Bank for access to DNA samples and cell lines. 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: www.whi.org/researchers/Documents%20%20Write%20 a%20Paper/WHI%20Investigator%20Long%20List.pdf. We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The 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. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. This study was supported by NIH/NIA U34AG051425-01 (Horvath), NIH/NCI R01CA210916 (Martin/Oshima), and NIH/NIEHS R01-ES020836 (Whitsel; Baccarelli; Hou). The funding bodies played no role in the design, the collection, analysis, or interpretation of the data. The experimental research was funded by the National Institute for Health Research (NIHR) through Health Protection Research Unit (Health Impact of Environ mental Hazards with King's College London) in partnership with Public Health England (PHE). The views expressed are those of the authors and not necessarily those of the funding agencies or PHE Publisher Copyright: © Horvath et al.

PY - 2018/7/1

Y1 - 2018/7/1

N2 - DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

AB - DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

KW - DNA methylation

KW - Epigenetics

KW - Fibroblasts

KW - Hutchinson-Gilford

KW - Progeria

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DO - 10.18632/aging.101508

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AN - SCOPUS:85050992380

SN - 1945-4589

VL - 10

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EP - 1775

JO - Aging

JF - Aging

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ER -

Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies

Abstract

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Keywords

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