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

被引：488

作者：

Horvath, Steve ^{[1
,2
]}

Oshima, Junko ^{[3
,4
]}

Martin, George M. ^{[3
]}

Lu, Ake T. ^{[1
]}

Quach, Austin ^{[1
]}

Cohen, Howard ^{[5
]}

Felton, Sarah ^{[6
]}

Matsuyama, Mieko ^{[7
]}

Lowe, Donna ^{[8
]}

Kabacik, Sylwia ^{[8
]}

Wilson, James G. ^{[9
]}

Reiner, Alex P. ^{[10
]}

Maierhofer, Anna ^{[11
]}

Flunkert, Julia ^{[11
]}

Aviv, Abraham ^{[12
]}

Hou, Lifang ^{[13
,14
]}

Baccarelli, Andrea A. ^{[15
,16
]}

Li, Yun ^{[17
,18
,19
]}

Stewart, James D. ^{[20
]}

Whitsel, Eric A. ^{[20
,21
]}

Ferrucci, Luigi ^{[22
]}

Matsuyama, Shigemi ^{[7
,23
]}

Raj, Kenneth ^{[8
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Fielding Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA

[3] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[4] Chiba Univ, Grad Sch Med, Dept Clin Cell Biol & Med, Chiba, Japan

[5] Elizabeth House, Warlingham CR6 9LF, Surrey, England

[6] Oxford Univ Hosp NHS Fdn Trust, Dept Dermatol, Oxford OX3 7LJ, England

[7] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA

[8] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Radiat Effects Dept, Didcot OX11 0RQ, Oxon, England

[9] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA

[10] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA

[11] Julius Maximilians Univ, Inst Human Genet, Wurzburg, Germany

[12] Rutgers State Univ, New Jersey Med Sch, Ctr Dev & Aging, Newark, NJ 07103 USA

[13] Northwestern Univ, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Ctr Populat Epigenet, Chicago, IL 60611 USA

[14] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA

[15] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Lab Environm Epigenet, New York, NY 10032 USA

[16] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, Lab Environm Epigenet, New York, NY 10032 USA

[17] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[18] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA

[19] Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA

[20] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA

[21] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27516 USA

[22] NIA, Longitudinal Studies Sect, Translat Gerontol Branch, NIH, Baltimore, MD 21224 USA

[23] Case Western Reserve Univ, Case Comprehens Ctr, Dept Pathol & Pharmacol, Cleveland, OH 44106 USA

来源：

AGING-US | 2018年 / 10卷 / 07期

关键词：

epigenetics; fibroblasts; DNA methylation; progeria; Hutchinson-Gilford; DNA METHYLATION AGE; FARNESYLATION INHIBITORS; MUTATIONS; REGULARIZATION; EXPRESSION; CHILDREN; PRELAMIN; DISEASE; CANCER; ONSET;

D O I：

10.18632/aging.101508

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1758 / 1775

页数：18

共 46 条

[1] Early Onset Mandibuloacral Dysplasia Due to Compound Heterozygous Mutations in ZMPSTE24 [J].

Ahmad, Zahid ;

Zackai, Elaine ;

Medne, Livija ;

Garg, Abhimanyu .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2010, 152A (11) :2703-2710

[2]

Bai S, 2014, CASE REP GENET, V2014

[3] A novel somatic mutation achieves partial rescue in a child with Hutchinson-Gilford progeria syndrome [J].

Bar, Daniel Z. ;

Arlt, Martin F. ;

Brazier, Joan F. ;

Norris, Wendy E. ;

Campbell, Susan E. ;

Chines, Peter ;

Larrieu, Delphine ;

Jackson, Stephen P. ;

Collins, Francis S. ;

Glover, Thomas W. ;

Gordon, Leslie B. .

JOURNAL OF MEDICAL GENETICS, 2017, 54 (03) :212-216

[4] Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity [J].

Barrowman, Jemima ;

Wiley, Patricia A. ;

Hudon-Miller, Sarah E. ;

Hrycyna, Christine A. ;

Michaelis, Susan .

HUMAN MOLECULAR GENETICS, 2012, 21 (18) :4084-4093

[5] Truncated prelamin A expression in HGPS-like patients: a transcriptional study [J].

Barthelemy, Florian ;

Navarro, Claire ;

Fayek, Racha ;

Da Silva, Nathalie ;

Roll, Patrice ;

Sigaudy, Sabine ;

Oshima, Junko ;

Bonne, Gisele ;

Papadopoulou-Legbelou, Kyriaki ;

Evangeliou, Athanasios E. ;

Spilioti, Martha ;

Lemerrer, Martine ;

Wevers, Ron A. ;

Morava, Eva ;

Robaglia-Schlupp, Andree ;

Levy, Nicolas ;

Bartoli, Marc ;

De Sandre-Giovannoli, Annachiara .

EUROPEAN JOURNAL OF HUMAN GENETICS, 2015, 23 (08) :1051-1061

[6] Epigenetic Predictor of Age [J].

Bocklandt, Sven ;

Lin, Wen ;

Sehl, Mary E. ;

Sanchez, Francisco J. ;

Sinsheimer, Janet S. ;

Horvath, Steve ;

Vilain, Eric .

PLOS ONE, 2011, 6 (06)

[7] Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells [J].

Cao, Kan ;

Graziotto, John J. ;

Blair, Cecilia D. ;

Mazzulli, Joseph R. ;

Erdos, Michael R. ;

Krainc, Dimitri ;

Collins, Francis S. .

SCIENCE TRANSLATIONAL MEDICINE, 2011, 3 (89)

[8] Leukocyte telomere length, T cell composition and DNA methylation age [J].

Chen, Brian H. ;

Carty, Cara L. ;

Kimura, Masayuki ;

Kark, Jeremy D. ;

Chen, Wei ;

Li, Shengxu ;

Zhang, Tao ;

Kooperberg, Charles ;

Levy, Daniel ;

Assimes, Themistocles ;

Absher, Devin ;

Horvath, Steve ;

Reiner, Alexander P. ;

Aviv, Abraham .

AGING-US, 2017, 9 (09) :1983-1995

[9] DNA methylation-based measures of biological age: meta-analysis predicting time to death [J].

Chen, Brian H. ;

Marioni, Riccardo E. ;

Colicino, Elena ;

Peters, Marjolein J. ;

Ward-Caviness, Cavin K. ;

Tsai, Pei-Chien ;

Roetker, Nicholas S. ;

Just, Allan C. ;

Demerath, Ellen W. ;

Guan, Weihua ;

Bressler, Jan ;

Fornage, Myriam ;

Studenski, Stephanie ;

Vandiver, Amy R. ;

Moore, Ann Zenobia ;

Tanaka, Toshiko ;

Kiel, Douglas P. ;

Liang, Liming ;

Vokonas, Pantel ;

Schwartz, Joel ;

Lunetta, Kathryn L. ;

Murabito, Joanne M. ;

Bandinelli, Stefania ;

Hernandez, Dena G. ;

Melzer, David ;

Nalls, Michael ;

Pilling, Luke C. ;

Price, Timothy R. ;

Singleton, Andrew B. ;

Gieger, Christian ;

Holle, Rolf ;

Kretschmer, Anja ;

Kronenberg, Florian ;

Kunze, Sonja ;

Linseisen, Jakob ;

Meisinger, Christine ;

Rathmann, Wolfgang ;

Waldenberger, Melanie ;

Visscher, Peter M. ;

Shah, Sonia ;

Wray, Naomi R. ;

McRae, Allan F. ;

Franco, Oscar H. ;

Hofman, Albert ;

Uitterlinden, Andre G. ;

Absher, Devin ;

Assimes, Themistocles ;

Levine, Morgan E. ;

Lu, Ake T. ;

Tsao, Philip S. .

AGING-US, 2016, 8 (09) :1844-1865

[10] DNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies [J].

Dugue, Pierre-Antoine ;

Bassett, Julie K. ;

Joo, JiHoon E. ;

Jung, Chol-Hee ;

Wong, Ee Ming ;

Moreno-Betancur, Margarita ;

Schmidt, Daniel ;

Makalic, Enes ;

Li, Shuai ;

Severi, Gianluca ;

Hodge, Allison M. ;

Buchanan, Daniel D. ;

English, Dallas R. ;

Hopper, John L. ;

Southey, Melissa C. ;

Giles, Graham G. ;

Milne, Roger L. .

INTERNATIONAL JOURNAL OF CANCER, 2018, 142 (08) :1611-1619

← 1 2 3 4 5 →