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GWAS of epigenetic aging rates in blood reveals a critical role for TERT.
Lu, Ake T; Xue, Luting; Salfati, Elias L; Chen, Brian H; Ferrucci, Luigi; Levy, Daniel; Joehanes, Roby; Murabito, Joanne M; Kiel, Douglas P; Tsai, Pei-Chien; Yet, Idil; Bell, Jordana T; Mangino, Massimo; Tanaka, Toshiko; McRae, Allan F; Marioni, Riccardo E; Visscher, Peter M; Wray, Naomi R; Deary, Ian J; Levine, Morgan E; Quach, Austin; Assimes, Themistocles; Tsao, Philip S; Absher, Devin; Stewart, James D; Li, Yun; Reiner, Alex P; Hou, Lifang; Baccarelli, Andrea A; Whitsel, Eric A; Aviv, Abraham; Cardona, Alexia; Day, Felix R; Wareham, Nicholas J; Perry, John R B; Ong, Ken K; Raj, Kenneth; Lunetta, Kathryn L; Horvath, Steve.
Afiliação
  • Lu AT; Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Xue L; Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
  • Salfati EL; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Chen BH; Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
  • Ferrucci L; National Heart, Lung and Blood Institute, Bethesda, MD, 20824-0105, USA.
  • Levy D; Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
  • Joehanes R; National Heart, Lung and Blood Institute, Bethesda, MD, 20824-0105, USA.
  • Murabito JM; National Heart, Lung and Blood Institute, Bethesda, MD, 20824-0105, USA.
  • Kiel DP; Department of Medicine, Section of General Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
  • Tsai PC; Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, 02215, USA.
  • Yet I; Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
  • Bell JT; Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
  • Mangino M; Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
  • Tanaka T; Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
  • McRae AF; Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
  • Marioni RE; Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Visscher PM; Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Wray NR; Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Deary IJ; Centre for Cognitive Aging and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
  • Levine ME; Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
  • Quach A; Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Assimes T; Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Tsao PS; Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Absher D; Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia.
  • Stewart JD; Centre for Cognitive Aging and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
  • Li Y; Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Reiner AP; Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • Hou L; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Baccarelli AA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • Whitsel EA; VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
  • Aviv A; HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
  • Cardona A; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • Day FR; Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • Wareham NJ; Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • Perry JRB; Fred Hutchinson Cancer Research Center Box 358080, WHI Clinical Coordinating Ctr/Public Health Sciences M3-A4, Seattle, WA, 98109, USA.
  • Ong KK; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, 60611, USA.
  • Raj K; Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, 60611, USA.
  • Lunetta KL; Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences Epidemiology, Columbia University Mailman School of Public Health, New York, NY, 10032, USA.
  • Horvath S; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
Nat Commun ; 9(1): 387, 2018 01 26.
Article em En | MEDLINE | ID: mdl-29374233
ABSTRACT
DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Envelhecimento / Telomerase / Metilação de DNA / Epigênese Genética Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adolescent / Adult / Aged / Aged80 / Child / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Envelhecimento / Telomerase / Metilação de DNA / Epigênese Genética Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adolescent / Adult / Aged / Aged80 / Child / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos