@article{cb4a631219ed49a3b3682108e21f0804,
title = "Genomic instability in the naturally and prematurely aged myocardium",
abstract = "Genomic instability, the unresolved accumulation of DNA variants, is hypothesized as one of the contributors to the natural aging process. We assessed the frequency of unresolved DNA damage reaching the transcriptome of the murine myocardium during the course of natural aging and in hearts from four distinct mouse models of premature aging with established aging-related cardiac dysfunctions. RNA sequencing and variant calling based on total RNA sequencing was compared between hearts from naturally aging mice, mice with cardiomyocyte-specific deficiency of Ercc1, a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity, Tert-deficient mice with reduced telomere length, and a mouse model of human Hutchinson- Gilford progeria syndrome (HGPS). Our results demonstrate that no enrichment in variants is evident in the naturally aging murine hearts until 2 y of age from the HGPS mouse model or mice with reduced telomere lengths. In contrast, a dramatic accumulation of variants was evident in Ercc1 cardiomyocyte-specific knockout mice with deficient DNA repair machinery, in mice with reduced mitochondrial antioxidant capacity, and in the intestine, liver, and lung of naturally aging mice. Our data demonstrate that genomic instability does not evidently contribute to naturally aging of the mouse heart in contrast to other organs and support the contention that the endogenous DNA repair machinery is remarkably active to maintain genomic integrity in cardiac cells throughout life.",
keywords = "CANCER, DEATH, DNA repair\ , DNA-DAMAGE, EXPRESSION, FRAMEWORK, LONGEVITY, MICE, MUTATION, NUCLEAR ABNORMALITIES, RNA-seq, TELOMERE LENGTH, aging\ , genomic instability\ , oxidative stress\ ",
author = "\{De Majo\}, F. and L. Martens and J.C. Hegenbarth and F. Ruhle and M.R. Hamczyk and R.M. Nevado and V. Andres and E. Hilbold and C. Bar and T. Thum and \{de Boer\}, M. and D.J. Duncker and B. Schroen and A.S. Armand and M. Stoll and \{De Windt\}, L.J.",
note = "Funding Information: F.D.M. is supported by HS-BAFTA and Kootstra fellowships of Maastricht University and a CVON-ARENA-PRIME fellowship. L.M. is supported by the fund Innovative Medical Research of the University of M{\"u}nster Medical School (R{\"U}121510). M.R.H. is supported by a Juan de la Cierva contract from the Spanish Ministerio de Ciencia, Innovaci{\'o}n y Universidades (IJC2019-040798-I). R.M.N. is the beneficiary of a predoctoral contract from the Spanish Ministerio de Educaci{\'o}n, Cultura y Deporte (FPU16/ 05027). V.A. is supported by the Spanish Ministerio de Ciencia e Innovaci{\'o}n (PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (AC16/ 00091) as member of the ERA-CVD JCT2016 EXPERT Network (European Union{\textquoteright}s Horizon 2020 Framework Programme), with cofunding from the European Regional Development Fund (“Una manera de hacer Europa”). The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Ministry for Research, Science and Innovation (MICIN), the ISCIII, the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence. C.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) (BA5631/ 2-1). T.T. was supported by the European Research Council (ERC) Consolidator Grant LONGHEART, by ERA-CVD JCT2016 EXPERT, and the DFG (TH903/ 22-1). D.J.D., M.S., and L.J.D.W. acknowledge support from the Dutch CardioVascular Initiative: the Netherlands Heart Foundation, Dutch Federation of University Medical Centers, ZonMW, and the Royal Netherlands Academy of Sciences (CVON-ARENA-PRIME, CVON-RACE-V, CVON-PREDICT-2). B.S. acknowledges funding by the Netherlands Heart Foundation (Dr. Dekker 2014T105 and CVON-SHE-PREDICTS-HF) and a VIDI Award 917.14.363 from the Dutch Research Council (NWO). A.S.A. was funded by Association Fran{\c c}aise contres les Myopathies (AFM 18802). F.D.M., T.T., and L.J.D.W. are supported by ERA-CVD JCT2016 EXPERT. M.S. is funded by the DFG (RTG2220, Project 281125614) and Marie Sk{\l}odowska-Curie Grant Agreement 81371. L.J.D.W. was further supported by ERC Consolidator Grant 311549 CALMIRS, a VICI Award 918-156-47 from NWO and Marie Sk{\l}odowska-Curie Grant Agreements 813716 and 765274. Funding Information: ACKNOWLEDGMENTS. F.D.M. is supported by HS-BAFTA and Kootstra fellowships of Maastricht University and a CVON-ARENA-PRIME fellowship. L.M. is supported by the fund Innovative Medical Research of the University of M{\"u}nster Medical School (R{\"U}121510). M.R.H. is supported by a Juan de la Cierva contract from the Spanish Ministerio de Ciencia, Innovaci{\'o}n y Univer-sidades (IJC2019-040798-I). R.M.N. is the beneficiary of a predoctoral contract from the Spanish Ministerio de Educaci{\'o}n, Cultura y Deporte (FPU16/ 05027). V.A. is supported by the Spanish Ministerio de Ciencia e Innovaci{\'o}n (PID2019-108489RB-I00) and the Instituto de Salud Carlos III (ISCIII) (AC16/ 00091) as member of the ERA-CVD JCT2016 EXPERT Network (European Union{\textquoteright}s Horizon 2020 Framework Programme), with cofunding from the European Regional Development Fund (“Una manera de hacer Europa”). The Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) is supported by the Ministry for Research, Science and Innovation (MICIN), the ISCIII, the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence. C.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) (BA5631/ 2-1). T.T. was supported by the European Research Council (ERC) Consolidator Grant LONGHEART, by ERA-CVD JCT2016 EXPERT, and the DFG (TH903/ 22-1). D.J.D., M.S., and L.J.D.W. acknowledge support from the Dutch CardioVascular Initiative: the Netherlands Heart Foundation, Dutch Federation of University Medical Centers, ZonMW, and the Royal Netherlands Academy of Sciences (CVON-ARENA-PRIME, CVON-RACE-V, CVON-PREDICT-2). B.S. acknowledges funding by the Netherlands Heart Foundation (Dr. Dekker 2014T105 and CVON-SHE-PREDICTS-HF) and a VIDI Award 917.14.363 from the Dutch Research Council (NWO). A.S.A. was funded by Association Fran{\c c}aise contres les Myopathies (AFM 18802). F.D.M., T.T., and L.J.D.W. are supported by ERA-CVD JCT2016 EXPERT. M.S. is funded by the DFG (RTG2220, Project 281125614) and Marie Sk{\l}odowska-Curie Grant Agreement 81371. L.J.D.W. was further supported by ERC Consolidator Grant 311549 CALMIRS, a VICI Award 918-156-47 from NWO and Marie Sk{\l}odowska-Curie Grant Agreements 813716 and 765274. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = sep,
day = "7",
doi = "10.1073/pnas.2022974118",
language = "English",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "36",
}