{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:22:19Z","timestamp":1791145339978,"version":"4.1.0"},"reference-count":58,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5571","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2002,5,17]]},"abstract":"<jats:p>\n                    One of the factors postulated to drive the aging process is the accumulation of DNA damage. Here, we provide strong support for this hypothesis by describing studies of mice with a mutation in\n                    <jats:italic>XPD<\/jats:italic>\n                    , a gene encoding a DNA helicase that functions in both repair and transcription and that is mutated in the human disorder trichothiodystrophy (TTD). TTD mice were found to exhibit many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early greying, cachexia, infertility, and reduced life-span. TTD mice carrying an additional mutation in\n                    <jats:italic>XPA<\/jats:italic>\n                    , which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. We hypothesize that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.\n                  <\/jats:p>","DOI":"10.1126\/science.1070174","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:54:32Z","timestamp":1027749272000},"page":"1276-1279","source":"Crossref","is-referenced-by-count":460,"title":["Premature Aging in Mice Deficient in DNA Repair and Transcription"],"prefix":"10.1126","volume":"296","author":[{"given":"Jan","family":"de Boer","sequence":"first","affiliation":[{"name":"Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaan Olle","family":"Andressoo","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"de Wit","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Huijmans","sequence":"additional","affiliation":[{"name":"MGC-Department of Clinical Genetics, CBG,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph B.","family":"Beems","sequence":"additional","affiliation":[{"name":"National Institute of Public Health and the Environment, Post Office Box 1, 3720 BA Bilthoven, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"van Steeg","sequence":"additional","affiliation":[{"name":"National Institute of Public Health and the Environment, Post Office Box 1, 3720 BA Bilthoven, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Weeda","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gijsbertus T. J.","family":"van der Horst","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wibeke","family":"van Leeuwen","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel P. N.","family":"Themmen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Reproduction, Post Office Box 1738, Erasmus University, 3000 DR Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morteza","family":"Meradji","sequence":"additional","affiliation":[{"name":"Department of Radiology, Sophia Kinderziekenhuis, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan H. J.","family":"Hoeijmakers","sequence":"additional","affiliation":[{"name":"Medical Genetics Center, Department of Cell Biology and Genetics, Center for Biomedical Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0596-25"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-431"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80567-X"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/35041682"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/35077232"},{"key":"e_1_3_1_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.286.5446.1897"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.7.768"},{"key":"e_1_3_1_9_2","unstructured":"D. Bootsma K. H. Kraemer J. E. Cleaver J. H. J. Hoeijmakers in The Genetic Basis of Cancer B. Vogelstein K. W. Kinzler Eds. (McGraw-Hill New York 1998) pp. 245\u2013274."},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00282072"},{"key":"e_1_3_1_11_2","first-page":"191","volume":"54","author":"Vermeulen W.","year":"1994","unstructured":"Vermeulen W., et al., Am. J. Hum. Genet. 54, 191 (1994).","journal-title":"Am. J. Hum. 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XPD +\/+ and XPD +\/R722W mice are referred to as wt mice and XPD R722W\/R722W mice are referred to as TTD mice. For proper comparison all mice used in these experiments were in a mixed 129\/C57Bl\/6 background and kept under identical conditions. XPA-deficient mice have been characterized previously (27). Genotyping was done as described in (18)."},{"key":"e_1_3_1_22_2","unstructured":"Supplementary materials and experimental procedures are available on Science Online at www.sciencemag.org\/cgi\/content\/full\/1070174\/DC1."},{"key":"e_1_3_1_23_2","unstructured":"J. de Boer et al. unpublished results."},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1988.tb02434.x"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod28.2.255"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0190-9622(93)70109-7"},{"key":"e_1_3_1_27_2","unstructured":"H. J. Bremer M. Duran J. Kamerling H. Przyrembel S. K. Wadman in Disturbances of Amino Acid Metabolism: Clinical Chemistry and Diagnosis (Urban and Schwarzenburg Baltimore-Munich 1981) pp. 80\u201382."},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/377169a0"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/377165a0"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1996.0201"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/0921-8777(94)00059-F"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/35041705"},{"key":"e_1_3_1_33_2","first-page":"165","volume":"14","author":"Oshima J.","year":"2000","unstructured":"Oshima J., In Vivo 14, 165 (2000).","journal-title":"In Vivo"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb06645.x"},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1086\/302063"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004310100845"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0047-6374(00)00095-6"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80580-2"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(99)00202-X"},{"key":"e_1_3_1_40_2","first-page":"183","volume":"14","author":"Campisi J.","year":"2000","unstructured":"Campisi J., In Vivo 14, 183 (2000).","journal-title":"In Vivo"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5259.258"},{"key":"e_1_3_1_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90390-X"},{"key":"e_1_3_1_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90105-1"},{"key":"e_1_3_1_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80223-8"},{"key":"e_1_3_1_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.070471597"},{"key":"e_1_3_1_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002259200"},{"key":"e_1_3_1_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80827-2"},{"key":"e_1_3_1_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.22.10499"},{"key":"e_1_3_1_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5302.990"},{"key":"e_1_3_1_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(06)00190-4"},{"key":"e_1_3_1_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.19.10770"},{"key":"e_1_3_1_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/35013197"},{"key":"e_1_3_1_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80854-5"},{"key":"e_1_3_1_54_2","first-page":"2775","volume":"9","author":"Yamaizumi M.","year":"1994","unstructured":"Yamaizumi M., Sugano T., Oncogene 9, 2775 (1994).","journal-title":"Oncogene"},{"key":"e_1_3_1_55_2","first-page":"823","volume":"13","author":"Ljungman M.","year":"1996","unstructured":"Ljungman M., Zhang F., Oncogene 13, 823 (1996).","journal-title":"Oncogene"},{"key":"e_1_3_1_56_2","unstructured":"G. Conforti T. Nardo M. D'Incalci"},{"key":"e_1_3_1_56_3","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203583"},{"key":"e_1_3_1_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/415045a"},{"key":"e_1_3_1_58_2","unstructured":"We thank J. den Hollander M. Gijbels R. Jankie and P. Kramer for excellent technical assistance; J. T. J. Uilenbroek for photographic work; L. Braam and coworkers for animal care; and D. Bootsma for stimulating interest and support. Supported by the Dutch Cancer Society (projects 94-763 98-1774 and 1800) the Spinoza premium and the Research Institute for Diseases in the Elderly. Funded by the Ministry of Education and Science and the Ministry of Health Welfare and Sports through the Netherlands Organization for Scientific Research; an NIH program grant (AG 17242-02); the European Community (QLRT-1999-02002); and the Louis Jeantet Foundation."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.1070174","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T23:02:57Z","timestamp":1704841377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.1070174"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2002,5,17]]},"references-count":58,"journal-issue":{"issue":"5571","published-print":{"date-parts":[[2002,5,17]]}},"alternative-id":["10.1126\/science.1070174"],"URL":"https:\/\/doi.org\/10.1126\/science.1070174","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1005715.79959","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1005715.66655","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1005715.77305","asserted-by":"object"}]},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2002,5,17]]}}}