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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,10,8]]},"abstract":"<jats:p>A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all 4 tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice.<\/jats:p>","DOI":"10.1073\/pnas.1905722116","type":"journal-article","created":{"date-parts":[[2019,9,23]],"date-time":"2019-09-23T20:34:31Z","timestamp":1569270871000},"page":"20482-20488","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":85,"title":["Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence"],"prefix":"10.1073","volume":"116","author":[{"given":"Cristian","family":"Tomasetti","sequence":"first","affiliation":[{"name":"Division of Biostatistics and Bioinformatics, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"},{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205;"},{"name":"Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Poling","sequence":"additional","affiliation":[{"name":"Pathology, Williamson Medical Center, Brentwood, TN 37207;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8709-0664","authenticated-orcid":false,"given":"Nicholas J.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205;"},{"name":"Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Nyall R.","family":"London","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith E.","family":"Pittman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Haffner","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205;"},{"name":"Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Baras","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baktiar","family":"Karim","sequence":"additional","affiliation":[{"name":"Pathology &amp; 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Pathol. 211, 114\u2013123 (2007).","journal-title":"J. Pathol."},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.stem.2012.09.009","article-title":"Identifying the stem cell of the intestinal crypt: Strategies and pitfalls","volume":"11","author":"Barker N.","year":"2012","unstructured":"N. Barker, A. van Oudenaarden, H. Clevers, Identifying the stem cell of the intestinal crypt: Strategies and pitfalls. Cell Stem Cell 11, 452\u2013460 (2012).","journal-title":"Cell Stem Cell"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1093\/geronj\/27.2.162","article-title":"Cell proliferation and renewal in aging mice","volume":"27","author":"Cameron I. L.","year":"1972","unstructured":"I. L. Cameron, Cell proliferation and renewal in aging mice. J. Gerontol. 27, 162\u2013172 (1972).","journal-title":"J. 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