PMID- 18565572 OWN - NLM STAT- MEDLINE DCOM- 20080930 LR - 20240415 IS - 0047-6374 (Print) IS - 0047-6374 (Linking) VI - 129 IP - 9 DP - 2008 Sep TI - Effect of Ames dwarfism and caloric restriction on spontaneous DNA mutation frequency in different mouse tissues. PG - 528-33 LID - 10.1016/j.mad.2008.04.013 [doi] AB - Genetic instability has been implicated as a causal factor in cancer and aging. Caloric restriction (CR) and suppression of the somatotroph axis significantly increase life span in the mouse and reduce multiple symptoms of aging, including cancer. To test if in vivo spontaneous mutation frequency is reduced by such mechanisms, we crossed long-lived Ames dwarf mice with a C57BL/6J line harboring multiple copies of the lacZ mutation reporter gene as part of a plasmid that can be recovered from tissues and organs into Escherichia coli to measure mutant frequencies. Four cohorts were studied: (1) ad lib wild-type; (2) CR wild-type; (3) ad lib dwarf; and (4) CR dwarf. While both CR wild-type and ad lib dwarf mice lived significantly longer than the ad lib wild-type mice, under CR conditions dwarf mice did not live any longer than ad lib wild-type mice. While this may be due to an as yet unknown adverse effect of the C57BL/6J background, it did not prevent an effect on spontaneous mutation frequencies at the lacZ locus, which were assessed in liver, kidney and small intestine of 7- and 15-month-old mice of all four cohorts. A lower mutant frequency in the ad lib dwarf background was observed in liver and kidney at 7 and 15 months of age and in small intestine at 15 months of age as compared to the ad lib wild-type. CR also significantly reduced spontaneous mutant frequency in kidney and small intestine, but not in liver. In a separate cohort of lacZ-C57BL/6J mice CR was also found to significantly reduce spontaneous mutant frequency in liver and small intestine, across three age levels. These results indicate that two major pro-longevity interventions in the mouse are associated with a reduced mutation frequency. This could be responsible, at least in part, for the enhanced longevity associated with Ames dwarfism and CR. FAU - Garcia, Ana Maria AU - Garcia AM AD - University of Texas at San Antonio, San Antonio, TX, USA. FAU - Busuttil, Rita A AU - Busuttil RA FAU - Calder, R Brent AU - Calder RB FAU - Dolle, Martijn E T AU - Dolle ME FAU - Diaz, Vivian AU - Diaz V FAU - McMahan, C Alex AU - McMahan CA FAU - Bartke, Andrzej AU - Bartke A FAU - Nelson, James AU - Nelson J FAU - Reddick, Robert AU - Reddick R FAU - Vijg, Jan AU - Vijg J LA - eng GR - R01 AG020438/AG/NIA NIH HHS/United States GR - R01 AG020438-05/AG/NIA NIH HHS/United States GR - R01 AG020438-09/AG/NIA NIH HHS/United States GR - AG20438/AG/NIA NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20080513 PL - Ireland TA - Mech Ageing Dev JT - Mechanisms of ageing and development JID - 0347227 RN - 9007-49-2 (DNA) SB - IM MH - Animals MH - *Caloric Restriction MH - DNA/*genetics/metabolism MH - DNA Mutational Analysis MH - Dwarfism, Pituitary/*genetics MH - Genomic Instability/genetics MH - Intestine, Small/metabolism MH - Kidney/metabolism MH - Liver/metabolism MH - Longevity/genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Organ Specificity/genetics PMC - PMC2581895 MID - NIHMS60755 EDAT- 2008/06/21 09:00 MHDA- 2008/10/01 09:00 PMCR- 2009/09/01 CRDT- 2008/06/21 09:00 PHST- 2008/02/22 00:00 [received] PHST- 2008/03/28 00:00 [revised] PHST- 2008/04/19 00:00 [accepted] PHST- 2008/06/21 09:00 [pubmed] PHST- 2008/10/01 09:00 [medline] PHST- 2008/06/21 09:00 [entrez] PHST- 2009/09/01 00:00 [pmc-release] AID - S0047-6374(08)00104-8 [pii] AID - 10.1016/j.mad.2008.04.013 [doi] PST - ppublish SO - Mech Ageing Dev. 2008 Sep;129(9):528-33. doi: 10.1016/j.mad.2008.04.013. Epub 2008 May 13.