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Xenobiotic-Metabolizing Enzymes Elevated in Multiple Mouse Models of Slow Aging.

dc.contributor.authorSteinbaugh, Michael Johnen_US
dc.date.accessioned2012-10-12T15:25:50Z
dc.date.availableNO_RESTRICTIONen_US
dc.date.available2012-10-12T15:25:50Z
dc.date.issued2012en_US
dc.date.submitted2012en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/94063
dc.description.abstractSingle gene mutations, dietary manipulations, and pharmacological agents can increase lifespan and delay aging in multiple species, including mice. Mutations that impair growth hormone (GH) and/or insulin-like growth factor 1 (IGF 1) production, as well as caloric restriction (CR), have been shown to enhance both longevity and resistance to multiple forms of cytotoxic stress. The mechanism that enables slow-aging mice to become more resistant to stress is not known. In this study, we discovered that the ERK mitogen-activated protein kinase (MAPK) signal cascade and xenobiotic-metabolizing enzymes (XME) are differentially regulated in multiple long-lived mouse models. Activation of the ERK pathway in response to cytotoxic stress (e.g. CdCl2, H2O2, paraquat, and UV-C light) was attenuated in cultured primary skin-derived fibroblasts from GH/IGF 1-deficient Snell dwarf mice and growth hormone receptor knockout (GHRKO) mice. Similar attenuation of ERK phosphorylation was also observed in liver tissue from Snell dwarf mice exposed to the oxidative toxin diquat. Xenobiotic metabolism plays a central role in detoxification of cytotoxic stressors and has been proposed to influence the rate of aging. XMEs are similarly upregulated in multiple GH/IGF 1-deficient dwarf mice and also in CR mice. In this study, we show that XME genes are similarly elevated in “crowded litter” (CL) mice, whose lifespan has been increased by food restriction limited to the first 3 weeks of life, and also in mice treated with rapamycin. Cytochrome P450s, flavin monooxygenases, hydroxyacid oxidase, and metallothioneins were found to be significantly elevated in similar proportions in each of the models of delayed aging tested, whether these are based on mutation, diet, drug treatment, or transient early intervention. The same pattern of mRNA elevation can be induced by 2 weeks of treatment with tert-butylhydroquinone (tBHQ), an oxidative stressor known to activate Nrf2-dependent target genes. These results suggest that upregulation of xenobiotic metabolism is a hallmark of long-lived mice and may facilitate screens for agents worth testing in intervention-based lifespan studies.en_US
dc.language.isoen_USen_US
dc.subjectAgingen_US
dc.subjectXenobiotic Metabolismen_US
dc.subjectCrowded Litteren_US
dc.subjectRapamycinen_US
dc.subjectNrf2en_US
dc.subjectERKen_US
dc.titleXenobiotic-Metabolizing Enzymes Elevated in Multiple Mouse Models of Slow Aging.en_US
dc.typeThesisen_US
dc.description.thesisdegreenamePhDen_US
dc.description.thesisdegreedisciplineCellular and Molecular Biologyen_US
dc.description.thesisdegreegrantorUniversity of Michigan, Horace H. Rackham School of Graduate Studiesen_US
dc.contributor.committeememberMiller, Richard A.en_US
dc.contributor.committeememberLjungman, Mats E Den_US
dc.contributor.committeememberHsu, Ao-Linen_US
dc.contributor.committeememberHammer, Gary D.en_US
dc.contributor.committeememberFerguson, David O.en_US
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biologyen_US
dc.subject.hlbtoplevelScienceen_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/94063/1/msteinba_1.pdf
dc.owningcollnameDissertations and Theses (Ph.D. and Master's)


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