Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan.
Xenobiotic metabolism has been proposed to play a role in modulating the rate of aging. Xenobiotic metabolizing enzymes (XME) are expressed at higher levels in calorically restricted mice (CR) and in GH/IGF-I-deficient, long-lived mutant mice. In this study, we show that many phase I XME genes are similarly upregulated in additional long-lived mouse models, including "crowded litter" (CL) mice, whose lifespan has been increased by food restriction limited to the first 3 wk of life, and in mice treated with rapamycin. Induction in the CL mice lasts at least through 22 mo of age, but induction by rapamycin is transient for many of the mRNAs. Cytochrome P-450s, 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 were based on mutation, diet, drug treatment, or transient early intervention. The same pattern of mRNA elevation could be induced by 2 wk of treatment with tert-butylhydroquinone, an oxidative toxin known to activate Nrf2-dependent target genes. These results suggest that elevation of phase I XMEs is a hallmark of long-lived mice and may facilitate screens for agents worth testing in intervention-based lifespan studies.
Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Michael J
MJ
Steinbaugh
Liou Y
LY
Sun
Andrzej
A
Bartke
Richard A
RA
Miller
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D031204:Caloric Restriction; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D005260:Female; D005415:Flavins / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006873:Hydroquinones / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010088:Oxidoreductases / Q000096:biosynthesis; D020123:Sirolimus / Q000494:pharmacology; D015854:Up-Regulation; D015262:Xenobiotics / Q000378:metabolism* / Q000494:pharmacology
D000975:Antioxidants; D005415:Flavins; D006873:Hydroquinones; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D008668:Metallothionein; C018855:2-tert-butylhydroquinone; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D020123:Sirolimus