Endocrinology and Metabolism

Activation of genes involved in xenobiotic metabolism is a shared signature of mouse models with extended lifespan

Michael J Steinbaugh, Liou Y. Sun, Andrzej Bartke, Richard A. Miller


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 weeks of life, and in mice treated with rapamycin. Induction in the CL mice lasts at least through 22 months of age, but induction by rapamycin is transient for many of the mRNAs. 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, an oxidative toxin known to active 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.

  • Xenobiotic Metabolism
  • Crowded Litter
  • Caloric Restriction
  • Rapamycin
  • Nrf2