Activation of genes involved in xenobiotic metabolism is a 1 shared signature of mouse models with extended lifespan

21 Xenobiotic metabolism has been proposed to play a role in modulating the rate of 22 aging. Xenobiotic-metabolizing enzymes (XME) are expressed at higher levels in 23 calorically restricted mice (CR) and in GH/IGF-I-deficient long-lived mutant mice. In this 24 study, we show that many phase I XME genes are similarly upregulated in additional 25 long-lived mouse models, including “crowded litter” (CL) mice, whose lifespan has been 26 increased by food restriction limited to the first 3 weeks of life, and in mice treated with 27 rapamycin. Induction in the CL mice lasts at least through 22 months of age, but 28 induction by rapamycin is transient for many of the mRNAs. Cytochrome P450s, flavin 29 monooxygenases, hydroxyacid oxidase, and metallothioneins were found to be 30 significantly elevated in similar proportions in each of the models of delayed aging 31 tested, whether these are based on mutation, diet, drug treatment, or transient early 32 intervention. The same pattern of mRNA elevation can be induced by 2 weeks of 33 treatment with tert-butylhydroquinone, an oxidative toxin known to active Nrf234 dependent target genes. These results suggest that elevation of phase I XMEs is a 35 hallmark of long-lived mice and may facilitate screens for agents worth testing in 36 intervention-based lifespan studies. 37