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

Abstract

Single 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.