Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Abstract

Lifespan of laboratory animals can be increased by genetic, pharmacological, and dietary interventions. Increased expression of genes involved in xenobiotic metabolism, together with resistance to xenobiotics, are frequent correlates of lifespan extension in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and mice. The Green Theory of Aging suggests that this association is causal, with the ability of cells to rid themselves of lipophilic toxins limiting normal lifespan. To test this idea, we experimentally increased resistance of Drosophila to the xenobiotic dichlordiphenyltrichlorethan (DDT), by artificial selection or by transgenic expression of a gene encoding a cytochrome P450. Although both interventions increased DDT resistance, neither increased lifespan. Furthermore, dietary restriction increased lifespan without increasing xenobiotic resistance, confirming that the two traits can be uncoupled. Reduced activity of the insulin/Igf signaling (IIS) pathway increases resistance to xenobiotics and extends lifespan in Drosophila, and can also increase longevity in C. elegans, mice, and possibly humans. We identified a nuclear hormone receptor, DHR96, as an essential mediator of the increased xenobiotic resistance of IIS mutant flies. However, the IIS mutants remained long-lived in the absence of DHR96 and the xenobiotic resistance that it conferred. Thus, in Drosophila IIS mutants, increased xenobiotic resistance and enhanced longevity are not causally connected. The frequent co-occurrence of the two traits may instead have evolved because, in nature, lowered IIS can signal the presence of pathogens. It will be important to determine whether enhanced xenobiotic metabolism is also a correlated, rather than a causal, trait in long-lived mice.lifespan | xenobiotic resistance | IIS | nuclear hormone receptor | DHR96

The neuronal receptor tyrosine kinase Alk is a target for longevity

“…We first examined lipid storage by measuring triglyceride (TAG) levels in flies expressing Alk DN in neurons; however, we observed no significant change in TAG storage in these flies (Figure a). We went on to examine the expression of genes encoding cytochrome P450 and glutathione transferase enzymes, a subset of which are established targets of IIS and foxo in Drosophila (Afschar et al, 2016). We observed an unexpected significant reduction in the mRNA levels for Cyp6a8 and a trend towards reduced mRNA levels for Cyp6g1 in the abdominal fat bodies of flies expressing Alk DN in neurons (Figure b,c), whereas we found no significant change in mRNA levels for GstD1 or GstE1 (Figure d,e).…”

Molecular Characterization and Expression Profiling of Nuclear Receptor Gene Families in Oriental Fruit Fly, Bactrocera Dorsalis (Hendel)

“…This indicated that HR96 may play roles in fat decomposition in the midgut. HR96 also was found to play an important role in the stress response of a variety of biomes [15].…”

Conserved and Exapted Functions of Nuclear Receptors in Animal Development

“…Mutations in the HR96 gene cause defects in triacyl glycerol and cholesterol metabolism, as well as increased sensitivity to xenobiotics such as phenobarbital and the insecticide DDT [77-81]. Research on HR96 has served as a model to understand cholesterol metabolism and detoxification [82,83].…”