Nuclear hormone receptors: Roles of xenobiotic detoxification and sterol homeostasis in healthy aging.

Health during aging can be improved by genetic, dietary and pharmacological interventions. Many of these increase resistance to various stressors, including xenobiotics. Up-regulation of xenobiotic detoxification genes is a transcriptomic signature shared by long-lived nematodes, flies and mice, suggesting that protection of cells from toxicity of xenobiotics may contribute to longevity. Expression of genes involved in xenobiotic detoxification is controlled by evolutionarily conserved transcriptional regulators. Three closely related subgroups of nuclear hormone receptors (NHRs) have a major role, and these include DAF-12 and NHR-8 in C. elegans, DHR96 in Drosophila and FXR, LXRs, PXR, CAR and VDR in mammals. In the invertebrates, these NHRs have been experimentally demonstrated to play a role in extension of lifespan by genetic and environmental interventions. NHRs represent critical hubs in that they regulate detoxification enzymes with broad substrate specificities, metabolizing both endo- and xeno-biotics. They also modulate homeostasis of steroid hormones and other endogenous cholesterol derivatives and lipid metabolism, and these roles, as well as xenobiotic detoxification, may contribute to the effects of NHRs on lifespan and health during aging, an issue that is being increasingly addressed in C. elegans and Drosophila. Disentangling the contribution of these processes to longevity will require more precise understanding of the molecular mechanisms by which each is effected, including identification of ligands and co-regulators of NHRs, patterns of tissue-specificity and mechanisms of interaction between tissues. The roles of vertebrate NHRs in determination of health during aging and lifespan have yet to be investigated.