Targeting farnesoid X receptor as aging intervention therapy.

Environmental toxicants have been linked to aging and age-related diseases. The emerging evidence has shown that the enhancement of detoxification gene expression is a common transcriptome marker of long-lived mice, <i>Drosophila melanogaster</i>, and <i>Caenorhabditis elegans</i>. Meanwhile, the resistance to toxicants was increased in long-lived animals. Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan(definition) both in <i>C. elegans</i> and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and <i>C. elegans</i>. The longevity effects of OCA were attenuated in <i>Fxr</i> ^-/- mice and <i>Fxr</i> homologous <i>nhr-8</i> and <i>daf-12</i> mutant <i>C. elegans</i>. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.