27-Hydroxymangiferolic Acid Extends Lifespan and Improves Neurodegeneration in Caenorhabditis elegans by Activating Nuclear Receptors

27-Hydroxymangiferolic acid (27-HMA) is a naturally occurring compound in mango fruits that exhibits diverse biological functions. Here, we show that 27-HMA activates the transcriptional activity of farnesoid X receptor (FXR), a nuclear receptor transcription factor, extending the lifespan and healthspan in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>). Meanwhile, the longevity-promoting effect of 27-HMA was attenuated in the mutants of <i>nhr-8</i> and <i>daf-12,</i> the FXR homologs, indicating that the longevity effects of 27-HMA in <i>C. elegans</i> may depend on nuclear hormone receptors (NHRs). Further analysis revealed potential associations between the longevity effects of 27-HMA and the insulin/insulin-like growth factor-1 signaling (IIS)/TORC1 pathway. Moreover, 27-HMA increased the toxin resistance of nematodes and activated the expression of detoxification genes, which rely on NHRs. Finally, 27-HMA improved the age-related neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD) <i>C. elegans</i> models. Taken together, our findings suggest that 27-HMA is a novel FXR agonist and may prolong lifespan and healthspan via activating NHRs.