A drug-like molecule engages nuclear hormone receptor DAF-12/FXR to regulate mitophagy and extend lifespan

Nat Aging. 2023 Dec;3(12):1529-1543. doi: 10.1038/s43587-023-00524-9. Epub 2023 Nov 13.


Autophagy-lysosomal function is crucial for maintaining healthy lifespan and preventing age-related diseases. The transcription factor TFEB plays a key role in regulating this pathway. Decreased TFEB expression is associated with various age-related disorders, making it a promising therapeutic target. In this study, we screened a natural product library and discovered mitophagy-inducing coumarin (MIC), a benzocoumarin compound that enhances TFEB expression and lysosomal function. MIC robustly increases the lifespan of Caenorhabditis elegans in an HLH-30/TFEB-dependent and mitophagy-dependent manner involving DCT-1/BNIP3 while also preventing mitochondrial dysfunction in mammalian cells. Mechanistically, MIC acts by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12/FXR, which, in turn, induces mitophagy and extends lifespan. In conclusion, our study uncovers MIC as a promising drug-like molecule that enhances mitochondrial function and extends lifespan by targeting DAF-12/FXR. Furthermore, we discovered DAF-12/FXR as a previously unknown upstream regulator of HLH-30/TFEB and mitophagy.

MeSH terms

  • Animals
  • Autophagy
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins* / genetics
  • Longevity / genetics
  • Mammals / metabolism
  • Mitophagy*
  • Receptors, Cytoplasmic and Nuclear / genetics


  • Receptors, Cytoplasmic and Nuclear
  • DAF-12 protein, C elegans
  • Caenorhabditis elegans Proteins
  • HLH-30 protein, C elegans
  • Basic Helix-Loop-Helix Transcription Factors