Luteolin and glycitein from Codonopsis pilosula ameliorate age-related locomotor decline in C. elegans via DAF-16-dependent but autophagy-divergent pathways.

As global population aging accelerates, maintaining locomotor function in later life has become a critical biomedical challenge. This study investigates the effects of three bioactive compounds-Luteolin (Lut), Glycitein (Gly), and α-Spinasterol (α-Spin)-isolated from the traditional Chinese medicinal herb Codonopsis pilosula (Dangshen), on age-related locomotor decline using the Caenorhabditis elegans (C.elegans) model. We demonstrate that Lut and Gly significantly ameliorate the deterioration of body bend and thrashing frequencies in aged nematodes. Further analysis reveals that both compounds mitigate age-associated sarcopenia by reducing abnormalities in muscle structure and mitochondrial morphology. Mechanistically, we found that the beneficial effects of Lut and Gly on locomotion are dependent on the transcription factor DAF-16/FOXO, as both compounds promote DAF-16 nuclear translocation and the effects are abolished upon daf-16 knockdown. However, these compounds diverge in their regulation of autophagy: Lut improves locomotion through an lgg-1-dependent autophagy-related process, whereas Gly exerts its effects independently of the autophagic pathway. In contrast, α-Spin, despite altering autophagosome levels, did not improve locomotor capacity. These findings elucidate the distinct pharmacological mechanisms of Codonopsis pilosula constituents, highlighting their potential as modulators of healthspan via DAF-16-dependent but mechanistically distinct pathways.