Puerarin extends lifespan and enhances the resistance to oxidative stress through AMPK/TFEB mediated autophagy in Caenorhabditis elegans.

As the aging population increases, exploring effective strategies to delay aging and promote healthy longevity has become a crucial topic in the life sciences. Puerarin (PUE) is a natural isoflavone derivative derived from Pueraria lobata, a plant widely recognized for its dual role as both a food and a medicinal herb. While PUE is known for its diverse pharmacological properties, its role in aging regulation and the associated molecular mechanisms are not yet fully elucidated. In this study, we found that PUE markedly extends the healthy lifespan of Caenorhabditis elegans and mitigates aging-related phenotypes, including lipofuscin accumulation and decreased locomotor capacity. Through genetic screening and functional validation, we demonstrated that PUE facilitates the nuclear translocation of the transcription factor HLH-30 (the mammalian homolog of TFEB) in an AMPK-dependent manner, thereby regulating autophagy. Importantly, this autophagic response was essential for the lifespan-extending effects of PUE. Additionally, PUE enhanced the oxidative stress resistance of C. elegans via the AMPK-TFEB signaling pathway, an effect characterized by reduced reactive oxygen species (ROS) accumulation and increased activities of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione (GSH). The findings establish a mechanistic rationale for applying PUE in aging delay and age-related disease prevention and underscore the potential significance of medicinal food plants in developing anti-aging strategies.