Perilla frutescens extract reduces fat accumulation and promotes longevity in Caenorhabditis elegans via modulation of the insulin/IGF-1 signaling pathway.

Perilla frutescens (PF) is rich in flavonoids and other secondary metabolites with antioxidant properties. This study explored the lifespan-modulating effects and underlying mechanisms of an ethyl acetate extract of PF leaves (EAEPF) using Caenorhabditis elegans (C. elegans) as a model organism. EAEPF treatment significantly prolonged lifespan, enhanced pharyngeal pumping and head thrashing frequencies, and reduced the accumulation of lipofuscin and reactive oxygen species (ROS). The extract improved antioxidant enzyme activity, decreased malondialdehyde (MDA) levels, and increased resistance to thermal and juglone-induced oxidative stress. EAEPF markedly reduced lipid storage in nematodes, indicating a lipid-lowering effect. Mechanistically, EAEPF activated the insulin/IGF-1 signaling (IIS) pathway, and upregulated the transcription factors DAF-16/FOXO and SKN-1/Nrf2, which in turn promoted the expression of downstream stress-response genes (sod-3, gst-4, hsp-16.2). EAEPF reprogrammed lipid metabolism and enhanced glutathione metabolism, may represent a potential source of nutritional hormetins. These findings demonstrated the potential of EAEPF as a nutraceutical for lifespan extension and healthspan improvement.