Crocin extends lifespan by mitigating oxidative stress and regulating lipid metabolism through the DAF-16/FOXO pathway

Aging represents a significant global challenge characterized by persistent oxidative stress and dysregulated lipid metabolism. Crocin, the primary bioactive constituent of saffron (<i>Crocus sativus</i> L.), is widely utilized as a natural food colorant and exhibits potent anti-inflammatory and antioxidant properties. Previous studies have demonstrated crocin's antioxidative, neuroprotective and memory-enhancing effects in aged rats; however, its direct impact on aging and the underlying mechanisms remain unexplored. In this study, we demonstrated that crocin treatment extended lifespan, enhanced survival under heat and juglone-induced oxidative stress, and reduced lipofuscin accumulation in the model organism <i>C. elegans</i>. Mechanistically, crocin activated DAF-16, the <i>C. elegans</i> homolog of human FOXO, resulting in the upregulation of key antioxidant genes (<i>gst-4</i>, <i>sod-3</i> and <i>hsp-16.2</i>). Notably, the lifespan-extension effect of crocin was abolished in a <i>daf-16</i> mutant, and its antioxidant effects were significantly attenuated in <i>daf-16</i> RNAi experiments conducted in N2, CL2166, CF1553 and TJ375 strains. Furthermore, crocin specifically reduced fat accumulation, and upregulated the expression of genes involved in lipid mobilization (<i>lipl-3</i>, <i>lipl-4</i>, <i>atgl-1</i> and <i>acs-2</i>) and unsaturated fatty acid synthesis (<i>fat-6</i> and <i>elo-2</i>) in aged nematodes. GC-MS analysis further demonstrated that crocin treatment elevated the levels of unsaturated fatty acids (C18:1n9, C20:4n-6, C20:4n-3 and C20:5n-3), an effect that was completely abolished under <i>daf-16</i> knockdown conditions. Collectively, these findings suggest that crocin promotes longevity in <i>C. elegans</i> by mitigating oxidative stress and modulating lipid metabolism through the DAF-16/FOXO pathway. These results highlight the potential of crocin as a promising strategy for treating aging and age-related diseases.