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 ( 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 . Mechanistically, crocin activated DAF-16, the homolog of human FOXO, resulting in the upregulation of key antioxidant genes (, and ). Notably, the lifespan-extension effect of crocin was abolished in a mutant, and its antioxidant effects were significantly attenuated in 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 (, , and ) and unsaturated fatty acid synthesis ( and ) 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 knockdown conditions. Collectively, these findings suggest that crocin promotes longevity in 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.