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

Abstract

Aging represents a significant global challenge characterized by persistent oxidative stress and dysregulated lipid metabolism. Crocin, the primary bioactive constituent of saffron (Crocus sativus 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 C. elegans. Mechanistically, crocin activated DAF-16, the C. elegans homolog of human FOXO, resulting in the upregulation of key antioxidant genes (gst-4, sod-3 and hsp-16.2). Notably, the lifespan-extension effect of crocin was abolished in a daf-16 mutant, and its antioxidant effects were significantly attenuated in daf-16 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 (lipl-3, lipl-4, atgl-1 and acs-2) and unsaturated fatty acid synthesis (fat-6 and elo-2) 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 daf-16 knockdown conditions. Collectively, these findings suggest that crocin promotes longevity in C. elegans 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.