Tangeretin promotes lifespan associated with insulin/insulin-like growth factor-1 signaling pathway and heat resistance in Caenorhabditis elegans

Tangeretin is a polymethoxylated flavonoid naturally occurred in citrus fruits with many pharmacological activities, such as anti-inflammatory, antiproliferative, and neuroprotective properties. A previous study reported that tangeretin-enriched orange extract could prolong the lifespan in Caenorhabditis elegans. However, the antiaging effect of tangeretin remains uncertain. In this study, we used the model organism C. elegans to conduct a lifespan test, observed the aging-related functional changes of nematodes, the fluorescence changes of stress-related proteins (DAF-16 and HSP-16.2) and its response to stress assay, and monitored the effect of tangeretin on the mRNA expression levels. The results showed that tangeretin supplementation (30 and 100 mu M) extended the mean lifespan, slowed aging-related functional declines, and increased the resistance against heat-shock stress. Furthermore, tangeretin upregulated the mRNA expression of daf-16, hsp-16.2, and hsp-16.49, promoted the nuclear localization of DAF-16, and enhanced the fluorescence intensity of HSP-16.2, while it had no effect on the lifespan of daf-2, age-1, and daf-16 mutants. The current findings suggest that tangeretin can significantly extend the lifespan and enhance heat stress tolerance in an insulin/insulin-like growth factor signaling dependent manner.