Kahweol, a coffee diterpene, increases lifespan via insulin/insulin-like growth factor-1 and AMP-activated protein kinase signaling pathways in Caenorhabditiselegans

Coffee is one of the most widely consumed beverages and is known to have many health benefits. Our previous study reported that kahweol, a diterpene found in coffee, reduced fat accumulation by reducing food intake in Caenorhabditis elegans. Based on the widely known observation of caloric restriction and lifespan, we determined if kahweol extends lifespan in C. elegans. Kahweol significantly extended the lifespan of wild-type C. elegans. However, kahweol increased the lifespan of the eat-2 null mutant that has a reduced food intake phenotype, suggesting that kahweol extends lifespan independent of reduced food intake. Therefore, we further determine the target of kahweol on lifespan extension. Kahweol had no effects on the lifespan of both daf-2 (the homolog of insulin/insulin-like growth factor-1 receptor) and daf-16 (the homolog of Forkhead box O transcription factor and a major downstream target of daf-2) null mutants, suggesting kahweol extended lifespan via insulin/insulin-like growth factor-1 signaling pathway. In addition, kahweol failed to extend lifespan in tub-1 (the homolog of TUB bipartite transcription factor) and aak-2 (the homolog of AMP-activated protein kinase) null mutants, suggesting these roles on kahweol’s effect on lifespan. However, the treatment of kahweol increased the lifespan in sir-2.1 (the homolog of NAD-dependent deacetylase sirtuin-1) and skn-1 (the homolog of nuclear factor erythroid 2-related factor 2) null mutants over the control, suggesting independent functions of these genes on kahweol’s lifespan extension. These results indicate that the insulin/insulin-like growth factor-1 signaling and AMPK pathways may play critical roles in extending lifespan by kahweol in C. elegans.