Sulforaphane Targets TRA-1/GLI Upstream of DAF-16/FOXO to Promote Longevity and Healthspan.

Broccoli-derived isothiocyanate sulforaphane inhibits inflammation and cancer. Sulforaphane may support healthy aging, but the underlying detailed mechanisms are unclear. We used the nematode model to address this question. Wild-type and 4 mutant worm strains were fed in the presence or absence of sulforaphane and food bacteria transfected with RNA interference gene constructs. Kaplan-Meier survival analysis, live imaging of mobility and pharyngeal pumping, fluorescence microscopy, RT-qPCR, and Western blotting were performed. In the wild type, sulforaphane prolonged lifespan and increased mobility and food intake because of sulforaphane-induced upregulation of the sex-determination transcription factor TRA-1, which is the ortholog of the human GLI mediator of sonic hedgehog signaling. In turn, the target gene , which is the ortholog of human FOXO and the major mediator of insulin/IGF-1 and aging signaling, was induced. By contrast, sulforaphane did not prolong lifespan and healthspan when or was inhibited by RNA interference or when worms with a loss-of-function mutation of the or genes were used. Conversely, the average lifespan of with hyperactive TRA-1 increased by 8.9%, but this longer survival was abolished by RNAi-mediated inhibition of . Our data suggest the involvement of sulforaphane in regulating healthy aging and prolonging lifespan by inducing the expression and nuclear translocation of TRA-1/GLI and its downstream target DAF-16/FOXO.