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

Abstract

Broccoli-derived isothiocyanate sulforaphane inhibits inflammation and cancer. Sulforaphane may support healthy aging, but the underlying detailed mechanisms are unclear. We used the C. elegans nematode model to address this question. Wild-type and 4 mutant C. elegans worm strains were fed in the presence or absence of sulforaphane and E. coli 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 tra-1 target gene daf-16, 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 tra-1 or daf-16 was inhibited by RNA interference or when worms with a loss-of-function mutation of the tra-1 or daf-16 genes were used. Conversely, the average lifespan of C. elegans with hyperactive TRA-1 increased by 8.9%, but this longer survival was abolished by RNAi-mediated inhibition of daf-16. 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.

Meta-Analysis of Caenorhabditis elegans Transcriptomics Implicates Hedgehog-Like Signaling in Host-Microbe Interactions

“…As such, functional changes associated with shifts in gene expression need to consider temporal and location information about the tissue in which these changes occur, to understand how information flows or is modulated, and what it means in a specific context. Indeed, HHLS is active throughout the development of the worm ( Hao et al, 2006c ; Kolotuev et al, 2009 ; Kouns et al, 2011 ; Oikonomou et al, 2011 ; Riveiro et al, 2017 ; Kume et al, 2019 ; Hong et al, 2021 ) and into aging ( Templeman et al, 2020 ; Ji et al, 2021 ), it concerns a variety of HRPs and PTRs with specific tissue-expression patterns ( Supplementary Figure 3 ) and non-redundant roles ( Zugasti et al, 2005 ; Hao et al, 2006b ; Baker et al, 2021 ). Tissue-specific omics datasets would thus greatly help disentangle the contributions of major tissues expressing HRPs and PTRs such as the nervous system, the hypodermis, the intestine, and the gonads, and of HHLS genes found co-expressed in several of them ( Supplementary Figure 3 ).…”

“…Finally, as C. elegans investment in reproduction often competes with mounting effective immune responses ( TeKippe and Aballay, 2010 ; Yunger et al, 2017 ; Anderson and Pukkila-Worley, 2020 ), HHLS could indirectly impact host-microbe interactions through their role in nematode reproduction, beyond the known developmental role of TRA-1 in sex determination ( Hodgkin, 1987 ; Berkseth et al, 2013 ; Ji et al, 2021 ), as shown for wrt-10 , ptc-1 , ptr-2 ( Kuwabara et al, 2000 ; MacNeil et al, 2013 ; Templeman et al, 2020 ).…”

“…Although the worm genome expresses a single Gli homolog (TRA-1) primarily involved in sex-determination ( Hodgkin and Brenner, 1977 ; Hodgkin, 1987 ; Ellis, 2020 ), the nematode HHLS pathway lacks the canonical Hedgehog intracellular transduction pathway, and the evolutionary function of the PTR and HRP family expansions remains unclear ( Baker et al, 2021 ). HHLS genes have been involved in C. elegans epithelial function and development ( Hao et al, 2006a ; Liegeois et al, 2006 ; Soloviev et al, 2011 ), cuticular structure and patterning ( Zugasti et al, 2005 ; Hao et al, 2006b , c ; Liegeois et al, 2006 ; Kouns et al, 2011 ; Chiyoda et al, 2021 ; Cohen et al, 2021 ), sensory organ formation ( Michaux et al, 2000 ; Liegeois et al, 2007 ; Oikonomou et al, 2011 ; Wang et al, 2017 ; van der Burght et al, 2020 ), neurogenesis ( Kume et al, 2019 ) and axonal guidance ( Riveiro et al, 2017 ), immunity ( Roberts et al, 2010 ; Lightfoot et al, 2016 ), lipid homeostasis ( Lin and Wang, 2017 ; Del Castillo et al, 2021 ), reproduction ( Kuwabara et al, 2000 ; Templeman et al, 2020 ), and longevity ( Ji et al, 2021 ). In particular, the HHLS pathway was found to mediate the impact of microbial metabolites on host lipid metabolism ( Lin and Wang, 2017 ), supporting a direct role in host-nematode interactions that could in part explain the diversification of HRP ligands and PTR receptors.…”

Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging

“…Similarly, EFL-1, promotes negative regulation of MPK-1 [ 64 , 65 ]. Genes regulated by TRA-1, which regulates hermaphrodite lifespan and healthspan upstream of the classical lifespan regulating transcription factor DAF-16 [ 66 ], were enriched among the genes upregulated in day 3 animals. Together, this makes a strong argument that krill oil achieves neuroprotection by slowing down the aging process.…”