Sulforaphane promotes C. elegans longevity and healthspan via DAF-16/DAF-2 insulin/IGF-1 signaling

Abstract

The broccoli-derived isothiocyanate sulforaphane inhibits inflammation, oxidative stress and cancer, but its effect on healthspan and longevity are unclear. We used the C. elegans nematode model and fed the wildtype and 9 mutant strains ±sulforaphane. The lifespan, phenotype, pharyngeal pumping, mobility, lipofuscin accumulation, and RNA and protein expression of the nematodes were assessed by using Kaplan-Meier survival analysis, in vivo live imaging, fluorescence microscopy, and qRT-PCR. Sulforaphane increased the lifespan and promoted a health-related phenotype by increasing mobility, appetite and food intake and reducing lipofuscin accumulation. Mechanistically, sulforaphane inhibited DAF-2-mediated insulin/insulin-like growth factor signaling and its downstream targets AGE-1, AKT-1/AKT-2. This was associated with increased nuclear translocation of the FOXO transcription factor homolog DAF - 16. In turn, the target genes sod-3 , mtl-1 and gst-4 , known to enhance stress resistance and lifespan, were upregulated. These results indicate that sulforaphane prolongs the lifespan and healthspan of C. elegans through insulin/IGF-1 signaling. Our results provide the basis for a nutritional sulforaphane-enriched strategy for the promotion of healthy aging and disease prevention.

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

“…To investigate the impact of sulforaphane, which is chemically a sulfur-containing isothiocyanate ( Figure 1A ), we fed synchronized L4 wild-type C. elegans larvae with E. coli OP50 food bacteria in the presence or absence of 100 µM sulforaphane. We chose this sulforaphane concentration because it is considered optimum to treat C. elegans ( Qi et al, 2021 ). The number of worms was recorded daily until no more live worms could be found from Day 33 onwards.…”

“…Lifespan assays were performed as recently described ( Qi et al, 2021 ). For synchronization, 30 gravid C. elegans worms were transferred to new NGM plates supplemented with E. coli OP50 food bacteria to lay eggs for 3 h. Next, the worms were picked and washed.…”

“…Worm mobility was used to reflect the functional state of motor neurons and muscle cells ( Mergoud Dit Lamarche et al, 2018 ), as recently described ( Qi et al, 2021 ). Synchronized L4 C. elegans larvae (n = 50/group) were maintained on NGM plates containing E. coli OP 50 bacteria or nontransfected or RNAi-transfected E. coli HT115 bacteria in the presence or absence of 100 µM sulforaphane.…”

“…In particular, the bioactive, anti-inflammatory isothiocyanate sulforaphane, which is abundant in broccoli, is particularly well studied ( Herr and Büchler, 2010 ). Sulforaphane acts antioxidative and inhibits insulin/IGF-1 signaling in the nematode Caenorhabditis ( C.) elegans ( Santín-Márquez et al, 2019 ; Qi et al, 2021 ). Additionally, sulforaphane reduces hepatic glucose production, improving glucose control in patients with type 2 diabetes ( Axelsson et al, 2017 ).…”

Hydrogen sulfide in ageing, longevity and disease

“…Furthermore, sulforaphane treatment in a human prostate cancer cell lines impeded cancer cell survival via H 2 S-mediated JNK and MAPK signalling [ 159 ]. Finally, the activity of sulforaphane was attributed largely to its potent activation of NRF2 by modification of KEAP1 [ 160 ] and insulin signalling [ 161 ], mechanisms that are also directly influenced by H 2 S signalling (see sections Post-translational modification (persulfidation) and Acarbose and IIS signalling). Given that sulforaphane is a compound that is essentially a naturally occurring H 2 S donor and has been shown to operate through biological mechanisms that are known H 2 S signalling pathways, there have been a surprisingly limited number of studies that directly monitor H 2 S levels following sulforaphane treatment, and none in the context of HGPS.…”