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.
Highlights
Global population aging is a challenge for worldwide health systems
To examine the involvement of tra-1 signaling, we inhibited TRA-1 by feeding E. coli HT115 bacteria transfected with tra-1 RNA interference (RNAi) constructs to the C. elegans RA7 strain, which expresses a TRA-1-GFP fusion protein (Mathies et al, 2004)
To further elucidate the sulforaphane-induced signaling cascade, which mediates longevity and an increased healthspan, we focused on the transcription factor DAF-16 because its binding by TRA-1 was recently detected (Hotzi et al, 2018), and DAF-16 signaling was associated with the longevity of C. elegans (Lin et al, 2018)
Summary
Global population aging is a challenge for worldwide health systems. By 2050, the world’s population aged 60 years and older is expected to reach two billion (World Health Organization and Ageing and health, 2018). The elderly are not necessarily healthier, and many do not match the WHO aims to maintain functional ability that enables wellbeing in older age (Crimmins, 2015; Olshansky, 2018; World Health Organization and Ageing and health, 2018). Aging today is reflected by lifestyle diseases such as heart diseases, diabetes, and Sulforaphane in C. elegans cancer (Niccoli and Partridge, 2012). Several lifestyle and nutritional strategies aim to promote healthy aging to lower biological age and thereby cancer risk
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