Dietary and environmental factors have opposite AhR-dependent effects on C. elegans healthspan

Abstract

Genetic, dietary, and environmental factors concurrently shape the aging process. The aryl hydrocarbon receptor (AhR) was discovered as a dioxin-binding transcription factor involved in the metabolism of different environmental toxicants in vertebrates. Since then, the variety of pathophysiological processes regulated by the AhR has grown, ranging from immune response, metabolic pathways, and aging. Many modulators of AhR activity may impact on aging and age-associated pathologies, but, whether their effects are AhR-dependent has never been explored. Here, using Caenorhabditis elegans , as an elective model organism for aging studies, we show for the first time that lack of Ce AHR-1 can have opposite effects on health and lifespan in a context-dependent manner. Using known mammalian AhR modulators we found that, ahr-1 protects against environmental insults (benzo(a)pyrene and UVB light) and identified a new role for AhR-bacterial diet interaction in animal lifespan, stress resistance, and age-associated pathologies. We narrowed down the dietary factor to a bacterially extruded metabolite likely involved in tryptophan metabolism. This is the first study clearly establishing C. elegans as a good model organism to investigate evolutionarily conserved functions of AhR-modulators and -regulated processes, indicating it can be exploited to contribute to the discovery of novel information about AhR in mammals.

Aryl hydrocarbon receptor-dependent and -independent pathways mediate curcumin anti-aging effects

“…cyp-13A5 and cyp-13A8, cyp-42A1) were increased by curcumin only in the absence of ahr-1 (Fig S1). These data, along with other works (Brinkmann et al, 2020b, Jones et al, 2013, suggest that cyps are likely not the major targets of CeAhR. This is also supported by our transcriptomic analysis in wild-type and ahr-1 mutants.…”

“…We used the following C. elegans strains: N2 [wild-type], CZ2485 [ahr-1(ju145)], NV38b Growth Media (NGM) plates and fed with E. coli OP50 according to methods described in (Brinkmann et al, 2020b). For the experiments, worms were synchronized on plates supplemented with E. coli HT115(DE3) on plates supplemented with 1 mM IPTG.…”

“…The expression of the strongest down-and up-regulated genes between wt and ahr-1 (Brinkmann et al, 2020b) was assessed by qPCR in wt vs. ahr-1 (B) and DMSO-vs. curcumin-treated nematodes (C). Boxplots show data of 3 experiments.…”

“…The copyright holder for this this version posted February 10, 2022. ; https://doi.org/10.1101/2022.02.10.479676 doi: bioRxiv preprint Of note, many compounds impacting aging or age-related diseases (Sakakibara et al, 2005, Okey et al, 1984, Gao et al, 2015 can modulate AhR activity (Denison et al, 2002, Ashida et al, 2000, Zhang et al, 2003. While activation of AhR by xenobiotics leads to different cancers in mammals (Mandal, 2005, Marinkovic et al, 2010, dietary and environmental factors were shown to have opposite AhR-dependent effects on C. elegans' health-span (Brinkmann et al, 2020b). Among the dietary AhR modulators, polyphenols such as curcumin have been largely studied for their pro-health effects.…”

Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein inC. elegans

“…Indeed, similarities between C. elegans pharyngeal muscle and the vertebrate heart in terms of anatomic development and physiology have been described, which suggest convergent evolution between two autonomous muscular pumps with similar biological roles [29]. Strikingly, automatic measurement through a microfluidic device [30] revealed that nuo-5 and lpd-5 RNAi-treated animals have an abnormal electropharyngeogram (EPG) with significantly decreased pump frequency ( Fig 2C ) and increased average inter-pump interval (IPI) as well as R o E ratio when compared to control nematodes ( Fig S2G,H ).…”