Ahr-bacterial diet interaction modulates aging and associated pathologies in C. elegans

Abstract

Genetic and environmental factors concurrently shape the aging process. The nematode Caenorhabditis elegans has been instrumental in the past 30 years to identify most genes and interventions nowadays known to modulate aging (Lopez-Otin et al. 2013, Tigges et al. 2014, Dato et al. 2017). The aryl-hydrocarbon-receptor (AhR) was discovered as a dioxin-binding transcription factor involved in the metabolism of different environmental toxicants and xenobiotics (Poland et al. 1976). Since then, the variety of pathophysiological processes regulated by the AhR has rapidly grown, ranging from the immune response to cell death and metabolic pathways, and we disclosed it promotes aging phenotypes across species (Eckers et al. 2016, Esser et al. 2018). Interestingly, many AhR modulators may impact on aging and age-associated pathologies, but, whether their effects are actually AhR-dependent has never been explored. Here, we show for the first time that lack of C. elegans AHR-1 affects health and lifespan in a context-dependent manner. Using known mammalian AhR modulators we found that, similar to mammals, ahr-1 has protective effects against environmental insults 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 involved in the observed AhR-dependent features 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. Significance StatementThe roundworm C. elegans has been instrumental for the identification of many of the genetic and environmental factors known to concurrently shape the aging process. The aryl-hydrocarbon-receptor (AhR) was originally discovered as a dioxin-binding transcription factor involved in the metabolism of environmental toxicants and, in the past, we found it promotes aging phenotypes across species. Many AhR modulators may impact on aging and age-associated pathologies, but, whether their effects are actually AhR-dependent has never been explored. We show here for the first time that C. elegans AhR has protective effects against environmental insults such as UVB radiations and the xenobiotic BaP and identified a new critical role for AhR-bacterial diet interaction in animal lifespan, stress resistance, and age-associated pathologies.