The MDT-15 Subunit of Mediator Interacts with Dietary Restriction to Modulate Longevity and Fluoranthene Toxicity in Caenorhabditis elegans

Abstract

Dietary restriction (DR), the limitation of calorie intake while maintaining proper nutrition, has been found to extend life span and delay the onset of age-associated disease in a wide range of species. Previous studies have suggested that DR can reduce the lethality of environmental toxins. To further examine the role of DR in toxin response, we measured life spans of the nematode Caenorhabditis elegans treated with the mutagenic polyaromatic hydrocarbon, fluoranthene (FLA). FLA is a direct byproduct of combustion, and is one of U.S. Environmental Protection Agency's sixteen priority environmental toxins. Treatment with 5 µg/ml FLA shortened the life spans of ad libitum fed nematodes, and DR resulted in increased sensitivity to FLA. To determine the role of detoxifying enzymes in the toxicity of FLA, we tested nematodes with mutations in the gene encoding the MDT-15 subunit of mediator, a transcriptional coactivator that regulates genes involved in fatty acid metabolism and detoxification. Mutation of mdt-15 increased the life span of FLA treated animals compared to wild-type animals with no difference observed between DR and ad libitum fed mdt-15 animals. We also examined mutants with altered insulin-IGF-1-like signaling (IIS), which is known to modulate life span and stress resistance in C. elegans independently of DR. Mutation of the genes coding for the insulin-like receptor DAF-2 or the FOXO-family transcription factor DAF16 did not alter the animals' susceptibility to FLA compared to wild type. Taken together, our results suggest that certain compounds have increased toxicity when combined with a DR regimen through increased metabolic activation. This increased metabolic activation appears to be mediated through the MDT-15 transcription factor and is independent of the IIS pathway.

Adaptive and Specialised Transcriptional Responses to Xenobiotic Stress in Caenorhabditis elegans Are Regulated by Nuclear Hormone Receptors

“…The two UGTs (UGT-8 and UGT-13) induced by thiabendazole in C. elegans may catalyse production of a glucosylated form identified during albendazole metabolism in C. elegans [39]. The responses to these xenobiotics are yet to be investigated in Drosophila but homologues to the CYP3 subfamily in mammals have been associated with resistance to other xenobiotics including imidacloprid [53]. In mammals, the metabolism of imidacloprid is far more complex than that of chloroquine and thiabendazole, with many more metabolites having been identified.…”

Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans

“…Life span experiments were conducted as previously described [ 65 ]. Bacterial deprivation was conducted by maintaining animals on UV-killed OP50 bacteria food until day 4 of adulthood and then transferring animals to NGM agar plates containing ampicillin but without a bacterial food source, as previously described [ 47 , 67 ].…”

Responses of bitter melon saponins to oxidative stress and aging via the IIS pathway linked with sir‐2.1 and hlh‐30

“…eat‐2 mutant was longevous due to dietary restriction with a decreased pumping rate (Schleit et al, 2011). Lifespan extension observed with BMS treatment in eat‐2 mutant showed that BMS' effects were not ascribed to the reduced food intake, but to other regulatory mechanisms.…”