Transcriptomics of a diet gene pair in C. elegans

Diet has a profound effect on cellular metabolism and incidence of age-related diseases. Animals adapt their physiology to different food-types, modulating complex life history traits like aging. The molecular mechanisms that determine the adaptive capacity to diet is less known. Here we identify a fluoride resistance gene flr-4 in C. elegans as a novel modulator of aging, dependent on the bacterial diet. Knocking flr-4 down early during development, specifically in the intestine prolongs life span. Mechanistically, flr-4 knockdown leads to increased expression of xenobiotic detoxification genes through the nuclear hormone receptor NHR-8, that is required for the extended life span. Importantly, the p38 MAPK pathway relays the information of food-type to modulate the expression of these cytoprotective genes. The upregulation of these genes occurs only when flr-4 mutant worms are fed E. coli HT115 but not the standard laboratory strain E. coli OP50. We show that in the flr-4 mutant, OP50 fails to activate p38MAPK signalling and consequently, the cytoprotective genes and as a result, cannot contribute towards life span extension. Finally, we show that flr-4 and dietary restriction may utilize similar pathways for longevity assurance, suggesting a crosstalk between diet quality and quantity. Together, our study establishes FLR-4-mediated upregulation of cytoprotective detoxification genes through p38 MAPK as a mechanism of dietary adaptation that modulates life span in C. elegans in response to different food-types.