Dietary restriction improves intestinal cellular fitness to enhance gut barrier function and lifespan in D. melanogaster

Loss of gut integrity is linked to various human diseases including inflammatory bowel disease.However, the mechanisms that lead to loss of barrier function remain poorly understood.Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the agerelated decline in intestinal integrity by enhancing enterocyte cellular fitness through up-regulation of dMyc in the intestinal epithelium.Reduction of dMyc in enterocytes induced cell death, which leads to increased gut permeability and reduced lifespan upon DR.Genetic mosaic and epistasis analyses suggest that cell competition, whereby neighboring cells eliminate unfit cells by apoptosis, mediates cell death in enterocytes with reduced levels of dMyc.We observed that enterocyte apoptosis was necessary for the increased gut permeability and shortened lifespan upon loss of dMyc.Furthermore, moderate activation of dMyc in the post-mitotic enteroblasts and enterocytes was sufficient to extend health-span on rich nutrient diets.We propose that dMyc acts as a barometer of enterocyte cell fitness impacting intestinal barrier function in response to changes in diet and age. Author summaryDietary restriction (DR) is a robust environmental method to slow aging and age-related diseases in diverse organisms.Age-related disruption of gut integrity has been observed in both mammals and fruit flies and is a determinant of lifespan.In Drosophila, DR is able to slow the age-related decline in gut integrity.Although commensal dysbiosis has been proposed as a leading cause of gut barrier dysfunction, antibiotic treatment does not prevent the age-related increase in gut permeability.We identify that an intrinsic mechanism regulates gut barrier function through regulation of enterocyte apoptosis by 'cell competition'.We show DR up-regulates dMyc expression in the gut which enhances enterocyte cellular fitness, prevents the age-related decline in gut integrity, and contributes to DRinduced lifespan extension.Conversely, on a rich diet, inhibition of dMyc in the