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Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms which lead to loss of barrier function remain poorly understood. Using D. melanogaster, we demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by enhancing enterocyte cellular fitness through upregulation of dMyc in the intestinal epithelium. Reduction of dMyc in enterocytes induces cell death through JNK signaling leading 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. Reducing enterocyte apoptosis partially rescued the increased gut permeability and shortened lifespan upon loss of dMyc. We propose that dMyc acts as a barometer of enterocyte cell fitness impacting intestinal homeostasis in response to changes in diet and age.

Akagi, Kazutaka and Wilson, Kenneth A. and Katewa, Subhash D. and Ortega, Mauricio and Simmons, Jesse and Kapuria, Subir and Sharma, Amit and Jasper, Heinrich and Kapahi, Pankaj, Dietary Restriction Improves Intestinal Cellular Fitness to Enhance Gut Barrier Function and Lifespan in D. Melanogaster (2018). Available at SSRN:

https://ssrn.com/abstract=3155743 or http://dx.doi.org/10.2139/ssrn.3155743

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