Authors: Kabil H; Kabil O; Banerjee R; Harshman LG; Pletcher SD
Abstract: The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine beta-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.Keywords: Animal Nutritional Physiological Phenomena/*physiology; Animals; Blotting, Western; Caloric Restriction; Chromatography, High Pressure Liquid; Cloning, Molecular; Computational Biology; Cystathionine beta-Synthase/genetics/*metabolism; Cysteine/*metabolism; DNA Primers/genetics; Drosophila/*physiology; Energy Intake/*physiology; Gene Expression Regulation, Enzymologic/physiology; Glutathione/metabolism; Longevity/genetics/*physiology; Methionine/*metabolism; Polymerase Chain Reaction; Protein Biosynthesis/physiology; RNA Interference; Triglycerides/metabolism
Journal: Proceedings of the National Academy of Sciences of the United States of America
Date: Sept. 21, 2011
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Kabil H, Kabil O, Banerjee R, Harshman LG, Pletcher SD (2011) Increased transsulfuration mediates longevity and dietary restriction in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 108: 16831-6.