Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Authors

Hadise Kabil, University of Michigan - Ann ArborFollow
Omer Kabil, University of Michigan - Ann Arbor
Ruma Banerjee, University of Michigan - Ann Arbor
Lawrence G. Harshman, University of Nebraska - LincolnFollow
Scott D. Pletcher, University of Michigan - Ann ArborFollow

Document Type

Article

Date of this Version

2011

Comments

Published in PNAS (2011) 108 (40): 16831–16836. doi:10.1073/pnas.1102008108/-/DCSupplemental.

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 β-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.