MOLECULAR MECHANISM OF LIFESPAN EXTENSION BY CALORIC RESTRICTION

Caloric Restriction(definition) (CR) can extend lifespan and/or confer health benefits in a wide range of species, including primates; however, the molecular mechanisms are not well understood. We investigate the mechanism by which CR extends lifespan using the single cell organism budding yeast as a model. We found that CR, implemented by glucose reduction, extends yeast replicative lifespan and induces a global change of transcriptional and translational programs. In particular, CR represses methionine biosynthetic enzymes and transporters, and adding extra methionine cancels the lifespan extension by CR without affecting the lifespan in the normal media. CR also induces a transient increase of proteasome expression by up-regulating the translation of a master regulator of proteasome genes Rpn4, and that Rpn4 deletion abolish the lifespan extension by CR. These findings suggest that CR’s longevity effect is mediated by methionine restriction, and that proteasome is a key downstream effector.