Nature 418: 344-348 (2002)

Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration

Su-Ju Lin, Matt Kaeberlein, Alex A. Andalis, Lori A. Sturtz, Pierre-Antoine Defossez, Valeria C. Culotta, Gerald R. Fink & Leonard Guarante

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA

Department of Environmental Health Sciences, Johns Hopkins University School of Public Health, Baltimore, Maryland 21205, USA.

Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. We established a model of CR in budding yeast Saccharomyces cerevisiae. In this system, lifespan can be extended by limiting glucose or by reducing the activity of the glucose-sensing cyclic-AMP-dependent kinase (PKA). Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide). In this study we explore how CR activates Sir2 to extend lifespan. Here we show that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process. We discuss how this metabolic strategy may apply to CR in animals.