Abstract: 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.Keywords: Adenosine Triphosphate/metabolism; Animals; Carbon/metabolism; Carbon Dioxide/metabolism; Cell Aging/*physiology; *Cell Respiration; Citric Acid Cycle; Cyclic AMP-Dependent Protein Kinases/genetics/metabolism; Electron Transport; Energy Intake/*physiology; Fermentation; Gene Expression Profiling; Gluconeogenesis; Glucose/*metabolism; Glycolysis; Histone Deacetylases/genetics/*metabolism; Longevity; Mitochondria/enzymology/metabolism; Mutation/genetics; NAD/metabolism; Oxidative Stress; Oxygen Consumption; Pyruvic Acid/metabolism; Saccharomyces cerevisiae/enzymology/genetics/growth & development/*metabolism; *Silent Information Regulator Proteins, Saccharomyces cerevisiae; Sirtuin 2; Sirtuins; Trans-Activators/genetics/*metabolism
Date: July 19, 2002
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Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418: 344-8.