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.
Publication types
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Adenosine Triphosphate / metabolism
- Animals
- Carbon / metabolism
- Carbon Dioxide / metabolism
- Cell Respiration*
- Cellular Senescence / physiology*
- Citric Acid Cycle
- Cyclic AMP-Dependent Protein Kinases / genetics
- Cyclic AMP-Dependent Protein Kinases / metabolism
- Electron Transport
- Energy Intake / physiology*
- Fermentation
- Gene Expression Profiling
- Gluconeogenesis
- Glucose / metabolism*
- Glycolysis
- Histone Deacetylases / genetics
- Histone Deacetylases / metabolism*
- Longevity
- Mitochondria / enzymology
- Mitochondria / metabolism
- Mutation / genetics
- NAD / metabolism
- Oxidative Stress
- Oxygen Consumption
- Pyruvic Acid / metabolism
- Saccharomyces cerevisiae / enzymology
- Saccharomyces cerevisiae / genetics
- Saccharomyces cerevisiae / growth & development
- Saccharomyces cerevisiae / metabolism*
- Silent Information Regulator Proteins, Saccharomyces cerevisiae*
- Sirtuin 2
- Sirtuins
- Trans-Activators / genetics
- Trans-Activators / metabolism*
Substances
- Silent Information Regulator Proteins, Saccharomyces cerevisiae
- Trans-Activators
- NAD
- Carbon Dioxide
- Carbon
- Pyruvic Acid
- Adenosine Triphosphate
- Cyclic AMP-Dependent Protein Kinases
- SIR2 protein, S cerevisiae
- Sirtuin 2
- Sirtuins
- Histone Deacetylases
- Glucose