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Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration


Calorie restriction (CR) extends lifespan in a wide spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals1,2,3,4. 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)5. Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide)5. 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.

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Figure 1: Calorie restriction (CR) and Hap4 overexpression extend lifespan and enhance rDNA silencing in a Sir2-dependent manner.
Figure 2: Respiration is required for calorie restriction (CR) and Hap4-overexpression-mediated lifespan extension.
Figure 3: Gene expression profile analysis of cells under calorie restriction (CR) and overexpressing Hap4.
Figure 4: Calorie restriction (CR) and Hap4 overexpression do not increase the oxidative stress response.


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We thank D. McNabb and members of the Guarente laboratory for suggestions; J. Smith for providing strains; T. Galitski for his contributions in the development of microarrays and analytical software tools; and T. Ideker for suggestions with microarray analysis. This work was supported by grants to L.G. from the National Institute of Health (NIH), The Ellison Medical Foundation, The Seaver Institute, and the Howard and Linda Stern Fund. S.-J.L. is supported by a NRSA individual award. G.R.F. is supported by the NIH and is an American Cancer Society Professor of Genetics. A.A.A. is supported by the NIH Training Grant in Genomic Sciences, sponsored by the Biotechnology Process Engineering Center. V.C.C. and L.A.S. are supported by grants from the NIH.

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Correspondence to Leonard Guarente.

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L.G. and S.-J.L. hold financial interests in Elixir Pharmaceuticals, Inc., M.K. holds financial interests in Longenity Inc., and G.R.F. holds financial interests in Microbia, Inc.

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Lin, SJ., Kaeberlein, M., Andalis, A. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002).

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