Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast

Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
PLoS Genetics (Impact Factor: 7.53). 12/2005; 1(5):e69. DOI: 10.1371/journal.pgen.0010069
Source: PubMed


A model for replicative life span extension by calorie restriction (CR) in yeast has been proposed whereby reduced glucose in the growth medium leads to activation of the NAD+-dependent histone deacetylase Sir2. One mechanism proposed for this putative activation of Sir2 is that CR enhances the rate of respiration, in turn leading to altered levels of NAD+ or NADH, and ultimately resulting in enhanced Sir2 activity. An alternative mechanism has been proposed in which CR decreases levels of the Sir2 inhibitor nicotinamide through increased expression of the gene coding for nicotinamidase, PNC1. We have previously reported that life span extension by CR is not dependent on Sir2 in the long-lived BY4742 strain background. Here we have determined the requirement for respiration and the effect of nicotinamide levels on life span extension by CR. We find that CR confers robust life span extension in respiratory-deficient cells independent of strain background, and moreover, suppresses the premature mortality associated with loss of mitochondrial DNA in the short-lived PSY316 strain. Addition of nicotinamide to the medium dramatically shortens the life span of wild type cells, due to inhibition of Sir2. However, even in cells lacking both Sir2 and the replication fork block protein Fob1, nicotinamide partially prevents life span extension by CR. These findings (1) demonstrate that respiration is not required for the longevity benefits of CR in yeast, (2) show that nicotinamide inhibits life span extension by CR through a Sir2-independent mechanism, and (3) suggest that CR acts through a conserved, Sir2-independent mechanism in both PSY316 and BY4742.

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Available from: Matt Kaeberlein
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    • "In this study, we endeavored to systematically study synergistic interactions with target of rapamycin (TOR) kinase activity. TOR is a primary integrator of proliferative signals, and aberrant signaling by this kinase contributes to cancer (Casadio et al., 1999; Inoki et al., 2005; Kaeberlein et al., 2005; Martin and Hall, 2005; Tee and Blenis, 2005; Tischmeyer et al., 2003). As clinical use of selective inhibitors of TOR complex 1 (TORC1; rapamycin and its derivatives, rapalogs) becomes more widespread in cancer treatment and ATP-competitive inhibitors of both TORC1 and TORC2 (including BEZ235, INK- 128/MLN0128, KU-0063794, and WYE-354) reach the clinic, the search for secondary targets to use in combination therapy will gain urgency. "
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