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Calorie restriction reduces rDNA recombination independently of rDNA silencing.

Riesen M, Morgan A - Aging Cell (2009)

Bottom Line: Although accumulation of extrachromosomal rDNA circles is specific to yeast aging, it is thought that Sirtuin activation represents a conserved longevity mechanism through which the beneficial effects of CR are mediated in various species.We show here that growing yeast on 0.05 or 0.5% glucose (severe and moderate CR, respectively) does not increase silencing at either sub-telomeric or rDNA loci compared with standard (2% glucose) media.In contrast, CR and deletion of the FOB1, HXK2, SCH9 and TOR1 genes, all significantly reduced rDNA recombination.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, UK.

ABSTRACT
Calorie restriction (CR) extends lifespan in yeast, worms, flies and mammals, suggesting that it acts via a conserved mechanism. In yeast, activation of the NAD-dependent histone deacetylase, Sir2, by CR is thought to increase silencing at the ribosomal DNA, thereby reducing the recombination-induced generation of extrachromosomal rDNA circles, hence increasing replicative lifespan. Although accumulation of extrachromosomal rDNA circles is specific to yeast aging, it is thought that Sirtuin activation represents a conserved longevity mechanism through which the beneficial effects of CR are mediated in various species. We show here that growing yeast on 0.05 or 0.5% glucose (severe and moderate CR, respectively) does not increase silencing at either sub-telomeric or rDNA loci compared with standard (2% glucose) media. Furthermore, rDNA silencing was unaffected in the hxk2Delta, sch9Delta and tor1Delta genetic mimics of CR, but inhibited by FOB1 deletion. All these interventions extend lifespan in multiple yeast backgrounds, revealing a poor correlation between rDNA silencing and longevity. In contrast, CR and deletion of the FOB1, HXK2, SCH9 and TOR1 genes, all significantly reduced rDNA recombination. This silencing-independent mechanism for suppressing rDNA recombination may therefore contribute to CR-mediated lifespan extension.

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Proposed mechanisms of lifespan extension by calorie restriction. Models 1 and 2 suggest that CR up-regulates Sir2 activity, which leads to increased gene silencing and decreased rDNA recombination. Consequently, less ERCs are formed, which extends the yeast replicative lifespan. Both models differ only in the events upstream of Sir2 activation. Model 1 suggests that the increase in respiration in response to nutrient deprivation modulates the NAD+/NADH ratio in favour of NAD+, whereas model 2 explains the increase in Sir2-activity via a rise in Pnc1 levels and consequently the degradation of the endogenous Sir2 inhibitor, nicotinamide. Model 3 bypasses Sir2-dependent gene silencing altogether and puts forward the Tor1/Sch9 kinase pathways as links between calorie restriction and lifespan extension; although the downstream mechanism has not been fully determined, this is postulated to involve reduced ribosomal protein synthesis.
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fig01: Proposed mechanisms of lifespan extension by calorie restriction. Models 1 and 2 suggest that CR up-regulates Sir2 activity, which leads to increased gene silencing and decreased rDNA recombination. Consequently, less ERCs are formed, which extends the yeast replicative lifespan. Both models differ only in the events upstream of Sir2 activation. Model 1 suggests that the increase in respiration in response to nutrient deprivation modulates the NAD+/NADH ratio in favour of NAD+, whereas model 2 explains the increase in Sir2-activity via a rise in Pnc1 levels and consequently the degradation of the endogenous Sir2 inhibitor, nicotinamide. Model 3 bypasses Sir2-dependent gene silencing altogether and puts forward the Tor1/Sch9 kinase pathways as links between calorie restriction and lifespan extension; although the downstream mechanism has not been fully determined, this is postulated to involve reduced ribosomal protein synthesis.

Mentions: Although the effect of glucose limitation in extending yeast replicative lifespan is not disputed, its mechanism of action is the subject of considerable controversy and heated debate. Three main models have been suggested, two of which centre on the evolutionarily conserved NAD-dependent histone deacetylase, Sir2 (Fig. 1). Initially, it was proposed that CR causes a metabolic shift away from fermentation and towards respiration, resulting in an increased NAD:NADH ratio, and thus increased Sir2 activity (Lin et al., 2000, 2002, 2004) (model 1). Alternatively (model 2), it was suggested that CR does not alter the NAD:NADH ratio, but rather acts by increasing expression of Pnc1, which degrades the endogenous Sir2 inhibitor nicotinamide, thus increasing Sir2 activity (Anderson et al., 2003). In both models, activation of Sir2 leads to increased rDNA silencing and a consequent reduction in recombination between rDNA repeats; this reduces the formation of extrachromosomal rDNA circles (Sinclair & Guarente, 1997) and so retards aging.


Calorie restriction reduces rDNA recombination independently of rDNA silencing.

Riesen M, Morgan A - Aging Cell (2009)

Proposed mechanisms of lifespan extension by calorie restriction. Models 1 and 2 suggest that CR up-regulates Sir2 activity, which leads to increased gene silencing and decreased rDNA recombination. Consequently, less ERCs are formed, which extends the yeast replicative lifespan. Both models differ only in the events upstream of Sir2 activation. Model 1 suggests that the increase in respiration in response to nutrient deprivation modulates the NAD+/NADH ratio in favour of NAD+, whereas model 2 explains the increase in Sir2-activity via a rise in Pnc1 levels and consequently the degradation of the endogenous Sir2 inhibitor, nicotinamide. Model 3 bypasses Sir2-dependent gene silencing altogether and puts forward the Tor1/Sch9 kinase pathways as links between calorie restriction and lifespan extension; although the downstream mechanism has not been fully determined, this is postulated to involve reduced ribosomal protein synthesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2805862&req=5

fig01: Proposed mechanisms of lifespan extension by calorie restriction. Models 1 and 2 suggest that CR up-regulates Sir2 activity, which leads to increased gene silencing and decreased rDNA recombination. Consequently, less ERCs are formed, which extends the yeast replicative lifespan. Both models differ only in the events upstream of Sir2 activation. Model 1 suggests that the increase in respiration in response to nutrient deprivation modulates the NAD+/NADH ratio in favour of NAD+, whereas model 2 explains the increase in Sir2-activity via a rise in Pnc1 levels and consequently the degradation of the endogenous Sir2 inhibitor, nicotinamide. Model 3 bypasses Sir2-dependent gene silencing altogether and puts forward the Tor1/Sch9 kinase pathways as links between calorie restriction and lifespan extension; although the downstream mechanism has not been fully determined, this is postulated to involve reduced ribosomal protein synthesis.
Mentions: Although the effect of glucose limitation in extending yeast replicative lifespan is not disputed, its mechanism of action is the subject of considerable controversy and heated debate. Three main models have been suggested, two of which centre on the evolutionarily conserved NAD-dependent histone deacetylase, Sir2 (Fig. 1). Initially, it was proposed that CR causes a metabolic shift away from fermentation and towards respiration, resulting in an increased NAD:NADH ratio, and thus increased Sir2 activity (Lin et al., 2000, 2002, 2004) (model 1). Alternatively (model 2), it was suggested that CR does not alter the NAD:NADH ratio, but rather acts by increasing expression of Pnc1, which degrades the endogenous Sir2 inhibitor nicotinamide, thus increasing Sir2 activity (Anderson et al., 2003). In both models, activation of Sir2 leads to increased rDNA silencing and a consequent reduction in recombination between rDNA repeats; this reduces the formation of extrachromosomal rDNA circles (Sinclair & Guarente, 1997) and so retards aging.

Bottom Line: Although accumulation of extrachromosomal rDNA circles is specific to yeast aging, it is thought that Sirtuin activation represents a conserved longevity mechanism through which the beneficial effects of CR are mediated in various species.We show here that growing yeast on 0.05 or 0.5% glucose (severe and moderate CR, respectively) does not increase silencing at either sub-telomeric or rDNA loci compared with standard (2% glucose) media.In contrast, CR and deletion of the FOB1, HXK2, SCH9 and TOR1 genes, all significantly reduced rDNA recombination.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, School of Biomedical Sciences, University of Liverpool, Crown Street, Liverpool, UK.

ABSTRACT
Calorie restriction (CR) extends lifespan in yeast, worms, flies and mammals, suggesting that it acts via a conserved mechanism. In yeast, activation of the NAD-dependent histone deacetylase, Sir2, by CR is thought to increase silencing at the ribosomal DNA, thereby reducing the recombination-induced generation of extrachromosomal rDNA circles, hence increasing replicative lifespan. Although accumulation of extrachromosomal rDNA circles is specific to yeast aging, it is thought that Sirtuin activation represents a conserved longevity mechanism through which the beneficial effects of CR are mediated in various species. We show here that growing yeast on 0.05 or 0.5% glucose (severe and moderate CR, respectively) does not increase silencing at either sub-telomeric or rDNA loci compared with standard (2% glucose) media. Furthermore, rDNA silencing was unaffected in the hxk2Delta, sch9Delta and tor1Delta genetic mimics of CR, but inhibited by FOB1 deletion. All these interventions extend lifespan in multiple yeast backgrounds, revealing a poor correlation between rDNA silencing and longevity. In contrast, CR and deletion of the FOB1, HXK2, SCH9 and TOR1 genes, all significantly reduced rDNA recombination. This silencing-independent mechanism for suppressing rDNA recombination may therefore contribute to CR-mediated lifespan extension.

Show MeSH