Yeast Life Span Extension by Depletion of 60S Ribosomal Subunits Is Mediated by Gcn4

Steffen, Kristan K.; MacKay, Vivian L.; Kerr, Emily O.; Tsuchiya, Mitsuhiro; Hu, Di; Fox, Lindsay A.; Dang, Nick; Johnston, Elijah D.; Oakes, Jonathan A.; Tchao, Bie N.; Pak, Diana N.; Fields, Stanley; Kennedy, Brian K.; Kaeberlein, Matt

doi:10.1016/j.cell.2008.02.037

Cited by 435 publications

(536 citation statements)

References 69 publications

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“…Activation of the TSP would be predicted to drain metabolites from the methionine cycle and limit availability of this amino acid for protein synthesis. Reduction of general translation is associated with DR longevity in Saccharomyces cerevisiae and C. elegans (21-23), perhaps through a mechanism whereby key mRNA are preferentially translated (21,24). We found that, as in yeast and nematodes, DR in flies resulted in a nearly 50% decrease in global levels of protein synthesis and in total protein levels ( Fig.…”

Section: Resultsmentioning

confidence: 73%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

154

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The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.hydrogen sulfide | essential amino acids | metabolism | healthspan F or a broad range of taxonomically diverse organisms, the quality of their diet acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. Lifespan is extended, for example, when food is restricted to an extent that falls short of inducing starvation. In mammals, this manipulation, which is often called dietary restriction (DR), not only increases lifespan but also imparts a broad-spectrum improvement in health during aging. In humans, for example, DR reduces risk factors for diabetes, cardiovascular disease, and cancer (1).Transsulfuration is an evolutionarily ancient metabolic process that involves a network of enzymes responsible for the metabolism of sulfur-containing amino acids. The transsulfuration pathway (TSP) has been studied extensively in mammals, in which it has been shown to direct the conversion of homocysteine to cysteine following the breakdown of methionine, an essential amino acid. Flux through the TSP is known to affect overall cellular metabolism by directly influencing cysteine and methionine levels. Methionine availability affects protein synthesis and methylation, and it has been implicated in murine aging (2). Cysteine availability controls the synthesis of glutathione (GSH), which is the chief regulator of cellular redox homeostasis and an important agent in xenobiotic detoxification (Fig. 1A). Patients with genetic defects in the TSP are characterized by high levels of homocysteine, low levels of GSH, and increased incidence of age-related path...

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Section: Resultsmentioning

confidence: 73%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

130

154

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“…However, it would be interesting in the future to study the impact of Maf1 on other Sch9 phenotypes such as cell size regulation and longevity (Jorgensen et al 2004;Kaeberlein et al 2005). In particular, regulation of tRNA and especially initiator tRNA Met levels by Maf1 could affect translation and, via Gcn4, longevity as recently observed (Steffen et al 2008). …”

Section: Sch9 Is a Central Coordinator Of Protein Synthesismentioning

confidence: 99%

Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis

Huber¹,

Bodenmiller²,

Uotila³

et al. 2009

Genes Dev.

316

404

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The target of rapamycin complex 1 (TORC1) is an essential multiprotein complex conserved from yeast to humans. Under favorable growth conditions, and in the absence of the macrolide rapamycin, TORC1 is active, and influences virtually all aspects of cell growth. Although two direct effectors of yeast TORC1 have been reported (Tap42, a regulator of PP2A phosphatases and Sch9, an AGC family kinase), the signaling pathways that couple TORC1 to its distal effectors were not well understood. To elucidate these pathways we developed and employed a quantitative, label-free mass spectrometry approach. Analyses of the rapamycin-sensitive phosphoproteomes in various genetic backgrounds revealed both documented and novel TORC1 effectors and allowed us to partition phosphorylation events between Tap42 and Sch9. Follow-up detailed characterization shows that Sch9 regulates RNA polymerases I and III, the latter via Maf1, in addition to translation initiation and the expression of ribosomal protein and ribosome biogenesis genes. This demonstrates that Sch9 is a master regulator of protein synthesis.[Keywords: Maf1; Sch9; TOR; phosphoproteomics; rapamycin; ribosome biogenesis] Supplemental material is available at http://www.genesdev.org.

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“…Strikingly, all of the long-lived RPG deletions encoded components of the large subunit of the ribosome, precluding the simplest model that reduced translation was coupled to lifespan extension, since many strains lacking small subunit components have reduced translation: e.g. long-lived yeast rpl31aD, rpl20bD, and rpl21aD strains have been shown by depressed overall polysome profiles to have decreased overall translation [68]. Instead, the mechanism, at least in part, entails activation of translation of GCN4, a transcription factor the own expression of which is regulated at the translational level.…”

Section: Introductionmentioning

confidence: 99%

“…Mutation of other translation initiation factors is associated with enhanced longevity in yeast and worms [1,16,41], as well as reduced expression of ribosomal protein genes (RPGs) [41,68,69]. The latter effect has been best studied via the yeast replicative ageing assay, where the lifespan of every viable RPG knockout was determined.…”

Section: Introductionmentioning

confidence: 99%

TOR and ageing: a complex pathway for a complex process

McCormick

Tsai

Kennedy

2011

Phil. Trans. R. Soc. B

Self Cite

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Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity.

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Yeast Life Span Extension by Depletion of 60S Ribosomal Subunits Is Mediated by Gcn4

Cited by 435 publications

References 69 publications

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis

TOR and ageing: a complex pathway for a complex process

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