Authors: Steffen KK; MacKay VL; Kerr EO; Tsuchiya M; Hu D; Fox LA; Dang N; Johnston ED; Oakes JA; Tchao BN; Pak DN; Fields S; Kennedy BK; Kaeberlein M
Abstract: In nearly every organism studied, reduced caloric intake extends life span. In yeast, span extension from dietary restriction is thought to be mediated by the highly conserved, nutrient-responsive target of rapamycin (TOR), protein kinase A (PKA), and Sch9 kinases. These kinases coordinately regulate various cellular processes including stress responses, protein turnover, cell growth, and ribosome biogenesis. Here we show that a specific reduction of 60S ribosomal subunit levels slows aging in yeast. Deletion of genes encoding 60S subunit proteins or processing factors or treatment with a small molecule, which all inhibit 60S subunit biogenesis, are each sufficient to significantly increase replicative life span. One mechanism by which reduced 60S subunit levels leads to life span extension is through induction of Gcn4, a nutrient-responsive transcription factor. Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms.Keywords: Basic-Leucine Zipper Transcription Factors; DNA-Binding Proteins/*physiology; Gene Deletion; Histone Deacetylases/physiology; Ribosomal Proteins/physiology; Ribosome Subunits, Large, Eukaryotic/*physiology; Saccharomyces cerevisiae/*physiology; Saccharomyces cerevisiae Proteins/*physiology; Silent Information Regulator Proteins, Saccharomyces cerevisiae/physiology; Sirtuin 2; Sirtuins/physiology; Transcription Factors/*physiology
Date: April 22, 2008
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Steffen KK, MacKay VL, Kerr EO, Tsuchiya M, Hu D, Fox LA, Dang N, Johnston ED, Oakes JA, Tchao BN, Pak DN, Fields S, Kennedy BK, Kaeberlein M (2008) Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4. Cell 133: 292-302.