Sulfur restriction extends fission yeast chronological lifespan through Ecl1 family genes by downregulation of ribosome (original) (raw)
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A novel gene, ecl1+, extends the chronological lifespan in fission yeast
FEMS Yeast Research, 2008
We have identified a novel gene from Schizosaccharomyces pombe that we have named ecl1 1 (extender of the chronological lifespan). When ecl1 1 is provided on a high-copy number plasmid, it extends the viability of both the Dsty1 MAP kinase mutant and the wild-type cells after entry into the stationary phase. ecl1 1 encodes an 80-amino acid polypeptide that had not been annotated in the current database. The ecl1 1-mRNA increases transiently when the growth phase is changed from the log phase to the stationary phase. The Ecl1 protein is localized in the nucleus. Calorie restriction extends the chronological lifespan of wild-type and Decl1 cells but not ecl1 1-overproducing cells. The Dpka1 mutant shows little, if any, additional extension of viability when Ecl1 is overproduced. The ste11 1 gene that is negatively controlled by Pka1 is up regulated when Ecl1 is overproduced. From these results we propose that the effect of Ecl1 overproduction may be mainly linked to and negatively affects the Pka1-dependent pathway.
Aging Cell, 2007
Calorie restriction (CR) extends the mean and maximum lifespan of a wide variety of organisms ranging from yeast to mammals, although the molecular mechanisms of action remain unclear. For the budding yeast Saccharomyces cerevisiae reducing glucose in the growth medium extends both the replicative and chronological lifespans (CLS). The conserved NAD+-dependent histone deacetylase, Sir2p, promotes replicative longevity in S. cerevisiae by suppressing recombination within the ribosomal DNA locus and has been proposed to mediate the effects of CR on aging. In this study, we investigated the functional relationships of the yeast Sirtuins (Sir2p, Hst1p, Hst2p, Hst3p and Hst4p) with CLS and CR. SIR2, HST2, and HST4 were not major regulators of CLS and were not required for the lifespan extension caused by shifting the glucose concentration from 2 to 0.5% (CR). Deleting HST1 or HST3 moderately shortened CLS, but did not prevent CR from extending lifespan. CR therefore works through a Sirtuin-independent mechanism in the chronological aging system. We also show that low temperature or high osmolarity additively extends CLS when combined with CR, suggesting that these stresses and CR act through separate pathways. The CR effect on CLS was not specific to glucose. Restricting other simple sugars such as galactose or fructose also extended lifespan. Importantly, growth on nonfermentable carbon sources that force yeast to exclusively utilize respiration extended lifespan at nonrestricted concentrations and provided no additional benefit when restricted, suggesting that elevated respiration capacity is an important determinant of chronological longevity.
Genomewide mechanisms of chronological longevity by dietary restriction in budding yeast
Aging cell, 2018
Dietary restriction is arguably the most promising nonpharmacological intervention to extend human life and health span. Yet, only few genetic regulators mediating the cellular response to dietary restriction are known, and the question remains which other regulatory factors are involved. Here, we measured at the genomewide level the chronological lifespan of Saccharomyces cerevisiae gene deletion strains under two nitrogen source regimens, glutamine (nonrestricted) and γ-aminobutyric acid (restricted). We identified 473 mutants with diminished or enhanced extension of lifespan. Functional analysis of such dietary restriction genes revealed novel processes underlying longevity by the nitrogen source quality, which also allowed us to generate a prioritized catalogue of transcription factors orchestrating the dietary restriction response. Importantly, deletions of transcription factors Msn2, Msn4, Snf6, Tec1, and Ste12 resulted in diminished lifespan extension and defects in cell cycl...
Gene regulatory changes in yeast during life extension by nutrient limitation
Experimental Gerontology, 2010
Genetic analyses aimed at identification of the pathways and downstream effectors of calorie restriction (CR) in the yeast Saccharomyces cerevisiae suggest the importance of central metabolism for the extension of replicative life span by CR. However, the limited gene expression studies to date are not informative, because they have been conducted using cells grown in batch culture which markedly departs from the conditions under which yeasts are grown during life span determinations. In this study, we have examined the gene expression changes that occur during either glucose limitation or elimination of nonessential amino acids, both of which enhance yeast longevity, culturing cells in a chemostat at equilibrium, which closely mimicks conditions they encounter during life span determinations. Expression of 59 genes was examined quantitatively by real-time, reverse transcriptase polymerase chain reaction (qRT-PCR), and the physiological state of the cultures was monitored. Extensive gene expression changes were detected, some of which were common to both CR regimes. The most striking of these was the induction of tricarboxylic acid (TCA) cycle and retrograde response target genes, which appears to be at least partially due to the up-regulation of the HAP4 gene. These gene regulatory events portend an increase in the generation of biosynthetic intermediates necessary for the production of daughter cells, which is the measure of yeast replicative life span.
Genes to Cells, 2012
+ , ecl2 + and ecl3 + genes encode highly homologous small proteins, and their over-expressions confer both H 2 O 2 stress resistance and chronological lifespan extension on Schizosaccharomyces pombe. However, the mechanisms of how these Ecl1 family proteins function have not been elucidated. In this study, we conducted microarray analysis and identified that the expression of genes involved in sexual development and stress responses was affected by the over-expression of Ecl1 family proteins. In agreement with the mRNA expression profile, the cells over-expressing Ecl1 family proteins showed high mating efficiency and resistant phenotype to H 2 O 2. We showed that the H 2 O 2-resistant phenotype depends on catalase Ctt1, and over-expression of ctt1 + does not affect chronological lifespan. Furthermore, we showed that six genes, ste11 + , spk1 + , hsr1 + , rsv2 + , hsp9 + and lsd90 + , whose expressions are increased in cells over-expressing Ecl1 family proteins are involved in chronological lifespan in fission yeast. Among these genes, the induction of ste11 + and hsr1 + was dependent on a transcription factor Prr1, and we showed that the extensions of chronological lifespan by Ecl1 family proteins are remarkably diminished in prr1 deletion mutant. From these results, we propose that Ecl1-family proteins conduct H 2 O 2 stress resistance and chronological lifespan extension in ctt1 +-and prr1 +-dependent manner, respectively.
Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
Nature, 2003
Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD +-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B 3 precursor nicotinamide 2. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and lowintensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms. Lifespan in the budding yeast S. cerevisiae is extended by a variety of stimuli such as heat stress, osmotic stress and the restriction of amino acids or glucose 1,3-5. The latter two regimens are considered to be mimics of calorie restriction in higher organisms. In S. cerevisiae, replicative age is defined as the number of divisions that a cell undergoes before dying. The yeast SIR2 gene, which encodes the founding member of a conserved family of NAD +-dependent deacetylases 6-9 , is required for lifespan extension by glucose restriction 1. Cells with an additional copy of SIR2 live 30% longer than the wild type, whereas sir2Δ strains age prematurely 10 owing to increased recombination at the ribosomal DNA (rDNA) locus 10,11. The importance of elucidating the yeast SIR2 pathway is underscored by increasing evidence that Sir2 proteins in higher organisms promote longevity and cell viability 12-15. Because Sir2 protein levels do not increase in response to calorie restriction 16 , lifespan extension must involve an increase in enzymatic activity of Sir2. One hypothesis is that Sir2 Correspondence and requests for materials should be addressed to D.A.S.
An intervention resembling caloric restriction prolongs life span and retards aging in yeast
Faseb Journal, 2000
The yeast Saccharomyces cerevisiae has a finite life span that is measured by the number of daughter cells an individual produces. The 20 genes known to determine yeast life span appear to function in more than one pathway, implicating a variety of physiological processes in yeast longevity. Less attention has been focused on environmental effects on yeast aging. We have examined the role that nutritional status plays in determining yeast life span. Reduction of the glucose concentration in the medium led to an increase in life span and to a delay in appearance of an aging phenotype. The increase in life span was the more extensive the lower the glucose levels. Life extension was also elicited by decreasing the amino acids content of the medium. This suggests that it is the decline in calories and not a particular nutrient that is responsible, in striking similarity to the effect on aging of caloric restriction in mammals. The caloric restriction effect did not require the induction of the retrograde response pathway, which signals the functional status of the mitochondrion and determines longevity. Furthermore, deletion of RTG3, a downstream mediator in this pathway, and caloric restriction had an additive effect, resulting in the largest increase (123%) in longevity described thus far in yeast. Thus, retrograde response and caloric restriction operate along distinct pathways in determining yeast longevity. These pathways may be exclusive, at least in part. This provides evidence for multiple mechanisms of metabolic control in yeast aging. Inasmuch as caloric restriction lowers blood glucose levels, this study raises the possibility that reduced glucose alters aging at the cellular level in mammals.
Calorie Restriction-Mediated Replicative Lifespan Extension in Yeast Is Non-Cell Autonomous
PLOS Biology, 2015
In laboratory yeast strains with Sir2 and Fob1 function, wild-type NAD + salvage is required for calorie restriction (CR) to extend replicative lifespan. CR does not significantly alter steady state levels of intracellular NAD + metabolites. However, levels of Sir2 and Pnc1, two enzymes that sequentially convert NAD + to nicotinic acid (NA), are up-regulated during CR. To test whether factors such as NA might be exported by glucose-restricted mother cells to survive later generations, we developed a replicative longevity paradigm in which mother cells are moved after 15 generations on defined media. The experiment reveals that CR mother cells lose the longevity benefit of CR when evacuated from their local environment to fresh CR media. Addition of NA or nicotinamide riboside (NR) allows a moved mother to maintain replicative longevity despite the move. Moreover, conditioned medium from CRtreated cells transmits the longevity benefit of CR to moved mother cells. Evidence suggests the existence of a longevity factor that is dialyzable but is neither NA nor NR, and indicates that Sir2 is not required for the longevity factor to be produced or to act. Data indicate that the benefit of glucose-restriction is transmitted from cell to cell in budding yeast, suggesting that glucose restriction may benefit neighboring cells and not only an individual cell.