Longevity Regulation in Saccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.     

Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin.

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.     

Chronological aging-induced apoptosis in yeast

Saccharomyces cerevisiae is the simplest among the major eukaryotic model organisms for aging and diseases. Longevity in the chronological life span paradigm is measured as the mean and maximum survival period of populations of non-dividing yeast. This paradigm has been used successfully to identify several life-regulatory genes and three evolutionary conserved pro-aging pathways. More recently, Schizosaccharomyces pombe has been shown to age chronologically in a manner that resembles that of S. cerevisiae and that depends on the activity of the homologues of two pro-aging proteins previously identified in the budding yeast. Both yeast show features of apoptotic death during chronological aging. Here, we review some fundamental aspects of the genetics of chronological aging and the overlap between yeast aging and apoptotic processes with particular emphasis on the identification of an aging/death program that favors the dedifferentiation and regrowth of a few better adapted mutants generated within populations of aging S. cerevisiae. We also describe the use of a genome-wide screening technique to gain further insights into the mechanisms of programmed death in populations of chronologically aging S. cerevisiae.     

The ABC transporters of Saccharomyces cerevisiae

The ABC transporters (ATP Binding Cassette) compose one of the bigest protein family with the great medical, industrial and economical impact. They are found in all organism from bacteria to man. ABC proteins are responsible for resistance of microorganism to antibiotics and fungicides and multidrug resistance of cancer cells. Mutations in ABC transporters genes cause seriuos deseases like cystic fibrosis, adrenoleucodystrophy or ataxia. Transport catalized by ABC proteins is charged with energy from the ATP hydrolysis. The ABC superfamily contains transporters, canals, receptors. Analysis of the Saccharomyces cerevisiae genome allowed to distinguish 30 potential ABC proteins which are classified into 6 subfamilies. The structural and functional similarity of the yeast and human ABC proteins allowes to use the S. cerevisiae as a model organism for ABC transporters characterisation. In this work the present state of knowleadge on yeast S. cerevisiae ABC proteins was summarised.     

国内酿酒酵母分子遗传与育种研究40年

酿酒酵母作为最简单的真核生物,是研究真核生物基本生命规律的重要模式系统,也是生物产业领域非常重要的微生物细胞工厂。在《微生物学通报》创刊40周年之际,本文综述了国内40年来在酿酒酵母分子遗传学与育种研究的重要进展,如分子遗传学研究手段的建立、重要功能基因的分析、重要生命过程的遗传基础和调控机制,以及酵母菌育种技术的建立与应用等。     

Reconstitution of human RNA interference in budding yeast

Although RNA-mediated interference (RNAi) is a widely conserved process among eukaryotes, including many fungi, it is absent from the budding yeast Saccharomyces cerevisiae. Three human proteins, Ago2, Dicer and TRBP, are sufficient for reconstituting the RISC complex in vitro. To examine whether the introduction of human RNAi genes can reconstitute RNAi in S. cerevisiae, genes encoding these three human proteins were introduced into S. cerevisiae. We observed both siRNA and siRNA- and RISC-dependent silencing of the target gene GFP. Thus, human Ago2, Dicer and TRBP can functionally reconstitute human RNAi in S. cerevisiae, in vivo, enabling the study and use of the human RNAi pathway in a facile genetic model organism.     

Dynamic analysis of dorsal closure in Drosophila: from genetics to cell biology

Recent studies on aging in model systems such as yeast and roundworms have revealed conserved regulation of the process in response to nutrient availability and specific genes that appear to mediate this regulation. Here we review these findings with a focus on the nematode Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae and highlight general features of the regulation of aging that may have implications for mammals.     

Candida albicans Mds3p,a conserved regulator of pH responses and virulence identified through insertional mutagenesis

Candida albicans is a commensal fungus that causes diverse infections after antibiotic use or immune debilitation. Gene discovery has been limited because the organism is an asexual diploid. We have developed a strategy that yields random homozygous insertion mutants. The strategy has permitted identification of several prospective essential genes. Many of these genes are homologous to nonessential Saccharomyces cerevisiae genes, and some have no S. cerevisiae homolog. These findings may expand the range of antifungal drug targets. We have also identified new genes required for pH-dependent filamentation, a trait previously associated with virulence. One newly identified gene, MDS3, is required for expression in alkaline media of two filamentation-associated genes, HWP1 and ECE1, but is not required for expression of other pH-response genes. In S. cerevisiae, the two MDS3 homologs are required for growth in alkaline media, thus arguing that Mds3p function in adaptation to external pH changes is conserved. Epistasis tests show that Mds3p contributes to virulence and alkaline pH responses independently of the well-characterized Rim101p pH-response pathway.     

Significant impact of protein dispensability on the instantaneous rate of protein evolution

The neutral theory of molecular evolution predicts that important proteins evolve more slowly than unimportant ones. High-throughput gene-knockout experiments in model organisms have provided information on the dispensability, and therefore importance, of thousands of proteins in a genome. However, previous studies of the correlation between protein dispensability and evolutionary rate were equivocal, and it has been proposed that the observed correlation is due to the covariation with the level of gene expression or is limited to duplicate genes. We here analyzed the gene dispensability data of the yeast Saccharomyces cerevisiae and estimated protein evolutionary rates by comparing S. cerevisiae with nine species of varying degrees of divergence from S. cerevisiae. The correlation between gene dispensability and evolutionary rate, although low, is highly significant, even when the gene expression level is controlled for or when duplicate genes are excluded. Our results thus support the hypothesis of lower evolution rates for more important proteins, a widely used principle in the daily practice of molecular biology. When the evolutionary rate is estimated from closely related species, the ratio between the mean rate of nonessential proteins to that of essential proteins is 1.4. This ratio declines to 1.1 when the evolutionary rate is estimated from distantly related species, suggesting that the importance of a protein may change in evolution, so the dispensability data obtained from a model organism only predicts a short-term rate of protein evolution. A comparison of the fitness contributions of orthologous genes in yeast and nematode supports this conclusion.     

Longevity genomics across species

Unbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms. Key pathways have been uncovered linking nutrient and growth factor cues to longevity. Quantitative measures of the degree to which aging is evolutionary conserved are now possible. A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.     

长寿和衰老基因及相关基因研究进展

简要介绍了长寿和衰老基因及相关基因在酵母、线虫、果蝇和哺乳动物中的最新遗传学研究进展；概述了“生物钟”、端粒和端粒酶在人类长寿和衰老进程中的重要作用。相信随着人类遗传学和分子生物学研究的深入，将有更多的长寿和衰老基因及相关基因被发现，为揭示衰老机制和延年益寿提供依据。     

细胞衰老相关基因的探索

细胞衰老与个体衰老、机体自我保护及细胞癌变等多种重要生理、病理现象密切相关,其机制研究可望应用于癌症治疗.简述了近年有关哺乳类动物细胞衰老相关基因的寻找过程.     

Comparative genomics: the key to understanding the Human Genome Project

The sequencing of the human genome is well underway. Technology has advanced, such that the total genomic sequence is possible, along with an extensive catalogue of genes via comprehensive cDNA libraries. With the recent completion of the Saccharomyces cerevisiae sequencing project and the imminent completion of that of Caenorhabditis elegans, the most frequently asked question is how much can sequence data alone tell us? The answer is that that a DNA sequence taken in isolation from a single organism reveals very little. The vast majority of DNA in most organisms is noncoding. Protein coding sequences or genes cannot function as isolated units without interaction with noncoding DNA and neighboring genes. This genomic environment is specific to each organism. In order to understand this we need to look at similar genes in different organisms, to determine how function and position has changed over the course of evolution. By understanding evolutionary processes we can gain a greater insight into what makes a gene and the wider processes of genetics and inheritance. Comparative genomics (with model organisms), once the poor relation of the human genome project, is starting to provide the key to unlock the DNA code.     

Three aldo-keto reductases of the yeast Saccharomyces cerevisiae

Saccharomyces cerevisiae is an industrially important yeast, which is also used extensively as a model eukaryote. The S. cerevisiae genome has been sequenced in its entirety and therefore represents an ideal organism in which to carry out functional analysis of genes. We have identified several open reading frames in the S. cerevisiae genome which show significant similarity to members of the aldo-keto reductase superfamily. The physiological roles of these gene products have not been previously determined, but their similarity to other enzymes suggests they may perform roles in carbohydrate metabolism and detoxification pathways. Cloning and expression of three of these enzymes has allowed their substrate specificities to be determined. Expression profiling and gene disruption analysis will allow potential roles for these enzymes within the cell to be examined.     

Aging, evolvability, and the individual benefit requirement; medical implications of aging theory controversies

There is a class of theories of aging (variously termed adaptive aging, aging by design, aging selected for its own sake, or programmed death theories) that hold that an organism design that limits life span conveys benefits and was selected specifically because it limits life span. These theories have enjoyed a resurgence of popularity because of the discovery of genes that promote aging in various organisms.However, traditional evolution theory has a core tenet that excludes the possibility of evolving and retaining an individually adverse organism design, i.e. a design characteristic that reduces the ability of individual organisms to survive or reproduce without any compensating individual benefit. Various theories of aging dating from the 1950s and based on traditional evolution theory enjoy substantial popularity. Therefore, any theorist proposing an adaptive theory of aging must necessarily also propose some adjustment to traditional evolution theory that specifically addresses the individual benefit issue. This paper describes an adaptive theory of aging and describes how one of the proposed adjustments (evolvability theory) supports adaptive aging.This issue is important because adaptive theories are generally more optimistic regarding prospects for medical intervention in the aging process and also suggest different approaches in achieving such intervention.     

Long-lived worms and aging

Several investigators have generated long-lived nematode worms (Caenorhabditis elegans) in the past decade by mutation of genes in the organism in order to study the genetics of aging and longevity. Dozens of longevity assurance genes (LAG) that dramatically increase the longevity of this organism have been identified. All long-lived mutants of C. elegans are also resistant to environmental stress, such as high temperature, reactive oxygen species (ROS), and ultraviolet irradiation. Double mutations of some LAGs further extended life span up to 400%, providing more insight into cellular mechanisms that put limits on the life span of organisms. With the availability of the LAG mutants and the combined DNA microarray and RNAi technology, the understanding of actual biochemical processes that determine life span is within reach: the downstream signal transduction pathway may regulate life span by up-regulating pro-longevity genes such as those that encode antioxidant enzymes and/or stress-response proteins, and down-regulating specific life-shortening genes. Furthermore, longevity could be modified through chemical manipulation. Results from these studies further support the free radical theory of aging, suggest that the molecular mechanism of aging process may be shared in all organisms, and provide insight for therapeutic intervention in age-related diseases.     

Genomic exploration of the hemiascomycetous yeasts: 10. Kluyveromyces thermotolerans

A genomic exploration of Kluyveromyces thermotolerans was performed by random sequence tag (RST) analysis. We sequenced 2653 RSTs corresponding to inserts sequenced from both ends. We performed a systematic comparison with a complete set of proteins from Saccharomyces cerevisiae, other completely sequenced genomes and SwissProt. We identified six mitochondrial genes and 1358-1496 nuclear genes by comparison with S. cerevisiae. In addition, 25 genes were identified by comparison with other organisms. This corresponds to about 24% of the estimated gene content of this organism. A lower level of conservation is observed with orthologues to genes of S. cerevisiae previously classified as orphans. Gene order was found to be conserved between S. cerevisiae and K. thermotolerans in 56.5% of studied cases.