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1
Sims, Kellie J., Stefka D. Spassieva, Eberhard O. Voit, and Lina M. Obeid. "Yeast sphingolipid metabolism: clues and connections." Biochemistry and Cell Biology 82, no. 1 (February 1, 2004): 45–61. http://dx.doi.org/10.1139/o03-086.
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This review of sphingolipid metabolism in the budding yeast Saccharomyces cerevisiae contains information on the enzymes and the genes that encode them, as well as connections to other metabolic pathways. Particular attention is given to yeast homologs, domains, and motifs in the sequence, cellular localization of enzymes, and possible protein–protein interactions. Also included are genetic interactions of special interest that provide clues to the cellular biological roles of particular sphingolipid metabolic pathways and specific sphingolipids.Key words : yeast, sphingolipid metabolism, subcellular localization, protein–protein interactions, stress response, aging.
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Bitterman, Kevin J., Oliver Medvedik, and David A. Sinclair. "Longevity Regulation in Saccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin." Microbiology and Molecular Biology Reviews 67, no. 3 (September 2003): 376–99. http://dx.doi.org/10.1128/mmbr.67.3.376-399.2003.
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SUMMARY 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.
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Musa, Marina, Matea Perić, Peter Bou Dib, Sandra Sobočanec, Ana Šarić, Anita Lovrić, Marina Rudan, et al. "Heat-induced longevity in budding yeast requires respiratory metabolism and glutathione recycling." Aging 10, no. 9 (September 17, 2018): 2407–27. http://dx.doi.org/10.18632/aging.101560.
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González-Jiménez, Maria del Carmen, Jaime Moreno-García, Teresa García-Martínez, Juan José Moreno, Anna Puig-Pujol, Fina Capdevilla, and Juan Carlos Mauricio. "Differential Analysis of Proteins Involved in Ester Metabolism in two Saccharomyces cerevisiae Strains during the Second Fermentation in Sparkling Wine Elaboration." Microorganisms 8, no. 3 (March 13, 2020): 403. http://dx.doi.org/10.3390/microorganisms8030403.
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The aromatic metabolites derived from yeast metabolism determine the characteristics of aroma and taste in wines, so they are considered of great industrial interest. Volatile esters represent the most important group and therefore, their presence is extremely important for the flavor profile of the wine. In this work, we use and compare two Saccharomyces cerevisiae yeast strains: P29, typical of sparkling wines resulting of second fermentation in a closed bottle; G1, a flor yeast responsible for the biological aging of Sherry wines. We aimed to analyze and compare the effect of endogenous CO2 overpressure on esters metabolism with the proteins related in these yeast strains, to understand the yeast fermentation process in sparkling wines. For this purpose, protein identification was carried out using the OFFGEL fractionator and the LTQ Orbitrap, following the detection and quantification of esters with gas chromatograph coupled to flame ionization detector (GC-FID) and stir-bar sorptive extraction, followed by thermal desorption and gas chromatography-mass spectrometry (SBSE-TD-GC-MS). Six acetate esters, fourteen ethyl esters, and five proteins involved in esters metabolism were identified. Moreover, significant correlations were established between esters and proteins. Both strains showed similar behavior. According to these results, the use of this flor yeast may be proposed for the sparkling wine production and enhance the diversity and the typicity of sparkling wine yeasts.
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Yu, Ruofan, Xiaohua Cao, and Weiwei Dang. "HIGH THROUGHPUT YEAST REPLICATIVE LIFESPAN SCREEN UNCOVERS HISTONE DEACETYLASE HDA AS NOVEL REGULATOR OF AGING." Innovation in Aging 3, Supplement_1 (November 2019): S876. http://dx.doi.org/10.1093/geroni/igz038.3210.
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Abstract In this work, we set out to develop a high throughput screening method, SEBYL (SEquencing Based Yeast replicative Lifespan screen), in order to identify new aging regulators in budding yeast. By utilizing SEBYL on yeast knockout collection, we were able to identify 285 long-lived gene deletions, of which a significant portion was proven to have extended lifespan by previous classical experiments. To demonstrate the ability of our method to discover new genes and pathways involved in aging process, we focused on characterizing one newly identified long-lived candidate emerged from the screening, histone deacetylase complex HDA, and found it regulates aging through mediating stress response pathways, especially DNA damage stress response. Presence of HDA complex inhibits expression of trehalose metabolism genes, which act as stress protectant. When HDA complex is mutated, trehalose genes are de-repressed, enhancing stress response and eventually promotes longevity. In summary, we conclude SEBYL to be time and energy saving, robust, and suitable for discovery of aging regulating genes using various preexisting yeast mutant collection resource.
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Váchová, Libuše, and Zdena Palková. "Aging and longevity of yeast colony populations: metabolic adaptation and differentiation." Biochemical Society Transactions 39, no. 5 (September 21, 2011): 1471–75. http://dx.doi.org/10.1042/bst0391471.
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Yeast multicellular colonies possess several traits that are absent from individual yeasts. These include the ability to synchronize colony population development and adapt its metabolism to different environmental changes, such as nutrient depletion. This, together with cell diversification to cell variants with distinct metabolic and other properties, contributes to the main goal of the colony population: to achieve longevity. In this respect, a benefit to individual cells is subordinated to the benefit to the whole population, exhibiting a kind of altruistic behaviour. For example, some colony cells located at particular positions undergo regulated cell dying and provide components to other cells located in more propitious areas. The enhancement of techniques that enable the in vivo investigation of three-dimensional spatiotemporal colony development may lead to new discoveries on metabolic differentiation and regulation in the near future.
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Orlandi, Ivan, Lilia Alberghina, and Marina Vai. "Nicotinamide, Nicotinamide Riboside and Nicotinic Acid—Emerging Roles in Replicative and Chronological Aging in Yeast." Biomolecules 10, no. 4 (April 15, 2020): 604. http://dx.doi.org/10.3390/biom10040604.
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Nicotinamide, nicotinic acid and nicotinamide riboside are vitamin B3 precursors of NAD+ in the human diet. NAD+ has a fundamental importance for cellular biology, that derives from its essential role as a cofactor of various metabolic redox reactions, as well as an obligate co-substrate for NAD+-consuming enzymes which are involved in many fundamental cellular processes including aging/longevity. During aging, a systemic decrease in NAD+ levels takes place, exposing the organism to the risk of a progressive inefficiency of those processes in which NAD+ is required and, consequently, contributing to the age-associated physiological/functional decline. In this context, dietary supplementation with NAD+ precursors is considered a promising strategy to prevent NAD+ decrease and attenuate in such a way several metabolic defects common to the aging process. The metabolism of NAD+ precursors and its impact on cell longevity have benefited greatly from studies performed in the yeast Saccharomyces cerevisiae, which is one of the most established model systems used to study the aging processes of both proliferating (replicative aging) and non-proliferating cells (chronological aging). In this review we summarize important aspects of the role played by nicotinamide, nicotinic acid and nicotinamide riboside in NAD+ metabolism and how each of these NAD+ precursors contribute to the different aspects that influence both replicative and chronological aging. Taken as a whole, the findings provided by the studies carried out in S. cerevisiae are informative for the understanding of the complex dynamic flexibility of NAD+ metabolism, which is essential for the maintenance of cellular fitness and for the development of dietary supplements based on NAD+ precursors.
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Sancho-Galán, Pau, Antonio Amores-Arrocha, Ana Jiménez-Cantizano, and Víctor Palacios. "Use of Multiflora Bee Pollen as a Flor Velum Yeast Growth Activator in Biological Aging Wines." Molecules 24, no. 9 (May 7, 2019): 1763. http://dx.doi.org/10.3390/molecules24091763.
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Flor velum yeast growth activators during biological aging are currently unknown. In this sense, this research focuses on the use of bee pollen as a flor velum activator. Bee pollen influence on viable yeast development, surface hydrophobicity, and yeast assimilable nitrogen has already been studied. Additionally, bee pollen effects on the main compounds related to flor yeast metabolism and wine sensory characteristics have been evaluated. “Fino” (Sherry) wine was supplemented with bee pollen using six different doses ranging from 0.1 to 20 g/L. Its addition in a dose equal or greater than 0.25 g/L can be an effective flor velum activator, increasing yeast populations and its buoyancy due to its content of yeast assimilable nitrogen and fatty acids. Except for the 20 g/L dose, pollen did not induce any significant effect on flor velum metabolism, physicochemical parameters, organic acids, major volatile compounds, or glycerol. Sensory analysis showed that low bee pollen doses increase wine’s biological aging attributes, obtaining the highest score from the tasting panel. Multiflora bee pollen could be a natural oenological tool to enhance flor velum development and wine sensory qualities. This study confirms association between the bee pollen dose applied and the flor velum growth rate. The addition of bee pollen could help winemakers to accelerate or reimplant flor velum in biologically aged wines.
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Nishimura, Akira, Yuki Yoshikawa, Kazuki Ichikawa, Tetsuma Takemoto, Ryoya Tanahashi, and Hiroshi Takagi. "Longevity Regulation by Proline Oxidation in Yeast." Microorganisms 9, no. 8 (August 2, 2021): 1650. http://dx.doi.org/10.3390/microorganisms9081650.
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Proline is a pivotal and multifunctional amino acid that is used not only as a nitrogen source but also as a stress protectant and energy source. Therefore, proline metabolism is known to be important in maintaining cellular homeostasis. Here, we discovered that proline oxidation, catalyzed by the proline oxidase Put1, a mitochondrial flavin-dependent enzyme converting proline into ∆1-pyrroline-5-carboxylate, controls the chronological lifespan of the yeast Saccharomyces cerevisiae. Intriguingly, the yeast strain with PUT1 deletion showed a reduced chronological lifespan compared with the wild-type strain. The addition of proline to the culture medium significantly increased the longevity of wild-type cells but not that of PUT1-deleted cells. We next found that induction of the transcriptional factor Put3-dependent PUT1 and degradation of proline occur during the aging of yeast cells. Additionally, the lifespan of the PUT3-deleted strain, which is deficient in PUT1 induction, was shorter than that of the wild-type strain. More importantly, the oxidation of proline by Put1 helped maintain the mitochondrial membrane potential and ATP production through the aging period. These results indicate that mitochondrial energy metabolism is maintained through oxidative degradation of proline and that this process is important in regulating the longevity of yeast cells.
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Jiménez-Lorenzo, Rafael, Vincent Farines, Jean-Marie Sablayrolles, Carole Camarasa, and Audrey Bloem. "New Insights into the Origin of Volatile Sulfur Compounds during Wine Fermentation and Their Evolution during Aging." Fermentation 8, no. 4 (March 23, 2022): 139. http://dx.doi.org/10.3390/fermentation8040139.
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Volatile sulfur compounds (VSCs) are associated with unpleasant reductive aromas and are responsible for an important reduction in wine quality, causing major economic losses. Understanding the origin of these compounds in wine remains a challenge, as their formation and further evolution during winemaking can involve both chemical and biological reactions. Comparing the VSCs profile (i) of fermenting synthetic grape juices supplemented with a selected VSC (eight compounds tested) and incubated in presence or absence of yeast, and (ii) during storage of wines under an accelerated aging procedure, allowed us to elucidate the chemical and metabolic connections between VSCs during fermentation and aging. Yeast metabolism, through the Ehrlich pathway and acetylation reactions, makes an important contribution to the formation of compounds such as methionol, 3-methylthiopropionate, 3-methylthiopropylacetate, 3-mercaptopropanol, 2-mercaptoethanol and thioesters. By contrast, chemical reactions are responsible for interconversions between thiols and disulfides, the formation of thiols from thioesters or, more surprisingly, the formation of ethylthiopropanol from methionol during fermentation. During aging, variations in heavy VSC concentrations, such as an increase in 3-methylthiopropylacetate and a decrease in ethyl-3-methylthiopropionate formation, were evidenced. Overall, this study highlights that it is essential to consider both yeast metabolism and the high chemical reactivity of VSCs to understand their formation and evolution during winemaking.
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Khandaker, AM, and A. Koc. "Deletion of mitochondrial inorganic pyrophosphatase gene extends life span in haploid yeast (Saccharomyces cerevisiae)." Journal of Biodiversity Conservation and Bioresource Management 3, no. 2 (April 25, 2018): 69–76. http://dx.doi.org/10.3329/jbcbm.v3i2.36030.
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Aging is a universal but poorly understood biological process and its underlying mechanisms are under intensive study. Mitochondria have a central role in the studies of aging hence they supply the majority of the organisms’ energy requirement from biological fuels. However, the role of mitochondria in the aging process is more complicated than the proposed theories of aging. We addressed a question by asking whether deletion to mitochondrial metabolism genes can extend life span in haploid cell of Saccharomyces cerevisiae (yeast). In this study, strains derived from the yeast open reading frame (ORF) deletions were screened through replicative aging assay in order to identify the mitochondrial metabolism genes that increase life span. This has resulted in the isolation of a long living (22% extended life span) mutant, ppa2Δ, which lack mitochondrial inorganic pyro phosphatase gene. The mitochondrial morphology of this long living mutant was analyzed by fluorescence microscopy. Compared to serpentine nature of wild type mitochondria, a different dynamics and distribution pattern was viewed, i.e. mitochondria were aggregated and formed colonies within the cytoplasm of this long lived cell. The aggregated mitochondrial mass was found to be intact from the young to old stage of life. Thus, this investigation reveals the longevity role of the mutant form of the gene PPA2 through an alteration of mitochondrial morphology.J. Biodivers. Conserv. Bioresour. Manag. 2017, 3(2): 69-76
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Ashrafi, Kaveh, Stephen S. Lin, Jill K. Manchester, and Jeffrey I. Gordon. "Sip2p and its partner Snf1p kinase affect aging in S. cerevisiae." Genes & Development 14, no. 15 (August 1, 2000): 1872–85. http://dx.doi.org/10.1101/gad.14.15.1872.
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For a number of organisms, the ability to withstand periods of nutrient deprivation correlates directly with lifespan. However, the underlying molecular mechanisms are poorly understood. We show that deletion of the N-myristoylprotein, Sip2p, reduces resistance to nutrient deprivation and shortens lifespan in Saccharomyces cerevisiae. This reduced lifespan is due to accelerated aging, as defined by loss of silencing from telomeres and mating loci, nucleolar fragmentation, and accumulation of extrachromosomal rDNA. Genetic studies indicate that sip2Δ produces its effect on aging by increasing the activity of Snf1p, a serine/threonine kinase involved in regulating global cellular responses to glucose starvation. Biochemical analyses reveal that as yeast age, hexokinase activity increases as does cellular ATP and NAD+ content. The change in glucose metabolism represents a new correlate of aging in yeast and occurs to a greater degree, and at earlier generational ages in sip2Δ cells. Sip2p and Snf1p provide new molecular links between the regulation of cellular energy utilization and aging.
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Wang, Siming, Juhui Qiao, Chunyan Jiang, Daian Pan, Shiting Yu, Jingjing Chen, Shichao Liu, Peiguang Zhang, Daqing Zhao, and Meichen Liu. "Ginsenoside Rg1 Delays Chronological Aging in a Yeast Model via CDC19- and SDH2-Mediated Cellular Metabolism." Antioxidants 12, no. 2 (January 28, 2023): 296. http://dx.doi.org/10.3390/antiox12020296.
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Ginsenosides, active substances in Panax ginseng C. A. Meyer (ginseng), extend lifespan in multiple species, ameliorate age-associated damage, and limit functional decline in multiple tissues. However, their active components and their molecular mechanisms are largely unknown. Here, ginsenoside Rg1 (Rg1) promoted longevity in Saccharomyces cerevisiae. Treatment with Rg1 decreased aging-mediated surface wrinkling, enhanced stress resistance, decreased reactive oxygen species’ production and apoptosis, improved antioxidant enzyme activity, and decreased the aging rate. Proteomic analysis indicated that Rg1 delays S. cerevisiae senescence by regulating metabolic homeostasis. Protein–protein interaction networks based on differential protein expression indicated that CDC19, a homologue of pyruvate kinase, and SDH2, the succinate dehydrogenase iron–sulfur protein subunit, might be the effector proteins involved in the regulation by Rg1. Further experiments confirmed that Rg1 improved specific parameters of mitochondrial bioenergetics and core enzymes in the glycolytic pathway. Mutant strains were constructed that demonstrated the relationships between metabolic homeostasis and the predicted target proteins of Rg1. Rg1 could be used in new treatments for slowing the aging process. Our results also provide a useful dataset for further investigations of the mechanisms of ginseng in aging.
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Bjedov, Ivana, and Linda Partridge. "A longer and healthier life with TOR down-regulation: genetics and drugs." Biochemical Society Transactions 39, no. 2 (March 22, 2011): 460–65. http://dx.doi.org/10.1042/bst0390460.
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Genetic down-regulation of a major nutrient-sensing pathway, TOR (target of rapamycin) signalling, can improve health and extend lifespan in evolutionarily distant organisms such as yeast and mammals. Recently, it has been demonstrated that treatment with a pharmacological inhibitor of the TOR pathway, rapamycin, can replicate those findings and improve aging in a variety of model organisms. The proposed underlying anti-aging mechanisms are down-regulated translation, increased autophagy, altered metabolism and increased stress resistance.
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Ogita, Akira, Wakae Murata, Ken Yamauchi, Akiko Sakai, Yoshihiro Yamaguchi, Toshio Tanaka, and Ken-ichi Fujita. "Immature Pear Extract Constituents Exert Multifaceted Anti-aging Effects." Innovation in Aging 5, Supplement_1 (December 1, 2021): 679. http://dx.doi.org/10.1093/geroni/igab046.2556.
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Abstract Cellular senescence causes a gradual loss of physiological functions and induces chronic diseases, which negatively affect the quality of human life. Intervention in the cellular senescence process may reduce the incidence of these diseases while delaying the progression of age-related diseases, thereby prolonging human lifespan. In our previous study, we found that extending the chronological lifespan of budding yeast cells, a suitable cellular model for research on mammalian cells, could be achieved by adding immature pear extract (iPE). Moreover, at the 2020 GSA meeting, using a colony-counting method, we reported that both hydrophilic (WiPE) and hydrophobic (OiPE) iPE components exhibited a chronological lifespan prolongation on yeast cells. In this study, the expression of sirtuin-related genes, which regulate cellular senescence, was verified by quantitative real-time reverse-transcription polymerase chain reaction. Interestingly, sirtuin-related gene expression was significantly increased in the WiPE-treated cells only, and OiPE could extend the chronological lifespan of yeast cells through the mechanisms not involved in sirtuin-related gene expression. In general, hydrophobic and hydrophilic components exhibit different degradation and metabolism in cells. Since each component has a different strategy of absorption and excretion in the body, we hypothesize that iPE with multiple active components will have multifaceted effects on anti-aging. Our research on elucidating the mechanism of lifespan extension by OiPE and its application to mammalian cells is ongoing.
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Porras-Agüera, Juan Antonio, Juan Carlos Mauricio, Jaime Moreno-García, Juan Moreno, and Teresa García-Martínez. "A Differential Proteomic Approach to Characterize the Cell Wall Adaptive Response to CO2 Overpressure during Sparkling Wine-Making Process." Microorganisms 8, no. 8 (August 4, 2020): 1188. http://dx.doi.org/10.3390/microorganisms8081188.
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In this study, a first proteomic approach was carried out to characterize the adaptive response of cell wall-related proteins to endogenous CO2 overpressure, which is typical of second fermentation conditions, in two wine Saccharomyces cerevisiae strains (P29, a conventional second fermentation strain, and G1, a flor yeast strain implicated in sherry wine making). The results showed a high number of cell wall proteins in flor yeast G1 under pressure, highlighting content at the first month of aging. The cell wall proteomic response to pressure in flor yeast G1 was characterized by an increase in both the number and content of cell wall proteins involved in glucan remodeling and mannoproteins. On the other hand, cell wall proteins responsible for glucan assembly, cell adhesion, and lipid metabolism stood out in P29. Over-represented proteins under pressure were involved in cell wall integrity (Ecm33p and Pst1p), protein folding (Ssa1p and Ssa2p), and glucan remodeling (Exg2p and Scw4p). Flocculation-related proteins were not identified under pressure conditions. The use of flor yeasts for sparkling wine elaboration and improvement is proposed. Further research based on the genetic engineering of wine yeast using those genes from protein biomarkers under pressure alongside the second fermentation in bottle is required to achieve improvements.
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Galdieri, Luciano, Tiantian Zhang, Daniella Rogerson, Rron Lleshi, and Ales Vancura. "Protein Acetylation and Acetyl Coenzyme A Metabolism in Budding Yeast." Eukaryotic Cell 13, no. 12 (October 17, 2014): 1472–83. http://dx.doi.org/10.1128/ec.00189-14.
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ABSTRACT Cells sense and appropriately respond to the physical conditions and availability of nutrients in their environment. This sensing of the environment and consequent cellular responses are orchestrated by a multitude of signaling pathways and typically involve changes in transcription and metabolism. Recent discoveries suggest that the signaling and transcription machineries are regulated by signals which are derived from metabolism and reflect the metabolic state of the cell. Acetyl coenzyme A (CoA) is a key metabolite that links metabolism with signaling, chromatin structure, and transcription. Acetyl-CoA is produced by glycolysis as well as other catabolic pathways and used as a substrate for the citric acid cycle and as a precursor in synthesis of fatty acids and steroids and in other anabolic pathways. This central position in metabolism endows acetyl-CoA with an important regulatory role. Acetyl-CoA serves as a substrate for lysine acetyltransferases (KATs), which catalyze the transfer of acetyl groups to the epsilon-amino groups of lysines in histones and many other proteins. Fluctuations in the concentration of acetyl-CoA, reflecting the metabolic state of the cell, are translated into dynamic protein acetylations that regulate a variety of cell functions, including transcription, replication, DNA repair, cell cycle progression, and aging. This review highlights the synthesis and homeostasis of acetyl-CoA and the regulation of transcriptional and signaling machineries in yeast by acetylation.
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Orozco, Helena, Emilia Matallana, and Agustín Aranda. "Wine yeast sirtuins and Gcn5p control aging and metabolism in a natural growth medium." Mechanisms of Ageing and Development 133, no. 5 (May 2012): 348–58. http://dx.doi.org/10.1016/j.mad.2012.03.013.
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de Figueiredo, Luis F., Toni I. Gossmann, Mathias Ziegler, and Stefan Schuster. "Pathway analysis of NAD+ metabolism." Biochemical Journal 439, no. 2 (September 28, 2011): 341–48. http://dx.doi.org/10.1042/bj20110320.
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NAD+ is well known as a crucial cofactor in the redox balance of metabolism. Moreover, NAD+ is degraded in ADP-ribosyl transfer reactions, which are important components of multitudinous signalling reactions. These include reactions linked to DNA repair and aging. In the present study, using the concept of EFMs (elementary flux modes), we established all of the potential routes in a network describing NAD+ biosynthesis and degradation. All known biosynthetic pathways, which include de novo synthesis starting from tryptophan as well as the classical Preiss–Handler pathway and NAD+ synthesis from other vitamin precursors, were detected as EFMs. Moreover, several EFMs were found that degrade NAD+, represent futile cycles or have other functionalities. The systematic analysis and comparison of the networks specific for yeast and humans document significant differences between species with regard to the use of precursors, biosynthetic routes and NAD+-dependent signalling.
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Jing, Jovian Lin, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber, and Mohammad Alfatah. "Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function." Cells 11, no. 5 (March 2, 2022): 862. http://dx.doi.org/10.3390/cells11050862.
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Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.
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Mołoń, Mateusz, Eliza Molestak, Monika Kula-Maximenko, Przemysław Grela, and Marek Tchórzewski. "Ribosomal Protein uL11 as a Regulator of Metabolic Circuits Related to Aging and Cell Cycle." Cells 9, no. 7 (July 21, 2020): 1745. http://dx.doi.org/10.3390/cells9071745.
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Aging is a biological phenomenon common to all living organisms. It is thought that the rate of aging is influenced by diverse factors, in many cases related to the control of energy metabolism, i.e., the so-called pro-longevity effects of starvation. Translation, regarded as the main energy consumption process, lies at the center of interest, as it has a significant impact on the longevity phenomenon. It has been shown that perturbations in the translational apparatus may lead to a lower rate of aging. Therefore, the main aim of this study was to investigate aging in relation to the protein biosynthesis circuit, taking into account the uL11 ribosomal protein as a vital ribosomal element. To this end, we used set of yeast mutants with deleted single uL11A or uL11B genes and a double disruptant uL11AB mutant. We applied an integrated approach analyzing a broad range of biological parameters of yeast mutant cells, especially the longevity phenomenon, supplemented with biochemical and high throughput transcriptomic and metobolomic approaches. The analysis showed that the longevity phenomenon is not fully related to the commonly considered energy restriction effect, thus the slow-down of translation does not represent the sole source of aging. Additionally, we showed that uL11 can be classified as a moonlighting protein with extra-ribosomal function having cell-cycle regulatory potential.
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Peluso, Augusto, Mads V. Damgaard, Marcelo A. S. Mori, and Jonas T. Treebak. "Age-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?" Nutrients 14, no. 1 (December 27, 2021): 101. http://dx.doi.org/10.3390/nu14010101.
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Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.
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Zeng, Nan, Ning Zhang, Xin Ma, Yunjiao Wang, Yating Zhang, Dandan Wang, Fangxiong Pu, and Bingxue Li. "Transcriptomics Integrated with Metabolomics: Assessing the Central Metabolism of Different Cells after Cell Differentiation in Aureobasidium pullulans NG." Journal of Fungi 8, no. 8 (August 22, 2022): 882. http://dx.doi.org/10.3390/jof8080882.
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When organisms are stimulated by external stresses, oxidative stress is induced, resulting in the production of large amounts of reactive oxygen species (ROS) that inhibit cell growth and accelerate cellular aging until death. Understanding the molecular mechanisms of abiotic stress is important to enhance cellular resistance, and Aureobasidium pullulans, a highly resistant yeast-like fungus, can use cellular differentiation to resist environmental stress. Here, swollen cells (SCs) from two different differentiation periods in Aureobasidium pullulans NG showed significantly higher antioxidant capacity and stress defense capacity than yeast-like cells (YL). The transcriptome and the metabolome of both cells were analyzed, and the results showed that amino acid metabolism, carbohydrate metabolism, and lipid metabolism were significantly enriched in SCs. Glyoxylate metabolism was significantly upregulated in carbohydrate metabolism, replacing the metabolic hub of the citric acid (TCA) cycle, helping to coordinate multiple metabolic pathways and playing an important role in the resistance of Aureobasidium pullulans NG to environmental stress. Finally, we obtained 10 key genes and two key metabolites in SCs, which provide valuable clues for subsequent validation. In conclusion, these results provide valuable information for assessing central metabolism-mediating oxidative stress in Aureobasidium pullulans NG, and also provide new ideas for exploring the pathways of eukaryotic resistance to abiotic stress.
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Stępień, Karolina, Adrianna Skoneczna, Monika Kula-Maximenko, Łukasz Jurczyk, and Mateusz Mołoń. "Depletion of the Origin Recognition Complex Subunits Delays Aging in Budding Yeast." Cells 11, no. 8 (April 7, 2022): 1252. http://dx.doi.org/10.3390/cells11081252.
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Precise DNA replication is pivotal for ensuring the accurate inheritance of genetic information. To avoid genetic instability, each DNA fragment needs to be amplified only once per cell cycle. DNA replication in eukaryotes starts with the binding of the origin recognition complex (ORC) to the origins of DNA replication. The genes encoding ORC subunits have been conserved across eukaryotic evolution and are essential for the initiation of DNA replication. In this study, we conducted an extensive physiological and aging-dependent analysis of heterozygous cells lacking one copy of ORC genes in the BY4743 background. Cells with only one copy of the ORC genes showed a significant decrease in the level of ORC mRNA, a delay in the G1 phase of the cell cycle, and an extended doubling time. Here, we also show that the reducing the levels of Orc1-6 proteins significantly extends both the budding and average chronological lifespans. Heterozygous ORC/orcΔ and wild-type diploid cells easily undergo haploidization during chronological aging. This ploidy shift might be related to nutrient starvation or the inability to survive under stress conditions. A Raman spectroscopy analysis helped us to strengthen the hypothesis of the importance of lipid metabolism and homeostasis in aging.
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Orlandi, Ivan, Damiano Pellegrino Coppola, Maurizio Strippoli, Rossella Ronzulli, and Marina Vai. "Nicotinamide supplementation phenocopies SIR2 inactivation by modulating carbon metabolism and respiration during yeast chronological aging." Mechanisms of Ageing and Development 161 (January 2017): 277–87. http://dx.doi.org/10.1016/j.mad.2016.06.006.
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Filteau, Marie, Guillaume Diss, Francisco Torres-Quiroz, Alexandre K. Dubé, Andrea Schraffl, Verena A. Bachmann, Isabelle Gagnon-Arsenault, et al. "Systematic identification of signal integration by protein kinase A." Proceedings of the National Academy of Sciences 112, no. 14 (March 23, 2015): 4501–6. http://dx.doi.org/10.1073/pnas.1409938112.
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Cellular processes and homeostasis control in eukaryotic cells is achieved by the action of regulatory proteins such as protein kinase A (PKA). Although the outbound signals from PKA directed to processes such as metabolism, growth, and aging have been well charted, what regulates this conserved regulator remains to be systematically identified to understand how it coordinates biological processes. Using a yeast PKA reporter assay, we identified genes that influence PKA activity by measuring protein–protein interactions between the regulatory and the two catalytic subunits of the PKA complex in 3,726 yeast genetic-deletion backgrounds grown on two carbon sources. Overall, nearly 500 genes were found to be connected directly or indirectly to PKA regulation, including 80 core regulators, denoting a wide diversity of signals regulating PKA, within and beyond the described upstream linear pathways. PKA regulators span multiple processes, including the antagonistic autophagy and methionine biosynthesis pathways. Our results converge toward mechanisms of PKA posttranslational regulation by lysine acetylation, which is conserved between yeast and humans and that, we show, regulates protein complex formation in mammals and carbohydrate storage and aging in yeast. Taken together, these results show that the extent of PKA input matches with its output, because this kinase receives information from upstream and downstream processes, and highlight how biological processes are interconnected and coordinated by PKA.
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Cordente, Antonio G., Damian Espinase Nandorfy, Mark Solomon, Alex Schulkin, Radka Kolouchova, Ian Leigh Francis, and Simon A. Schmidt. "Aromatic Higher Alcohols in Wine: Implication on Aroma and Palate Attributes during Chardonnay Aging." Molecules 26, no. 16 (August 17, 2021): 4979. http://dx.doi.org/10.3390/molecules26164979.
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The higher alcohols 2-phenylethanol, tryptophol, and tyrosol are a group of yeast-derived compounds that have been shown to affect the aroma and flavour of fermented beverages. Five variants of the industrial wine strain AWRI796, previously isolated due to their elevated production of the ‘rose-like aroma’ compound 2-phenylethanol, were characterised during pilot-scale fermentation of a Chardonnay juice. We show that these variants not only increase the concentration of 2-phenylethanol but also modulate the formation of the higher alcohols tryptophol, tyrosol, and methionol, as well as other volatile sulfur compounds derived from methionine, highlighting the connections between yeast nitrogen and sulfur metabolism during fermentation. We also investigate the development of these compounds during wine storage, focusing on the sulfonation of tryptophol. Finally, the sensory properties of wines produced using these strains were quantified at two time points, unravelling differences produced by biologically modulating higher alcohols and the dynamic changes in wine flavour over aging.
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Kitada, Munehiro, Yoshio Ogura, Itaru Monno, Jing Xu, and Daisuke Koya. "Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress." Biomedicines 9, no. 2 (January 29, 2021): 130. http://dx.doi.org/10.3390/biomedicines9020130.
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Enhanced oxidative stress is closely related to aging and impaired metabolic health and is influenced by diet-derived nutrients and energy. Recent studies have shown that methionine restriction (MetR) is related to longevity and metabolic health in organisms from yeast to rodents. The effect of MetR on lifespan extension and metabolic health is mediated partially through a reduction in oxidative stress. Methionine metabolism is involved in the supply of methyl donors such as S-adenosyl-methionine (SAM), glutathione synthesis and polyamine metabolism. SAM, a methionine metabolite, activates mechanistic target of rapamycin complex 1 and suppresses autophagy; therefore, MetR can induce autophagy. In the process of glutathione synthesis in methionine metabolism, hydrogen sulfide (H2S) is produced through cystathionine-β-synthase and cystathionine-γ-lyase; however, MetR can induce increased H2S production through this pathway. Similarly, MetR can increase the production of polyamines such as spermidine, which are involved in autophagy. In addition, MetR decreases oxidative stress by inhibiting reactive oxygen species production in mitochondria. Thus, MetR can attenuate oxidative stress through multiple mechanisms, consequently associating with lifespan extension and metabolic health. In this review, we summarize the current understanding of the effects of MetR on lifespan extension and metabolic health, focusing on the reduction in oxidative stress.
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Li, Wei, Libo Sun, Qiuli Liang, Juan Wang, Weike Mo, and Bing Zhou. "Yeast AMID Homologue Ndi1p Displays Respiration-restricted Apoptotic Activity and Is Involved in Chronological Aging." Molecular Biology of the Cell 17, no. 4 (April 2006): 1802–11. http://dx.doi.org/10.1091/mbc.e05-04-0333.
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Apoptosis-inducing factor (AIF) and AIF-homologous mitochondrion-associated inducer of death (AMID) are both mitochondrial flavoproteins that trigger caspase-independent apoptosis. Phylogenetic analysis suggests that these two proteins evolutionarily diverge back from their common prokaryote ancestor. Compared with AIF, the proapoptotic nature of AMID and its mode of action are much less clarified. Here, we show that overexpression of yeast AMID homologue internal NADH dehydrogenase (NDI1), but not external NADH dehydrogenase (NDE1), can cause apoptosis-like cell death, and this effect can be repressed by increased respiration on glucose-limited media. This result indicates that the regulatory network of energy metabolism, in particular the cross-talk between mitochondria and the rest of the cell, is involved in Ndi1p-induced yeast cell apoptosis. The apoptotic effect of NDI1 overexpression is associated with increased production of reactive oxygen species (ROS) in mitochondria. In addition, NDI1 overexpression in sod2 background causes cell lethality in both fermentable and semifermentable media. Interruption of certain components in the electron transport chain can suppress the growth inhibition from Ndi1p overexpression. We finally show that disruption of NDI1 or NDE1 decreases ROS production and elongates the chronological life span of yeast, accompanied by the loss of survival fitness. Implication of these findings for Ndi1p-induced apoptosis is discussed.
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Tungmunnithum, Duangjai, Samantha Drouet, and Christophe Hano. "Flavonoids from Sacred Lotus Stamen Extract Slows Chronological Aging in Yeast Model by Reducing Oxidative Stress and Maintaining Cellular Metabolism." Cells 11, no. 4 (February 9, 2022): 599. http://dx.doi.org/10.3390/cells11040599.
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Nelumbo nucifera is one of the most valuable medicinal species of the Nelumbonaceae family that has been consumed since the ancient historic period. Its stamen is an indispensable ingredient for many recipes of traditional medicines, and has been proved as a rich source of flavonoids that may provide an antiaging action for pharmaceutical or medicinal applications. However, there is no intense study on antiaging potential and molecular mechanisms. This present study was designed to fill in this important research gap by: (1) investigating the effects of sacred lotus stamen extract (LSE) on yeast lifespan extension; and (2) determining their effects on oxidative stress and metabolism to understand the potential antiaging action of its flavonoids. A validated ultrasound-assisted extraction method was also employed in this current work. The results confirmed that LSE is rich in flavonoids, and myricetin-3-O-glucose, quercetin-3-O-glucuronic acid, kaempferol-3-O-glucuronic acid, and isorhamnetin-3-O-glucose are the most abundant ones. In addition, LSE offers a high antioxidant capacity, as evidenced by different in vitro antioxidant assays. This present study also indicated that LSE delayed yeast (Saccharomyces cerevisiae, wild-type strain DBY746) chronological aging compared with untreated control yeast and a positive control (resveratrol) cells. Moreover, LSE acted on central metabolism, gene expressions (SIR2 and SOD2), and enzyme regulation (SIRT and SOD enzymatic activities). These findings are helpful to open the door for the pharmaceutical and medical sectors to employ this potential lotus raw material in their future pharmaceutical product development.
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Váchová, Libuše, Ladislava Hatáková, Michal Čáp, Michaela Pokorná, and Zdena Palková. "Rapidly Developing Yeast Microcolonies Differentiate in a Similar Way to Aging Giant Colonies." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/102485.
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During their development and aging on solid substrates, yeast giant colonies produce ammonia, which acts as a quorum sensing molecule. Ammonia production is connected with alkalization of the surrounding medium and with extensive reprogramming of cell metabolism. In addition, ammonia signaling is important for both horizontal (colony centre versus colony margin) and vertical (upper versus lower cell layers) colony differentiations. The centre of an aging differentiated giant colony is thus composed of two major cell subpopulations, the subpopulation of long-living, metabolically active and stress-resistant cells that form the upper layers of the colony and the subpopulation of stress-sensitive starving cells in the colony interior. Here, we show that microcolonies originating from one cell pass through similar developmental phases as giant colonies. Microcolony differentiation is linked to ammonia signaling, and cells similar to the upper and lower cells of aged giant colonies are formed even in relatively young microcolonies. A comparison of the properties of these cells revealed a number of features that are similar in microcolonies and giant colonies as well as a few that are only typical of chronologically aged giant colonies. These findings show that colony ageper seis not crucial for colony differentiation.
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Stallone, Giovanni, Barbara Infante, Concetta Prisciandaro, and Giuseppe Grandaliano. "mTOR and Aging: An Old Fashioned Dress." International Journal of Molecular Sciences 20, no. 11 (June 6, 2019): 2774. http://dx.doi.org/10.3390/ijms20112774.
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Aging is a physiologic/pathologic process characterized by a progressive impairment of cellular functions, supported by the alterations of several molecular pathways, leading to an increased cell susceptibility to injury. This deterioration is the primary risk factor for several major human pathologies. Numerous cellular processes, including genomic instability, telomere erosion, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular signal transduction represent common denominators of aging in different organisms. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved nutrient sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the hypothesis that the mTOR signalling network plays a pivotal role in modulating aging. mTOR is emerging as the most robust mediator of the protective effects of various forms of dietary restriction, which has been shown to extend lifespan and slow the onset of age-related diseases across species. Herein we discuss the role of mTor signalling network in the development of classic age-related diseases, focused on cardiovascular system, immune response, and cancer.
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Orlandi, Ivan, Rossella Ronzulli, Nadia Casatta, and Marina Vai. "Ethanol and Acetate Acting as Carbon/Energy Sources Negatively Affect Yeast Chronological Aging." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/802870.
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InSaccharomyces cerevisiae, the chronological lifespan (CLS) is defined as the length of time that a population of nondividing cells can survive in stationary phase. In this phase, cells remain metabolically active, albeit at reduced levels, and responsive to environmental signals, thus simulating the postmitotic quiescent state of mammalian cells. Many studies on the main nutrient signaling pathways have uncovered the strong influence of growth conditions, including the composition of culture media, on CLS. In this context, two byproducts of yeast glucose fermentation, ethanol and acetic acid, have been proposed as extrinsic proaging factors. Here, we report that ethanol and acetic acid, at physiological levels released in the exhausted medium, both contribute to chronological aging. Moreover, this combined proaging effect is not due to a toxic environment created by their presence but is mainly mediated by the metabolic pathways required for their utilization as carbon/energy sources. In addition, measurements of key enzymatic activities of the glyoxylate cycle and gluconeogenesis, together with respiration assays performed in extreme calorie restriction, point to a long-term quiescent program favoured by glyoxylate/gluconeogenesis flux contrary to a proaging one based on the oxidative metabolism of ethanol/acetate via TCA and mitochondrial respiration.
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Lauinger, Linda, and Peter Kaiser. "Sensing and Signaling of Methionine Metabolism." Metabolites 11, no. 2 (January 31, 2021): 83. http://dx.doi.org/10.3390/metabo11020083.
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Availability of the amino acid methionine shows remarkable effects on the physiology of individual cells and whole organisms. For example, most cancer cells, but not normal cells, are hyper dependent on high flux through metabolic pathways connected to methionine, and diets restricted for methionine increase healthy lifespan in model organisms. Methionine’s impact on physiology goes beyond its role in initiation of translation and incorporation in proteins. Many of its metabolites have a major influence on cellular functions including epigenetic regulation, maintenance of redox balance, polyamine synthesis, and phospholipid homeostasis. As a central component of such essential pathways, cells require mechanisms to sense methionine availability. When methionine levels are low, cellular response programs induce transcriptional and signaling states to remodel metabolic programs and maintain methionine metabolism. In addition, an evolutionary conserved cell cycle arrest is induced to ensure cellular and genomic integrity during methionine starvation conditions. Methionine and its metabolites are critical for cell growth, proliferation, and development in all organisms. However, mechanisms of methionine perception are diverse. Here we review current knowledge about mechanisms of methionine sensing in yeast and mammalian cells, and will discuss the impact of methionine imbalance on cancer and aging.
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Bradshaw, Patrick C. "Acetyl-CoA Metabolism and Histone Acetylation in the Regulation of Aging and Lifespan." Antioxidants 10, no. 4 (April 8, 2021): 572. http://dx.doi.org/10.3390/antiox10040572.
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Acetyl-CoA is a metabolite at the crossroads of central metabolism and the substrate of histone acetyltransferases regulating gene expression. In many tissues fasting or lifespan extending calorie restriction (CR) decreases glucose-derived metabolic flux through ATP-citrate lyase (ACLY) to reduce cytoplasmic acetyl-CoA levels to decrease activity of the p300 histone acetyltransferase (HAT) stimulating pro-longevity autophagy. Because of this, compounds that decrease cytoplasmic acetyl-CoA have been described as CR mimetics. But few authors have highlighted the potential longevity promoting roles of nuclear acetyl-CoA. For example, increasing nuclear acetyl-CoA levels increases histone acetylation and administration of class I histone deacetylase (HDAC) inhibitors increases longevity through increased histone acetylation. Therefore, increased nuclear acetyl-CoA likely plays an important role in promoting longevity. Although cytoplasmic acetyl-CoA synthetase 2 (ACSS2) promotes aging by decreasing autophagy in some peripheral tissues, increased glial AMPK activity or neuronal differentiation can stimulate ACSS2 nuclear translocation and chromatin association. ACSS2 nuclear translocation can result in increased activity of CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and other HATs to increase histone acetylation on the promoter of neuroprotective genes including transcription factor EB (TFEB) target genes resulting in increased lysosomal biogenesis and autophagy. Much of what is known regarding acetyl-CoA metabolism and aging has come from pioneering studies with yeast, fruit flies, and nematodes. These studies have identified evolutionary conserved roles for histone acetylation in promoting longevity. Future studies should focus on the role of nuclear acetyl-CoA and histone acetylation in the control of hypothalamic inflammation, an important driver of organismal aging.
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Tonini, Claudia, Marco Segatto, Francesca Martino, Luisa Cigliano, Martina Nazzaro, Laura Barberio, Maurizio Mandalà, and Valentina Pallottini. "Effects of Late-Life Caloric Restriction on Age-Related Alterations in the Rat Cortex and Hippocampus." Nutrients 13, no. 1 (January 15, 2021): 232. http://dx.doi.org/10.3390/nu13010232.
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Background: A major problem of aging is the disruption of metabolic homeostasis. This is particularly relevant in the brain where it provokes neurodegeneration. Caloric restriction is a physiologic intervention known to delay the deleterious consequences of aging in several species ranging from yeast to mammals. To date, most studies on experimental models have started this dietary intervention from weaning, which is very difficult to be translated to human beings. Here, we study the effects of a more realistic dietary regimen in rats, starting at an advanced age and lasting for six months. Methods: we analyzed in the cortex and hippocampus, the proteins involved in the energetic balance of the cells, cholesterol metabolism, oxidative stress response, inflammation, synaptic impairment, and brain trophism. Results: our results suggest that caloric restriction in late life can revert only some age-related changes studied here.
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van der Laan, Kiran J., Aryan Morita, Felipe P. Perona-Martinez, and Romana Schirhagl. "Evaluation of the Oxidative Stress Response of Aging Yeast Cells in Response to Internalization of Fluorescent Nanodiamond Biosensors." Nanomaterials 10, no. 2 (February 20, 2020): 372. http://dx.doi.org/10.3390/nano10020372.
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Fluorescent nanodiamonds (FNDs) are proposed to be used as free radical biosensors, as they function as magnetic sensors, changing their optical properties depending on their magnetic surroundings. Free radicals are produced during natural cell metabolism, but when the natural balance is disturbed, they are also associated with diseases and aging. Sensitive methods to detect free radicals are challenging, due to their high reactivity and transiency, providing the need for new biosensors such as FNDs. Here we have studied in detail the stress response of an aging model system, yeast cells, upon FND internalization to assess whether one can safely use this biosensor in the desired model. This was done by measuring metabolic activity, the activity of genes involved in different steps and the locations of the oxidative stress defense systems and general free radical activity. Only minimal, transient FND-related stress effects were observed, highlighting excellent biocompatibility in the long term. This is a crucial milestone towards the applicability of FNDs as biosensors in free radical research.
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Liu, Yaxin, and Xin Jie Chen. "Adenine Nucleotide Translocase, Mitochondrial Stress, and Degenerative Cell Death." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/146860.
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Mitochondria are intracellular organelles involved in ATP synthesis, apoptosis, calcium signaling, metabolism, and the synthesis of critical metabolic cofactors. Mitochondrial dysfunction is associated with age-related degenerative diseases. How mitochondrial dysfunction causes cell degeneration is not well understood. Recent studies have shown that mutations in the adenine nucleotide translocase (Ant) cause aging-dependent degenerative cell death (DCD) in yeast, which is sequentially manifested by inner membrane stress, mitochondrial DNA (mtDNA) loss, and progressive loss of cell viability. Ant is an abundant protein primarily involved in ADP/ATP exchange across the mitochondrial inner membrane. It also mediates basal proton leak and regulates the mitochondrial permeability transition pore. Missense mutations in the human Ant1 cause several degenerative diseases which are commonly manifested by fractional mtDNA deletions. Multiple models have been proposed to explain the Ant1-induced pathogenesis. Studies from yeast have suggested that in addition to altered nucleotide transport properties, the mutant proteins cause a global stress on the inner membrane. The mutant proteins likely interfere with general mitochondrial biogenesis in a dominant-negative manner, which secondarily destabilizes mtDNA. More recent work revealed that the Ant-induced DCD is suppressed by reduced cytosolic protein synthesis. This finding suggests a proteostatic crosstalk between mitochondria and the cytosol, which may play an important role for cell survival during aging.
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Lesur, Isabelle, and Judith L. Campbell. "The Transcriptome of Prematurely Aging Yeast Cells Is Similar to That of Telomerase-deficient Cells." Molecular Biology of the Cell 15, no. 3 (March 2004): 1297–312. http://dx.doi.org/10.1091/mbc.e03-10-0742.
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To help define the pathologies associated with yeast cells as they age, we analyzed the transcriptome of young and old cells isolated by elutriation, which allows isolation of biochemical quantities of old cells much further advanced in their life span than old cells prepared by the biotin-streptavidin method. Both 18-generation-old wild-type yeast and 8-generation-old cells from a prematurely aging mutant (dna2-1), with a defect in DNA replication, were evaluated. Genes involved in gluconeogenesis, the glyoxylate cycle, lipid metabolism, and glycogen production are induced in old cells, signifying a shift toward energy storage. We observed a much more extensive generalized stress response known as the environmental stress response (ESR), than observed previously in biotin-streptavidin-isolated cells, perhaps because the elutriated cells were further advanced in their life span. In addition, there was induction of DNA repair genes that fall in the so-called DNA damage “signature” set. In the dna2-1 mutant, energy production genes were also induced. The response in the dna2-1 strain is similar to the telomerase delete response, genes whose expression changes during cellular senescence in telomerase-deficient cells. We propose that these results suggest, albeit indirectly, that old cells are responding to genome instability.
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Ralser, Markus, Mirjam M. Wamelink, Eduard A. Struys, Christian Joppich, Sylvia Krobitsch, Cornelis Jakobs, and Hans Lehrach. "A catabolic block does not sufficiently explain how 2-deoxy-d-glucose inhibits cell growth." Proceedings of the National Academy of Sciences 105, no. 46 (November 11, 2008): 17807–11. http://dx.doi.org/10.1073/pnas.0803090105.
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The glucose analogue 2-deoxy-d-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG. This finding indicates that 2-DG does not block cell growth solely by preventing glucose catabolism. In addition, 2-DG provoked similar concentration changes of sugar-phosphate intermediates in wild-type and 2-DG-resistant yeast strains and in human primary fibroblasts. Finally, a genome-wide analysis revealed 19 2-DG-resistant yeast knockouts of genes implicated in carbohydrate metabolism and mitochondrial homeostasis, as well as ribosome biogenesis, mRNA decay, transcriptional regulation, and cell cycle. Thus, processes beyond the metabolic block are essential for the biological properties of 2-DG.
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Bartke, Andrzej, Liou Y. Sun, and Valter Longo. "Somatotropic Signaling: Trade-Offs Between Growth, Reproductive Development, and Longevity." Physiological Reviews 93, no. 2 (April 2013): 571–98. http://dx.doi.org/10.1152/physrev.00006.2012.
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Growth hormone (GH) is a key determinant of postnatal growth and plays an important role in the control of metabolism and body composition. Surprisingly, deficiency in GH signaling delays aging and remarkably extends longevity in laboratory mice. In GH-deficient and GH-resistant animals, the “healthspan” is also extended with delays in cognitive decline and in the onset of age-related disease. The role of hormones homologous to insulin-like growth factor (IGF, an important mediator of GH actions) in the control of aging and lifespan is evolutionarily conserved from worms to mammals with some homologies extending to unicellular yeast. The combination of reduced GH, IGF-I, and insulin signaling likely contributes to extended longevity in GH or GH receptor-deficient organisms. Diminutive body size and reduced fecundity of GH-deficient and GH-resistant mice can be viewed as trade-offs for extended longevity. Mechanisms responsible for delayed aging of GH-related mutants include enhanced stress resistance and xenobiotic metabolism, reduced inflammation, improved insulin signaling, and various metabolic adjustments. Pathological excess of GH reduces life expectancy in men as well as in mice, and GH resistance or deficiency provides protection from major age-related diseases, including diabetes and cancer, in both species. However, there is yet no evidence of increased longevity in GH-resistant or GH-deficient humans, possibly due to non-age-related deaths. Results obtained in GH-related mutant mice provide striking examples of mutations of a single gene delaying aging, reducing age-related disease, and extending lifespan in a mammal and providing novel experimental systems for the study of mechanisms of aging.
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Jazwinski, S. Michal. "The retrograde response links metabolism with stress responses, chromatin-dependent gene activation, and genome stability in yeast aging." Gene 354 (July 2005): 22–27. http://dx.doi.org/10.1016/j.gene.2005.03.040.
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Baroni, Maurizio D., Sonia Colombo, Olivier Libens, Rani Pallavi, Marco Giorgio, and Enzo Martegani. "In S. cerevisiae hydroxycitric acid antagonizes chronological aging and apoptosis regardless of citrate lyase." Apoptosis 25, no. 9-10 (July 14, 2020): 686–96. http://dx.doi.org/10.1007/s10495-020-01625-1.
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Abstract Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in Saccharomyces cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism, similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations.
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Alao, John-Patrick, Luc Legon, and Charalampos Rallis. "Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast." Cells 10, no. 2 (February 2, 2021): 305. http://dx.doi.org/10.3390/cells10020305.
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Cells have developed response systems to constantly monitor environmental changes and accordingly adjust growth, differentiation, and cellular stress programs. The evolutionarily conserved, nutrient-responsive, mechanistic target of rapamycin signaling (mTOR) pathway coordinates basic anabolic and catabolic cellular processes such as gene transcription, protein translation, autophagy, and metabolism, and is directly implicated in cellular and organismal aging as well as age-related diseases. mTOR mediates these processes in response to a broad range of inputs such as oxygen, amino acids, hormones, and energy levels, as well as stresses, including DNA damage. Here, we briefly summarize data relating to the interplays of the mTOR pathway with DNA damage response pathways in fission yeast, a favorite model in cell biology, and how these interactions shape cell decisions, growth, and cell-cycle progression. We, especially, comment on the roles of caffeine-mediated DNA-damage override. Understanding the biology of nutrient response, DNA damage and related pharmacological treatments can lead to the design of interventions towards improved cellular and organismal fitness, health, and survival.
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Princová, Jarmila, Clàudia Salat-Canela, Petr Daněk, Anna Marešová, Laura de Cubas, Jürg Bähler, José Ayté, Elena Hidalgo, and Martin Převorovský. "Perturbed fatty-acid metabolism is linked to localized chromatin hyperacetylation, increased stress-response gene expression and resistance to oxidative stress." PLOS Genetics 19, no. 1 (January 10, 2023): e1010582. http://dx.doi.org/10.1371/journal.pgen.1010582.
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Oxidative stress is associated with cardiovascular and neurodegenerative diseases, diabetes, cancer, psychiatric disorders and aging. In order to counteract, eliminate and/or adapt to the sources of stress, cells possess elaborate stress-response mechanisms, which also operate at the level of regulating transcription. Interestingly, it is becoming apparent that the metabolic state of the cell and certain metabolites can directly control the epigenetic information and gene expression. In the fission yeast Schizosaccharomyces pombe, the conserved Sty1 stress-activated protein kinase cascade is the main pathway responding to most types of stresses, and regulates the transcription of hundreds of genes via the Atf1 transcription factor. Here we report that fission yeast cells defective in fatty acid synthesis (cbf11, mga2 and ACC/cut6 mutants; FAS inhibition) show increased expression of a subset of stress-response genes. This altered gene expression depends on Sty1-Atf1, the Pap1 transcription factor, and the Gcn5 and Mst1 histone acetyltransferases, is associated with increased acetylation of histone H3 at lysine 9 in the corresponding gene promoters, and results in increased cellular resistance to oxidative stress. We propose that changes in lipid metabolism can regulate the chromatin and transcription of specific stress-response genes, which in turn might help cells to maintain redox homeostasis.
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Kawauchi, Moriyuki, Mika Nishiura, and Kazuhiro Iwashita. "Fungus-Specific Sirtuin HstD Coordinates Secondary Metabolism and Development through Control of LaeA." Eukaryotic Cell 12, no. 8 (May 31, 2013): 1087–96. http://dx.doi.org/10.1128/ec.00003-13.
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ABSTRACT The sirtuins are members of the NAD + -dependent histone deacetylase family that contribute to various cellular functions that affect aging, disease, and cancer development in metazoans. However, the physiological roles of the fungus-specific sirtuin family are still poorly understood. Here, we determined a novel function of the fungus-specific sirtuin HstD/ Aspergillus oryzae Hst4 (AoHst4), which is a homolog of Hst4 in A. oryzae yeast. The deletion of all histone deacetylases in A. oryzae demonstrated that the fungus-specific sirtuin HstD/AoHst4 is required for the coordination of fungal development and secondary metabolite production. We also show that the expression of the laeA gene, which is the most studied fungus-specific coordinator for the regulation of secondary metabolism and fungal development, was induced in a Δ hstD strain. Genetic interaction analysis of hstD / Aohst4 and laeA clearly indicated that HstD/AoHst4 works upstream of LaeA to coordinate secondary metabolism and fungal development. The hstD/Aohst4 and laeA genes are fungus specific but conserved in the vast family of filamentous fungi. Thus, we conclude that the fungus-specific sirtuin HstD/AoHst4 coordinates fungal development and secondary metabolism via the regulation of LaeA in filamentous fungi.
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Pascual-Ahuir, Amparo, Sara Manzanares-Estreder, and Markus Proft. "Pro- and Antioxidant Functions of the Peroxisome-Mitochondria Connection and Its Impact on Aging and Disease." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–17. http://dx.doi.org/10.1155/2017/9860841.
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Peroxisomes and mitochondria are the main intracellular sources for reactive oxygen species. At the same time, both organelles are critical for the maintenance of a healthy redox balance in the cell. Consequently, failure in the function of both organelles is causally linked to oxidative stress and accelerated aging. However, it has become clear that peroxisomes and mitochondria are much more intimately connected both physiologically and structurally. Both organelles share common fission components to dynamically respond to environmental cues, and the autophagic turnover of both peroxisomes and mitochondria is decisive for cellular homeostasis. Moreover, peroxisomes can physically associate with mitochondria via specific protein complexes. Therefore, the structural and functional connection of both organelles is a critical and dynamic feature in the regulation of oxidative metabolism, whose dynamic nature will be revealed in the future. In this review, we will focus on fundamental aspects of the peroxisome-mitochondria interplay derived from simple models such as yeast and move onto discussing the impact of an impaired peroxisomal and mitochondrial homeostasis on ROS production, aging, and disease in humans.
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Huang, Zifeng, Chang’e Wang, Jie Chen, Xiaoyu He, Kewen Chen, Xiaoqin Jiang, Chao Zhao, and Bin Liu. "Ameliorating Effect on Glycolipid Metabolism of Spirulina Functional Formulation Combination from Traditional Chinese Medicine." Oxidative Medicine and Cellular Longevity 2022 (July 13, 2022): 1–14. http://dx.doi.org/10.1155/2022/3910116.
Full textAbstract:
Insulin resistance is the major factor involved in the pathogenesis of type 2 diabetes. Although the oral drug metformin (MH) is widely used to reduce hyperglycemia, it is associated with adverse effects. Therefore, there is an urgent need to search for safe and natural foods that do not cause adverse effects as alternatives to commercial drugs. In this study, the active substances from Spirulina platensis, Grifola frondosa, Panax ginseng, and chromium-rich yeast were used to obtain Spirulina functional formulations (SFFs), and its therapeutic effects on mice with glycolipid metabolism disorder (GLD) were investigated. Results showed that SFFs not only improved glycolipid metabolism and reduced inflammation in mice with GLD but also showed good regenerative effects on the liver, jejunum, and cecum tissues. Moreover, SFFs could inhibit the growth of harmful microbes in the intestine and promote the proliferation of beneficial bacteria, thereby promoting the production of short-chain fatty acids and further regulating GLD. Additionally, SFFs significantly increased the expression of INS, INSR, IRS-1, PI3K, AKT-1, and GLUT-4 genes and significantly decreased that of GSK-3β in the INS/PI3K/GLUT-4 signaling pathway. Therefore, the findings of this study suggest that SFFs can be further developed as a new class of therapeutic agents against GLD.
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Burstein, Michelle T., and Vladimir I. Titorenko. "A mitochondrially targeted compound delays aging in yeast through a mechanism linking mitochondrial membrane lipid metabolism to mitochondrial redox biology." Redox Biology 2 (2014): 305–7. http://dx.doi.org/10.1016/j.redox.2014.01.011.
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Rizzetto, Lisa, Elena Zanni, Daniela Uccelletti, Ileana Ferrero, and Paola Goffrini. "Extension of Chronological Lifespan by Hexokinase Mutation inKluyveromyces lactisInvolves Increased Level of the Mitochondrial Chaperonin Hsp60." Journal of Aging Research 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/946586.
Full textAbstract:
Oxidative damage, mitochondrial dysfunction, genomic instability, and telomere shortening represent all molecular processes proposed as causal factors in aging. Lifespan can be increased by metabolism through an influence on such processes. Glucose reduction extends chronological lifespan (CLS) ofSaccharomyces cerevisiaethrough metabolic adaptation to respiration. To answer the question if the reduced CLS could be ascribed to glucoseper seor to glucose repression of respiratory enzymes, we used theKluyveromyces lactisyeast, where glucose repression does not affect the respiratory function. We identified the unique hexokinase, encoded byRAG5gene, as an important player in influencing yeast lifespan by modulating mitochondrial functionality and the level of the mitochondrial chaperonin Hsp60. In this context, this hexokinase might have a regulatory role in the influence of CLS, shedding new light on the complex regulation played by hexokinases.