Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
1.
PLoS Genet ; 10(2): e1004113, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24516402

RESUMO

Dietary restriction extends longevity in organisms ranging from bacteria to mice and protects primates from a variety of diseases, but the contribution of each dietary component to aging is poorly understood. Here we demonstrate that glucose and specific amino acids promote stress sensitization and aging through the differential activation of the Ras/cAMP/PKA, PKH1/2 and Tor/S6K pathways. Whereas glucose sensitized cells through a Ras-dependent mechanism, threonine and valine promoted cellular sensitization and aging primarily by activating the Tor/S6K pathway and serine promoted sensitization via PDK1 orthologs Pkh1/2. Serine, threonine and valine activated a signaling network in which Sch9 integrates TORC1 and Pkh signaling via phosphorylation of threonines 570 and 737 and promoted intracellular relocalization and transcriptional inhibition of the stress resistance protein kinase Rim15. Because of the conserved pro-aging role of nutrient and growth signaling pathways in higher eukaryotes, these results raise the possibility that similar mechanisms contribute to aging in mammals.


Assuntos
Proteínas Quinases Dependentes de 3-Fosfoinositídeo/genética , Envelhecimento/metabolismo , Longevidade/genética , Proteínas Quinases/genética , Proteínas de Saccharomyces cerevisiae/genética , Transdução de Sinais/genética , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Envelhecimento/genética , Animais , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Alimentos , Regulação Fúngica da Expressão Gênica , Glucose/metabolismo , Camundongos , Proteínas Quinases/metabolismo , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/metabolismo , Serina/metabolismo , Estresse Fisiológico/genética , Treonina/metabolismo , Fatores de Transcrição/genética , Valina/metabolismo
2.
Cells ; 13(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38334680

RESUMO

The aging process is inherently complex, involving multiple mechanisms that interact at different biological scales. The nematode Caenorhabditis elegans is a simple model organism that has played a pivotal role in aging research following the discovery of mutations extending lifespan. Longevity pathways identified in C. elegans were subsequently found to be conserved and regulate lifespan in multiple species. These pathways intersect with fundamental hallmarks of aging that include nutrient sensing, epigenetic alterations, proteostasis loss, and mitochondrial dysfunction. Here we summarize recent data obtained in C. elegans highlighting the importance of studying aging at both the tissue and temporal scale. We then focus on the neuromuscular system to illustrate the kinetics of changes that take place with age. We describe recently developed tools that enabled the dissection of the contribution of the insulin/IGF-1 receptor ortholog DAF-2 to the regulation of worm mobility in specific tissues and at different ages. We also discuss guidelines and potential pitfalls in the use of these new tools. We further highlight the opportunities that they present, especially when combined with recent transcriptomic data, to address and resolve the inherent complexity of aging. Understanding how different aging processes interact within and between tissues at different life stages could ultimately suggest potential intervention points for age-related diseases.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Insulina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Envelhecimento/metabolismo
3.
iScience ; 27(5): 109789, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38746662

RESUMO

Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because SIN3 haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of C. elegans SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, sin-3 mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and in vivo imaging, and altered oxygen consumption. Metabolomic analysis of sin-3 mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.

4.
Subcell Biochem ; 57: 101-21, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22094419

RESUMO

The two paradigms to study aging in Saccharomyces cerevisiae are the chronological life span (CLS) and the replicative life span (RLS). The chronological life span is a measure of the mean and maximum survival time of non-dividing yeast populations while the replicative life span is based on the mean and maximum number of daughter cells generated by an individual mother cell before cell division stops irreversibly. Here we review the principal discoveries associated with yeast chronological aging and how they are contributing to the understanding of the aging process and of the molecular mechanisms that may lead to healthy aging in mammals. We will focus on the mechanisms of life span regulation by the Tor/Sch9 and the Ras/adenylate Ras/adenylate cyclase/PKA pathways with particular emphasis on those implicating age-dependent oxidative oxidative stress stress and DNA damage/repair.


Assuntos
Envelhecimento/fisiologia , Divisão Celular , Saccharomyces cerevisiae/crescimento & desenvolvimento , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Dano ao DNA , Ingestão de Energia , Metabolismo Energético , Regulação Fúngica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Longevidade , Modelos Biológicos , Neoplasias/genética , Neoplasias/metabolismo , Estresse Oxidativo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transdução de Sinais , Fatores de Tempo
5.
PLoS Genet ; 6(7): e1001024, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20657825

RESUMO

The study of the chronological life span of Saccharomyces cerevisiae, which measures the survival of populations of non-dividing yeast, has resulted in the identification of homologous genes and pathways that promote aging in organisms ranging from yeast to mammals. Using a competitive genome-wide approach, we performed a screen of a complete set of approximately 4,800 viable deletion mutants to identify genes that either increase or decrease chronological life span. Half of the putative short-/long-lived mutants retested from the primary screen were confirmed, demonstrating the utility of our approach. Deletion of genes involved in vacuolar protein sorting, autophagy, and mitochondrial function shortened life span, confirming that respiration and degradation processes are essential for long-term survival. Among the genes whose deletion significantly extended life span are ACB1, CKA2, and TRM9, implicated in fatty acid transport and biosynthesis, cell signaling, and tRNA methylation, respectively. Deletion of these genes conferred heat-shock resistance, supporting the link between life span extension and cellular protection observed in several model organisms. The high degree of conservation of these novel yeast longevity determinants in other species raises the possibility that their role in senescence might be conserved.


Assuntos
Genoma Fúngico , Longevidade/genética , Saccharomyces cerevisiae/genética , Envelhecimento/genética , Autofagia , Deleção de Genes , Metilação , Mitocôndrias , Biossíntese de Proteínas , Transporte Proteico , RNA de Transferência/metabolismo , Saccharomyces cerevisiae/fisiologia , Vacúolos/metabolismo
6.
Nucleic Acids Res ; 38(1): 143-58, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19880387

RESUMO

In an attempt to elucidate the underlying longevity-promoting mechanisms of mutants lacking SCH9, which live three times as long as wild type chronologically, we measured their time-course gene expression profiles. We interpreted their expression time differences by statistical inferences based on prior biological knowledge, and identified the following significant changes: (i) between 12 and 24 h, stress response genes were up-regulated by larger fold changes and ribosomal RNA (rRNA) processing genes were down-regulated more dramatically; (ii) mitochondrial ribosomal protein genes were not up-regulated between 12 and 60 h as wild type were; (iii) electron transport, oxidative phosphorylation and TCA genes were down-regulated early; (iv) the up-regulation of TCA and electron transport was accompanied by deep down-regulation of rRNA processing over time; and (v) rRNA processing genes were more volatile over time, and three associated cis-regulatory elements [rRNA processing element (rRPE), polymerase A and C (PAC) and glucose response element (GRE)] were identified. Deletion of AZF1, which encodes the transcriptional factor that binds to the GRE element, reversed the lifespan extension of sch9Delta. The significant alterations in these time-dependent expression profiles imply that the lack of SCH9 turns on the longevity programme that extends the lifespan through changes in metabolic pathways and protection mechanisms, particularly, the regulation of aerobic respiration and rRNA processing.


Assuntos
Regulação Fúngica da Expressão Gênica , Proteínas Serina-Treonina Quinases/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Ciclo do Ácido Cítrico/genética , Transporte de Elétrons/genética , Perfilação da Expressão Gênica , Cinética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação Oxidativa , Regiões Promotoras Genéticas , Processamento Pós-Transcricional do RNA , RNA Ribossômico/metabolismo , Elementos de Resposta , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Estresse Fisiológico/genética , Fatores de Transcrição/metabolismo
7.
PLoS Genet ; 5(5): e1000467, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19424415

RESUMO

The effect of calorie restriction (CR) on life span extension, demonstrated in organisms ranging from yeast to mice, may involve the down-regulation of pathways, including Tor, Akt, and Ras. Here, we present data suggesting that yeast Tor1 and Sch9 (a homolog of the mammalian kinases Akt and S6K) is a central component of a network that controls a common set of genes implicated in a metabolic switch from the TCA cycle and respiration to glycolysis and glycerol biosynthesis. During chronological survival, mutants lacking SCH9 depleted extracellular ethanol and reduced stored lipids, but synthesized and released glycerol. Deletion of the glycerol biosynthesis genes GPD1, GPD2, or RHR2, among the most up-regulated in long-lived sch9Delta, tor1Delta, and ras2Delta mutants, was sufficient to reverse chronological life span extension in sch9Delta mutants, suggesting that glycerol production, in addition to the regulation of stress resistance systems, optimizes life span extension. Glycerol, unlike glucose or ethanol, did not adversely affect the life span extension induced by calorie restriction or starvation, suggesting that carbon source substitution may represent an alternative to calorie restriction as a strategy to delay aging.


Assuntos
Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Animais , Restrição Calórica , Carbono/metabolismo , Respiração Celular , Ciclo do Ácido Cítrico , Meios de Cultura , Etanol/metabolismo , Perfilação da Expressão Gênica , Genes Fúngicos , Glicerol/metabolismo , Glicólise , Longevidade , Modelos Biológicos , Mutação , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismo
8.
Life Sci Alliance ; 5(3)2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34893559

RESUMO

Changes in histone post-translational modifications are associated with aging through poorly defined mechanisms. Histone 3 lysine 4 (H3K4) methylation at promoters is deposited by SET1 family methyltransferases acting within conserved multiprotein complexes known as COMPASS. Previous work yielded conflicting results about the requirement for H3K4 methylation during aging. Here, we reassessed the role of SET1/COMPASS-dependent H3K4 methylation in Caenorhabditis elegans lifespan and fertility by generating set-2(syb2085) mutant animals that express a catalytically inactive form of SET-2, the C. elegans SET1 homolog. We show that set-2(syb2085) animals retain the ability to form COMPASS, but have a marked global loss of H3K4 di- and trimethylation (H3K4me2/3). Reduced H3K4 methylation was accompanied by loss of fertility, as expected; however, in contrast to earlier studies, set-2(syb2085) mutants displayed a significantly shortened, not extended, lifespan and had normal intestinal fat stores. Other commonly used set-2 mutants were also short-lived, as was a cfp-1 mutant that lacks the SET1/COMPASS chromatin-targeting component. These results challenge previously held views and establish that WT H3K4me2/3 levels are essential for normal lifespan in C. elegans.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Fertilidade/genética , Histona-Lisina N-Metiltransferase/deficiência , Longevidade/genética , Proteínas Nucleares/deficiência , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Catálise , Ativação Enzimática , Histonas/metabolismo , Metilação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo
9.
PLoS Genet ; 4(1): e13, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18225956

RESUMO

Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.


Assuntos
Restrição Calórica , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Fatores de Transcrição/metabolismo , Proteínas ras/metabolismo , AMP Cíclico/metabolismo , Regulação Fúngica da Expressão Gênica , Mutação/genética , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Quinases/metabolismo , Elementos de Resposta , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Transdução de Sinais , Temperatura , Fatores de Tempo
10.
Biol Open ; 10(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495210

RESUMO

Auxins are plant growth regulators that influence most aspects of plant development through complex mechanisms. The development of an auxin-inducible degradation (AID) system has enabled rapid, conditional protein depletion in yeast and cultured cells. More recently, the system was successfully adapted to Caenorhabditiselegans to achieve auxin-dependent degradation of targets in all tissues and developmental stages. Whether auxin treatment alone has an impact on nematode physiology is an open question. Here we show that indole-3-acetic acid (IAA), the auxin most commonly used to trigger AID in worms, functions through the conserved IRE-1/XBP-1 branch of the Unfolded Protein Response (UPR) to promote resistance to endoplasmic reticulum (ER) stress. Because the UPR not only plays a central role in restoring ER homeostasis, but also promotes lipid biosynthesis and regulates lifespan, we suggest that extreme caution should be exercised when using the AID system to study these and related processes.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Indolacéticos/farmacologia , Substâncias Protetoras/farmacologia , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Desenvolvimento Embrionário/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos
11.
Biochim Biophys Acta ; 1783(7): 1280-5, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18445486

RESUMO

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.


Assuntos
Apoptose/fisiologia , Senescência Celular , Saccharomyces cerevisiae/fisiologia , Schizosaccharomyces/fisiologia , Envelhecimento , Apoptose/genética , Regulação Fúngica da Expressão Gênica , Genes Fúngicos , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética
12.
J Cell Biol ; 166(7): 1055-67, 2004 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-15452146

RESUMO

Aging is believed to be a nonadaptive process that escapes the force of natural selection. Here, we challenge this dogma by showing that yeast laboratory strains and strains isolated from grapes undergo an age- and pH-dependent death with features of mammalian programmed cell death (apoptosis). After 90-99% of the population dies, a small mutant subpopulation uses the nutrients released by dead cells to grow. This adaptive regrowth is inversely correlated with protection against superoxide toxicity and life span and is associated with elevated age-dependent release of nutrients and increased mutation frequency. Computational simulations confirm that premature aging together with a relatively high mutation frequency can result in a major advantage in adaptation to changing environments. These results suggest that under conditions that model natural environments, yeast organisms undergo an altruistic and premature aging and death program, mediated in part by superoxide. The role of similar pathways in the regulation of longevity in organisms ranging from yeast to mice raises the possibility that mammals may also undergo programmed aging.


Assuntos
Adaptação Fisiológica/genética , Envelhecimento/metabolismo , Saccharomyces cerevisiae/metabolismo , Superóxidos/metabolismo , Envelhecimento/genética , Senilidade Prematura/genética , Senilidade Prematura/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Meios de Cultura/farmacologia , Meio Ambiente , Peróxido de Hidrogênio/farmacologia , Mutação/efeitos dos fármacos , Mutação/genética , Estresse Oxidativo/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Especificidade da Espécie , Inanição
13.
Cells ; 8(4)2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974922

RESUMO

Cellular adaptation to environmental stress relies on a wide range of tightly controlled regulatory mechanisms, including transcription. Changes in chromatin structure and organization accompany the transcriptional response to stress, and in some cases, can impart memory of stress exposure to subsequent generations through mechanisms of epigenetic inheritance. In the budding yeast Saccharomyces cerevisiae, histone post-translational modifications, and in particular histone methylation, have been shown to confer transcriptional memory of exposure to environmental stress conditions through mitotic divisions. Recent evidence from Caenorhabditis elegans also implicates histone methylation in transgenerational inheritance of stress responses, suggesting a more widely conserved role in epigenetic memory.


Assuntos
Caenorhabditis elegans/metabolismo , Histonas/metabolismo , Saccharomyces cerevisiae/metabolismo , Estresse Fisiológico/genética , Animais , Caenorhabditis elegans/genética , Epigênese Genética , Células HeLa , Humanos , Padrões de Herança , Metilação , Processamento de Proteína Pós-Traducional , Saccharomyces cerevisiae/genética
14.
BMC Genomics ; 8: 219, 2007 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-17617911

RESUMO

BACKGROUND: Three kinases: Sch9, PKA and TOR, are suggested to be involved in both the replicative and chronological ageing in yeast. They function in pathways whose down-regulation leads to life span extension. Several stress response proteins, including two transcription factors Msn2 and Msn4, mediate the longevity extension phenotype associated with decreased activity of either Sch9, PKA, or TOR. However, the mechanisms of longevity, especially the underlying transcription program have not been fully understood. RESULTS: We measured the gene expression profiles in wild type yeast and three long-lived mutants: sch9Delta, ras2Delta, and tor1Delta. To elucidate the transcription program that may account for the longevity extension, we identified the transcription factors that are systematically and significantly associated with the expression differentiation in these mutants with respect to wild type by integrating microarray expression data with motif and ChIP-chip data, respectively. Our analysis suggests that three stress response transcription factors, Msn2, Msn4 and Gis1, are activated in all the three mutants. We also identify some other transcription factors such as Fhl1 and Hsf1, which may also be involved in the transcriptional modification in the long-lived mutants. CONCLUSION: Combining microarray expression data with other data sources such as motif and ChIP-chip data provides biological insights into the transcription modification that leads to life span extension. In the chronologically long-lived mutant: sch9Delta, ras2Delta, and tor1Delta, several common stress response transcription factors are activated compared with the wild type according to our systematic transcription inference.


Assuntos
Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica , Longevidade/genética , Saccharomyces cerevisiae/genética , Transcrição Gênica , Motivos de Aminoácidos , Sequência de Bases , Imunoprecipitação da Cromatina , Redes Reguladoras de Genes , Genes Fúngicos , Dados de Sequência Molecular , Proteínas de Saccharomyces cerevisiae/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética
15.
Methods Mol Biol ; 371: 89-95, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17634576

RESUMO

The chronological life span of yeast, which is measured as the survival time of populations of nondividing cells, has been used successfully for the identification of key pathways responsible for the regulation of aging. These pathways have remarkable similarities with those that regulate the life span in higher eukaryotes, suggesting that longevity depends on the activity of genes and signaling pathways that share a common evolutionary origin. Thus, the unicellular Saccharomyces cerevisiae is a simple model system that can provide significant insights into the human genetics and molecular biology of aging. Here, we describe the standard procedures to measure the chronological life span, including both the normal and calorie restriction paradigms.


Assuntos
Longevidade/fisiologia , Modelos Biológicos , Saccharomyces cerevisiae/fisiologia , Transdução de Sinais/fisiologia , Evolução Biológica , Restrição Calórica , Humanos , Saccharomyces cerevisiae/citologia
16.
Aging (Albany NY) ; 9(7): 1745-1769, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28758895

RESUMO

In yeast, the broadly conserved acyl-CoA-binding protein (ACBP) is a negative regulator of stress resistance and longevity. Here, we have turned to the nematode C. elegans as a model organism in which to determine whether ACBPs play similar roles in multicellular organisms. We systematically inactivated each of the seven C. elegans ACBP paralogs and found that one of them, maa-1 (which encodes membrane-associated ACBP 1), is indeed involved in the regulation of longevity. In fact, loss of maa-1 promotes lifespan extension and resistance to different types of stress. Through genetic and gene expression studies we have demonstrated that HIF-1, a master transcriptional regulator of adaptation to hypoxia, plays a central role in orchestrating the anti-aging response induced by MAA-1 deficiency. This response relies on the activation of molecular chaperones known to contribute to maintenance of the proteome. Our work extends to C. elegans the role of ACBP in aging, implicates HIF-1 in the increase of lifespan of maa-1-deficient worms, and sheds light on the anti-aging function of HIF-1. Given that both ACBP and HIF-1 are highly conserved, our results suggest the possible involvement of these proteins in the age-associated decline in proteostasis in mammals.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Inibidor da Ligação a Diazepam/metabolismo , Regulação da Expressão Gênica/fisiologia , Fator 1 Induzível por Hipóxia/metabolismo , Longevidade/fisiologia , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Inibidor da Ligação a Diazepam/genética , Deleção de Genes , Fator 1 Induzível por Hipóxia/genética , Longevidade/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-26903948

RESUMO

Steroid hormones regulate physiological processes in species ranging from plants to humans. A wide range of steroid hormones exist, and their contributions to processes, such as growth, reproduction, development, and aging, is almost always complex. Understanding the biosynthetic pathways that generate steroid hormones and the signaling pathways that mediate their effects is thus of fundamental importance. In this work, we review recent advances in (i) the biological role of steroid hormones in the roundworm Caenorhabditis elegans and (ii) the development of novel methods to facilitate the detection and identification of these molecules. Our current understanding of steroid signaling in this simple organism serves to illustrate the challenges we face moving forward. First, it seems clear that we have not yet identified all of the enzymes responsible for steroid biosynthesis and/or degradation. Second, perturbation of steroid signaling affects a wide range of phenotypes, and subtly different steroid molecules can have distinct effects. Finally, steroid hormone levels are critically important, and minute variations in quantity can profoundly impact a phenotype. Thus, it is imperative that we develop innovative analytical tools and combine them with cutting-edge approaches including comprehensive and highly selective liquid chromatography coupled to mass spectrometry based on new methods such as supercritical fluid chromatography coupled to mass spectrometry (SFC-MS) if we are to obtain a better understanding of the biological functions of steroid signaling.

18.
J Neurosci ; 22(9): 3484-92, 2002 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11978825

RESUMO

The amyloid beta-peptide (Abeta) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha), which can be either neurotoxic or neuroprotective. We show that neuron death in cocultures of rat cortical microglia and neurons activated by lipopolysaccharide (LPS) or Abeta1-42 plus interferon gamma (IFNgamma) is caused by short-lived diffusible molecules and follows the generation of superoxide and/or peroxynitrite as determined by electron paramagnetic spectroscopy. Neurotoxicity induced by LPS or Abeta1-42 plus IFNgamma is blocked by inhibitors of NO synthesis and by the peroxynitrite (ONOO-) decomposition catalysts FeTMPyP [5,10,15,20-tetrakis(n-methyl-4'-pyridyl)porphinato iron (III) chloride] and FeTPPS [5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride] but not by the TNF-alpha inhibitor pentoxifylline. The specificity of FeTMPyP for ONOO- was confirmed by its ability to block the toxicity of a peroxynitrite donor but not of NO donors or of high levels of superoxide in a yeast mutant lacking superoxide dismutase 1. These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Abeta1-42 neurotoxicity and Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/toxicidade , Ácido Peroxinitroso/metabolismo , Animais , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Espectroscopia de Ressonância de Spin Eletrônica , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Interferon gama/farmacologia , Compostos de Ferro/farmacologia , Microglia/citologia , Microglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Pentoxifilina/farmacologia , Ratos , Ratos Endogâmicos F344 , Superóxidos/metabolismo , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
19.
Mech Ageing Dev ; 126(1): 11-6, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15610757

RESUMO

The use of simple model systems such as Saccharomyces cerevisiae and Caenorhabditis elegans has played a primary role in the identification of proteins and pathways that regulate the aging process in eukaryotes. Recent findings have shown that analogous pathways regulate aging in higher eukaryotes and suggest a conserved origin for the molecular mechanisms that regulate stress-resistance and longevity. Genomics approaches that allow the simultaneous monitoring of the expression of thousands of genes are beginning to reveal the complexity of the molecular changes required to extend life span. Here we describe how analysis of the gene expression profiles of wild-type and long-lived yeast aging chronologically can be used to identify proteins that increase stress-resistance and longevity. We also discuss a novel genomics method for the identification of chronologically long-lived yeast mutants.


Assuntos
Regulação Fúngica da Expressão Gênica/genética , Genômica/métodos , Longevidade/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Regulação Fúngica da Expressão Gênica/fisiologia , Longevidade/fisiologia , Saccharomyces cerevisiae/fisiologia , Proteínas de Saccharomyces cerevisiae/biossíntese
20.
Genetics ; 163(1): 35-46, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12586694

RESUMO

Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Delta mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods--mitochondrial Sod2 and cytosolic CuZnSod (Sod1)--delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.


Assuntos
Proteínas Fúngicas , Proteínas Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Superóxido Dismutase/metabolismo , Aconitato Hidratase/metabolismo , Proteínas de Ligação a DNA/metabolismo , Mutação , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa