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1.
J Neuroinflammation ; 20(1): 192, 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37608305

RESUMO

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the temporal dynamics of neuroinflammation and metabolomics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6 J mice were exposed to wood smoke every other day for 2 weeks at an average exposure concentration of 0.5 mg/m3. Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-day post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of CD31Hi and CD31Med expressors, with wood smoke inhalation causing an increased proportion of CD31Hi. These populations of CD31Hi and CD31Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b+/CD45low) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules, such as glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD+ metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD+ abundance on day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated with wildfire smoke exposure.


Assuntos
NAD , Doenças Neuroinflamatórias , Feminino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Biomassa , Hipocampo , Ácido Glutâmico , Metabolômica , Fumaça/efeitos adversos
2.
Int J Mol Sci ; 24(22)2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-38003352

RESUMO

We have shown that multiple tRNA synthetase inhibitors can increase lifespan in both the nematode C. elegans and the budding yeast S. cerevisiae by acting through the conserved transcription factor Gcn4 (yeast)/ATF-4 (worms). To further understand the biology downstream from this conserved transcription factor in the yeast model system, we looked at two different yeast models known to have upregulated Gcn4 and GCN4-dependent increased replicative lifespan. These two models were rpl31aΔ yeast and yeast treated with the tRNA synthetase inhibitor borrelidin. We used both proteomic and RNAseq analysis of a block experimental design that included both of these models to identify GCN4-dependent changes in these two long-lived strains of yeast. Proteomic analysis of these yeast indicate that the long-lived yeast have increased abundances of proteins involved in amino acid biosynthesis. The RNAseq of these same yeast uncovered further regulation of protein degradation, identifying the differential expression of genes associated with autophagy and the ubiquitin-proteasome system (UPS). The data presented here further underscore the important role that GCN4 plays in the maintenance of protein homeostasis, which itself is an important hallmark of aging. In particular, the changes in autophagy and UPS-related gene expression that we have observed could also have wide-ranging implications for the understanding and treatment of diseases of aging that are associated with protein aggregation.


Assuntos
Aminoacil-tRNA Sintetases , Proteínas de Saccharomyces cerevisiae , Animais , Saccharomyces cerevisiae/metabolismo , Longevidade/genética , Proteólise , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Multiômica , Proteômica , Fatores de Transcrição/metabolismo , Ubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Aminoacil-tRNA Sintetases/genética , Proteínas Fúngicas/metabolismo , Regulação Fúngica da Expressão Gênica , Biossíntese de Proteínas
3.
Mol Cell ; 39(5): 659-61, 2010 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-20832716

RESUMO

In this issue of Molecular Cell, Feser et al. (2010) show that aging yeast lose chromatin-associated histones and, furthermore, that correcting this deficiency robustly enhances replicative life span, indicating that loss of normal chromatin packing contributes to the aging process.

4.
Proc Natl Acad Sci U S A ; 112(38): 11977-82, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26351681

RESUMO

Budding yeast divides asymmetrically, giving rise to a mother cell that progressively ages and a daughter cell with full lifespan. It is generally assumed that mother cells retain damaged, lifespan limiting materials ("aging factors") through asymmetric division. However, the identity of these aging factors and the mechanisms through which they limit lifespan remain poorly understood. Using a flow cytometry-based, high-throughput approach, we quantified the asymmetric partitioning of the yeast proteome between mother and daughter cells during cell division, discovering 74 mother-enriched and 60 daughter-enriched proteins. While daughter-enriched proteins are biased toward those needed for bud construction and genome maintenance, mother-enriched proteins are biased towards those localized in the plasma membrane and vacuole. Deletion of 23 of the 74 mother-enriched proteins leads to lifespan extension, a fraction that is about six times that of the genes picked randomly from the genome. Among these lifespan-extending genes, three are involved in endosomal sorting/endosome to vacuole transport, and three are nitrogen source transporters. Tracking the dynamic expression of specific mother-enriched proteins revealed that their concentration steadily increases in the mother cells as they age, but is kept relatively low in the daughter cells via asymmetric distribution. Our results suggest that some mother-enriched proteins may increase to a concentration that becomes deleterious and lifespan-limiting in aged cells, possibly by upsetting homeostasis or leading to aberrant signaling. Our study provides a comprehensive resource for analyzing asymmetric cell division and aging in yeast, which should also be valuable for understanding similar phenomena in other organisms.


Assuntos
Proteoma/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Divisão Celular Assimétrica , Citometria de Fluxo , Ontologia Genética , Proteínas de Fluorescência Verde/metabolismo , Ensaios de Triagem em Larga Escala , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Tempo
5.
Geroscience ; 46(2): 1755-1773, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37749371

RESUMO

We have recently shown that multiple tRNA synthetase inhibitors can greatly increase lifespan in multiple models by acting through the conserved transcription factor ATF4. Here, we show that these compounds, and several others of the same class, can greatly upregulate mammalian ATF4 in cells in vitro, in a dose dependent manner. Further, RNASeq analysis of these cells pointed toward changes in protein turnover. In subsequent experiments here we show that multiple tRNA synthetase inhibitors can greatly upregulate activity of the ubiquitin proteasome system (UPS) in cells in an ATF4-dependent manner. The UPS plays an important role in the turnover of many damaged or dysfunctional proteins in an organism. Increasing UPS activity has been shown to enhance the survival of Huntington's disease cell models, but there are few known pharmacological enhancers of the UPS. Additionally, we see separate ATF4 dependent upregulation of macroautophagy upon treatment with tRNA synthetase inhibitors. Protein degradation is an essential cellular process linked to many important human diseases of aging such as Alzheimer's disease and Huntington's disease. These drugs' ability to enhance proteostasis more broadly could have wide-ranging implications in the treatment of important age-related neurodegenerative diseases.


Assuntos
Aminoacil-tRNA Sintetases , Doença de Huntington , Animais , Humanos , Doença de Huntington/metabolismo , Longevidade , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Mamíferos/metabolismo
6.
Nat Cell Biol ; 26(9): 1571-1584, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39117797

RESUMO

Caloric restriction and intermittent fasting prolong the lifespan and healthspan of model organisms and improve human health. The natural polyamine spermidine has been similarly linked to autophagy enhancement, geroprotection and reduced incidence of cardiovascular and neurodegenerative diseases across species borders. Here, we asked whether the cellular and physiological consequences of caloric restriction and fasting depend on polyamine metabolism. We report that spermidine levels increased upon distinct regimens of fasting or caloric restriction in yeast, flies, mice and human volunteers. Genetic or pharmacological blockade of endogenous spermidine synthesis reduced fasting-induced autophagy in yeast, nematodes and human cells. Furthermore, perturbing the polyamine pathway in vivo abrogated the lifespan- and healthspan-extending effects, as well as the cardioprotective and anti-arthritic consequences of fasting. Mechanistically, spermidine mediated these effects via autophagy induction and hypusination of the translation regulator eIF5A. In summary, the polyamine-hypusination axis emerges as a phylogenetically conserved metabolic control hub for fasting-mediated autophagy enhancement and longevity.


Assuntos
Autofagia , Caenorhabditis elegans , Restrição Calórica , Jejum , Longevidade , Espermidina , Autofagia/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Espermidina/metabolismo , Espermidina/farmacologia , Animais , Humanos , Caenorhabditis elegans/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Fatores de Iniciação de Peptídeos/genética , Fator de Iniciação de Tradução Eucariótico 5A , Drosophila melanogaster/metabolismo , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Camundongos , Masculino , Camundongos Endogâmicos C57BL
7.
MicroPubl Biol ; 20232023.
Artigo em Inglês | MEDLINE | ID: mdl-37854099

RESUMO

WLSplot is an R package used to easily analyze lifespan survival data, and display results graphically as a survival curve with useful labels and statistical information auto-generated from the data and added to the graph, within a single function. It is designed primarily with Caenorhabditis elegans lifespan data in mind initially but can easily be used for other types of survival data. The WLSplot GitHub repository provides a blank template spreadsheet to be used for collecting lifespan data, instructions on how to install and run WLSplot, and examples covering RNAi, Genotype, or Drug lifespan experimental set-ups. WLSplot can analyze and plot multiple experiments in bulk while correctly italicizing worm gene names and adding asterisks and p-values to the plot legend when a significantly different lifespan from the designated control lifespan is seen. This is returned as an editable scalable vector graphics (svg) file for each output, and WLSplot can also return the summary of the directly plotted data so that the researcher can do their own further manipulation, in addition to being able to edit the output svg files.

8.
Front Toxicol ; 5: 1267667, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37900096

RESUMO

Aging is a complex biological process involving multiple interacting mechanisms and is being increasingly linked to environmental exposures such as wildfire smoke. In this review, we detail the hallmarks of aging, emphasizing the role of telomere attrition, cellular senescence, epigenetic alterations, proteostasis, genomic instability, and mitochondrial dysfunction, while also exploring integrative hallmarks - altered intercellular communication and stem cell exhaustion. Within each hallmark of aging, our review explores how environmental disasters like wildfires, and their resultant inhaled toxicants, interact with these aging mechanisms. The intersection between aging and environmental exposures, especially high-concentration insults from wildfires, remains under-studied. Preliminary evidence, from our group and others, suggests that inhaled wildfire smoke can accelerate markers of neurological aging and reduce learning capabilities. This is likely mediated by the augmentation of circulatory factors that compromise vascular and blood-brain barrier integrity, induce chronic neuroinflammation, and promote age-associated proteinopathy-related outcomes. Moreover, wildfire smoke may induce a reduced metabolic, senescent cellular phenotype. Future interventions could potentially leverage combined anti-inflammatory and NAD + boosting compounds to counter these effects. This review underscores the critical need to study the intricate interplay between environmental factors and the biological mechanisms of aging to pave the way for effective interventions.

9.
Res Sq ; 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37333410

RESUMO

Smoke from wildland fires has been shown to produce neuroinflammation in preclinical models, characterized by neural infiltrations of neutrophils and monocytes, as well as altered neurovascular endothelial phenotypes. To address the longevity of such outcomes, the present study examined the neuroinflammatory and metabolomic temporal dynamics after inhalation exposures from biomass-derived smoke. 2-month-old female C57BL/6J mice were exposed to wood smoke every other day for two weeks at an average exposure concentration of 0.5mg/m 3 . Subsequent serial euthanasia occurred at 1-, 3-, 7-, 14-, and 28-days post-exposure. Flow cytometry of right hemispheres revealed two endothelial populations of PECAM (CD31), high and medium expressors, with wood smoke inhalation causing an increased proportion of PECAM Hi . These populations of PECAM Hi and PECAM Med were associated with an anti-inflammatory and pro-inflammatory response, respectively, and their inflammatory profiles were largely resolved by the 28-day mark. However, activated microglial populations (CD11b + /CD45 low ) remained higher in wood smoke-exposed mice than controls at day 28. Infiltrating neutrophil populations decreased to levels below controls by day 28. However, the MHC-II expression of the peripheral immune infiltrate remained high, and the population of neutrophils retained an increased expression of CD45, Ly6C, and MHC-II. Utilizing an unbiased approach examining the metabolomic alterations, we observed notable hippocampal perturbations in neurotransmitter and signaling molecules like glutamate, quinolinic acid, and 5-α-dihydroprogesterone. Utilizing a targeted panel designed to explore the aging-associated NAD + metabolic pathway, wood smoke exposure drove fluctuations and compensations across the 28-day time course, ending with decreased hippocampal NAD + abundance at day 28. Summarily, these results indicate a highly dynamic neuroinflammatory environment, with potential resolution extending past 28 days, the implications of which may include long-term behavioral changes, systemic and neurological sequalae directly associated wtith wildfire smoke exposure.

10.
Curr Genomics ; 13(7): 500-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23633910

RESUMO

Whole-genome studies involving a phenotype of interest are increasingly prevalent, in part due to a dramatic increase in speed at which many high throughput technologies can be performed coupled to simultaneous decreases in cost. This type of genome-scale methodology has been applied to the phenotype of lifespan, as well as to whole-transcriptome changes during the aging process or in mutants affecting aging. The value of high throughput discovery-based science in this field is clearly evident, but will it yield a true systems-level understanding of the aging process? Here we review some of this work to date, focusing on recent findings and the unanswered puzzles to which they point. In this context, we also discuss recent technological advances and some of the likely future directions that they portend.

11.
iScience ; 25(11): 105410, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36388960

RESUMO

Deletion of genes encoding ribosomal proteins extends lifespan in yeast. This increases translation of the functionally conserved transcription factor Gcn4, and lifespan extension in these mutants is GCN4-dependent. Gcn4 is also translationally upregulated by uncharged tRNAs, as are its C aenorhabditis elegans and mammalian functional orthologs. Here, we show that cytosolic tRNA synthetase inhibitors upregulate Gcn4 translation and extend yeast lifespan in a Gcn4-dependent manner. This cytosolic tRNA synthetase inhibitor is also able to extend the lifespan of C. elegans in an atf-4-dependent manner. We show that mitochondrial tRNA synthetase inhibitors greatly extend the lifespan of C. elegans, and this depends on atf-4. This suggests that perturbations of both cytosolic and mitochondrial translation may act in part via the same downstream pathway. These findings establish GCN4 orthologs as conserved longevity factors and, as long-lived mice exhibit elevated ATF4, leave open the possibility that tRNA synthetase inhibitors could also extend lifespan in mammals.

12.
Aging Cell ; 21(11): e13712, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36181361

RESUMO

The budding yeast Saccharomyces cerevisiae (S. cerevisiae) has relatively short lifespan and is genetically tractable, making it a widely used model organism in aging research. Here, we carried out a systematic and quantitative investigation of yeast aging with single-cell resolution through transcriptomic sequencing. We optimized a single-cell RNA sequencing (scRNA-seq) protocol to quantitatively study the whole transcriptome profiles of single yeast cells at different ages, finding increased cell-to-cell transcriptional variability during aging. The single-cell transcriptome analysis also highlighted key biological processes or cellular components, including oxidation-reduction process, oxidative stress response (OSR), translation, ribosome biogenesis and mitochondrion that underlie aging in yeast. We uncovered a molecular marker of FIT3, indicating the early heterogeneity during aging in yeast. We also analyzed the regulation of transcription factors and further characterized the distinctive temporal regulation of the OSR by YAP1 and proteasome activity by RPN4 during aging in yeast. Overall, our data profoundly reveal early heterogeneity during aging in yeast and shed light on the aging dynamics at the single cell level.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , RNA-Seq , Fatores de Transcrição/genética
13.
Transl Med Aging ; 4: 1-10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33134648

RESUMO

Aging is a fundamental biological process that is still not fully understood. As many of the most significant human diseases have aging as their greatest risk factor, a better understanding of aging potentially has enormous practical implications in treating these diseases. The nematode C. elegans is an exceptionally useful genetic model organism that had been used with great success to shed light on many genes and pathways that are involved in aging. Many of these pathways and mechanisms have been shown to be conserved through mammals. The standard methods for assaying survival in C. elegans to measure changes in lifespan are tedious and time consuming. This limits the throughput and productivity of C. elegans aging researchers. In recent years, many inroads have been made into automating various facets of the collection and analysis of C. elegans lifespan experimental data. The advances described in this review all work to ameliorate some of the hurdles that come with manual worm lifespan scoring, by automating or eliminating some of the most time consuming aspects of the assay. By greatly increasing the throughput of lifespan assays, these methods will enable types of experiments (e.g., drug library screens) whose scale is currently impractical. These methods have already proved exceptionally useful, and some of them are likely to be the predecessors of even more refined methods that could lead to breakthroughs in the ability to study lifespan in C. elegans. This could in turn potentially revolutionize our understanding of the basic biology of aging, and one day lead to treatments that could offset or delay age-related diseases in humans.

14.
Transl Med Aging ; 4: 141-148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33542965

RESUMO

Plate reader-based methods for high-throughput measurement of growth rate, cellular survival, and chronological lifespan are a compelling addition to the already powerful toolbox of budding yeast Saccharomyces cerevisiae genetics. These methods have overcome many of the limits of traditional yeast biology techniques, but also present a new bottleneck at the point of data-analysis. Herein, we describe SPOCK (Survival Percentage and Outgrowth Collection Kit), an R-based package for the analysis of data created by high-throughput plate reader based methods. This package allows for the determination of chronological lifespan, cellular growth rate, and survival in an efficient, robust, and reproducible fashion.

15.
Sci Adv ; 6(32): eaba1306, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32821821

RESUMO

Caloric restriction (CR) is known to extend life span across species; however, the molecular mechanisms are not well understood. We investigate the mechanism by which glucose restriction (GR) extends yeast replicative life span, by combining ribosome profiling and RNA-seq with microfluidic-based single-cell analysis. We discovered a cross-talk between glucose sensing and the regulation of intracellular methionine: GR down-regulated the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration; external supplementation of methionine cancels the life span extension by GR. Furthermore, genetic perturbations that decrease methionine synthesis/uptake extend life span. These observations suggest that intracellular methionine mediates the life span effects of various nutrient and genetic perturbations, and that the glucose-methionine cross-talk is a general mechanism for coordinating the nutrient status and the translation/growth of a cell. Our work also implicates proteasome as a downstream effector of the life span extension by GR.


Assuntos
Longevidade , Metionina , Suplementos Nutricionais , Glucose/farmacologia , Saccharomyces cerevisiae/genética
16.
Cell Metab ; 31(3): 549-563.e7, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32084377

RESUMO

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity.


Assuntos
Citosol/metabolismo , Longevidade , Mitocôndrias/metabolismo , Biossíntese de Proteínas , Transdução de Sinais , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Citosol/efeitos dos fármacos , Doxiciclina/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Fenótipo , Biossíntese de Proteínas/efeitos dos fármacos , Proteoma/metabolismo , Interferência de RNA , Proteínas Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Estresse Fisiológico/genética , Fatores de Transcrição/metabolismo , Transcriptoma/efeitos dos fármacos , Transcriptoma/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
17.
Antioxid Redox Signal ; 29(10): 973-984, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29020802

RESUMO

SIGNIFICANCE: Reductionist studies have contributed greatly to our understanding of the basic biology of aging in recent years but we still do not understand fundamental mechanisms for many identified drugs and pathways. Use of systems approaches will help us move forward in our understanding of aging. Recent Advances: Recent work described here has illustrated the power of systems biology to inform our understanding of aging through the study of (i) diet restriction, (ii) neurodegenerative disease, and (iii) biomarkers of aging. CRITICAL ISSUES: Although we do not understand all of the individual genes and pathways that affect aging, as we continue to uncover more of them, we have now also begun to synthesize existing data using systems-level approaches, often to great effect. The three examples noted here all benefit from computational approaches that were unknown a few years ago, and from biological insights gleaned from multiple model systems, from aging laboratories as well as many other areas of biology. FUTURE DIRECTIONS: Many new technologies, such as single-cell sequencing, advances in epigenetics beyond the methylome (specifically, assay for transposase-accessible chromatin with high throughput sequencing ), and multiomic network studies, will increase the reach of systems biologists. This suggests that approaches similar to those described here will continue to lead to striking findings, and to interventions that may allow us to delay some of the many age-associated diseases in humans; perhaps sooner that we expect. Antioxid. Redox Signal. 29, 973-984.


Assuntos
Envelhecimento/metabolismo , Biologia de Sistemas , Envelhecimento/genética , Animais , Humanos
18.
Elife ; 72018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479271

RESUMO

Aging impairs the activation of stress signaling pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here, we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient Caenorhabditis elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Longevidade/efeitos dos fármacos , Minociclina/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Inibidores da Síntese de Proteínas/metabolismo , Proteostase/efeitos dos fármacos , Animais , Agregação Patológica de Proteínas/prevenção & controle , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo
19.
Aging Cell ; 16(4): 785-796, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28568901

RESUMO

Sgf73, a core component of SAGA, is the yeast orthologue of ataxin-7, which undergoes CAG-polyglutamine repeat expansion leading to the human neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Deletion of SGF73 dramatically extends replicative lifespan (RLS) in yeast. To further define the basis for Sgf73-mediated RLS extension, we performed ChIP-Seq, identified 388 unique genomic regions occupied by Sgf73, and noted enrichment in promoters of ribosomal protein (RP)-encoding genes. Of 388 Sgf73 binding sites, 33 correspond to 5' regions of genes implicated in RLS extension, including 20 genes encoding RPs. Furthermore, half of Sgf73-occupied, RLS-linked RP genes displayed significantly reduced expression in sgf73Δ mutants, and double null strains lacking SGF73 and a Sgf73-regulated, RLS-linked RP gene exhibited no further increase in replicative lifespan. We also found that sgf73Δ mutants display altered acetylation of Ifh1, an important regulator of RP gene transcription. These findings implicate altered ribosomal protein expression in sgf73Δ yeast RLS and highlight altered acetylation as a pathway of relevance for SCA7 neurodegeneration.


Assuntos
Deleção de Genes , Regulação Fúngica da Expressão Gênica , Histona Acetiltransferases/genética , Regiões Promotoras Genéticas , Proteínas Ribossômicas/genética , Saccharomyces cerevisiae/genética , Acetilação , Ataxina-7/deficiência , Ataxina-7/genética , Sequência de Bases , Sítios de Ligação , Divisão Celular , Histona Acetiltransferases/deficiência , Humanos , Viabilidade Microbiana , Anotação de Sequência Molecular , Ligação Proteica , Proteínas Ribossômicas/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia , Transativadores/genética , Transativadores/metabolismo
20.
Cell Rep ; 17(10): 2542-2552, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27926859

RESUMO

The role of the mTOR inhibitor, rapamycin, in regulation of adiposity remains controversial. Here, we evaluate mTOR signaling in lipid metabolism in adipose tissues of Lmna-/- mice, a mouse model for dilated cardiomyopathy and muscular dystrophy. Lifespan extension by rapamycin is associated with increased body weight and fat content, two phenotypes we link to suppression of elevated energy expenditure. In both white and brown adipose tissue of Lmna-/- mice, we find that rapamycin inhibits mTORC1 but not mTORC2, leading to suppression of elevated lipolysis and restoration of thermogenic protein UCP1 levels, respectively. The short lifespan and metabolic phenotypes of Lmna-/- mice can be partially rescued by maintaining mice at thermoneutrality. Together, our findings indicate that altered mTOR signaling in Lmna-/- mice leads to a lipodystrophic phenotype that can be rescued with rapamycin, highlighting the effect of loss of adipose tissue in Lmna-/- mice and the consequences of altered mTOR signaling.


Assuntos
Tecido Adiposo/metabolismo , Lamina Tipo A/genética , Serina-Treonina Quinases TOR/genética , Termogênese/genética , Proteína Desacopladora 1/genética , Animais , Lamina Tipo A/metabolismo , Lipólise/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Camundongos , Sirolimo/administração & dosagem , Serina-Treonina Quinases TOR/metabolismo , Proteína Desacopladora 1/metabolismo
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