Regulation of the one carbon folate cycle as a shared metabolic signature of longevity

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Июнь 9, 2021

Abstract The metabolome represents a complex network of biological events that reflects the physiologic state organism in health and disease. Additionally, specific metabolites metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry obtain metabolomic profiles canonical longevity C. elegans identify regulating life span. By leveraging across pathways, found one carbon metabolism folate cycle pervasively regulated common. We observed similar changes long-lived mouse models reduced insulin/IGF signaling. Genetic manipulation pathway enzymes supplementation with reveal regulation shared causal mechanism proteoprotection. Such interventions impact methionine cycle, restriction as an underlying mechanism. This comparative approach reveals key nodes enhance healthy ageing.

Язык: Английский

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The association of arsenic exposure and arsenic metabolism with all-cause, cardiovascular and cancer mortality in the Strong Heart Study

Environment International, Год журнала: 2021, Номер 159, С. 107029 - 107029

Опубликована: Дек. 8, 2021

The effect of low-moderate levels arsenic exposure and metabolism on mortality remains uncertain. We used data from a prospective cohort study in 3600 men women aged 45 to 75 years living Arizona, Oklahoma, North South Dakota. biomarker inorganic was the sum urine (iAs), monomethylated (MMA) dimethylated (DMA) compounds (ƩAs) at baseline. proportions iAs, MMA DMA over ƩiAs, expressed as iAs%, MMA%, DMA%, respectively, were biomarkers metabolism. Arsenic associated with all-cause, cardiovascular, cancer mortality. For each interquartile range (IQR) increase ƩAs (12.5 μg/L, overall 0.7–194.1 μg/L), adjusted hazard ratios (aHRs) 1.28 (95% CI 1.16–1.41) for all-cause mortality, (1.08–1.52) cardiovascular 1.15 (0.92–1.44) aHR IQR when iAs% is decreasing, 1.52 1.16–1.99) disease, 0.73 (0.55–0.98) cancer, 1.03 (0.90–1.19) These findings highlight need implement public health measures protect populations involuntary research advance biological clinical understanding arsenic-related effects general populations.

Язык: Английский

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Loss of N-terminal acetyltransferase A activity induces thermally unstable ribosomal proteins and increases their turnover in Saccharomyces cerevisiae

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 27, 2023

Abstract Protein N-terminal (Nt) acetylation is one of the most abundant modifications in eukaryotes, covering ~50-80 % proteome, depending on species. Cells with defective Nt-acetylation display a wide array phenotypes such as impaired growth, mating defects and increased stress sensitivity. However, pleiotropic nature these effects has hampered our understanding functional impact protein Nt-acetylation. The main enzyme responsible for throughout eukaryotic kingdom acetyltransferase NatA. Here we employ multi-dimensional proteomics approach to analyze Saccharomyces cerevisiae lacking NatA activity, which causes global proteome remodeling. Pulsed-SILAC experiments reveals that NatA-deficient strains consistently increase degradation ribosomal proteins compared wild type. Explaining this phenomenon, thermal profiling uncovers decreased thermostability ribosomes NatA-knockouts. Our data are agreement role promoting stability parts by enhancing avidity protein-protein interactions folding.

Язык: Английский

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Ribosomal Biogenesis and Heterogeneity in Development, Disease, and Aging

Epigenomes, Год журнала: 2023, Номер 7(3), С. 17 - 17

Опубликована: Авг. 11, 2023

Although reported in the literature, ribosome heterogeneity is a phenomenon whose extent and implications cell organismal biology not fully appreciated. This has been case due to lack of appropriate techniques approaches. Heterogeneity can arise from alternative use differential content protein RNA constituents, as well post-transcriptional post-translational modifications. In few examples we have, it apparent that ribosomal offers an additional level potential for gene expression regulation might be way towards tuning metabolism, stress, growth programs external internal stimuli needs. Here, introduce biogenesis discuss various occasions. We conclude systematic approach multiple organisms will needed delineate this biological its contributions growth, aging, disease. Finally, mutations their roles

Язык: Английский

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Ageing-associated long non-coding RNA extends lifespan and reduces translation in non-dividing cells

EMBO Reports, Год журнала: 2024, Номер 25(11), С. 4921 - 4949

Опубликована: Окт. 2, 2024

Genomes produce widespread long non-coding RNAs (lncRNAs) of largely unknown functions. We characterize aal1 (ageing-associated lncRNA), which is induced in quiescent fission yeast cells. Deletion shortens the chronological lifespan non-dividing cells, while ectopic overexpression prolongs their lifespan, indicating that acts trans. Overexpression represses ribosomal-protein gene expression and inhibits cell growth, genetically interacts with coding genes functioning protein translation. The lncRNA localizes to cytoplasm associates ribosomes. Notably, decreases cellular ribosome content binds rpl1901 mRNA, encoding a ribosomal protein. levels are reduced ~2-fold by aal1, sufficient extend lifespan. Remarkably, Drosophila boosts fly propose reduces decreasing Rpl1901 levels, thus attenuating translational capacity promoting longevity. Although not conserved, its effect flies suggests animals feature related mechanisms modulate ageing, based on conserved machinery.

Язык: Английский

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A cell-nonautonomous mechanism of yeast chronological aging regulated by caloric restriction and one-carbon metabolism

Journal of Biological Chemistry, Год журнала: 2020, Номер 296, С. 100125 - 100125

Опубликована: Ноя. 26, 2020

Caloric restriction (CR) improves health span and life of organisms ranging from yeast to mammals. Understanding the mechanisms involved will uncover future interventions for aging-associated diseases. In budding yeast, Saccharomyces cerevisiae, CR is commonly defined by reduced glucose in growth medium, which extends both replicative chronological (CLS). We found that conditioned media collected stationary-phase cultures extended CLS when supplemented into nonrestricted (NR) cultures, suggesting a potential cell-nonautonomous mechanism CR-induced regulation. Chromatography untargeted metabolomics media, as well transcriptional responses associated with longevity effect, pointed specific amino acids enriched (CRCM) functional molecules, L-serine being particularly strong candidate. Indeed, supplementing NR through dependent on one-carbon metabolism pathway, thus implicating this conserved central metabolic hub wide variety model nonhuman primates, implying cellular processes pathways must mediate beneficial effects or somehow be impacted dietary regimen (1Fontana L. Partridge Longo V.D. Extending healthy span--from humans.Science. 2010; 328: 321-326Crossref PubMed Scopus (1836) Google Scholar). including autophagy, target rapamycin (TOR) signaling, AMP-activated protein kinase (AMPK) signaling have each been implicated regulating aging most models (2Kapahi P. Kaeberlein M. Hansen Dietary lifespan: Lessons invertebrate models.Ageing Res. Rev. 2017; 39: 3-14Crossref (124) system, typically characterized reducing initial concentration medium 2% (nonrestricted; NR) 0.5% lower, overall (3Jiang J.C. Jaruga E. Repnevskaya M.V. Jazwinski S.M. An intervention resembling caloric prolongs retards yeast.FASEB J. 2000; 14: 2135-2137Crossref (276) Scholar, 4Lin S.J. Andalis A.A. Sturtz L.A. Defossez P.A. Culotta V.C. Fink G.R. Guarente Calorie cerevisiae lifespan increasing respiration.Nature. 2002; 418: 344-348Crossref (826) Glucose robustly (RLS) (CLS) 5Reverter-Branchat G. Cabiscol Tamarit Ros Oxidative damage proteins chronological-aged cerevisiae: common targets prevention calorie restriction.J. Biol. Chem. 2004; 279: 31983-31989Abstract Full Text PDF (170) 6Smith Jr., D.L. McClure J.M. Matecic Smith J.S. independently sirtuins.Aging Cell. 2007; 6: 649-662Crossref (176) Scholar), latter number days nondividing cells maintain proliferative capacity liquid culture after entering stationary phase, quantified upon transfer fresh nutrient (7Fabrizio The cerevisiae.Aging 2003; 2: 73-81Crossref (387) 8MacLean Harris N. Piper P.W. Chronological phase cells; investigating factors might influence ageing postmitotic tissues higher organisms.Yeast. 2001; 18: 499-509Crossref (113) As becomes limiting toward end exponential growth, switch fermentative (metabolism ethanol) mitochondrial-driven oxidative ethanol organic produced during fermentation. This “diauxic shift” accompanied dramatic changes transcription, translation, profiles facilitate slower cell using nonfermentable carbon sources (9DeRisi J.L. Iyer V.R. Brown P.O. Exploring genetic control gene expression genomic scale.Science. 1997; 278: 680-686Crossref (3599) 10Gasch A.P. Spellman P.T. Kao C.M. Carmel-Harel O. Eisen M.B. Storz Botstein D. Genomic programs response environmental changes.Mol. 11: 4241-4257Crossref (3561) ultimately leading cycle exit quiescence. largely hinges an adaptive depletion, consisting (G0), called quiescence (11Allen C. Buttner S. Aragon A.D. Thomas J.A. Meirelles Jaetao J.E. Benn Ruby S.W. Veenhuis Madeo F. Werner-Washburne Isolation quiescent nonquiescent cultures.J. Cell 2006; 174: 89-100Crossref (217) 12Gray J.V. Petsko G.A. Johnston G.C. Ringe Singer R.A. "Sleeping beauty": cerevisiae.Microbiol. Mol. 68: 187-206Crossref (419) Yeast therefore considered stem such neurons muscle fiber (13Jones Rando T.A. Emerging paradigms ageing.Nat. 2011; 13: 506-512Crossref 14Longo Shadel G.S. Kennedy B. Replicative cerevisiae.Cell Metab. 2012; 16: 18-31Abstract (359) 15Ruetenik A. Barrientos Exploiting post-mitotic neurodegeneration.Front. Neurosci. 2018; 400Crossref (7) Since has profound impact long-term survival, fully understanding intracellular extracellular underlying complex transition quiescence, how influences them, interest. enhances several occur diauxic shift, Snf1 (16Wierman Maqani Strickler Li optimizing pathway.Mol. 37: e00562-16Crossref (22) mitochondrial respiration ATP production (6Smith 17Choi Lee C.K. Maintenance atp level correlates survival yeast.Biochem. Biophys. Commun. 2013; 439: 126-131Crossref (16) 18Ocampo Liu Schroeder E.A. Mitochondrial respiratory thresholds regulate its extension restriction.Cell 55-67Abstract (116) 19Tahara E.B. Cunha F.M. Basso T.O. Della Bianca B.E. Gombert A.K. Kowaltowski A.J. hysteretically primes more effective metabolism.PLoS One. 8: e56388Crossref (18) accumulation storage carbohydrate trehalose (20Kyryakov Beach Richard Burstein M.T. Leonov Levy Titorenko V.I. altering pattern age-related concentration.Front. Physiol. 3: 256Crossref (51) improved G1 arrest (21Weinberger Feng Paul Hontz R.D. Vujcic Singh K.K. Huberman Burhans W.C. DNA replication stress determinant yeast.PLoS e748Crossref (85) addition CR, there are other manipulations extend CLS, inhibition TOR (22Powers 3rd, R.W. Caldwell S.D. B.K. Fields Extension decreased tor pathway signaling.Genes Dev. 20: 174-184Crossref (705) Scholar) methionine (23Johnson Johnson F.B. Methionine activates retrograde confers tolerance mouse human cells.PLoS 2014; 9: e97729Crossref (82) 24Ruckenstuhl Netzberger Entfellner I. Carmona-Gutierrez Kickenweiz T. Stekovic Gleixner Schmid Klug Sorgo A.G. Eisenberg Marino Koziel R. Jansen-Durr et al.Lifespan requires autophagy-dependent vacuolar acidification.PLoS Genet. 10: e1004347Crossref (120) unicellular organism, modifications usually expected cell-autonomous direct expression, metabolism, response. However, regulation also linked driven cell-derived (25Burtner C.R. Murakami C.J. A molecular yeast.Cell Cycle. 2009; 1256-1270Crossref (253) 26Fabrizio Battistella Vardavas Gattazzo Liou L.L. Diaspro Dossen J.W. Gralla Superoxide mediator altruistic program cerevisiae.J. 166: 1055-1067Crossref (291) For example, acetic acid released assays accumulates acidifies media. resulting sensing lead elevated superoxide (27Weinberger Mesquita Caroll Marks Yang H. Zhang Z. Ludovico Growth promotes inducing anions inhibit quiescence.Aging. 709-726Crossref (81) apoptosis, Importantly, suppressed 28Hu Wei Mirzaei Madia Mirisola Amparo Chagoury Tor-sch9 deficiency catabolism ketone body-like promote longevity.Aging 457-467Crossref (38) contributing CLS. Buffering pH transferring water effectively protects 29Ludovico Sousa M.J. Silva Leao C.L. Corte-Real commits programmed death process acid.Microbiology. 147: 2409-2415Crossref (390) Longevity-associated classically described rodent models, where circulating identified heterochronic parabiosis experiments (30McCay Pope Lunsford W. Sperling Sambhavaphol Parabiosis between old young rats.Gerontologia. 1957; 1: 7-17Crossref (31) mesencephalic astrocyte-derived neurotrophic factor (MANF) younger against liver older (31Sousa-Victor Neves Cedron-Craft Ventura P.B. Liao C.Y. Riley R.R. Soifer van Bruggen Kolumam Villeda S.A. Lamba D.A. Jasper MANF regulates immune homeostasis damage.Nat. 2019; 276-290Crossref (26) overexpression Drosophila Interestingly, some act autonomous manner, insulin-like transcription FOXO, can organismal via (32Hwangbo D.S. Gershman Tu M.P. Palmer Tatar dFOXO controls insulin signalling brain fat body.Nature. 429: 562-566Crossref (710) 33Qin Hubbard E.J. Non-autonomous DAF-16/FOXO activity antagonizes loss elegans germline stem/progenitor cells.Nat. 2015; 7107Crossref (27) raising possibility widespread than previously thought. Despite single organisms, utilizes metabolites cell–cell communication mating, differentiation, sporulation. Recognition opposite haploid mating types (a-cells α-cells) occurs pheromone peptides a-factor α-factor (34Haber Mating-type genes MAT switching cerevisiae.Genetics. 191: 33-64Crossref (244) whereas pseudohyphal dense colonies mediated quorum acid–derived aromatic alcohols, tryptophol, phenylethanol (35Chen Feedback morphogenesis fungi alcohols.Genes 1150-1161Crossref (279) densely crowded highly sensitive gene–nutrient interactions (36Smith Maharrey C.H. Carey White Hartman IV Gene-nutrient interaction markedly lifespan.Exp. Gerontol. 2016; 86: 113-123Crossref (12) would seem subject mechanisms. unidentified high-molecular-weight (>5000 Da) stimulating (37Herker Jungwirth Lehmann K.A. Maldener Frohlich K.U. Wissing Fehr Sigrist leads apoptosis yeast.J. 164: 501-507Crossref (428) Similarly, our lab observed isolated glucose-restricted referred throughout current study, (38Wierman Valsakumar V. Bekiranov Functional analysis reveals overlapping distinct features chronologically long-lived populations.Aging. 7: 177-194Crossref (8) presence one proteins, peptides, contribute were interested elucidating these order provide new insights about To end, we utilized combination chromatography, metabolomics, targeted mass spectrometry identify candidate abundant CRCM (NRCM). Longevity was traced multiple cultures. focused further and, process, investigate extension, concentrated NRCM day 5 BY4741, used strain (Fig. 1A). Each concentrate then titrated SC at 1:10, 1:20, 1:50 ratios. reasoned increase chances detecting if low-abundance molecules. BY4741 initially analyzed 384-well quantitative high-throughput array phenotyping (Q-HTCP) system allowed 96 replicates condition S1A). With Q-HTCP, indicated lower L parameter y-axis, representing time it takes small aliquot spotted onto YPD plate reach ½ maximum density 39Santos Laflin Broadway Burnet Hartheimer Rodgers High-resolution profiling human-like auxotrophy availability.Geroscience. 2020; (Online ahead print)https://doi.org/10.1007/s11357-020-00265-2Crossref (2) If viable spotted, less max growth. Compared (dH2O), supplementation clearly lowered dose-dependent manner S1A), corresponding curves S1B). contrast, only had minor (1:10 1:20) levels, significantly concentrations putative present CRCM. tested whether dilution grown larger 10 ml standard microcolony viability assay (see Experimental Procedures). shown Figure. 1, B C, diluted (2% vol/vol) 1:100 (1% while effect (vol/vol). auxotrophic histidine, leucine, methionine, uracil, next confirmed could prototrophic strain, FY4, D E). concluded NRCM. preliminary Figures 1 S1 provided evidence titratable question their chemical nature identities. earlier study aged release large (>5 kD) heat-stable compounds improve population determine contained factors, treated Proteinase K, DNase I, RNase A, phenol/chloroform, autoclaving, freezing, but none any (data not shown). Instead, smaller 5000 Da, fraction passing Amicon Ultra-4 centrifugal filter unit (5000 MW cutoff) extending equivalent starting material 2A). result demonstrated CR-associated here different higher-molecular-weight size active CLS-modifying molecules size-exclusion rigorously 150 down final volume 2.5 (60-fold). Precipitates removed centrifugation, remaining soluble fractionated Sephadex G-10 column, limit ∼700 Da. Fractions added 1:5 ratio detected qualitative spot test 2B). At 11, clear peak fractions 21 22 CRCM, 700 Da high levels potentially mask fractions. peaked 18–19 columns, 21–22 2C, red arrows). 11 16–18 due 2, B–C). Based chromatography resistance various treatments heat, phenol extraction, nuclease digestion, etc., water-soluble separable acid. Knowing comparative approach generate metabolite reasoning differential abundance source 3A). Enrichment compared (Table S1) performed MetaboAnalyst (40Chong Wishart Xia Using 4.0 comprehensive integrative data analysis.Curr. Protoc. Bioinformatics. e86Crossref (623) (relative circle size) measure considers centrality 3B). categories (shaded red) related acids, L-alanine, L-aspartate, L-glutamate L-glycine, L-serine, L-threonine biosynthesis, two highest scores gain additional functional, transcriptomics NRCM, 3C), goal identifying physiological metabolites. Following inoculation conditions, harvested 6 h (log phase), 24 (late shift), (stationary RNA-seq mRNAs three biological replicates. Principal component (PCA) major variance within points 3D), consistent massive early log-phase cells, no upregulated downregulated CRCM- NRCM-supplemented samples H2O-supplemented (FDR <0.05), microarray showing (0.5% glucose) little log point, however, CRCM-supplemented diverged NRCM- PCA plot 3E) showed many differentially regulated NRCM-treated (Fig.3F). differentiated S2A), though still exclusively altered S2B). top GO term CRCM-upregulated α-amino catabolic S2), results indicating metabolism. telomeric subtelomeric ORFs tightly repressed CRCM-treated 3G, S2C, Tables S4, S5), general repression chromatin condensation may enhanced (41Laporte Courtout Tollis Sagot Quiescent forms telomere hyperclusters nuclear membrane vicinity multifaceted involving Esc1, Sir complex, condensation.Mol. 27: 1875-1884Crossref 42Swygert S.G. Kim Wu X. Fu Hsieh T.H. O.J. Eisenman R.N. Shendure McKnight J.N. Tsukiyama Condensin-dependent compaction represses globally quiescence.Mol. 73: 533-546.e534Abstract (24) h, terms function respiration, robust shift S3). Furthermore, YCL064C (CHA1) gene, adjacent heterochromatic HML locus, stood out 3G Table S4). CHA1 encodes predominantly (L-threonine) deaminase catabolizes nitrogen case pyruvate (43Petersen J.G. Kielland-Brandt M.C. Nilsson-Tillgren Bornaes Holmberg Molecular genetics serine threonine 1988; 119: 527-534Crossref 44Ramos Wiame Occurrence cerevisiae.Eur. Biochem. 1982; 123: 571-576Crossref (28) It strongly exogenous

Язык: Английский

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Spatially Enriched Paralog Rearrangements Argue Functionally Diverse Ribosomes Arise during Cold Acclimation in Arabidopsis

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(11), С. 6160 - 6160

Опубликована: Июнь 7, 2021

Ribosome biogenesis is essential for plants to successfully acclimate low temperature. Without dedicated steps supervising the 60S large subunits (LSUs) maturation in cytosol, e.g., Rei-like (REIL) factors, fail accumulate dry weight and grow at suboptimal temperatures. Around REIL, final cytosolic include proofreading assembly of functional ribosomal centers such as polypeptide exit tunnel P-Stalk, respectively. In consequence, these substructures their assembly, especially during temperatures, might be changed provoke need quality controls. To test this, we blocked ribosome cold acclimation using two independent reil double mutant genotypes tested changes proteomes. Additionally, normalized our datasets a blank responsiveness wild-type Arabidopsis genotype. This allowed us neglect any reil-specific effects that may happen due presence or absence factor LSU maturation, thus allowing cold-induced early nucleolar biogenesis. As result, report triggers reprogramming structural proteome. The alters abundance specific RP families and/or paralogs non-translational translational polysome fractions, phenomenon known substoichiometry. Next, whether cold-substoichiometry was spatially confined regions complex. terms proteoforms, remodeling ribosomes after stimulus significantly constrained (PET), i.e., REIL binding site. transcripts, induces are P-Stalk head. three modulated represent possible targets mechanisms constrain translation by controlled heterogeneity. We propose non-random heterogeneity specialized contribute preferential ultimately even rigorous selection transcripts needed rapid proteome shifts successful acclimation.

Язык: Английский

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De Novo Assembly and Annotation of the Complete Genome Sequence of Myxococcus xanthus DZ2

Microbiology Resource Announcements, Год журнала: 2022, Номер 11(5)

Опубликована: Апрель 6, 2022

We report the assembly and annotation of a high-quality genome sequence for Myxococcus xanthus strain DZ2 (GenBank accession number CP080538), created using combination short reads generated DNBSEQ technology (BGI Genomics) long high-fidelity (HiFi) Pacific Biosciences (PacBio) technology.

Язык: Английский

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Ribosomal proteins: mutant phenotypes by the numbers and associated gene expression changes

Open Biology, Год журнала: 2020, Номер 10(8)

Опубликована: Авг. 1, 2020

Ribosomal proteins are highly conserved, many universally so among organisms. All ribosomal structural parts of the same molecular machine, ribosome. However, when mutated individually, they often lead to distinct and intriguing phenotypes, including specific human pathologies. This review is an attempt collect analyse all reported phenotypes each protein mutant in several eukaryotes ( Saccharomyces cerevisiae , Caenorhabditis elegans Drosophila melanogaster Danio rerio Mus musculus Homo sapiens ). These were processed with unbiased computational approaches reveal associations between different contributions individual genes. An overview gene expression changes mutants, emphasis on ribosome profiling studies, also presented. The available data point patterns that may account for most observed phenotypes. information presented here inform future studies about basis arise from mutations proteins.

Язык: Английский

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Inhibition of Ribosome Assembly and Ribosome Translation Has Distinctly Different Effects on Abundance and Paralogue Composition of Ribosomal Protein mRNAs in Saccharomyces cerevisiae

mSystems, Год журнала: 2023, Номер 8(1)

Опубликована: Янв. 18, 2023

Many mutations in genes for ribosomal proteins (r-proteins) and assembly factors cause cell stress altered fate, resulting congenital diseases collectively called ribosomopathies. Even though all such depress the cell's protein synthesis capacity, they generate many different phenotypes, suggesting that are not due simply to insufficient capacity. To learn more, we investigated how global transcriptome Saccharomyces cerevisiae responds reduced generated two ways: abolishing of new ribosomes inhibiting function. Our results showed mechanism by which is obstructed affects differentially: mRNA abundance increases during abolition ribosome formation but decreases inhibition Interestingly, ratio between mRNAs from some, all, pairs paralogous encoding slightly versions a given r-protein changed differently types stress, expression specific may contribute response. Unexpectedly, transcripts translation remained relatively unaffected stresses. On other hand, state apparatus did affect physiology: levels some directly related also differentially, coordinately with genes, response IMPORTANCE Mutations or variety These typically ascribed reduction capacity synthesis. Paradoxically, result wide disease even reduce Here, show changes depending on reduced. Most strikingly, function had opposite effects proteins, while no systematic responses. Thus, process contributes decisively composition. This emphasis concept understanding ribosomopathies

Язык: Английский

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