3 research outputs found

    Inter-individual variability and temporal scaling in the aging transcriptome

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    Gràcies als amplis esforços d'investigació, la nostra comprensió dels mecanismes fisiològics de l'envelliment ha progressat enormement. Recentment, les tecnologies òmiques han permès l'estudi a tot el genoma dels canvis relacionats amb l'edat. No obstant això, les anàlisis òmiques sovint passen per alt la naturalesa estocàstica, dinàmica i complexa de l'envelliment. Per aquest motiu, desenredar les relacions causa-efecte s'ha demostrat difícil. En aquesta tesi, analitzem l'efecte de l'envelliment sobre el transcriptoma en Caenorhabditis elegans, estudiant els canvis en l'expressió gènica a mesura que varien i covarien entre individus, al llarg del temps, i en resposta a múltiples intervencions que modulen la longevitat. En primer lloc, hem desenvolupat un protocol d'ARN-seq d'individus únics que ens permet mesurar la variabilitat transcriptòmica interindividual. Hem trobat que les diferències interindividuals en la mida dels teixits són el principal contribuent a la variabilitat transcriptòmica interindividual. Després de tenir en compte aquestes diferències, hem utilitzat la covariabilitat interindividual per reconstruir una xarxa de coexpressió gènica. Aquesta xarxa ens ha permès identificar mòduls funcionals alterats per la senyalització de la insulina/IGF-1. En segon lloc, hem fet servir un sistema degron induïble per auxina per comparar la dinàmica temporal de l'envelliment i l'expressió gènica en nou poblacions que envelleixen a diferents velocitats. Hem recopilat mesures transcriptòmiques temporals i trobem que només el cinc per cent de les trajectòries transcriptòmiques es reescalen temporalment a la par que la longevitat. En tercer lloc, hem col·laborat amb un laboratori que treballa amb la prohibitina, una proteïna mitocondrial que pot allargar o escurçar la longevitat segons el context. Hem trobat canvis coordinats en l'expressió gènica en múltiples soques compromeses metabòlicament que poden explicar aquests efectes dependents del context. Per concloure, presentem noves maneres de relacionar la longevitat i els canvis transcriptòmics, proporcionant així una visió de com les intervencions de modulació de la longevitat afecten l'envelliment.Thanks to extensive research efforts, our understanding of the physiological mechanisms underlying aging has immensely progressed. Recently, omics technologies have enabled the genome-wide study of age-related changes. Nevertheless, omics analyses often overlook the stochastic, dynamic, and complex nature of aging. Consequently, untangling cause-effect relationships has proven challenging. In this thesis, we analyze the effect of aging on the transcriptome in Caenorhabditis elegans, studying gene expression changes as they vary and covary between individuals, over time, and in response to multiple lifespan-modulating interventions. First, we developed a single individual RNA-seq protocol that allows us to measure inter-individual transcriptomic variability. We found that inter-individual differences in tissue size are the main contributor to inter-individual transcriptomic variability. After accounting for these differences, we utilized inter-individual covariability to reconstruct a gene co-expression network. This network allowed us to identify functional communities altered by insulin/IGF-1 signaling. Second, we used an auxin-inducible degron system to compare the temporal dynamics of aging and gene expression across nine differentially aging populations. We collected time-resolved transcriptomic measurements and found that only five percent of transcriptomic trajectories are temporally rescaled in the same way as lifespan. Third, we collaborated with a laboratory working on prohibitin, a mitochondrial protein that can extend or shorten lifespan depending on the context. We found coordinated changes in gene expression across multiple metabolically compromised strains that may explain context-dependent effects. To conclude, we present novel ways to relate lifespan and transcriptomic changes, thus providing insight on how lifespan-modulating interventions ultimately impact aging

    A hierarchical process model links behavioral aging and lifespan in C. elegans

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    Aging involves a transition from youthful vigor to geriatric infirmity and death. Individuals who remain vigorous longer tend to live longer, and within isogenic populations of C. elegans the timing of age-associated vigorous movement cessation (VMC) is highly correlated with lifespan. Yet, many mutations and interventions in aging alter the proportion of lifespan spent moving vigorously, appearing to "uncouple" youthful vigor from lifespan. To clarify the relationship between vigorous movement cessation, death, and the physical declines that determine their timing, we developed a new version of the imaging platform called "The Lifespan Machine". This technology allows us to compare behavioral aging and lifespan at an unprecedented scale. We find that behavioral aging involves a time-dependent increase in the risk of VMC, reminiscent of the risk of death. Furthermore, we find that VMC times are inversely correlated with remaining lifespan across a wide range of genotypes and environmental conditions. Measuring and modelling a variety of lifespan-altering interventions including a new RNA-polymerase II auxin-inducible degron system, we find that vigorous movement and lifespan are best described as emerging from the interplay between at least two distinct physical declines whose rates co-vary between individuals. In this way, we highlight a crucial limitation of predictors of lifespan like VMC-in organisms experiencing multiple, distinct, age-associated physical declines, correlations between mid-life biomarkers and late-life outcomes can arise from the contextual influence of confounding factors rather than a reporting by the biomarker of a robustly predictive biological age.This project was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 852201), the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa (CEX2020-001049-S, MCIN/AEI /10.13039/501100011033), the CERCA Programme/Generalitat de Catalunya, the MEIC Excelencia award BFU2017-88615-P, and an award from the Glenn Foundation for Medical Research to NS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

    Neuronal temperature perception induces specific defenses that enable C. elegans to cope with the enhanced reactivity of hydrogen peroxide at high temperature

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    Hydrogen peroxide is the most common reactive chemical that organisms face on the microbial battlefield. The rate with which hydrogen peroxide damages biomolecules required for life increases with temperature, yet little is known about how organisms cope with this temperature-dependent threat. Here, we show that Caenorhabditis elegans nematodes use temperature information perceived by sensory neurons to cope with the temperature-dependent threat of hydrogen peroxide produced by the pathogenic bacterium Enterococcus faecium. These nematodes preemptively induce the expression of specific hydrogen peroxide defenses in response to perception of high temperature by a pair of sensory neurons. These neurons communicate temperature information to target tissues expressing those defenses via an insulin/IGF1 hormone. This is the first example of a multicellular organism inducing their defenses to a chemical when they sense an inherent enhancer of the reactivity of that chemical
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