Biology subjects

Donertas, H. M.

Publications and source records attributed to Donertas, H. M..

9 recordsLinked to original sources

bioRxiv2026

Temporal multi-omic profiling of immune, gut, and microbiome responses to ischemic stroke reveals convergence of host and microbial perturbations one week after brain injury

Ischemic stroke poses a significant medical challenge with limited therapy options, therefore detailed understanding of stroke-associated pathophysiological processes across systems and organs is crucial for further research and identification of novel therapeutic targets. In this manuscript, we provide parallel multi-omic host and gut microbiome characterization on several timepoints (day 1, 7 and 14) in the mouse experimental stroke model (middle cerebral artery occlusion, MCAo). Expanding existing host-derived datasets, we profiled transcriptomes from microglia, brain-infiltrating leukocytes and peripheral leukocytes using single cell RNA sequencing. Our data deliver time-resolved characterization of microglial subtypes and highlight heterogeneous dendritic cell populations as main interaction partners of microglia on all timepoints. In peripheral blood, we did not observe large transcriptomic differences when comparing the immune subsets from MCAo and sham-operated control animals. Here, the neutrophils exhibited most transcriptomic changes on day 1 among all blood leukocytes. Parallel proteomic analysis of 5 intestinal segments (duodenum, jejunum, ileum, caecum and colon) and mesenteric lymph nodes highlighted day 7 as the most important timepoint for changes in the gut-related metabolic pathways especially in the jejunum and colon. Specific hypothesis testing revealed compartmentalized regulation of gut-related immune pathways and proteins related to gut permeability. Finally, gut microbiome analyses (longitudinal metatranscriptomics including day -1, 3, 7, 14, and metagenomics from day 14) highlighted temporally matched changes in microbial gene expression (with day 7 emerging again as the most relevant timepoint), larger overall community perturbations when compared to baseline from day -1 in stroke animals and expansion of facultative anaerobes on day 7. Graphical abstractWe performed longitudinal multi-omic host and gut microbiota profiling from experimental stroke and sham control mice. Our data indicate marked differences in brain-infiltrating leukocytes and microglia already on early timepoints after surgery, whereas stroke-specific changes in gut proteomics, bacterial gene expression and community structure emerge on day 7 after middle cerebral artery occlusion/sham surgery. Created in https://BioRender.com O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/727504v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@129eff8org.highwire.dtl.DTLVardef@49c401org.highwire.dtl.DTLVardef@e32b22org.highwire.dtl.DTLVardef@24f6df_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.

Mitochondrial dysfunction is a prominent hallmark of aging contributing to the functional decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we initially used proteomics, genetics and functional tests in wild type C. elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that safeguard longevity amid persistent mitochondrial inefficiency. Strikingly, these analyses and subsequent transcriptomic and functional tests in the human system revealed aging-associated decline of phosphatidylcholine (PC) synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, we found that ectopic boosting of PC levels via diet restores late life mitochondrial integrity in vivo and rescues metabolic plasticity in cell culture tests. Our work thus uncovered a novel natural driver of mitochondrial aging that is malleable by dietary interventions.

cell biology↗

bioRxiv2020

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes and also the whole transcriptome, we observed that the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes. HighlightsO_LITranscriptomic changes are more similar within mutant mice that show either lengthened or shortened lifespan C_LIO_LIThe major transcriptomic differences between long- and short-lived mice are in genes controlling mitochondrial metabolism C_LIO_LIGene expression changes in short-lived, progeroid, mutant mice resemble those seen during normal ageing C_LI

genomics↗

bioRxiv2019

Transposable element landscape in Drosophila populations selected for longevity

Transposable elements (TEs) inflict numerous negative effects on health and fitness as they replicate by integrating into new regions of the host genome. Even though organisms employ powerful mechanisms to demobilize TEs, transposons gradually lose repression during aging. The rising TE activity causes genomic instability and was implicated in age-dependent neurodegenerative diseases, inflammation and the determination of lifespan. It is therefore conceivable that long-lived individuals have improved TE silencing mechanisms resulting in reduced TE expression relative to their shorter-lived counterparts and fewer genomic insertions. Here, we test this hypothesis by performing the first genome-wide analysis of TE insertions and expression in populations of Drosophila melanogaster selected for longevity through late-life reproduction for 50-170 generations from four independent studies. Contrary to our expectation, TE families were generally more abundant in long-lived populations compared to non-selected controls. Although simulations showed that this was not expected under neutrality, we found little evidence for selection driving TE abundance differences. Additional RNA-seq analysis revealed a tendency for reducing TE expression in selected populations, which might be more important for lifespan than regulating genomic insertions. We further find limited evidence of parallel selection on genes related to TE regulation and transposition. However, telomeric TEs were genomically and transcriptionally more abundant in long-lived flies, suggesting improved telomere maintenance as a promising TE-mediated mechanism for prolonging lifespan. Our results provide a novel viewpoint indicating that reproduction at old age increases the opportunity of TEs to be passed on to the next generation with little impact on longevity.

evolutionary biology↗

bioRxiv2019

Meta-Analysis of the Gene Expression Profiles of Aging Brain Reveals Consistent Increase in Heterogeneity

Cells in largely non-mitotic tissues such as the brain are prone to stochastic (epi-)genetic alterations that may cause increased variability between cells and individuals over time. Although increased inter-individual heterogeneity in gene expression was previously reported, whether this process starts during development or if it is restricted to the aging period has not yet been studied. The regulatory dynamics and functional significance of putative aging-related heterogeneity are also unknown. Here we address these by a meta-analysis of 19 transcriptome datasets from diverse human brain regions. We observed a significant increase in inter-individual heterogeneity during aging (20+ years) compared to postnatal development (0 to 20 years). Increased heterogeneity during aging was consistent among different brain regions at the gene level and associated with lifespan regulation and neuronal functions. Overall, our results show that increased expression heterogeneity is a characteristic of aging human brain, and may influence aging-related changes in brain functions.

genomics↗

bioRxiv2019

The variability of expression of many genes and most functional pathways is observed to increase with age in brain transcriptome data

Ageing is broadly defined as a time-dependent progressive decline in the functional and physiological integrity of organisms. Previous studies and evolutionary theories of ageing suggest that ageing is not a programmed process but reflects dynamic stochastic events. In this study, we test whether transcriptional noise shows an increase with age, which would be expected from stochastic theories. Using human brain transcriptome dataset, we analysed the heterogeneity in the transcriptome for individual genes and functional pathways, employing different analysis methods and pre-processing steps. We show that unlike expression level changes, changes in heterogeneity are highly dependent on the methodology and the underlying assumptions. Although the particular set of genes that can be characterized as differentially variable is highly dependent on the methods, we observe a consistent increase in heterogeneity at every level, independent of the method. In particular, we demonstrate a weak but reproducible transcriptome-wide shift towards an increase in heterogeneity, with twice as many genes significantly increasing as opposed to decreasing their heterogeneity. Furthermore, this pattern of increasing heterogeneity is not specific but is associated with a wide range of pathways.

genomics↗

bioRxiv2018

Using the drug-protein interactome to identify anti-ageing compounds for humans

Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.\n\nAuthor SummaryHuman life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.

bioinformatics↗

bioRxiv2018

Gene Expression-Based Drug Repurposing to Target Ageing

Ageing is the largest risk factor for a variety of non-communicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both life- and health-span. Ageing is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target-centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat ageing in human brain. Using multiple gene expression datasets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterise ageing. Then, we compared these changes in gene expression with drug perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as anti-ageing drugs by reversing the detrimental changes that occur during ageing, others by mimicking the cellular defense mechanisms. The drugs that we identified included significant number of already identified pro-longevity drugs, indicating that the method can discover de novo drugs that meliorate ageing. The approach has the advantages that, by using data from human brain ageing data it focuses on processes relevant in human ageing and that it is unbiased, making it possible to discover new targets for ageing studies.

systems biology↗

bioRxiv2018

Mutation accumulation differentially impacts ageing in mammalian tissues

Medawars mutation accumulation (MA) hypothesis explains ageing by the declining force of natural selection with age: slightly deleterious germline mutations that are functional in old age are not effectively eliminated by selection and therefore lead to ageing-related phenotypes. Although widely cited, empirical support for the MA hypothesis, particularly molecular evidence, has remained limited. Here we test one of its predictions, that genes relatively highly expressed in old adults vs. young adults should be under weaker purifying selection than those relatively highly expressed in young adults. To do so, we combine 23 RNA-sequencing and 35 microarray gene expression datasets (including 9 tissues from 5 mammalian species) with protein and regulatory sequence conservation estimates across mammals. We identify age-related decrease in transcriptome conservation (ADICT) in four tissues, brain, liver, lung, and artery, but not in other tissues, most notably muscle and heart. ADICT is driven both by decreased expression of highly conserved genes and up-regulation of poorly conserved genes during ageing, in line with the MA hypothesis. Lowly conserved and up-regulated genes in ADICT-associated tissues have overlapping functional properties, particularly involving apoptosis and inflammation, with no evidence for a history of positive selection. Our results suggest that tissues vary in how evolution has shaped their ageing patterns. We find that in some tissues, genes up-regulated during ageing, possibly in response to accumulating cellular and histological damage, are under weaker purifying selection than other genes. We propose that accumulation of slightly deleterious substitutions in these genes may underlie their suboptimal regulation and activity during ageing, shaping senescent phenotypes such as inflammaging.

evolutionary biology↗