Publications

@article{nokey,

title = {Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier},

author = {Francesca Tomatis and Susana Rosa and Susana Simões and Marta Barão and Carlos Jesus and João Novo and Emanuel Barth and Manja Marz and Lino Ferreira},

doi = {10.1186/s12951-024-03019-w},

year  = {2024},

date = {2024-12-02},

journal = {Journal of Nanobiotechnology},

volume = {22},

abstract = {Background

Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in the bloodstream. Therefore, inspiration can be taken from aging to develop new strategies for the transient opening of the BBB for drug delivery to the brain.

Results

Here, we evaluated the impact of small EVs (sEVs) enriched with microRNAs (miRNAs) overexpressed during aging, with the capacity to interfere transiently with the BBB. Initially, we investigated whether the miRNAs were overexpressed in sEVs collected from plasma of aged individuals. Next, we evaluated the opening properties of the miRNA-enriched sEVs in a static or dynamic (under flow) human in vitro BBB model. Our results showed that miR-383-3p-enriched sEVs significantly increased BBB permeability in a reversible manner by decreasing the expression of claudin 5, an important tight junction protein of brain endothelial cells (BECs) of the BBB, mediated in part by the knockdown of activating transcription factor 4 (ATF4).

Conclusions

Our findings suggest that engineered sEVs have potential as a strategy for the temporary BBB opening, making it easier for drugs to reach the brain when injected into the bloodstream.},

keywords = {aging, extracellular vesicles, ncRNAs},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation.},

author = {Diana M Morales-Prieto and José M Murrieta-Coxca and Milan Stojiljkovic and Celia Diezel and Priska E Streicher and Julian A Henao-Restrepo and Franziska Röstel and Julia Lindner and Otto W Witte and Sebastian Weis and Christian Schmeer and Manja Marz},

doi = {10.3390/cells11040625},

year  = {2022},

date = {2022-02-11},

journal = {Cells},

volume = {11},

issue = {4},

pages = {625},

abstract = {Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap, Tgf-β, Cd68, and Iba1, were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap, was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation.},

keywords = {aging, extracellular vesicles},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging},

author = {Emanuel Barth and Akash Srivastava and Diane Wengerodt and Milan Stojiljkovic and Hubertus Axer and Otto W Witte and Alexandra Kretz and Manja Marz

},

doi = {10.18632/aging.203788},

year  = {2021},

date = {2021-12-19},

journal = {Aging},

volume = {13},

number = {24},

pages = {25694-25716},

abstract = {The circadian clock system influences the biology of life by establishing circadian rhythms in organisms, tissues, and cells, thus regulating essential biological processes based on the day/night cycle. Circadian rhythms change over a lifetime due to maturation and aging, and disturbances in the control of the circadian system are associated with several age-related pathologies. However, the impact of chronobiology and the circadian system on healthy organ and tissue aging remains largely unknown. Whether aging-related changes of the circadian system's regulation follow a conserved pattern across different species and tissues, hence representing a common driving force of aging, is unclear. Based on a cross-sectional transcriptome analysis covering 329 RNA-Seq libraries, we provide indications that the circadian system is subjected to aging-related gene alterations shared between evolutionarily distinct species, such as Homo sapiens, Mus musculus, Danio rerio, and Nothobranchius furzeri. We discovered differentially expressed genes by comparing tissue-specific transcriptional profiles of mature, aged, and old-age individuals and report on six genes (per2, dec2, cirp, klf10, nfil3, and dbp) of the circadian system, which show conserved aging-related expression patterns in four organs of the species examined. Our results illustrate how the circadian system and aging might influence each other in various tissues over a long lifespan and conceptually complement previous studies tracking short-term diurnal and nocturnal gene expression oscillations.},

keywords = {aging, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:20,

title = {Robustness during Aging—Molecular Biological and Physiological Aspects},

author = {Emanuel Barth and Patricia Sieber and Heiko Stark and Stefan Schuster},

doi = {10.3390/cells9081862},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Cells},

volume = {9},

number = {8},

pages = {1862},

publisher = {MDPI AG},

abstract = {Understanding the process of aging is still an important challenge to enable healthy aging and to prevent age-related diseases. Most studies in age research investigate the decline in organ functionality and gene activity with age. The focus on decline can even be considered a paradigm in that field. However, there are certain aspects that remain surprisingly stable and keep the organism robust. Here, we present and discuss various properties of robust behavior during human and animal aging, including physiological and molecular biological features, such as the hematocrit, body temperature, immunity against infectious diseases and others. We examine, in the context of robustness, the different theories of how aging occurs. We regard the role of aging in the light of evolution.},

keywords = {aging, review},

pubstate = {published},

tppubtype = {article}

}

@article{Srivastava:20,

title = {Tissue-specific Gene Expression Changes Are Associated with Aging in Mice},

author = {Akash Srivastava and Emanuel Barth and Maria A. Ermolaeva and Madlen Guenther and Christiane Frahm and Manja Marz and Otto W. Witte},

doi = {10.1016/j.gpb.2020.12.001},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Genomics Proteomics Bioinformatics},

volume = {18},

number = {4},

pages = {430--442},

publisher = {Elsevier BV},

abstract = {Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue’s specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.},

keywords = {aging, differential expression analysis, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Barth:19,

title = {Conserved aging-related signatures of senescence and inflammation in different tissues and species.},

author = {Emanuel Barth and Akash Srivastava and Milan Stojiljkovic and Christiane Frahm and Hubertus Axer and Otto W Witte and Manja Marz},

doi = {10.18632/aging.102345},

year  = {2019},

date = {2019-02-26},

urldate = {2019-02-26},

journal = {Aging},

volume = {11},

number = {19},

pages = {8556—8572},

abstract = {Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual's life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.},

keywords = {aging, liver, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Sieber:19,

title = {The landscape of the alternatively spliced transcriptome remains stable during aging across different species and tissues},

author = {Patricia Sieber and Emanuel Barth and Manja Marz},

doi = {10.1101/541417},

year  = {2019},

date = {2019-02-05},

urldate = {2019-02-05},

journal = {bioRxiv},

pages = {541417},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Aging is characterized by a decline of cellular homeostasis over time, leading to various severe disorders and death. Alternative splicing is an important regulatory level of gene expression and thus takes on a key role in the maintenance of accurate cell and tissue function. Missplicing of certain genes has already been linked to several age-associated diseases, such as progeria, Alzheimer’s disease, Parkinson’s disease and cancer. Nevertheless, many studies focus only on transcriptional variations of single genes or the expression changes of spliceosomal genes, coding for the proteins that aggregate to the spliceosomal machinery. Little is known on the general change of present and switching isoforms in different tissues over time. In this descriptive RNA-Seq study, we report differences and commonalities of isoform usage during aging among different tissues within one species and compare changes of alternative splicing among different, evolutionarily distinct species. Although we identified a multitude of differntially spliced genes among different time points, we observed little to no general changes in the transcriptomic landscape of the investigated samples. Although there is undoubtedly considerable influence of specifically spliced genes on certain age-associated processes, this work shows that alternative splicing remains stable for the majority of genes with aging.},

keywords = {aging, RNA / transcriptomics, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{Chen:18,

title = {Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation},

author = {Zhiyang Chen and Elias Moris Amro and Friedrich Becker and Martin Hölzer and Seyed Mohammad Mahdi Rasa and Sospeter Ngoci Njeru and Bing Han and Simone Di Sanzo and Yulin Chen and Duozhuang Tang and Si Tao and Ronny Haenold and Marco Groth and Vasily S. Romanov and Joanna M. Kirkpatrick and Johann M. Kraus and Hans A. Kestler and Manja Marz and Alessandro Ori and Francesco Neri and Yohei Morita and K. Lenhard Rudolph},

doi = {10.1084/jem.20181505},

year  = {2018},

date = {2018-12-07},

urldate = {2018-01-01},

journal = {J Exp Med},

volume = {216},

number = {1},

pages = {152--175},

publisher = {Rockefeller University Press},

abstract = {Organism aging is characterized by increased inflammation and decreased stem cell function, yet the relationship between these factors remains incompletely understood. This study shows that aged hematopoietic stem and progenitor cells (HSPCs) exhibit increased ground-stage NF-κB activity, which enhances their responsiveness to undergo differentiation and loss of self-renewal in response to inflammation. The study identifies Rad21/cohesin as a critical mediator of NF-κB signaling, which increases chromatin accessibility in the vicinity of NF-κB target genes in response to inflammation. Rad21 is required for normal differentiation, but limits self-renewal of hematopoietic stem cells (HSCs) during aging and inflammation in an NF-κB–dependent manner. HSCs from aged mice fail to down-regulate Rad21/cohesin and inflammation/differentiation signals in the resolution phase of inflammation. Inhibition of cohesin/NF-κB reverts hypersensitivity of aged HSPCs to inflammation-induced differentiation and myeloid-biased HSCs with disrupted/reduced expression of Rad21/cohesin are increasingly selected during aging. Together, Rad21/cohesin-mediated NF-κB signaling limits HSPC function during aging and selects for cohesin-deficient HSCs with myeloid-skewed differentiation.},

keywords = {aging, differential expression analysis, DNA / genomics},

pubstate = {published},

tppubtype = {article}

}

@article{Morales-Prieto:18a,

title = {Peripheral blood exosomes pass blood-brain-barrier and induce glial cell activation},

author = {Diana M. Morales-Prieto and Milan Stojiljkovic and Celia Diezel and Priska-Elisabeth Streicher and Franziska Roestel and Julia Lindner and Sebastian Weis and Christian Schmeer and Manja Marz},

doi = {10.1101/471409},

year  = {2018},

date = {2018-11-29},

urldate = {2018-11-29},

journal = {bioRxiv},

pages = {471409},

publisher = {Cold Spring Harbor Laboratory},

abstract = {Background Exosomes are involved in intracellular communication and contain proteins, mRNAs, miRNAs, and signaling molecules. Exosomes were shown to act as neuroinflammatory mediators involved in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS). Brain aging has been associated to increased neuroinflammation. In addition, a decreased extracellular vesicle concentration was observed in aging tissues. The specific mechanisms how exosomes and aging are connected are not known yet.



Results Here we have shown that peripheral injection had almost no effect on selected gene expression in the liver. However, exosome injection has led to changes in the specific markers of glial cell activation (CD68, Iba1, GFAP). Interestingly, only injection of exosomes isolated from aged mice induced significant activation of astrocyte cells, as shown by increased GFAP expression.



Conclusion Transcription levels of genes GFAP, TGF-β, CD68, Iba1 known to be involved in glial cell function are significantly changing after introduction of peripheral extracellular vesicles. Exosomes were able to pass blood brain barrier and induce glial cell activation. GFAP known to be a specific astrocyte activation marker was significantly higher expressed after injection of old but not young exosomes, indicating a possible role of exosomes in the mechanisms of brain aging.},

keywords = {aging, extracellular vesicles, liver, ncRNAs},

pubstate = {published},

tppubtype = {article}

}

@article{Baumgart:17,

title = {A miRNA catalogue and ncRNA annotation of the short-living fish \textit{Nothobranchius furzeri}},

author = {Mario Baumgart and Emanuel Barth and Aurora Savino and Marco Groth and Philipp Koch and Andreas Petzold and Ivan Arisi and Matthias Platzer and Manja Marz and Alessandro Cellerino},

doi = {10.1186/s12864-017-3951-8},

year  = {2017},

date = {2017-09-05},

urldate = {2017-01-01},

journal = {BMC Genomics},

volume = {18},

pages = {693},

abstract = {The short-lived fish Nothobranchius furzeri is the shortest-lived vertebrate that can be cultured in captivity and was recently established as a model organism for aging research. Small non-coding RNAs, especially miRNAs, are implicated in age dependent control of gene expression. Here, we present a comprehensive catalogue of miRNAs and several other non-coding RNA classes (ncRNAs) for Nothobranchius furzeri. Analyzing multiple small RNA-Seq libraries, we show most of these identified miRNAs are expressed in at least one of seven Nothobranchius species. Additionally, duplication and clustering of N. furzeri miRNAs was analyzed and compared to the four fish species Danio rerio, Oryzias latipes, Gasterosteus aculeatus and Takifugu rubripes. A peculiar characteristic of N. furzeri, as compared to other teleosts, was a duplication of the miR-29 cluster. The completeness of the catalogue we provide is comparable to that of the zebrafish. This catalogue represents a basis to investigate the role of miRNAs in aging and development in this species.},

keywords = {aging, annotation, ncRNAs, RNA / transcriptomics},

pubstate = {published},

tppubtype = {article}

}

@article{Marz:15,

title = {MicroRNAs as biomarker of Parkinson disease? Small but mighty},

author = {Manja Marz and Manuela Ferracin and Christine Klein},

doi = {10.1212/WNL.0000000000001275},

year  = {2015},

date = {2015-01-16},

urldate = {2015-01-01},

journal = {Neurology},

volume = {84},

pages = {636--638},

abstract = {Although first described in 1993,1 microRNAs (miRNAs) have only recently emerged as important regulators of gene expression in the context of Parkinson disease (PD).2 miRNAs belong to the class of small non–protein coding RNAs, which mediate the posttranscriptional gene silencing of target RNA transcripts. Specifically, miRNAs are 18- to 25-nucleotide single-stranded RNA, which can inhibit gene expression by binding to the 3′ untranslated region of target genes (figure, A). Of note, the miRNA machinery has a critical role in the biology of dopamine neurons, the predominant cell type affected by neurodegeneration in PD. When eliminating mature miRNAs by deleting Dicer, the ribonuclease required for the early steps of miRNA biogenesis (figure), a nearly complete loss of the dopaminergic neuronal phenotype is observed in a murine cellular model.3 Several subsequent studies addressed the role of miRNAs in PD pathogenesis by focusing on known PD genes and gene products, such as α-synuclein or LRRK2, and identified miRNAs specifically regulating the expression of these proteins.4,5},

keywords = {aging, ncRNAs},

pubstate = {published},

tppubtype = {article}

}