Search

Abstract Background Alzheimer’s disease has been known for more than 100 years and the underlying molecular mechanisms are not yet completely understood. The identification of genes involved in the processes in Alzheimer affected brain is an important step towards such an understanding. Genes differentially expressed in diseased and healthy brains are promising candidates. Results Based on microarray data we identify potential biomarkers as well as biomarker combinations using three feature selection methods: information gain, mean decrease accuracy of random forest and a wrapper of genetic algorithm and support vector machine (GA/SVM). Information gain and random forest are two commonly used methods. We compare their output to the results obtained from GA/SVM. GA/SVM is rarely used for the analysis of microarray data, but it is able to identify genes capable of classifying tissues into different classes at least as well as the two reference methods. Conclusion Compared to the other methods, GA/SVM has the advantage of finding small, less redundant sets of genes that, in combination, show superior classification characteristics. The biological significance of the genes and gene pairs is discussed.

Abstract Background The prediction of transcription factor binding sites is difficult for many reasons. Thus, filtering methods are needed to enrich for biologically relevant (true positive) matches in the large amount of computational predictions that are frequently generated from promoter sequences. Results ReXSpecies 2 filters predictions of transcription factor binding sites and generates a set of figures displaying them in evolutionary context. More specifically, it uses position specific scoring matrices to search for motifs that specify transcription factor binding sites. It removes redundant matches and filters the remaining matches by the phylogenetic group that the matrices belong to. It then identifies potential transcriptional modules, and generates figures that highlight such modules, taking evolution into consideration. Module formation, scoring by evolutionary criteria and visual clues reduce the amount of predictions to a manageable scale. Identification of transcription factor binding sites of particular functional importance is left to expert filtering. ReXSpecies 2 interacts with genome browsers to enable scientists to filter predictions together with other sequence-related data. Conclusions Based on ReXSpecies 2, we derive plausible hypotheses about the regulation of pluripotency. Our tool is designed to analyze transcription factor binding site predictions considering their common pattern of occurrence, highlighting their evolutionary history.

Abstract Background Experimentally validated data on gene regulation are hard to obtain. In particular, information about transcription factor binding sites in regulatory regions are scattered around in the literature. This impedes their systematic in-context analysis, e.g. the inference of their conservation in evolutionary history. Results We demonstrate the power of integrative bioinformatics by including curated transcription factor binding site information into the UCSC genome browser, using wiki and custom tracks, which enable easy publication of annotation data. Data integration allows to investigate the evolution of gene regulation of the pluripotency-associated genes Oct4, Sox2 and Nanog. For the first time, experimentally validated transcription factor binding sites in the regulatory regions of all three genes were assembled together based on manual curation of data from 39 publications. Using the UCSC genome browser, these data were then visualized in the context of multi-species conservation based on genomic alignment. We confirm previous hypotheses regarding the evolutionary age of specific regulatory patterns, establishing their "deep homology". We also confirm some other principles of Carroll's "Genetic theory of Morphological Evolution", such as "mosaic pleiotropy", exemplified by the dual role of Sox2 reflected in its regulatory region. Conclusions We were able to elucidate some aspects of the evolution of gene regulation for three genes associated with pluripotency. Based on the expected return on investment for the community, we encourage other scientists to contribute experimental data on gene regulation (original work as well as data collected for reviews) to the UCSC system, to enable studies of the evolution of gene regulation on a large scale, and to report their findings. Reviewers This article was reviewed by Dr. Gustavo Glusman and Dr. Juan Caballero, Institute for Systems Biology, Seattle, USA (nominated by Dr. Doron Lancet, Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel), Dr. Niels Grabe, TIGA Center (BIOQUANT) and Medical Systems Biology Group, Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Germany (nominated by Dr. Mikhail Gelfand, Department of Bioinformatics, Institute of Information Transfer Problems, Russian Academy of Science, Moscow, Russian Federation) and Dr. Franz-Josef Müller, Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA, USA and University Hospital for Psychiatry and Psychotherapy (part of ZIP gGmbH), University of Kiel, Germany (nominated by Dr. Trey Ideker, University of California, San Diego, La Jolla CA, United States).

Abstract Background Targeted therapy approaches have been successfully introduced into the treatment of several cancers. The multikinase inhibitor Sorafenib has antitumor activity in solid tumors and its effects on acute lymphoblastic leukemia (ALL) cells are still unclear. Methods ALL cell lines (SEM, RS4;11 and Jurkat) were treated with Sorafenib alone or in combination with cytarabine, doxorubicin or RAD001. Cell count, apoptosis and necrosis rates, cell cycle distribution, protein phosphorylation and metabolic activity were determined. Results Sorafenib inhibited the proliferation of ALL cells by cell cycle arrest accompanied by down-regulation of CyclinD3 and CDK4. Furthermore, Sorafenib initiated apoptosis by cleavage of caspases 3, 7 and PARP. Apoptosis and necrosis rates increased significantly with most pronounced effects after 96 h. Antiproliferative effects of Sorafenib were associated with a decreased phosphorylation of Akt (Ser473 and Thr308), FoxO3A (Thr32) and 4EBP-1 (Ser65 and Thr70) as early as 0.5 h after treatment. Synergistic effects were seen when Sorafenib was combined with other cytotoxic drugs or a mTOR inhibitor emphasizing the Sorafenib effect. Conclusion Sorafenib displays significant antileukemic activity in vitro by inducing cell cycle arrest and apoptosis. Furthermore, it influences PI3K/Akt/mTOR signaling in ALL cells.

Abstract Background Protein-protein interaction (PPI) is fundamental to many biological processes. In the course of evolution, biological networks such as protein-protein interaction networks have developed. Biological networks of different species can be aligned by finding instances (e.g. proteins) with the same common ancestor in the evolutionary process, so-called orthologs. For a better understanding of the evolution of biological networks, such aligned networks have to be explored. Visualization can play a key role in making the various relationships transparent. Results We present a novel visualization system for aligned biological networks in 3D space that naturally embeds existing 2D layouts. In addition to displaying the intra-network connectivities, we also provide insight into how the individual networks relate to each other by placing aligned entities on top of each other in separate layers. We optimize the layout of the entire alignment graph in a global fashion that takes into account inter- as well as intra-network relationships. The layout algorithm includes a step of merging aligned networks into one graph, laying out the graph with respect to application-specific requirements, splitting the merged graph again into individual networks, and displaying the network alignment in layers. In addition to representing the data in a static way, we also provide different interaction techniques to explore the data with respect to application-specific tasks. Conclusion Our system provides an intuitive global understanding of aligned PPI networks and it allows the investigation of key biological questions. We evaluate our system by applying it to real-world examples documenting how our system can be used to investigate the data with respect to these key questions. Our tool VANLO (Visualization of Aligned Networks with Layout Optimization) can be accessed at http://www.math-inf.uni-greifswald.de/VANLO.

Abstract Background Annotated phylogenetic trees that display the evolution of transcription factor binding in regulatory regions are useful for e.g. 1) narrowing down true positive predicted binding sites, providing predictions for binding sites that can be tested experimentally, and 2) giving insight into the evolution of gene regulation and regulatory networks. Results We describe ReXSpecies, a web-server that processes the sequence information of a regulatory region for multiple species and associated (predicted) transcription factor binding sites into two figures: a) An annotated alignment of sequence and binding sites, consolidated and filtered for ease of use, and b) an annotated tree labeled by the gain and loss of binding sites, where the tree can be calculated from the data or taken from a trusted taxonomy, and the labels are calculated based on standard or Dollo parsimony. For genes involved in mammalian pluripotency, ReXSpecies trees highlight useful patterns of transcription factor binding site gain and loss, e.g. for the Oct and Sox group of factors in the 3' untranslated region of the cystic fibrosis transmembrane conductance regulator gene, which closely match experimental data. Conclusion ReXSpecies post-processes the information provided by transcription factor binding site prediction tools, in order to compare data from many species. The tool eases visualization and successive interpretation of transcription factor binding data in an evolutionary context. The ReXSpecies URL can be found in the Availability and requirements section.

Abstract Background In the genomic age, gene trees may contain large amounts of data making them hard to read and understand. Therefore, an automated simplification is important. Results We present a simplification tool for gene trees called TreeSimplifier. Based on species tree information and HUGO gene names, it summarizes "monophyla". These monophyla correspond to subtrees of the gene tree where the evolution of a gene follows species phylogeny, and they are simplified to single leaves in the gene tree. Such a simplification may fail, for example, due to genes in the gene tree that are misplaced. In this way, misplaced genes can be identified. Optionally, our tool glosses over a limited degree of "paraphyly" in a further simplification step. In both simplification steps, species can be summarized into groups and treated as equivalent. In the present study we used our tool to derive a simplified tree of 397 leaves from a tree of 1138 leaves. Comparing the simplified tree to a "cartoon tree" created manually, we note that both agree to a high degree. Conclusion Our automatic simplification tool for gene trees is fast, accurate, and effective. It yields results of similar quality as manual simplification. It should be valuable in phylogenetic studies of large protein families. The software is available at http://www.uni-muenster.de/Bioinformatics/services/treesim/.

Abstract Background Recent progress in cDNA and EST sequencing is yielding a deluge of sequence data. Like database search results and proteome databases, this data gives rise to inferred protein sequences without ready access to the underlying genomic data. Analysis of this information (e.g. for EST clustering or phylogenetic reconstruction from proteome data) is hampered because it is not known if two protein sequences are isoforms (splice variants) or not (i.e. paralogs/orthologs). However, even without knowing the intron/exon structure, visual analysis of the pattern of similarity across the alignment of the two protein sequences is usually helpful since paralogs and orthologs feature substitutions with respect to each other, as opposed to isoforms, which do not. Results The IsoSVM tool introduces an automated approach to identifying isoforms on the protein level using a support vector machine (SVM) classifier. Based on three specific features used as input of the SVM classifier, it is possible to automatically identify isoforms with little effort and with an accuracy of more than 97%. We show that the SVM is superior to a radial basis function network and to a linear classifier. As an example application we use IsoSVM to estimate that a set of Xenopus laevis EST clusters consists of approximately 81% cases where sequences are each other's paralogs and 19% cases where sequences are each other's isoforms. The number of isoforms and paralogs in this allotetraploid species is of interest in the study of evolution. Conclusion We developed an SVM classifier that can be used to distinguish isoforms from paralogs with high accuracy and without access to the genomic data. It can be used to analyze, for example, EST data and database search results. Our software is freely available on the Web, under the name IsoSVM.

Objectives: To validate and test the generalisability of the SASKit-ML pipeline, a prepublished feature selection and machine learning pipeline for the prediction of health deterioration after a stroke or pancreatic adenocarcinoma event, by using it to identify biomarkers of health deterioration in chronic disease., Design: This is a validation study using a predefined protocol applied to multiple publicly available datasets, including longitudinal data from cohorts with type 2 diabetes (T2D), inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and various cancers. The datasets were chosen to mimic as closely as possible the SASKit cohort, a prospective, longitudinal cohort study., Data Sources: Public data were used from the T2D (77 patients with potential pre-diabetes and 18 controls) and IBD (49 patients with IBD and 12 controls) branches of the Human Microbiome Project (HMP), RA Map (RA-MAP, 92 patients with RA, 22 controls) and The Cancer Genome Atlas (TCGA, 16 cancers)., Methods: Data integration steps were performed in accordance with the prepublished study protocol, generating features to predict disease outcomes using 10-fold cross-validated random survival forests., Outcome Measures: Health deterioration was assessed using disease-specific clinical markers and endpoints across different cohorts. In the HMP-T2D cohort, the worsening of glycated haemoglobin (HbA1c) levels (5.7% or more HbA1c in the blood), fasting plasma glucose (at least 100 mg/dL) and oral glucose tolerance test (at least 140) results were considered. For the HMP-IBD cohort, a worsening by at least 3 points of a disease-specific severity measure, the "Simple Clinical Colitis Activity Index" or "Harvey-Bradshaw Index" indicated an event. For the RA-MAP cohort, the outcome was defined as the worsening of the "Disease Activity Score 28" or "Simple Disease Activity Index" by at least five points, or the worsening of the "Health Assessment Questionnaire" score or an increase in the number of swollen/tender joints were evaluated. Finally, the outcome for all TCGA datasets was the progression-free interval., Results: Models for the prediction of health deterioration in T2D, IBD, RA and 16 cancers were produced. The T2D (C-index of 0.633 and Integrated Brier Score (IBS) of 0.107) and the RA (C-index of 0.654 and IBS of 0.150) models were modestly predictive. The IBD model was uninformative. TCGA models tended towards modest predictive power., Conclusions: The SASKit-ML pipeline produces informative and useful features with the power to predict health deterioration in a variety of diseases and cancers; however, this performance is disease-dependent., Competing Interests: Competing interests: UW reports grants and personal fees from Merz Pharma, personal fees from Amarin, personal fees from Bristol-Myers Squibb, personal fees from Canon Medical Systems, personal fees from Daiichi Sankyo, personal fees from Ipsen Pharma, personal fees from Pfizer, personal fees from Thieme and personal fees from Elsevier Press, all outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

As scientists investigated the molecular mechanisms of the biology of aging, they discovered that these are malleable and can enhance healthy longevity by intervening in the drivers of aging, which are leading to disease, dysfunction and death. These exciting observations gave birth to the field of geroscience. As the mechanisms of aging affect almost all mechanisms of life, detailed molecular mechanistic knowledge must be gained or expanded by considering and integrating as many types of data as possible, from genes and transcripts to socioenvironmental factors. Such a large-scale integration of large amounts of data will in turn profit from "deep" bioinformatics analyses that provide insights beyond contextualizing and interpreting the data in the light of knowledge from databases such as the Gene Ontology. The authors suggest that "deep" bioinformatics, employing methods based on artificial intelligence, will be a key ingredient of future analyses., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Glaucoma is the leading cause of blindness worldwide. However, its surgical treatment, in particular via trabeculectomy, can be complicated by fibrosis. In current clinical practice, application of the drug, Mitomycin C, prevents or delays fibrosis, but can lead to additional side effects, such as bleb leakage and hypotony. Previous in silico drug screening and in vitro testing has identified the known antibiotic, josamycin, as a possible alternative antifibrotic medication with potentially fewer side effects. However, a suitable ocular delivery mechanism for the hydrophobic drug to the surgical site does not yet exist. Therefore, the focus of this paper is the development of an implantable drug delivery system for sustained delivery of josamycin after glaucoma surgery based on crosslinked γ-cyclodextrin. γ-Cyclodextrin is a commonly used solubilizer which was shown to complex with josamycin, drastically increasing the drug's solubility in aqueous solutions. A simple γ-cyclodextrin crosslinking method produced biocompatible hydrogels well-suited for implantation. The crosslinked γ - cyclodextrin retained the ability to form complexes with josamycin, resulting in a 4-fold higher drug loading efficiency when compared to linear dextran hydrogels, and prolonged drug release over 4 days.

Background: The combination of senescence triggers with senolytic drugs is considered a promising new approach to cancer therapy. Here, we studied the efficacy of the genotoxic agent etoposide (Eto) and irradiation in inducing senescence of Panc02 pancreatic cancer cells, and the capability of the Bcl-2 inhibitor navitoclax (ABT-263; Nav) to trigger senolysis., Methods: Panc02 cells were treated with Eto or irradiated with 5-20 Gy before exposure to Nav. Cell survival, proliferation, and senescence were assessed by trypan blue staining, quantification of DNA synthesis, and staining of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, respectively. Levels of mRNA were determined by real-time polymerase chain reaction, and protein expression was analyzed by immunoblotting. Panc02 cells were also grown as pancreatic tumors in mice, which were subsequently treated with Eto and Nav., Results: Eto and irradiation had an antiproliferative effect on Panc02 cells that was significantly or tendentially enhanced by Nav. In vivo, Eto and Nav together, but not Eto alone, significantly reduced the proportion of proliferating cells. The expression of the senescence marker γH2AX and tumor infiltration with T-cells were not affected by the treatment. In vitro, almost all Eto-exposed cells and a significant proportion of cells irradiated with 20 Gy were SA-β-Gal-positive. Application of Nav reduced the percentage of SA-β-Gal-positive cells after irradiation but not after pretreatment with Eto. In response to triggers of senescence, cultured Panc02 cells showed increased protein levels of γH2AX and the autophagy marker LC3B-II, and higher mRNA levels of Cdkn1a, Mdm2, and PAI-1, while the effects of Nav were variable., Conclusions: In vitro and in vivo, the combination of senescence triggers with Nav inhibited tumor cell growth more effectively than the triggers alone. Our data also provide some evidence for senolytic effects of Nav in vitro., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2024 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Disease prevention and health promotion in and for old age have become increasingly more important. Nevertheless, more (national) research and implementation in practice is needed, as the international comparison shows., Objective: To develop guiding principles for research and practice on prevention and health promotion in and for old age., Material and Methods: As part of an iterative process, members of the German Society of Gerontology and Geriatrics came together in workshops and symposia to formulate key guiding principles and fields of action for prevention and health promotion., Results: The following were worked out: 1) prevention and health promotion are useful and possible up to oldest age, 2) prevention and health promotion for advanced age should start early, 3) prevention and health promotion must take into account the diversity and heterogeneity of the life situations of old people, 4) prevention and health promotion promote and demand self-determination and participation, 5) prevention of multiple illnesses must be given greater attention, 6) prevention of the need for long-term care and prevention in long-term care must be treated equally, 7) prevention and health promotion must be thought of in terms of life worlds and across sectors, paying particular attention to aspects of social inequality and a focus on resources, 8) prevention and health promotion and the related research must be interdisciplinary and transdisciplinary and be applied at different levels, from molecular to societal., Discussion: The guiding principles outline the focal points of future-oriented ageing, health and healthcare research and open up fields of action but also show the limits of this approach for political decision-makers, researchers and practitioners., (© 2023. The Author(s).)

In this paper, we present a comprehensive computational framework aimed at suggesting genes whose transcriptional regulation is likely to be influenced by their chromosomal position. This framework provides a user-friendly web interface, enabling researchers to explore the positional properties of all human genes and their orthologs across species, with a focus on their relation to the telomeres. Our approach involves multiple scoring methods, each adjustable by users, representing different features of the genes' positional variation across species. The resulting rankings can be combined to identify candidate genes that may be subject to position effects. Furthermore, the ranking can be tailored to a specific set of reference genes. We evaluate the method within the context of TPE-OLD, a mechanism where telomeres can exert a direct influence on gene expression across considerable genomic distances, and empower researchers to delve deeper into genes of interest, analyzing their position across species and estimating their susceptibility to position effects like TPE-OLD. We also provide simple enrichment analyses of user-provided gene lists in relation to top-ranking candidate genes., (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Climate extremes and rising energy prices present interconnected global health risks. Technical solutions can be supplemented with biomedical approaches to promote healthy longevity in hot and cold conditions. In summer, reducing basal metabolic rate through mild caloric restriction or CR mimetics, such as resveratrol, can potentially be used to lower body temperature. In winter, activating brown adipose tissue (BAT) for non-shivering thermogenesis and improved metabolic health can help adaptation to colder environments. Catechins found in green tea and in other food could be alternatives to drugs for these purposes. This review examines and discusses the biomedical evidence supporting the use of CR mimetics and BAT activators for health benefits amid increasingly extreme temperatures.

The major risk factor for chronic disease is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. The senolytic combination of the tyrosine-kinase inhibitor dasatinib and the flavonol quercetin is frequently used in clinical trials aiming to eliminate senescent cells. Here, our goal was to computationally identify natural senotherapeutic repurposing candidates that may substitute dasatinib based on their similarity in gene expression effects. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib + quercetin formula., (© 2024. The Author(s).)

The search for biomarkers that quantify biological aging (particularly 'omic'-based biomarkers) has intensified in recent years. Such biomarkers could predict aging-related outcomes and could serve as surrogate endpoints for the evaluation of interventions promoting healthy aging and longevity. However, no consensus exists on how biomarkers of aging should be validated before their translation to the clinic. Here, we review current efforts to evaluate the predictive validity of omic biomarkers of aging in population studies, discuss challenges in comparability and generalizability and provide recommendations to facilitate future validation of biomarkers of aging. Finally, we discuss how systematic validation can accelerate clinical translation of biomarkers of aging and their use in gerotherapeutic clinical trials., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In oocyte biology, the zona pellucida has long been known to operate three extracellular functions downstream of the secretory pathway, namely, encasing the oocytes in ovarian follicles, mediating sperm-oocyte interaction, and preventing premature embryo contact with oviductal epithelium. The present study uncovers a fourth function that is fundamentally distinct from the other three, being critical for embryonic cell survival in mice. Intriguingly, the three proteins of the mouse zona pellucida (ZP1, ZP2, ZP3) were found abundantly present also inside the embryo 4 days after fertilization, as shown by mass spectrometry, immunoblotting, and immunofluorescence. Contrary to current understanding of the roles of ZP proteins, ZP3 was associated more with the cytoskeleton than with secretory vesicles in the subcortical region of metaphase II oocytes and zygotes, and was excluded from regions of cell-cell contact in cleavage-stage embryos. Trim-away-mediated knockdown of ZP3 in fertilized oocytes hampered the first zygotic cleavage, while ZP3 overexpression supported blastocyst formation. Transcriptome analysis of ZP3-knockdown embryos pointed at defects of cytoplasmic translation in the context of embryonic genome activation. This conclusion was supported by reduced protein synthesis in the ZP3-knockdown and by the lack of cleavage arrest when Trim-away was postponed from the one-cell to the late two-cell stage. These data place constraints on the notion that zona proteins only operate in the extracellular space, revealing also a role during the oocyte-to-embryo transition. Ultimately, these data recruit ZP3 into the family of maternal factors that contribute to developmental competence of mouse oocytes., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice., Competing Interests: Declaration of interests M.M., V.S., M.P.S., and V.N.G. have filed patents on measuring aging. C.H. is affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria and an honorary research fellow at the Department of Women’s Cancer, EGA Institute for Women’s Health, University College London, United Kingdom. C.H. and M.W. are shareholders of Sola Diagnostics GmbH and named as inventors on a patent on an epigenetic clock indicative of breast cancer risk. J.N.J. is affiliated with the Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, USA and the XPRIZE Foundation, Culver City, CA, USA. J.N.J. also serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences, eLife, and Experimental Gerontology. D.W.B. is affiliated with the Child Brain Development Network, Canadian Institute for Advanced Research and SocioMed Research Nucleus, Universidad Mayor, Santiago, Chile. D.W.B. also serves on the advisory board for the American Federation for Aging Research (AFAR)’s Finding Aging biomarkers by Searching existing Trials (FAST) Initiative and the editorial board of Journals of Gerontology Series A Biological Sciences and is an inventor of DunedinPACE, a Duke University and University of Otago invention licensed to TruDiagnostic. A.A.C. is a founder, president, and majority shareholder at Oken Health. I.B. is affiliated with the SOMT University of Physiotherapy, Amersfoort, The Netherlands and is a member of the clinical advisory board of Rejuvenate Biomed. M.W. is affiliated with the Institute for Biomedical Aging Research, Universität Innsbruck, Austria. N.B. is the Scientific Director of the American Federation for Aging Research (AFAR), on the board of the executive committee of the Longevity Biotech Association, and advisor on the Board of the Academy for Health and Lifespan Research. M.K. is an employee and shareholder of Optispan Inc., a company developing tools to enable science-based personalized and preventative geromedicine. The Regents of the University of California is the sole owner of a patent application directed at GrimAge and other epigenetic clocks for which S.H. is a named inventor. S.H. is also a founder and paid consultant of the nonprofit Epigenetic Clock Development Foundation that licenses patents surrounding epigenetic clocks. A.B.M. is the Chief Medical Officer of NU. V.N.G. is a scientific advisor to Retro and Dior. M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, and Mirvie. M.P.S. is also a scientific advisor of Jupiter, Neuvivo, Swaza, and Mitrix. V.S. is co-founder, SAB chair, and head of research of Turn Biotechnologies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The most important predictors for outcomes after ischemic stroke, that is, for health deterioration and death, are chronological age and stroke severity; gender, genetics and lifestyle/environmental factors also play a role. Of all these, only the latter can be influenced after the event. Recurrent stroke may be prevented by antiaggregant/anticoagulant therapy, angioplasty of high-grade stenoses, and treatment of cardiovascular risk factors. Blood cell composition and protein biomarkers such as C-reactive protein or interleukins in serum are frequently considered as biomarkers of outcome. Here we aim to provide an up-to-date protein biomarker signature that allows a maximum of mechanistic understanding, to predict health deterioration following stroke. We thus surveyed protein biomarkers that were reported to be predictive for outcome after ischemic stroke, specifically considering biomarkers that predict long-term outcome (≥ 3 months) and that are measured over the first days following the event. We classified the protein biomarkers as immune‑inflammatory, coagulation-related, and adhesion-related biomarkers. Some of these biomarkers are closely related to cellular senescence and, in particular, to the inflammatory processes that can be triggered by senescent cells. Moreover, the processes that underlie inflammation, hypercoagulation and cellular senescence connect stroke to cancer, and biomarkers of cancer-associated thromboembolism, as well as of sarcopenia, overlap strongly with the biomarkers discussed here. Finally, we demonstrate that most of the outcome-predicting protein biomarkers form a close-meshed functional interaction network, suggesting that the outcome after stroke is partially determined by an interplay of molecular processes relating to inflammation, coagulation, cell adhesion and cellular senescence., (© 2022. The Author(s).)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown., Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient (Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically transplanted Ucp2 wild-type (WT) PDAC cells (cell lines Panc02 and 6606PDA) in vivo and to study strain-dependent differences of the PDAC microenvironment., Results: Measurements of tumor weights and quantification of proliferating cells indicated a significant growth advantage of Panc02 and 6606PDA cells in WT mice compared to Ucp2 KO mice. In tumors in the knockout strain, higher levels of interferon-γ mRNA despite similar numbers of tumor-infiltrating T cells were observed. 6606PDA cells triggered a stronger stromal reaction in Ucp2 KO mice than in WT animals. Accordingly, pancreatic stellate cells from Ucp2 KO mice proliferated at a higher rate than cells of the WT strain when they were incubated with conditioned media from PDAC cells., Conclusions: Ucp2 modulates PDAC microenvironment in a way that favors tumor progression and implicates an altered stromal response as one of the underlying mechanisms., (Copyright © 2022 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)