Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
1.
Ann N Y Acad Sci ; 1507(1): 70-83, 2022 01.
Article in English | MEDLINE | ID: covidwho-1673249

ABSTRACT

For many years, it was believed that the aging process was inevitable and that age-related diseases could not be prevented or reversed. The geroscience hypothesis, however, posits that aging is, in fact, malleable and, by targeting the hallmarks of biological aging, it is indeed possible to alleviate age-related diseases and dysfunction and extend longevity. This field of geroscience thus aims to prevent the development of multiple disorders with age, thereby extending healthspan, with the reduction of morbidity toward the end of life. Experts in the field have made remarkable advancements in understanding the mechanisms underlying biological aging and identified ways to target aging pathways using both novel agents and repurposed therapies. While geroscience researchers currently face significant barriers in bringing therapies through clinical development, proof-of-concept studies, as well as early-stage clinical trials, are underway to assess the feasibility of drug evaluation and lay a regulatory foundation for future FDA approvals in the future.


Subject(s)
Aging/genetics , Aging/metabolism , Congresses as Topic/trends , Longevity/physiology , Research Report , Autophagy/physiology , COVID-19/genetics , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/therapy , Humans , Metabolomics/methods , Metabolomics/trends , Nervous System Diseases/genetics , Nervous System Diseases/metabolism , Nervous System Diseases/therapy , Stem Cell Transplantation/methods , Stem Cell Transplantation/trends
2.
Cells ; 11(3)2022 01 29.
Article in English | MEDLINE | ID: covidwho-1667056

ABSTRACT

Epigenetic alterations pose one major hallmark of organismal aging. Here, we provide an overview on recent findings describing the epigenetic changes that arise during aging and in related maladies such as neurodegeneration and cancer. Specifically, we focus on alterations of histone modifications and DNA methylation and illustrate the link with metabolic pathways. Age-related epigenetic, transcriptional and metabolic deregulations are highly interconnected, which renders dissociating cause and effect complicated. However, growing amounts of evidence support the notion that aging is not only accompanied by epigenetic alterations, but also at least in part induced by those. DNA methylation clocks emerged as a tool to objectively determine biological aging and turned out as a valuable source in search of factors positively and negatively impacting human life span. Moreover, specific epigenetic signatures can be used as biomarkers for age-associated disorders or even as targets for therapeutic approaches, as will be covered in this review. Finally, we summarize recent potential intervention strategies that target epigenetic mechanisms to extend healthy life span and provide an outlook on future developments in the field of longevity research.


Subject(s)
Epigenomics , Longevity , Aging/genetics , DNA Methylation/genetics , Epigenesis, Genetic , Humans , Longevity/genetics
3.
EMBO Rep ; 23(2): e53658, 2022 02 03.
Article in English | MEDLINE | ID: covidwho-1547826

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the coronavirus disease 2019 (COVID-19), known to be more common in the elderly, who also show more severe symptoms and are at higher risk of hospitalization and death. Here, we show that the expression of the angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 cell receptor, increases during aging in mouse and human lungs. ACE2 expression increases upon telomere shortening or dysfunction in both cultured mammalian cells and in vivo in mice. This increase is controlled at the transcriptional level, and Ace2 promoter activity is DNA damage response (DDR)-dependent. Both pharmacological global DDR inhibition of ATM kinase activity and selective telomeric DDR inhibition by the use of antisense oligonucleotides prevent Ace2 upregulation following telomere damage in cultured cells and in mice. We propose that during aging telomere dysfunction due to telomeric shortening or damage triggers DDR activation and this causes the upregulation of ACE2, the SARS-CoV-2 cell receptor, thus contributing to make the elderly more susceptible to the infection.


Subject(s)
Aging , Angiotensin-Converting Enzyme 2/genetics , COVID-19 , DNA Damage , Telomere , Aged , Aging/genetics , Animals , Humans , Mice , SARS-CoV-2 , Telomere/genetics
4.
J Mol Cell Cardiol ; 164: 13-16, 2022 03.
Article in English | MEDLINE | ID: covidwho-1527886

ABSTRACT

Aged males disproportionately succumb to increased COVID-19 severity, hospitalization, and mortality compared to females. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) facilitate SARS-CoV-2 viral entry and may have sexually dimorphic regulation. As viral load dictates disease severity, we investigated the expression, protein levels, and activity of ACE2 and TMPRSS2. Our data reveal that aged males have elevated ACE2 in both mice and humans across organs. We report the first comparative study comprehensively investigating the impact of sex and age in murine and human levels of ACE2 and TMPRSS2, to begin to elucidate the sex bias in COVID-19 severity.


Subject(s)
Aging/metabolism , Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/epidemiology , Gene Expression Regulation, Enzymologic , Receptors, Virus/biosynthesis , SARS-CoV-2/physiology , Sex Characteristics , Aging/genetics , Angiotensin-Converting Enzyme 2/genetics , Animals , Disease Susceptibility , Female , Heart/virology , Humans , Intestine, Small/enzymology , Intestine, Small/virology , Kidney/enzymology , Kidney/virology , Lung/enzymology , Lung/virology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Myocardium/enzymology , Organ Specificity , Receptors, Virus/genetics , Serine Endopeptidases/biosynthesis , Serine Endopeptidases/genetics , Young Adult
5.
J Mol Med (Berl) ; 100(2): 285-301, 2022 02.
Article in English | MEDLINE | ID: covidwho-1505851

ABSTRACT

The risk of severe COVID-19 increases with age as older patients are at highest risk. Thus, there is an urgent need to identify how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with blood components during aging. We investigated the whole blood transcriptome from the Genotype-Tissue Expression (GTEx) database to explore differentially expressed genes (DEGs) translated into proteins interacting with viral proteins during aging. From 22 DEGs in aged blood, FASLG, CTSW, CTSE, VCAM1, and BAG3 were associated with immune response, inflammation, cell component and adhesion, and platelet activation/aggregation. Males and females older than 50 years old overexpress FASLG, possibly inducing a hyperinflammatory cascade. The expression of cathepsins (CTSW and CTSE) and the anti-apoptotic co-chaperone molecule BAG3 also increased throughout aging in both genders. By exploring single-cell RNA-sequencing data from peripheral blood of SARS-CoV-2-infected patients, we found FASLG and CTSW expressed in natural killer cells and CD8 + T lymphocytes, whereas BAG3 was expressed mainly in CD4 + T cells, naive T cells, and CD14 + monocytes. In addition, T cell exhaustion was associated with increased expression of CCL4L2 and DUSP4 over blood aging. LAG3, PDCD1, TIGIT, VCAM1, HLA-DRA, and TOX also increased in individuals aged 60-69 years old; conversely, the RGS2 gene decreased with aging. We further identified a distinct gene expression profile associated with type I interferon signaling following blood aging. These results revealed changes in blood molecules potentially related to SARS-CoV-2 infection throughout aging, emphasizing them as therapeutic candidates for aggressive clinical manifestation of COVID-19. KEY MESSAGES: • Prediction of host-viral interactions in the whole blood transcriptome during aging. • Expression levels of FASLG, CTSW, CTSE, VCAM1, and BAG3 increase in aged blood. • Blood interactome reveals targets involved with immune response, inflammation, and blood clots. • SARS-CoV-2-infected patients with high viral load showed FASLG overexpression. • Gene expression profile associated with T cell exhaustion and type I interferon signaling were affected with blood aging.


Subject(s)
Aging/blood , Blood Proteins/analysis , COVID-19/genetics , SARS-CoV-2/pathogenicity , Transcriptome , Adult , Aged , Aging/genetics , Blood/metabolism , Blood Chemical Analysis , Blood Proteins/genetics , Blood Proteins/metabolism , Blood Vessels/metabolism , Blood Vessels/virology , COVID-19/blood , COVID-19/immunology , COVID-19/physiopathology , Cardiovascular Physiological Phenomena/genetics , Cardiovascular System/metabolism , Cardiovascular System/virology , Cohort Studies , Female , Genetic Association Studies , Humans , Immunity, Innate/genetics , Male , Middle Aged , Young Adult
6.
Nat Med ; 27(6): 1012-1024, 2021 06.
Article in English | MEDLINE | ID: covidwho-1472229

ABSTRACT

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.


Subject(s)
Aging/genetics , Communicable Diseases/genetics , Pneumonia/genetics , Sepsis/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Aging/pathology , Biological Specimen Banks , Chromosome Aberrations , Communicable Diseases/complications , Communicable Diseases/microbiology , Digestive System Diseases/epidemiology , Digestive System Diseases/genetics , Digestive System Diseases/microbiology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Hematologic Neoplasms/complications , Hematologic Neoplasms/genetics , Hematologic Neoplasms/microbiology , Humans , Male , Middle Aged , Mosaicism , Pneumonia/epidemiology , Pneumonia/microbiology , Risk Factors , Sepsis/epidemiology , Sepsis/microbiology , Urogenital Abnormalities/epidemiology , Urogenital Abnormalities/genetics , Urogenital Abnormalities/microbiology , Young Adult
7.
Int J Mol Sci ; 22(17)2021 Aug 27.
Article in English | MEDLINE | ID: covidwho-1374428

ABSTRACT

Age is a major risk factor for severe outcome of the 2019 coronavirus disease (COVID-19). In this study, we followed the hypothesis that particularly patients with accelerated epigenetic age are affected by severe outcomes of COVID-19. We investigated various DNA methylation datasets of blood samples with epigenetic aging signatures and performed targeted bisulfite amplicon sequencing. Overall, epigenetic clocks closely correlated with the chronological age of patients, either with or without acute respiratory distress syndrome. Furthermore, lymphocytes did not reveal significantly accelerated telomere attrition. Thus, these biomarkers cannot reliably predict higher risk for severe COVID-19 infection in elderly patients.


Subject(s)
Aging/genetics , COVID-19/pathology , Epigenesis, Genetic , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/virology , Case-Control Studies , CpG Islands , DNA Methylation , Female , Humans , Male , Middle Aged , Respiratory Distress Syndrome/etiology , SARS-CoV-2/isolation & purification , Telomere/metabolism , Telomere Shortening
8.
Exp Gerontol ; 150: 111361, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1272416

ABSTRACT

RT-qPCR is the most reliable molecular method for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we analyzed results of RT-qPCR obtained for 3044 patients diagnosed as SARS-CoV-2-positive using four different molecular tests utilizing five RNA sequences. The analysis showed that patients' age inversely correlates with threshold cycle (Ct) values for RdRP gene (LightMix® Modular Wuhan CoV RdRP-gene by Roche Diagnostics) and RdRP+S genes (MutaPLEX® Coronavirus RT-PCR kit by Immundiagnostic). At the same time, there was no correlation between age and Ct values for E, N, and ORF1ab genes. When patients were grouped by age, mean Ct values for RdRP gene in older patients were significantly lower compared with younger individuals. Collectively, our report indicates that older SARS-CoV-2-infected individuals exhibit higher viremia at diagnosis than younger patients, which may reflect impaired functioning of their immune response and predispose to more severe disease and worse prognosis.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Aging/genetics , Humans , RNA-Dependent RNA Polymerase , Real-Time Polymerase Chain Reaction
9.
Int J Mol Sci ; 22(11)2021 Jun 07.
Article in English | MEDLINE | ID: covidwho-1259510

ABSTRACT

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p < 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p < 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (< 60 years).


Subject(s)
Aging/genetics , COVID-19/genetics , COVID-19/physiopathology , CpG Islands , Telomere Shortening , Telomere/metabolism , Adult , Aged , Angiotensin-Converting Enzyme 2/blood , Biomarkers , COVID-19/complications , COVID-19/etiology , DNA Methylation , Dipeptidyl Peptidase 4/blood , Epigenomics , Female , High-Throughput Nucleotide Sequencing , Host Microbial Interactions , Humans , Male , Middle Aged , Risk Factors , Survivors
10.
Proc Natl Acad Sci U S A ; 118(22)2021 06 01.
Article in English | MEDLINE | ID: covidwho-1232098

ABSTRACT

Comprehensive and accurate comparisons of transcriptomic distributions of cells from samples taken from two different biological states, such as healthy versus diseased individuals, are an emerging challenge in single-cell RNA sequencing (scRNA-seq) analysis. Current methods for detecting differentially abundant (DA) subpopulations between samples rely heavily on initial clustering of all cells in both samples. Often, this clustering step is inadequate since the DA subpopulations may not align with a clear cluster structure, and important differences between the two biological states can be missed. Here, we introduce DA-seq, a targeted approach for identifying DA subpopulations not restricted to clusters. DA-seq is a multiscale method that quantifies a local DA measure for each cell, which is computed from its k nearest neighboring cells across a range of k values. Based on this measure, DA-seq delineates contiguous significant DA subpopulations in the transcriptomic space. We apply DA-seq to several scRNA-seq datasets and highlight its improved ability to detect differences between distinct phenotypes in severe versus mildly ill COVID-19 patients, melanomas subjected to immune checkpoint therapy comparing responders to nonresponders, embryonic development at two time points, and young versus aging brain tissue. DA-seq enabled us to detect differences between these phenotypes. Importantly, we find that DA-seq not only recovers the DA cell types as discovered in the original studies but also reveals additional DA subpopulations that were not described before. Analysis of these subpopulations yields biological insights that would otherwise be undetected using conventional computational approaches.


Subject(s)
Aging/genetics , COVID-19/genetics , Cell Lineage/genetics , Melanoma/genetics , RNA, Small Cytoplasmic/genetics , Skin Neoplasms/genetics , Aging/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/virology , Brain/cytology , Brain/metabolism , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Cell Lineage/immunology , Cytokines/genetics , Cytokines/immunology , Datasets as Topic , Dendritic Cells/immunology , Dendritic Cells/virology , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Melanoma/immunology , Melanoma/pathology , Monocytes/immunology , Monocytes/virology , Phenotype , RNA, Small Cytoplasmic/immunology , SARS-CoV-2/pathogenicity , Severity of Illness Index , Single-Cell Analysis/methods , Skin Neoplasms/immunology , Skin Neoplasms/pathology , T-Lymphocytes/immunology , T-Lymphocytes/virology , Transcriptome
11.
Int J Mol Sci ; 21(18)2020 Sep 05.
Article in English | MEDLINE | ID: covidwho-1215392

ABSTRACT

The transcription factor T cell factor 1 (TCF1), a pioneer transcription factor as well as a downstream effector of WNT/ß-catenin signaling, is indispensable for T cell development in the thymus. Recent studies have highlighted the additional critical role of TCF1 in peripheral T cell responses to acute and chronic infections as well as cancer. Here, we review the regulatory functions of TCF1 in the differentiation of T follicular helper cells, memory T cells and recently described stem-like exhausted T cells, where TCF1 promotes less differentiated stem-like cell states by controlling common gene-regulatory networks. These studies also provide insights into the mechanisms of defective T cell responses in older individuals. We discuss alterations in TCF1 expression and related regulatory networks with age and their consequences for T cell responses to infections and vaccination. The increasing understanding of the pathways regulating TCF1 expression and function in aged T cells holds the promise of enabling the design of therapeutic interventions aiming at improving T cell responses in older individuals.


Subject(s)
Cell Differentiation/physiology , T Cell Transcription Factor 1/metabolism , T-Lymphocytes/metabolism , Aging/genetics , Aging/physiology , Animals , CD8-Positive T-Lymphocytes/immunology , Cellular Senescence/genetics , Cellular Senescence/physiology , Gene Expression Regulation/genetics , Hematopoiesis/physiology , Humans , Lymphocyte Activation/immunology , T Cell Transcription Factor 1/physiology , Transcription Factors/genetics , Transcription Factors/metabolism , Wnt Signaling Pathway/physiology
12.
Dis Model Mech ; 14(1)2021 01 22.
Article in English | MEDLINE | ID: covidwho-1110058

ABSTRACT

Human lifespan is now longer than ever and, as a result, modern society is getting older. Despite that, the detailed mechanisms behind the ageing process and its impact on various tissues and organs remain obscure. In general, changes in DNA, RNA and protein structure throughout life impair their function. Haematopoietic ageing refers to the age-related changes affecting a haematopoietic system. Aged blood cells display different functional aberrations depending on their cell type, which might lead to the development of haematologic disorders, including leukaemias, anaemia or declining immunity. In contrast to traditional bulk assays, which are not suitable to dissect cell-to-cell variation, single-cell-level analysis provides unprecedented insight into the dynamics of age-associated changes in blood. In this Review, we summarise recent studies that dissect haematopoietic ageing at the single-cell level. We discuss what cellular changes occur during haematopoietic ageing at the genomic, transcriptomic, epigenomic and metabolomic level, and provide an overview of the benefits of investigating those changes with single-cell precision. We conclude by considering the potential clinical applications of single-cell techniques in geriatric haematology, focusing on the impact on haematopoietic stem cell transplantation in the elderly and infection studies, including recent COVID-19 research.


Subject(s)
Aging/physiology , Hematopoietic System/physiology , Single-Cell Analysis/methods , Aging/genetics , Animals , Bone Marrow/physiology , DNA Damage , Epigenome , Glycolysis , Hematopoietic Stem Cell Transplantation , Humans , Mutation , Transcriptome
13.
FEBS J ; 288(24): 7123-7142, 2021 12.
Article in English | MEDLINE | ID: covidwho-1085289

ABSTRACT

The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen-specific short-lived effector T cells while in parallel developing long-lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th-10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID-19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age-associated changes occur at the level of the T-cell population as well as the functionality of its cellular constituents. The system highly relies on the self-renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age-related defects and improve immune responses in older adults are increasingly within reach.


Subject(s)
Aging/immunology , COVID-19/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Adaptive Immunity , Aged , Aging/genetics , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Differentiation , Cell Proliferation , Dual Specificity Phosphatase 6/genetics , Dual Specificity Phosphatase 6/immunology , Gene Expression Regulation , Humans , MicroRNAs/genetics , MicroRNAs/immunology , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/immunology , Positive Regulatory Domain I-Binding Factor 1/genetics , Positive Regulatory Domain I-Binding Factor 1/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , T-Lymphocytes, Cytotoxic/virology , T-Lymphocytes, Helper-Inducer/virology , T-Lymphocytes, Regulatory/virology
14.
Aging (Albany NY) ; 13(1): 1-15, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-1068118

ABSTRACT

The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.


Subject(s)
Aging/genetics , COVID-19/genetics , Telomere Shortening , Telomere/genetics , Adult , Age Factors , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/drug therapy , Female , Humans , Male , Middle Aged , Risk Assessment , Risk Factors , Severity of Illness Index
15.
Cell Rep ; 33(3): 108286, 2020 10 20.
Article in English | MEDLINE | ID: covidwho-880155

ABSTRACT

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.


Subject(s)
Aging/genetics , Diffuse Intrinsic Pontine Glioma/genetics , Polycomb Repressive Complex 1/metabolism , Astrocytoma/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Child , Child, Preschool , Chromatin/genetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/metabolism , Epigenomics , Female , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Histones/metabolism , Humans , Lysine/metabolism , Male , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Polycomb Repressive Complex 1/antagonists & inhibitors , Polycomb Repressive Complex 1/genetics
16.
Nat Commun ; 12(1): 4, 2021 01 04.
Article in English | MEDLINE | ID: covidwho-1007630

ABSTRACT

Age is a major risk factor for severe coronavirus disease-2019 (COVID-19). Here, we interrogate the transcriptional features and cellular landscape of the aging human lung. By intersecting these age-associated changes with experimental data on SARS-CoV-2, we identify several factors that may contribute to the heightened severity of COVID-19 in older populations. The aging lung is transcriptionally characterized by increased cell adhesion and stress responses, with reduced mitochondria and cellular replication. Deconvolution analysis reveals that the proportions of alveolar type 2 cells, proliferating basal cells, goblet cells, and proliferating natural killer/T cells decrease with age, whereas alveolar fibroblasts, pericytes, airway smooth muscle cells, endothelial cells and IGSF21+ dendritic cells increase with age. Several age-associated genes directly interact with the SARS-CoV-2 proteome. Age-associated genes are also dysregulated by SARS-CoV-2 infection in vitro and in patients with severe COVID-19. These analyses illuminate avenues for further studies on the relationship between age and COVID-19.


Subject(s)
Aging/genetics , COVID-19/genetics , Lung/physiology , A549 Cells , Adult , Aged , Aging/metabolism , Aging/pathology , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Endothelial Cells/pathology , Female , Fibroblasts/pathology , Gene Expression , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Pericytes/pathology , RNA-Seq , SARS-CoV-2/isolation & purification , Transcriptome , Young Adult
17.
Ageing Res Rev ; 66: 101234, 2021 03.
Article in English | MEDLINE | ID: covidwho-971018

ABSTRACT

Epidemiological data convey severe prognosis and high mortality rate for COVID-19 in elderly men affected by age-related diseases. These subjects develop local and systemic hyper-inflammation, which are associated with thrombotic complications and multi-organ failure. Therefore, understanding SARS-CoV-2 induced hyper-inflammation in elderly men is a pressing need. Here we focus on the role of extracellular DNA, mainly mitochondrial DNA (mtDNA) and telomeric DNA (telDNA) in the modulation of systemic inflammation in these subjects. In particular, extracellular mtDNA is regarded as a powerful trigger of the inflammatory response. On the contrary, extracellular telDNA pool is estimated to be capable of inhibiting a variety of inflammatory pathways. In turn, we underpin that telDNA reservoir is progressively depleted during aging, and that it is scarcer in men than in women. We propose that an increase in extracellular mtDNA, concomitant with the reduction of the anti-inflammatory telDNA reservoir may explain hyper-inflammation in elderly male affected by COVID-19. This scenario is reminiscent of inflamm-aging, the portmanteau word that depicts how aging and aging related diseases are intimately linked to inflammation.


Subject(s)
COVID-19 , Aged , Aging/genetics , DNA, Mitochondrial/genetics , Female , Humans , Inflammation , Male , SARS-CoV-2
18.
FEBS J ; 288(17): 5055-5070, 2021 09.
Article in English | MEDLINE | ID: covidwho-894751

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a large-scale pandemic that is afflicting millions of individuals in over 200 countries. The clinical spectrum caused by SARS-CoV-2 infections can range from asymptomatic infection to mild undifferentiated febrile illness to severe respiratory disease with multiple complications. Elderly patients (aged 60 and above) with comorbidities such as cardiovascular diseases and diabetes mellitus appear to be at highest risk of a severe disease outcome. To protect against pulmonary immunopathology caused by SARS-CoV-2 infection, the host primarily depends on two distinct defense strategies: resistance and disease tolerance. Resistance is the ability of the host to suppress and eliminate incoming viruses. By contrast, disease tolerance refers to host responses that promote host health regardless of their impact on viral replication. Disruption of either resistance or disease tolerance mechanisms or both could underpin predisposition to elevated risk of severe disease during viral infection. Aging can disrupt host resistance and disease tolerance by compromising immune functions, weakening of the unfolded protein response, progressive mitochondrial dysfunction, and altering metabolic processes. A comprehensive understanding of the molecular mechanisms underlying declining host defense in elderly individuals could thus pave the way to provide new opportunities and approaches for the treatment of severe COVID-19.


Subject(s)
Aging/genetics , COVID-19/genetics , Disease Resistance/genetics , SARS-CoV-2/pathogenicity , Aged , COVID-19/pathology , COVID-19/virology , Host-Pathogen Interactions/genetics , Humans , Immune Tolerance/genetics , Pandemics , SARS-CoV-2/genetics , Virus Replication/genetics
19.
Protein Cell ; 11(10): 740-770, 2020 10.
Article in English | MEDLINE | ID: covidwho-709445

ABSTRACT

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Subject(s)
Aging/immunology , Betacoronavirus , Coronavirus Infections/immunology , Immune System/immunology , Pandemics , Pneumonia, Viral/immunology , Single-Cell Analysis , Adult , Aged , Aged, 80 and over , Aging/genetics , CD4-Positive T-Lymphocytes/metabolism , COVID-19 , Cell Lineage , Chromatin Assembly and Disassembly , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokines/biosynthesis , Cytokines/genetics , Disease Susceptibility , Flow Cytometry/methods , Gene Expression Profiling , Gene Expression Regulation, Developmental , Gene Rearrangement , Humans , Immune System/cytology , Immune System/growth & development , Immunocompetence/genetics , Inflammation/genetics , Inflammation/immunology , Mass Spectrometry/methods , Middle Aged , SARS-CoV-2 , Sequence Analysis, RNA , Transcriptome , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL