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1.
FASEB J ; 36(2): e22124, 2022 02.
Article in English | MEDLINE | ID: mdl-34972249

ABSTRACT

Nerve growth factor-induced gene B (Nur77) has been shown to ameliorate several biological processes in chronic diseases, including inflammatory response, cellular proliferation, and metabolism. Chronic kidney disease (CKD) is characterized by tubulointerstitial fibrosis for which no targeted therapies are available as yet. In this study, we performed in vivo and in vitro experiments to demonstrate that Nur77 targets fibrosis signals and attenuates renal tubulointerstitial fibrosis during the aging process. We observed that the TGF-ß/Smads signal pathway was significantly suppressed by Nur77, suggesting that Nur77 controlled the activation of key steps in TGF-ß/Smads signaling. We further showed that Nur77 interacted with Smad7, the main repressor of nuclear translocation of Smad2/3, and stabilized Smad7 protein homeostasis. Nur77 deficiency resulted in Smad7 degradation, aggravating Smad2/3 phosphorylation, and promoting transcription of its downstream target genes, ACTA2 and collagen I. Our findings demonstrate that Nur77 is a potential therapeutic target for age-related kidney diseases including CKD. Maintenance of Nur77 may be an effective strategy for blocking renal tubulointerstitial fibrosis and improving renal function in the elderly.


Subject(s)
Aging/metabolism , Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism , Renal Insufficiency, Chronic/metabolism , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Aging/genetics , Animals , Fibrosis , Mice , Mice, Knockout , Nuclear Receptor Subfamily 4, Group A, Member 1/genetics , Renal Insufficiency, Chronic/genetics , Smad Proteins/genetics , Transforming Growth Factor beta/genetics
2.
Exp Neurol ; 347: 113913, 2022 01.
Article in English | MEDLINE | ID: mdl-34752785

ABSTRACT

INTRODUCTION: Neural stem cell (NSC) transplantation offers great potential for treating ischemic stroke. Clinically, ischemia followed by reperfusion results in robust cerebrovascular injury that upregulates proinflammatory factors, disrupts neurovascular units, and causes brain cell death. NSCs possess multiple actions that can be exploited for reducing the severity of neurovascular injury. Our previous studies in young adult mice showed that human NSC transplantation during the subacute stage diminishes stroke pathophysiology and improves behavioral outcome. METHODS: We employed a well-established and commonly used stroke model, middle cerebral artery occlusion with subsequent reperfusion (MCAO/R). Here, we assessed the outcomes of hNSC transplantation 48 h post-MCAO (24 h post-transplant) in aged mouse brains in response to stroke because aging is a crucial risk factor for cerebral ischemia. Next, we tested whether administration of the integrin α5ß1 inhibitor, ATN-161, prior to hNSC transplantation further affects stoke outcome as compared with NSCs alone. RNA sequencing (RNA-seq) was used to assess the impact of hNSC transplantation on differentially expressed genes (DEGs) on a transcriptome-wide level. RESULTS: Here, we report that hNSC-engrafted brains with or without ATN-161 showed significantly reduced infarct size, and attenuated the induction of proinflammatory factors and matrix metalloproteases. RNA-seq analysis revealed DEGs and molecular pathways by which hNSCs induce a beneficial post-stroke outcome in aged stroke brains. 811 genes were differentially expressed (651 downregulated and 160 upregulated) in hNSC-engrafted stroke brains. Functional pathway analysis identified enriched and depleted pathways in hNSC-engrafted aged mouse stroke brains. Depletion of pathways following hNSC-engraftment included signaling involving neuroinflammation, acute phase response, leukocyte extravasation, and phagosome formation. On the other hand, enrichment of pathways in hNSC-engrafted brains was associated with PPAR signaling, LXR/RXR activation, and inhibition of matrix metalloproteases. Hierarchical cluster analysis of DEGs in hNSC-engrafted brains indicate decreased expression of genes encoding TNF receptors, proinflammatory factors, apoptosis factors, adhesion and leukocyte extravasation, and Toll-like receptors. CONCLUSIONS: Our study is the first to show global transcripts differentially expressed following hNSC transplantation in the subacute phase of stroke in aged mice. The outcome of our transcriptome study would be useful to develop new therapies ameliorating early-stage stroke injury.


Subject(s)
Aging/genetics , Neural Stem Cells/physiology , Stem Cell Transplantation/methods , Stroke/genetics , Stroke/therapy , Transcriptome/physiology , Aging/drug effects , Aging/metabolism , Animals , Cells, Cultured , Cerebral Infarction/genetics , Cerebral Infarction/metabolism , Cerebral Infarction/therapy , Fetus , Gene Expression Regulation , Humans , Male , Mice , Mice, Inbred C57BL , Neural Stem Cells/drug effects , Neural Stem Cells/transplantation , Oligopeptides/administration & dosage , Stroke/metabolism , Transcriptome/drug effects
4.
Int J Mol Sci ; 22(24)2021 Dec 10.
Article in English | MEDLINE | ID: mdl-34948115

ABSTRACT

Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1GFP/+ mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.


Subject(s)
Aging/metabolism , Choroidal Neovascularization/metabolism , Down-Regulation , Macular Degeneration/metabolism , Myeloid Cells/metabolism , Retina/metabolism , Aging/genetics , Aging/pathology , Animals , Choroidal Neovascularization/genetics , Choroidal Neovascularization/pathology , Gene Expression Profiling , Lasers/adverse effects , Macular Degeneration/genetics , Macular Degeneration/pathology , Mice , Mice, Transgenic , Myeloid Cells/pathology , Retina/pathology
5.
Int J Mol Sci ; 22(19)2021 Sep 29.
Article in English | MEDLINE | ID: mdl-34638891

ABSTRACT

The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans, and cell cultures. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people. An organoid culture is an in vitro 3D cell-culture technology that reproduces the physiological and cellular composition of the tissues and/or organs. This technology is being used in the cancer field to predict the response of a patient-derived tumor to a certain drug or treatment serving as patient stratification and drug-guidance approaches. Modeling aging with patient-derived organoids has a tremendous potential as a preclinical model tool to discover new biomarkers of aging, to predict adverse outcomes during aging, and to design personalized approaches for the prevention and treatment of aging-related diseases and geriatric syndromes. This could represent a novel approach to study chronological and/or biological aging, paving the way to personalized interventions targeting the biology of aging.


Subject(s)
Aging/genetics , Cell Culture Techniques/methods , Epigenomics/methods , Genomic Instability/genetics , Genomics/methods , Organoids/metabolism , Aging/metabolism , Animals , Humans , Models, Genetic , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/pathology , Organoids/cytology
6.
Int J Cardiol ; 345: 98-104, 2021 Dec 15.
Article in English | MEDLINE | ID: mdl-34710491

ABSTRACT

Programmed cell death 5 (PDCD5) is a tumor suppressor gene that regulates the cell cycle, apoptosis and immune responses. However, the physiological function of Pdcd5 in cardiac aging remains unknown. We find that Pdcd5 mRNA and protein levels were significantly increased in the heart of mice with age. Therefore, we hypothesize that Pdcd5 regulates cardiac aging. To test the hypothesis, we generated muscle-specific Pdcd5-deficient mice. Mature adult Pdcd5-deficient mice had normal cardiac morphology and function. In naturally aged mice, Pdcd5 deficiency alleviated age-related cardiac phenotypes including reduced fibrosis and suppressed cardiomyocyte hypertrophy. Moreover, muscle-specific Pdcd5 deficiency attenuated cellular senescence in the heart as demonstrated by decreased number of senescence-associated ß-galactosidase-positive cells, diminished p53, p21 and p16 expression, and reduced the senescence-associated secretory phenotype. Apoptotic cell death was reduced by Pdcd5 deficiency in the heart as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay, which was coincident with diminished Bcl-2-associated X protein, and enhanced B-cell lymphoma 2 and X-linked inhibitor of apoptosis protein expression. Mitochondrial quality in cardiomyocytes was improved by Pdcd5 deficiency through increased Parkin-mediated mitophagy. In addition, Pdcd5 deficiency alleviated doxorubicin-induced premature cellular senescence and cardiac aging. Furthermore, Pdcd5 protein abundance was significantly correlated with p53 protein abundance, and Pdcd5 interacted with p53 in the heart. Taken together, our results reveal that Pdcd5 deficiency attenuates cardiac aging by reducing cellular senescence and apoptosis, and increasing Parkin-mediated mitophagy, likely through p53. Pdcd5 is a novel regulator of cardiac aging and a potential therapeutic target.


Subject(s)
Aging , Cellular Senescence , Aging/genetics , Animals , Apoptosis , Apoptosis Regulatory Proteins/genetics , Mice , Mitophagy , Myocytes, Cardiac , Neoplasm Proteins
7.
Kidney Int ; 100(5): 980-983, 2021 11.
Article in English | MEDLINE | ID: mdl-34688387

ABSTRACT

Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park et al., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question.


Subject(s)
Renal Insufficiency, Chronic , Telomere , Aging/genetics , Humans , Mendelian Randomization Analysis , Renal Insufficiency, Chronic/genetics , Telomere/genetics , Telomere Shortening
8.
Int J Mol Sci ; 22(17)2021 Sep 05.
Article in English | MEDLINE | ID: mdl-34502524

ABSTRACT

Platelets play a critical role in hemostasis and thrombus formation. Platelets are small, anucleate, and short-lived blood cells that are produced by the large, polyploid, and hematopoietic stem cell (HSC)-derived megakaryocytes in bone marrow. Approximately 3000 platelets are released from one megakaryocyte, and thus, it is important to understand the physiologically relevant mechanism of development of mature megakaryocytes. Many genes, including several key transcription factors, have been shown to be crucial for platelet biogenesis. Mutations in these genes can perturb megakaryopoiesis or thrombopoiesis, resulting in thrombocytopenia. Metabolic changes owing to inflammation, ageing, or diseases such as cancer, in which platelets play crucial roles in disease development, can also affect platelet biogenesis. In this review, I describe the characteristics of platelets and megakaryocytes in terms of their differentiation processes. The role of several critical transcription factors have been discussed to better understand the changes in platelet biogenesis that occur during disease or ageing.


Subject(s)
Aging/metabolism , Blood Platelets/metabolism , Hematopoietic Stem Cells/metabolism , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Thrombocytopenia/metabolism , Thrombopoiesis , Transcription Factors/metabolism , Aging/genetics , Aging/pathology , Animals , Blood Platelets/pathology , Cell Differentiation , Hematopoietic Stem Cells/pathology , Humans , Megakaryocytes/metabolism , Megakaryocytes/pathology , Mutation , Neoplasm Proteins/genetics , Neoplasms/genetics , Neoplasms/pathology , Thrombocytopenia/genetics , Thrombocytopenia/pathology , Transcription Factors/genetics
9.
Ageing Res Rev ; 71: 101458, 2021 11.
Article in English | MEDLINE | ID: mdl-34500043

ABSTRACT

Cellular senescence is a stress response, which can be evoked in all type of somatic cells by different stimuli. Senescent cells accumulate in the body and participate in aging and aging-related diseases mainly by their secretory activity, commonly known as senescence-associated secretory phenotype-SASP. Senescence is typically described as cell cycle arrest. This definition stems from the original observation concerning limited cell division potential of human fibroblasts in vitro. At present, the process of cell senescence is attributed also to cancer cells and to non-proliferating post-mitotic cells. Many cellular signaling pathways and specific and unspecific markers contribute to the complex, dynamic and heterogeneous phenotype of senescent cells. Considering the diversity of cells that can undergo senescence upon different inducers and variety of mechanisms involved in the execution of this process, we ask if there is a common signature of cell senescence. It seems that cell cycle arrest in G0, G1 or G2 is indispensable for cell senescence; however, to ensure irreversibility of divisions, the exit from the cell cycle to the state, which we call a GS (Gero Stage), is necessary. The DNA damage, changes in nuclear architecture and chromatin rearrangement are involved in signaling pathways leading to altered gene transcription and secretion of SASP components. Thus, nuclear changes and SASP are vital features of cell senescence that, together with temporal arrest in the cell cycle (G1 or/and G2), which may be followed by polyploidisation/depolyploidisation or exit from the cell cycle leading to permanent proliferation arrest (GS), define the signature of cellular senescence.


Subject(s)
Aging , Cellular Senescence , Aging/genetics , DNA Damage , Fibroblasts , Humans , Signal Transduction
10.
Blood Adv ; 5(20): 4285-4290, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34496012

ABSTRACT

During aging, hematopoietic stem cell (HSC) function wanes with important biological and clinical implications for benign and malignant hematology, and other comorbidities, such as cardiovascular disease. However, the molecular mechanisms regulating HSC aging remain incompletely defined. GATA2 haploinsufficiency driven clinical syndromes initially result in primary immunodeficiencies and routinely evolve into hematologic malignancies on acquisition of further epigenetic mutations in both young and older patients. Using a conditional mouse model of Gata2 haploinsufficiency, we discover that during aging Gata2 promotes HSC proliferation, monocytosis, and loss of the common lymphoid progenitor. Aging of Gata2 haploinsufficient mice also offsets enhanced HSC apoptosis and decreased granulocyte-macrophage progenitor number normally observed in young Gata2 haploinsufficient mice. Transplantation of elderly Gata2 haploinsufficient HSCs impairs HSC function with evidence of myeloid bias. Our data demonstrate that Gata2 regulates HSC aging and suggest the mechanisms by which Gata2 mediated HSC aging has an impact on the evolution of malignancies in GATA2 haploinsufficiency syndromes.


Subject(s)
GATA2 Deficiency , Aged , Aging/genetics , Animals , Cell Proliferation , GATA2 Transcription Factor/genetics , Hematopoiesis , Hematopoietic Stem Cells , Humans , Mice
11.
FASEB J ; 35(10): e21943, 2021 10.
Article in English | MEDLINE | ID: mdl-34582065

ABSTRACT

Neural cells are continuously subjected to oxidative stress arising from electrochemical activity, and cellular protection systems can turn on the oxidative stress response to detect and alleviate adverse conditions. However, the function and mechanism of the protective systems are complicated and remain largely elusive. We report that PTENα, an isoform of the PTEN family, mediates defense signaling in response to oxidative stress during brain aging. We show that genetic ablation of Ptenα in mice increases oxidative stress and results in neuronal cell death, culminating in accelerated decline of cognition and motor coordination as age increases. PTENα maintains COX activity and promotes energy metabolism through abrogating NEDD4L-mediated degradation of COX4 in response to oxidative stress. In the presence of Parkinson's disease-associated mutation, PTENα loses the capability to protect COX4 and ameliorate defects caused by Ptenα deletion. Our study reveals an important role of PTENα in response to oxidative stress. We propose that dysregulation of PTENα signaling may accelerate the rate of brain aging and promote the development of neurodegenerative disorders.


Subject(s)
Aging/metabolism , Brain/metabolism , Oxidative Stress , PTEN Phosphohydrolase/metabolism , Aging/genetics , Animals , Brain/cytology , Cell Line , Electron Transport Complex IV/metabolism , Humans , Male , Mice , Nedd4 Ubiquitin Protein Ligases/metabolism , Neurons/metabolism , PTEN Phosphohydrolase/chemistry , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics
12.
Int J Mol Sci ; 22(18)2021 Sep 10.
Article in English | MEDLINE | ID: mdl-34575986

ABSTRACT

Amino acids, as nutrients, are expected to improve sleep disorders. This study aimed to evaluate the generation- and age-dependent sleep-improving effects of γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP) coadministration. The differentially expressed genes and generation-related behavior after the administration of a GABA/5-HTP mixture were measured in a Drosophila model, while age-related changes in gene expression and oxidative stress-related parameters were measured in a mouse model. The GABA/5-HTP-treated group showed significant behavioral changes compared to the other groups. Sequencing revealed that the GABA/5-HTP mixture influenced changes in nervous system-related genes, including those involved in the regulation of the expression of behavioral and synaptic genes. Additionally, total sleep time increased with age, and nighttime sleep time in the first- and third-generation flies was significantly different from that of the control groups. The GABA/5-HTP mixture induced significant changes in the expression of sleep-related receptors in both models. Furthermore, the GABA/5-HTP mixture reduced levels of ROS and ROS reaction products in an age-dependent manner. Therefore, the increase in behavioral changes caused by GABA/5-HTP mixture administration was effective in eliminating ROS activity across generations and ages.


Subject(s)
5-Hydroxytryptophan/pharmacology , Amino Acids/pharmacology , Locomotion/drug effects , Sleep Wake Disorders/drug therapy , gamma-Aminobutyric Acid/pharmacology , Aging/drug effects , Aging/genetics , Aging/pathology , Animals , Central Nervous System/drug effects , Central Nervous System/metabolism , Central Nervous System/pathology , Disease Models, Animal , Gene Expression Regulation/drug effects , Humans , Locomotion/physiology , Mice , Nutrients/pharmacology , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Sleep Wake Disorders/metabolism , Sleep Wake Disorders/pathology
13.
Int J Mol Sci ; 22(18)2021 Sep 13.
Article in English | MEDLINE | ID: mdl-34576030

ABSTRACT

Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere-CHIP-atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.


Subject(s)
Atherosclerosis/genetics , Cardiovascular Diseases/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA-Binding Proteins/genetics , Dioxygenases/genetics , Repressor Proteins/genetics , Aging/genetics , Aging/pathology , Atherosclerosis/pathology , Cardiovascular Diseases/pathology , Clonal Evolution/genetics , Clonal Hematopoiesis/genetics , Humans , Mutation/genetics , Telomere/genetics
14.
Int J Mol Sci ; 22(18)2021 Sep 13.
Article in English | MEDLINE | ID: mdl-34576052

ABSTRACT

Recently, network controllability studies have proposed several frameworks for the control of large complex biological networks using a small number of life molecules. However, age-related changes in the brain have not been investigated from a controllability perspective. In this study, we compiled the gene expression profiles of four normal brain regions from individuals aged 20-99 years and generated dynamic probabilistic protein networks across their lifespan. We developed a new algorithm that efficiently identified critical proteins in probabilistic complex networks, in the context of a minimum dominating set controllability model. The results showed that the identified critical proteins were significantly enriched with well-known ageing genes collected from the GenAge database. In particular, the enrichment observed in replicative and premature senescence biological processes with critical proteins for male samples in the hippocampal region led to the identification of possible new ageing gene candidates.


Subject(s)
Aging/genetics , Brain/metabolism , Protein Interaction Maps/genetics , Adult , Aged , Aged, 80 and over , Aging/pathology , Algorithms , Brain/pathology , Computational Biology , Databases, Genetic , Female , Gene Expression Regulation/genetics , Gene Regulatory Networks/genetics , Hippocampus/metabolism , Hippocampus/pathology , Humans , Male , Middle Aged , Transcriptome/genetics
15.
Redox Biol ; 47: 102128, 2021 11.
Article in English | MEDLINE | ID: mdl-34562874

ABSTRACT

Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6-/-) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6-/- old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.


Subject(s)
Endoribonucleases , MicroRNAs , Aging/genetics , Animals , Apoptosis Regulatory Proteins , Endoplasmic Reticulum Stress , Endoribonucleases/genetics , Endoribonucleases/metabolism , Humans , Membrane Proteins/genetics , Mice , Oxidation-Reduction , Protein Processing, Post-Translational , /metabolism
16.
BMC Genomics ; 22(1): 696, 2021 Sep 26.
Article in English | MEDLINE | ID: mdl-34565328

ABSTRACT

BACKGROUND: Aging and inflammation are important components of Parkinson's disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers. RESULTS: We estimated epigenetic mitotic age using the "epiTOC" epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p = 2.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR = 2.11, 95 % CI = 1.56, 2.86, p = 1.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R = 0.27, p = 6.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline. CONCLUSIONS: The current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.


Subject(s)
Aging , Parkinson Disease , Aging/genetics , Blood Cells , Cell Lineage/genetics , DNA Methylation , Epigenesis, Genetic , Humans , Parkinson Disease/genetics
17.
J Health Soc Behav ; 62(3): 436-453, 2021 09.
Article in English | MEDLINE | ID: mdl-34528488

ABSTRACT

Research on biological embedding of the social environment has been expedited by increased availability of biomarkers. Recently, this arsenal of measures has been expanded to include epigenetic clocks that indicate in years the extent to which an individual is older or younger than their chronological age. These measures of biological aging, especially GrimAge, are robust predictors of both illness and time to death. Importantly for sociologists, several studies have linked social conditions to these indices of aging. The present study extends this research using longitudinal data from a sample of 223 black women participating in the Family and Community Health Study. We find that changes in income and living arrangements over an 11-year period predict changes in speed of biological aging. These results provide further support for the idea that epigenetic aging is a mechanism whereby social conditions become biologically embedded. The utility of epigenetic clocks for sociological studies of health are discussed.


Subject(s)
DNA Methylation , Social Conditions , Aging/genetics , Epigenesis, Genetic , Epigenomics , Female , Humans
18.
Int J Mol Sci ; 22(17)2021 Aug 27.
Article in English | MEDLINE | ID: mdl-34502212

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
19.
Rejuvenation Res ; 24(5): 377-389, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34486398

ABSTRACT

In our recent transcriptomic meta-analysis, we used random forest machine learning to accurately predict age in human blood, bone, brain, heart, and retina tissues given gene inputs. Although each tissue-specific model utilized a unique number of genes for age prediction, we found that the following six genes were prioritized in all five tissues: CHI3L2, CIDEC, FCGR3A, RPS4Y1, SLC11A1, and VTCN1. Since being selected for age prediction in multiple tissues is unique, we decided to explore these pan-tissue clock genes in greater detail. In the present study, we began by performing over-representation and network topology-based enrichment analyses in the Gene Ontology Biological Process database. These analyses revealed that the immunological terms "response to protozoan," "immune response," and "positive regulation of immune system process" were significantly enriched by these clock inputs. Expression analyses in mouse and human tissues identified that these inputs are frequently upregulated or downregulated with age. A detailed literature search showed that all six genes had noteworthy connections to age-related disease. For example, mice deficient in Cidec are protected against various metabolic defects, while suppressing VTCN1 inhibits age-related cancers in mouse models. Using a large multitissue transcriptomic dataset, we additionally generate a novel, minimalistic aging clock that can predict human age using just these six genes as inputs. Taken all together, these six genes are connected to diverse aspects of aging.


Subject(s)
Aging , Machine Learning , Aging/genetics , Animals , Gene Expression Profiling , Gene Ontology , Immune System , Mice
20.
Elife ; 102021 09 01.
Article in English | MEDLINE | ID: mdl-34467851

ABSTRACT

Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a 'hallmark' of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome and surprisingly observe a lack of enrichment across 24 age-related traits. Within nine other organelles, we find no enrichment with one exception: the nucleus, where enrichment emanates from nuclear transcription factors. In agreement, we find that genes encoding several organelles tend to be 'haplosufficient,' while we observe strong purifying selection against heterozygous protein-truncating variants impacting the nucleus. Our work identifies common variation near transcription factors as having outsize influence on age-related trait risk, motivating future efforts to determine if and how this inherited variation then contributes to observed age-related organelle deterioration.


Subject(s)
Aging/genetics , Genetic Variation , Organelles/metabolism , Quantitative Trait, Heritable , DNA, Mitochondrial/genetics , Humans , Oxidative Phosphorylation
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