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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.
Int J Mol Sci ; 22(16)2021 Aug 23.
Article in English | MEDLINE | ID: covidwho-1662696

ABSTRACT

Magnesium (Mg) is a pivotal and very complex component of healthy aging in the cardiovascular-muscle-bone triad. Low Mg levels and low Mg intake are common in the general aging population and are associated with poorer outcomes than higher levels, including vascular calcification, endothelial dysfunction, osteoporosis, or muscle dysfunction/sarcopenia. While Mg supplementation appears to reverse these processes and benefit the triad, more randomized clinical trials are needed. These will allow improvement of preventive and curative strategies and propose guidelines regarding the pharmaceutical forms and the dosages and durations of treatment in order to optimize and adapt Mg prescription for healthy aging and for older vulnerable persons with comorbidities.


Subject(s)
Cardiovascular Diseases/metabolism , Magnesium/metabolism , Osteoporosis/metabolism , Sarcopenia/metabolism , Aging/metabolism , Animals , Bone and Bones/metabolism , Healthy Aging/metabolism , Humans , Muscle Strength/physiology , Muscle, Skeletal/metabolism
3.
Int J Mol Sci ; 23(2)2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1625531

ABSTRACT

The health scourge imposed on humanity by the COVID-19 pandemic seems not to recede. This fact warrants refined and novel ideas analyzing different aspects of the illness. One such aspect is related to the observation that most COVID-19 casualties were older males, a tendency also noticed in the epidemics of SARS-CoV in 2003 and the Middle East respiratory syndrome in 2012. This gender-related difference in the COVID-19 death toll might be directly involved with testosterone (TEST) and its plasmatic concentration in men. TEST has been demonstrated to provide men with anti-inflammatory and immunological advantages. As the plasmatic concentration of this androgen decreases with age, the health benefit it confers also diminishes. Low plasmatic levels of TEST can be determinant in the infection's outcome and might be related to a dysfunctional cell Ca2+ homeostasis. Not only does TEST modulate the activity of diverse proteins that regulate cellular calcium concentrations, but these proteins have also been proven to be necessary for the replication of many viruses. Therefore, we discuss herein how TEST regulates different Ca2+-handling proteins in healthy tissues and propose how low TEST concentrations might facilitate the replication of the SARS-CoV-2 virus through the lack of modulation of the mechanisms that regulate intracellular Ca2+ concentrations.


Subject(s)
COVID-19/metabolism , COVID-19/mortality , Testosterone/metabolism , Age Factors , Aged , Aging/metabolism , Animals , COVID-19/etiology , Calcium Signaling , Humans , Inflammation/metabolism , Male , Morbidity
4.
Sci Rep ; 11(1): 23993, 2021 12 14.
Article in English | MEDLINE | ID: covidwho-1585801

ABSTRACT

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia-reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.


Subject(s)
Aging/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Cardiomyopathies/metabolism , Castration/adverse effects , Serine Endopeptidases/metabolism , Animals , Bronchioles/metabolism , Disease Models, Animal , Female , Gene Expression Regulation , Kidney Tubules/metabolism , Liver/metabolism , Male , Mice , Pulmonary Alveoli/metabolism , Virus Internalization
5.
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
6.
Clin Immunol ; 232: 108857, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433069

ABSTRACT

Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.


Subject(s)
COVID-19/metabolism , COVID-19/pathology , Inflammation Mediators/metabolism , Inflammation/metabolism , Inflammation/pathology , Age Factors , Aged , Aging/metabolism , Aging/pathology , Cytokines/metabolism , Female , Humans , Inflammation/virology , Male , Middle Aged , Risk Factors , SARS-CoV-2/pathogenicity , Severity of Illness Index
7.
Int J Mol Med ; 48(2)2021 Aug.
Article in English | MEDLINE | ID: covidwho-1304768

ABSTRACT

Aging causes skeletal muscle atrophy, and myofiber loss can be a critical component of this process. In 1989, Rosenberg emphasized the importance of the loss of skeletal muscle mass that occurs with aging and coined the term 'sarcopenia'. Since then, sarcopenia has attracted considerable attention due to the aging population in developed countries. The presence of sarcopenia is closely related to staggering, falls and even frailty in the elderly, which in turn leads to the need for nursing care. Sarcopenia is often associated with a poor prognosis in the elderly. Therefore, it is crucial to investigate the causes and pathogenesis of sarcopenia, and to develop and introduce interventional strategies in line with these causes and pathogenesis. Sarcopenia can be a primary component of physical frailty. The association between sarcopenia, frailty and locomotive syndrome is complex; however, sarcopenia is a muscle­specific concept that is relatively easy to approach in research. In the elderly, a lack of exercise, malnutrition and hormonal changes lead to neuromuscular junction insufficiency, impaired capillary blood flow, reduced repair and regeneration capacity due to a decrease in the number of muscle satellite cells, the infiltration of inflammatory cells and oxidative stress, resulting in muscle protein degradation exceeding synthesis. In addition, mitochondrial dysfunction causes metabolic abnormalities, such as insulin resistance, which may lead to quantitative and qualitative abnormalities in skeletal muscle, resulting in sarcopenia. The present review article focuses on age­related primary sarcopenia and outlines its pathogenesis and mechanisms.


Subject(s)
Aging/metabolism , Cytokines/metabolism , Muscle Proteins/metabolism , Muscle, Skeletal/metabolism , Muscular Atrophy/metabolism , Sarcopenia/metabolism , Aged , Aging/physiology , Humans , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Atrophy/physiopathology , Myofibrils/metabolism , Sarcopenia/pathology , Sarcopenia/physiopathology , Satellite Cells, Skeletal Muscle/metabolism
8.
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
9.
Cells ; 10(3)2021 03 15.
Article in English | MEDLINE | ID: covidwho-1136461

ABSTRACT

Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1-7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.


Subject(s)
Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/metabolism , Peptidyl-Dipeptidase A/metabolism , Receptors, Angiotensin/metabolism , Renin-Angiotensin System/drug effects , Aging/metabolism , Aging/pathology , Animals , Autoimmunity/drug effects , Autoimmunity/genetics , COVID-19/drug therapy , COVID-19/genetics , Cardiovascular Diseases/genetics , Cardiovascular Diseases/metabolism , Humans , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Receptors, Angiotensin/genetics , Regeneration/drug effects , Regeneration/genetics , Regeneration/physiology , Renin-Angiotensin System/genetics , Renin-Angiotensin System/physiology , Vulvodynia/immunology , Vulvodynia/physiopathology
10.
JCI Insight ; 6(6)2021 03 22.
Article in English | MEDLINE | ID: covidwho-1088356

ABSTRACT

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.


Subject(s)
Aging/physiology , Influenza A virus , Influenza, Human/pathology , Lung/pathology , Pneumonia, Viral/pathology , SARS-CoV-2 , T-Lymphocytes, Regulatory/pathology , Age Factors , Aging/metabolism , Animals , COVID-19/complications , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Humans , Influenza, Human/complications , Influenza, Human/metabolism , Influenza, Human/virology , Lung/metabolism , Mice, Inbred C57BL , Pneumonia, Viral/etiology , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , T-Lymphocytes, Regulatory/metabolism
12.
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
13.
Front Endocrinol (Lausanne) ; 11: 569633, 2020.
Article in English | MEDLINE | ID: covidwho-948034

ABSTRACT

Covid19 is a worldwide pandemic challenge that started in Wuhan, China and spread to almost all countries on the planet within a few months. The causative virus was found to be highly contagious and, until now, considerably difficult to contain. A look at the epidemiological distribution of the disease over the planet has raised a number of questions whose answers could help us understand the behavior of the virus and consequently leads us to possible means of limitation of its spread or even flattening of the curve of morbidity and mortality. After the third decade of life, there is a progressive decline of growth hormone (GH) secretion by approximately 15% for every decade of adult life. The data from highly affected countries suggest a more aggressive course in the elderly, a double-time affection of males more than females, and the vulnerability of some risk groups of patients. Our observation is that GH deficiency is a common factor in all vulnerable patient groups. We think that there is a need for studying the role of growth hormone in the unique epidemiological pattern of Covid-19 so that it might help in the early detection and management of the high-risk groups as appropriate.


Subject(s)
Aging/pathology , COVID-19/epidemiology , COVID-19/metabolism , Human Growth Hormone/metabolism , SARS-CoV-2/isolation & purification , Aging/metabolism , COVID-19/virology , Humans , Prevalence , Risk Factors
14.
Ageing Res Rev ; 64: 101201, 2020 12.
Article in English | MEDLINE | ID: covidwho-907102

ABSTRACT

The COVID-19 pandemic poses an imminent threat to humanity, especially to the elderly. The molecular mechanisms underpinning the age-dependent disparity for disease progression is not clear. COVID-19 is both a respiratory and a vascular disease in severe patients. The damage endothelial system provides a good explanation for the various complications seen in COVID-19 patients. These observations lead us to suspect that endothelial cells are a barrier that must be breached before progression to severe disease. Endothelial intracellular defences are largely dependent of the activation of the interferon (IFN) system. Nevertheless, low type I and III IFNs are generally observed in COVID-19 patients suggesting that other intracellular viral defence systems are also activated to protect the young. Intriguingly, Nitric oxide (NO), which is the main intracellular antiviral defence, has been shown to inhibit a wide array of viruses, including SARS-CoV-1. Additionally, the increased risk of death with diseases that have underlying endothelial dysfunction suggest that endothelial NOS-derived nitric oxide could be the main defence mechanism. NO decreases dramatically in the elderly, the hyperglycaemic and the patients with low levels of vitamin D. However, eNOS derived NO occurs at low levels, unless it is during inflammation and co-stimulated by bradykinin. Regrettably, the bradykinin-induced vasodilation also progressively declines with age, thereby decreasing anti-viral NO production as well. Intriguingly, the inverse correlation between the percentage of WT eNOS haplotype and death per 100K population could potentially explain the disparity of COVID-19 mortality between Asian and non-Asian countries. These changes with age, low bradykinin and NO, may be the fundamental reasons that intracellular innate immunity declines with age leading to more severe COVID-19 complications.


Subject(s)
Aging/metabolism , COVID-19/metabolism , COVID-19/mortality , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/metabolism , Age Factors , Bradykinin , COVID-19/enzymology , COVID-19/genetics , Endothelial Cells/metabolism , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Haplotypes , Humans , Immunity, Innate , Nitric Oxide Synthase Type III/genetics , SARS-CoV-2/pathogenicity
15.
Int J Mol Sci ; 21(21)2020 Oct 26.
Article in English | MEDLINE | ID: covidwho-895371

ABSTRACT

Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.


Subject(s)
Aging/metabolism , Coronavirus Infections/metabolism , Interleukin-6/metabolism , Neoplasms/metabolism , Pneumonia, Viral/metabolism , Aging/pathology , Animals , COVID-19 , Coronavirus Infections/pathology , Humans , Interleukin-6/genetics , Neoplasms/pathology , Pandemics , Pneumonia, Viral/pathology , Signal Transduction
16.
PLoS One ; 15(10): e0240647, 2020.
Article in English | MEDLINE | ID: covidwho-895060

ABSTRACT

The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 (ACE2). We used a number of bioinformatics tools to computationally characterize ACE2 by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of ACE2 mRNA than any other organ. By immunohistochemistry, duodenum, kidney and testis showed strong signals, whereas the signal was weak in the respiratory tract. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of ACE2-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in the renin-angiotensin system, ACE2 may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the ACE2 gene as well as a new putative short form of ACE2. These include several interferon-stimulated response elements sites for STAT1, IRF8, and IRF9. Our results also confirmed that age and gender play no significant role in the regulation of ACE2 mRNA expression in the lung.


Subject(s)
Betacoronavirus/physiology , Computational Biology , Coronavirus Infections/virology , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/virology , Receptors, Virus/physiology , Aging/metabolism , Angiotensin-Converting Enzyme 2 , Binding Sites , COVID-19 , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Female , Gene Expression Regulation, Enzymologic , Gene Ontology , Humans , Interferons/physiology , Lung/metabolism , Male , Metalloproteases/biosynthesis , Metalloproteases/genetics , Neovascularization, Physiologic/physiology , Organ Specificity , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Promoter Regions, Genetic , RNA, Messenger/biosynthesis , Receptors, Virus/biosynthesis , Receptors, Virus/genetics , Renin-Angiotensin System/physiology , SARS-CoV-2 , Sex Characteristics , Single-Cell Analysis , Transcription Factors/metabolism , Transcription Initiation Site , Virus Attachment
17.
Drug Discov Today ; 25(6): 959-964, 2020 06.
Article in English | MEDLINE | ID: covidwho-828446

ABSTRACT

To celebrate the 25th anniversary of the cloning of the first mammalian p21-activated kinases (PAKs) (RAC/CDC42-activated kinases) by Ed Manser, the first international PAK symposium was held in NYC in October 2019. Among six distinct PAKs in mammals, PAK1 is the major 'pathogenic kinase', the abnormal activation of which is responsible for a wide variety of diseases and disorders including cancers, ageing processes and infectious and inflammatory diseases such as pandemic coronaviral infection. Recently, for a clinical application, a few potent (highly cell-permeable and water-soluble) PAK1 blockers have been developed from natural or synthetic PAK1 blockers (triptolide, vitamin D3 and ketorolac) via a series of 'chemical evolutions' that boost pharmacological activities >500 times.


Subject(s)
p21-Activated Kinases/antagonists & inhibitors , Aging/drug effects , Aging/metabolism , Animals , Enzyme Inhibitors/pharmacology , Evolution, Chemical , Humans , Inflammation/drug therapy , Inflammation/metabolism , Mammals/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism
18.
Cells ; 9(9)2020 08 26.
Article in English | MEDLINE | ID: covidwho-730307

ABSTRACT

Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising of exosomes, apoptotic bodies, and microvesicles. Of the extracellular vesicles, exosomes are the most widely sorted and extensively explored for their contents and function. The size of the nanovesicular structures (exosomes) range from 30 to 140 nm and are present in various biological fluids such as saliva, plasma, urine etc. These cargo-laden extracellular vesicles arise from endosome-derived multivesicular bodies and are known to carry proteins and nucleic acids. Exosomes are involved in multiple physiological and pathological processes, including cellular senescence. Exosomes mediate signaling crosstalk and play a critical role in cell-cell communications. Exosomes have evolved as potential biomarkers for aging-related diseases. Aging, a physiological process, involves a progressive decline of function of organs with a loss of homeostasis and increasing probability of illness and death. The review focuses on the classic view of exosome biogenesis, biology, and age-associated changes. Owing to their ability to transport biological information among cells, the review also discusses the interplay of senescent cell-derived exosomes with the aging process, including the susceptibility of the aging population to COVID-19 infections.


Subject(s)
Aging/metabolism , Cardiovascular Diseases/metabolism , Cell Communication , Cellular Senescence , Coronavirus Infections/metabolism , Diabetes Mellitus/metabolism , Exosomes/metabolism , Extracellular Vesicles/metabolism , Neurodegenerative Diseases/metabolism , Pneumonia, Viral/metabolism , Aged , Aged, 80 and over , Animals , Betacoronavirus , Biomarkers/metabolism , COVID-19 , Coronavirus Infections/virology , Humans , Mice , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
19.
Turk J Med Sci ; 50(6): 1504-1512, 2020 10 22.
Article in English | MEDLINE | ID: covidwho-709719

ABSTRACT

The aim of this review is to summarize current studies on the relationship between melatonin and aging. Nowadays, age-related diseases come into prominence, and identifying age-related changes and developing proper therapeutic approaches are counted as some of the major issues regarding community health. Melatonin is the main hormone of the pineal gland. Melatonin is known to influence many biological processes in the body, including circadian rhythms, the immune system, and neuroendocrine and cardiovascular functions.Melatoninrhythms also reflect the biological process of aging. Aging is an extremely complex and multifactorial process. Melatonin levels decline considerably with aging and its decline is associated with several age-related diseases. Aging is closely associated with oxidative damage and mitochondrial dysfunction. Free radical reactions initiated by the mitochondria constitute the inherent aging process. Melatonin plays a pivotal role in preventing age-related oxidative stress. Coronavirus disease 2019 (COVID-19) fatality rates increase with chronic diseases and age, where melatonin levels decrease. For this reason, melatonin supplementation in elderly could be beneficial in COVID-19 treatment. Therefore, studies on the usage of melatonin in COVID-19 treatment are needed.


Subject(s)
Aging , Antioxidants/therapeutic use , Coronavirus Infections/drug therapy , Melatonin/therapeutic use , Oxidative Stress/drug effects , Pneumonia, Viral/drug therapy , Aged , Aging/metabolism , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Betacoronavirus , COVID-19 , Coronavirus Infections/virology , Dietary Supplements , Humans , Melatonin/metabolism , Melatonin/pharmacology , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2
20.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Article in English | MEDLINE | ID: covidwho-709116

ABSTRACT

As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques ( Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b + and CD8 + cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b + cells, and persistent infiltration of CD8 + cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.


Subject(s)
Aging/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Cytokines/immunology , Macaca mulatta/immunology , Pneumonia, Viral/immunology , T-Lymphocytes/immunology , Age Factors , Aging/metabolism , Animals , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/veterinary , Coronavirus Infections/virology , Cytokines/metabolism , Inflammation/immunology , Inflammation/veterinary , Inflammation/virology , Lung/immunology , Lung/pathology , Lung/virology , Macaca mulatta/virology , Monkey Diseases/immunology , Monkey Diseases/virology , Pandemics/veterinary , Pneumonia, Viral/veterinary , Pneumonia, Viral/virology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/veterinary , Severe Acute Respiratory Syndrome/virology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Viral Load/immunology , Viral Load/veterinary , Virus Replication/immunology
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