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1.
Theranostics ; 12(6): 2722-2740, 2022.
Article in English | MEDLINE | ID: covidwho-1780236

ABSTRACT

Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.


Subject(s)
Metformin , Aging/pathology , Cellular Senescence , Genomic Instability , Humans , Metformin/pharmacology , Metformin/therapeutic use , Telomere
2.
PLoS One ; 17(2): e0263791, 2022.
Article in English | MEDLINE | ID: covidwho-1700510

ABSTRACT

OBJECTIVES: This study examined the association between dog and cat ownership, the onset of disability and all-cause mortality in an older population. Dog and cat owners take more regular exercise and have closer social relationships than non-owners. We further assess the beneficial effects of these moderating variables on the onset of disability and mortality. METHODS: Dog and cat ownership data were collected from 11233 community-dwelling adults age 65 years and older. These data were matched with data about the onset of disability held by the Japanese long-term care insurance system. Local registry data were used to ascertain all-cause mortality. RESULTS: During the approximately 3.5 year follow-up period, 17.1% of the sample suffered onset of disability, and 5.2% died. Logistic regression analysis indicated that, compared with a reference group of those who had never owned a dog (odds ratio fixed at 1.0), older adults who were currently dog owners had a significantly lower odds ratio of onset of disability (OR = 0.54 95% CI: 0.37-0.79). Our results further show that regular exercise interacts with dog ownership to reduce the risk of disability. The association of dog and/or cat ownership with all-cause mortality was not statistically significant. CONCLUSIONS: Dog ownership appears to protect against incident disability among older Japanese adults. Additional benefits are gained from ownership combined with regular exercise. Daily dog care may have an important role to play in health promotion and successful aging.


Subject(s)
Aging/psychology , Independent Living/statistics & numerical data , Ownership/statistics & numerical data , Pets , Aged , Aged, 80 and over , Aging/pathology , Animals , Disabled Persons/statistics & numerical data , Dogs , Female , Humans , Japan , Male
3.
Cells ; 10(12)2021 11 30.
Article in English | MEDLINE | ID: covidwho-1613627

ABSTRACT

The COVID-19 pandemic drastically highlighted the vulnerability of the elderly population towards viral and other infectious threats, illustrating that aging is accompanied by dysregulated immune responses currently summarized in terms like inflammaging and immunoparalysis. To gain a better understanding on the underlying mechanisms of the age-associated risk of adverse outcome in individuals experiencing a SARS-CoV-2 infection, we analyzed the impact of age on circulating monocyte phenotypes, activation markers and inflammatory cytokines including interleukin 6 (IL-6), IL-8 and tumor necrosis factor (TNF) in the context of COVID-19 disease progression and outcome in 110 patients. Our data indicate no age-associated differences in peripheral monocyte counts or subset composition. However, age and outcome are associated with differences in monocyte activation status. Moreover, a distinct cytokine pattern of IL-6, IL-8 and TNF in elderly survivors versus non-survivors, which consolidates over the time of hospitalization, suggests that older patients with adverse outcomes experience an inappropriate immune response, reminiscent of an inflammaging driven immunoparalysis. Our study underscores the value, necessity and importance of longitudinal monitoring in elderly COVID-19 patients, as dynamic changes after symptom onset can be observed, which allow for a differentiated insight into confounding factors that impact the complex pathogenesis following an infection with SARS-CoV-2.


Subject(s)
Aging/pathology , COVID-19/blood , COVID-19/pathology , Cytokines/blood , Monocytes/pathology , Acute Disease , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers/metabolism , Humans , Longitudinal Studies , Middle Aged , Neutrophils/metabolism , Prospective Studies , SARS-CoV-2 , Young Adult
4.
Cells ; 10(12)2021 11 30.
Article in English | MEDLINE | ID: covidwho-1542429

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic associated with substantial morbidity and mortality worldwide, with particular risk for severe disease and mortality in the elderly population. SARS-CoV-2 infection is driven by a pathological hyperinflammatory response which results in a dysregulated immune response. Current advancements in aging research indicates that aging pathways have fundamental roles in dictating healthspan in addition to lifespan. Our review discusses the aging immune system and highlights that senescence and aging together, play a central role in COVID-19 pathogenesis. In our review, we primarily focus on the immune system response to SARS-CoV-2 infection, the interconnection between severe COVID-19, immunosenescence, aging, vaccination, and the emerging problem of Long-COVID. We hope to highlight the importance of identifying specific senescent endotypes (or "sendotypes"), which can used as determinants of COVID-19 severity and mortality. Indeed, identified sendotypes could be therapeutically exploited for therapeutic intervention. We highlight that senolytics, which eliminate senescent cells, can target aging-associated pathways and therefore are proving attractive as potential therapeutic options to alleviate symptoms, prevent severe infection, and reduce mortality burden in COVID-19 and thus ultimately enhance healthspan.


Subject(s)
Aging/pathology , COVID-19/pathology , SARS-CoV-2/physiology , Animals , Biomarkers/metabolism , Cellular Senescence , Humans
5.
Cells ; 10(11)2021 11 12.
Article in English | MEDLINE | ID: covidwho-1526806

ABSTRACT

Aging affects all tissues and organs. Aging of the immune system results in the severe disruption of its functions, leading to an increased susceptibility to infections, an increase in autoimmune disorders and cancer incidence, and a decreased response to vaccines. Lymph nodes are precisely organized structures of the peripheral lymphoid organs and are the key sites coordinating innate and long-term adaptive immune responses to external antigens and vaccines. They are also involved in immune tolerance. The aging of lymph nodes results in decreased cell transport to and within the nodes, a disturbance in the structure and organization of nodal zones, incorrect location of individual immune cell types and impaired intercellular interactions, as well as changes in the production of adequate amounts of chemokines and cytokines necessary for immune cell proliferation, survival and function, impaired naïve T- and B-cell homeostasis, and a diminished long-term humoral response. Understanding the causes of these stromal and lymphoid microenvironment changes in the lymph nodes that cause the aging-related dysfunction of the immune system can help to improve long-term immune responses and the effectiveness of vaccines in the elderly.


Subject(s)
Aging/pathology , Immunosenescence , Lymph Nodes/pathology , Lymph Nodes/physiopathology , Animals , Cellular Microenvironment , Humans , Models, Biological , Neutrophils/pathology
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.
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
8.
Sci Rep ; 11(1): 17968, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1402115

ABSTRACT

The impact of overlapping risk factors on coronavirus disease (COVID-19) severity is unclear. To evaluate the impact of type 2 diabetes (T2D) and obesity on COVID-19 severity, we conducted a cohort study with 28,095 anonymized COVID-19 patients using data from the COVID-19 Research Database from January 1, 2020 to November 30, 2020. The mean age was 50.8 ± 17.5 years, and 11,802 (42%) patients were male. Data on age, race, sex, T2D complications, antidiabetic medication prescription, and body mass index ≥ 30 kg/m2 (obesity) were analysed using Cox proportional hazard models, with hospitalization risk and critical care within 30 days of COVID-19 diagnosis as the main outcomes. The risk scores were 0-4 for age ≥ 65 years, male sex, T2D, and obesity. Among the participants, 11,294 (61.9%) had obesity, and 4445 (15.8%) had T2D. T2D, obesity, and male sex were significantly associated with COVID-19 hospitalization risk. Regarding hospitalization risk scores, compared with those for hospitalization risk score 0 and critical care risk score 0, hazard ratios [95% confidence intervals] were 19.034 [10.470-34.600] and 55.803 [12.761-244.015] (P < 0.001) (P < 0.001), respectively, for risk score 4. Complications from diabetes and obesity increased hospitalization and critical care risks for COVID-19 patients.


Subject(s)
COVID-19/pathology , Critical Care/statistics & numerical data , Diabetes Mellitus, Type 2/pathology , Obesity/pathology , Severity of Illness Index , Aged , Aging/pathology , COVID-19/drug therapy , Diabetes Complications/pathology , Female , Hospitalization/statistics & numerical data , Humans , Hypoglycemic Agents/therapeutic use , Intensive Care Units/statistics & numerical data , Male , Metformin/therapeutic use , Middle Aged , Risk Factors , SARS-CoV-2 , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , United States
9.
Cell ; 184(19): 4953-4968.e16, 2021 09 16.
Article in English | MEDLINE | ID: covidwho-1363913

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.


Subject(s)
COVID-19/pathology , Interferons/metabolism , Respiratory System/virology , Severity of Illness Index , Age Factors , Aging/pathology , COVID-19/genetics , COVID-19/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression Regulation , Humans , Interferons/genetics , Leukocytes/pathology , Leukocytes/virology , Lung/pathology , Lung/virology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Viral Load
10.
Cytokine ; 148: 155628, 2021 12.
Article in English | MEDLINE | ID: covidwho-1347569

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a potentially life-threatening disease, defined as Coronavirus Disease 19 (COVID-19). The most common signs and symptoms of this pathological condition include cough, fever, shortness of breath, and sudden onset of anosmia, ageusia, or dysgeusia. The course of COVID-19 is mild or moderate in more than 80% of cases, but it is severe or critical in about 14% and 5% of infected subjects respectively, with a significant risk of mortality. SARS-CoV-2 related infection is characterized by some pathogenetic events, resembling those detectable in other pathological conditions, such as sepsis and severe acute pancreatitis. All these syndromes are characterized by some similar features, including the coexistence of an exuberant inflammatory- as well as an anti-inflammatory-response with immune depression. Based on current knowledge concerning the onset and the development of acute pancreatitis and sepsis, we have considered these syndromes as a very interesting paradigm for improving our understanding of pathogenetic events detectable in patients with COVID-19. The aim of our review is: 1)to examine the pathogenetic mechanisms acting during the emergence of inflammatory and anti-inflammatory processes in human pathology; 2)to examine inflammatory and anti-inflammatory events in sepsis, acute pancreatitis, and SARS-CoV-2 infection and clinical manifestations detectable in patients suffering from these syndromes also according to the age and gender of these individuals; as well as to analyze the possible common and different features among these pathological conditions; 3)to obtain insights into our knowledge concerning COVID-19 pathogenesis. This approach may improve the management of patients suffering from this disease and it may suggest more effective diagnostic approaches and schedules of therapy, depending on the different phases and/or on the severity of SARS-CoV-2 infection.


Subject(s)
Aging/pathology , COVID-19/pathology , Pancreatitis/pathology , Sepsis/pathology , Sex Characteristics , COVID-19/immunology , COVID-19/virology , Female , Humans , Male , SARS-CoV-2
11.
J Clin Invest ; 131(4)2021 02 15.
Article in English | MEDLINE | ID: covidwho-1172781

ABSTRACT

Alveolar macrophages orchestrate the response to viral infections. Age-related changes in these cells may underlie the differential severity of pneumonia in older patients. We performed an integrated analysis of single-cell RNA-Seq data that revealed homogenous age-related changes in the alveolar macrophage transcriptome in humans and mice. Using genetic lineage tracing with sequential injury, heterochronic adoptive transfer, and parabiosis, we found that the lung microenvironment drove an age-related resistance of alveolar macrophages to proliferation that persisted during influenza A viral infection. Ligand-receptor pair analysis localized these changes to the extracellular matrix, where hyaluronan was increased in aged animals and altered the proliferative response of bone marrow-derived macrophages to granulocyte macrophage colony-stimulating factor (GM-CSF). Our findings suggest that strategies targeting the aging lung microenvironment will be necessary to restore alveolar macrophage function in aging.


Subject(s)
Aging/immunology , Cellular Microenvironment/immunology , Lung/immunology , Macrophages, Alveolar/immunology , Aging/pathology , Animals , Humans , Lung/pathology , Macrophages, Alveolar/pathology , Mice , Mice, Transgenic , RNA-Seq
12.
Cell ; 184(8): 1990-2019, 2021 04 15.
Article in English | MEDLINE | ID: covidwho-1163481

ABSTRACT

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.


Subject(s)
Aging , Cellular Senescence , Lung Diseases , Lung , Adaptive Immunity , Aged , Aging/immunology , Aging/pathology , COVID-19/immunology , COVID-19/pathology , Humans , Lung/immunology , Lung/pathology , Lung Diseases/immunology , Lung Diseases/pathology , Oxidative Stress
13.
Cells ; 10(3)2021 03 12.
Article in English | MEDLINE | ID: covidwho-1167427

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.


Subject(s)
COVID-19/immunology , Cellular Senescence/immunology , T-Lymphocytes/immunology , Thymus Gland/immunology , Aged , Aged, 80 and over , Aging/immunology , Aging/pathology , Autoimmunity , COVID-19/drug therapy , COVID-19/physiopathology , Humans , Inflammation/immunology , Inflammation/pathology , SARS-CoV-2/immunology , Thymus Gland/drug effects , Thymus Gland/physiopathology , Thymus Gland/virology
14.
PLoS Pathog ; 17(3): e1009420, 2021 03.
Article in English | MEDLINE | ID: covidwho-1154087

ABSTRACT

To simultaneously determine clinical and immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old females and males, 681 coronavirus disease 2019 (COVID-19) patients and 369 normal controls (NCs) were analyzed based on age and sex classifications using multiple linear regression analysis. Compared to the age-matched NCs, both young and old male and female non-comorbid COVID-19 patients had lower lymphocyte counts and alanine aminotransferase (ALT) concentration, and only young male and female patients had lower neutrophil counts. Compared to young patients, both old males and females had significantly higher plasma ALT and AST concentrations. Compared to young and old females, age-matched males had higher plasma ALT and AST concentrations, but only young males had higher C-reactive protein (CRP) concentration. Compared to females, old males, but not young males, showed higher incidence of critical illness. Compared to young patients, old females had more leukocyte and neutrophil counts above the normal upper limit and B cell count below the normal lower limit (NLL), while old males had more lymphocyte and natural killer (NK) cell counts below the NLL. No sex or age associations with B cell and NK cell counts were observed. However, there were age-dependent decreases in CD8+ T-cell counts in both male and female COVID-19 patients. Age was negatively associated with CD8+ T cell counts but positively associated with neutrophil count, CRP, ALT, and AST concentrations, and sex (females) was negatively associated with neutrophil count, CRP, ALT, and AST concentrations. The present study suggests that SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences relating to negative associations with CD8+ T cell count and positive associations with inflammatory responses and liver damage. Thus, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19.


Subject(s)
Aging/immunology , COVID-19/immunology , Lymphocytes/immunology , SARS-CoV-2/immunology , Sex Characteristics , Adolescent , Adult , Age Factors , Aged , Aging/pathology , COVID-19/pathology , Female , Humans , Lymphocyte Count , Lymphocytes/pathology , Male , Middle Aged , Sex Factors
15.
J R Soc Interface ; 18(176): 20200982, 2021 03.
Article in English | MEDLINE | ID: covidwho-1138038

ABSTRACT

Here, we report that COVID-19 hospitalization rates follow an exponential relationship with age, doubling for every 16 years of age or equivalently increasing by 4.5% per year of life (R2 = 0.98). This mirrors the well-studied exponential decline of both thymus volume and T-cell production, which halve every 16 years. COVID-19 can therefore be added to the list of other diseases with this property, including those caused by methicillin-resistant Staphylococcus aureus, MERS-CoV, West Nile virus, Streptococcus pneumoniae and certain cancers, such as chronic myeloid leukaemia and brain cancers. In addition, the incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. Since these properties are shared with some non-contagious diseases, we hypothesized that the age dependence does not come from social-mixing patterns, i.e. that the probability of hospitalization given infection rises exponentially, doubling every 16 years. A Bayesian analysis of daily hospitalizations, incorporating contact matrices, found that this relationship holds for every age group except for the under 20s. While older adults have fewer contacts than young adults, our analysis suggests that there is an approximate cancellation between the effects of fewer contacts for the elderly and higher infectiousness due to a higher probability of developing severe disease. Our model fitting suggests under 20s have 49-75% additional immune protection beyond that predicted by strong thymus function alone, consistent with increased juvenile cross-immunity from other viruses. We found no evidence for differences between age groups in susceptibility to infection or infectiousness to others (given disease state), i.e. the only important factor in the age dependence of hospitalization rates is the probability of hospitalization given infection. These findings suggest the existence of a T-cell exhaustion threshold, proportional to thymic output and that clonal expansion of peripheral T-cells does not affect disease risk. The strikingly simple inverse relationship between risk and thymic T-cell output adds to the evidence that thymic involution is an important factor in the decline of the immune system with age and may also be an important clue in understanding disease progression, not just for COVID-19 but other diseases as well.


Subject(s)
Aging/immunology , COVID-19/pathology , Hospitalization/statistics & numerical data , SARS-CoV-2 , T-Lymphocytes/physiology , Thymus Gland/cytology , Adolescent , Adult , Aged , Aged, 80 and over , Aging/pathology , Bayes Theorem , Child , Female , Humans , Male , Middle Aged , Risk Factors , Young Adult
16.
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
17.
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
18.
Lab Invest ; 101(3): 274-279, 2021 03.
Article in English | MEDLINE | ID: covidwho-968368

ABSTRACT

Disorders involving injury to tissue stem cells that ensure normal tissue homeostasis and repair have potential to show unusually devastating clinical consequences. Acute graft-versus-host disease (aGVHD) is one condition where relatively few cytotoxic immune cells target skin stem cells to produce significant morbidity and mortality. By analogy, SARS-CoV-2 is a vector that initially homes to pulmonary stem cells that preferentially express the ACE2 receptor, thus potentially incurring similarly robust pathological consequences. In older individuals, stem cell number and/or function become depleted due to pathways independent of disease-related injury to these subpopulations. Accordingly, pathologic targeting of stem cells in conditions like aGVHD and COVID-19 infection where these cells are already deficient due to the aging process may have dire consequences in elderly individuals. A hypothesis is herein advanced that, as with aGVHD, lung stem cell targeting is a potential co-factor in explaining age-related severity of COVID-19 infection.


Subject(s)
COVID-19/etiology , Graft vs Host Disease/etiology , SARS-CoV-2 , Age Factors , Aging/immunology , Aging/pathology , COVID-19/immunology , COVID-19/pathology , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Humans , Lung/immunology , Lung/pathology , Models, Biological , Risk Factors , SARS-CoV-2/pathogenicity , Skin/immunology , Skin/pathology , Stem Cells/immunology , Stem Cells/pathology
19.
Front Endocrinol (Lausanne) ; 11: 557333, 2020.
Article in English | MEDLINE | ID: covidwho-952965

ABSTRACT

Problems: An outbreak of novel coronavirus (2019-nCov) infection is now widespread in multiple countries. Compared with adult patients, elderly patients have not received enough attention. The aim of the meta-analysis was to assess the clinical characteristics of elder patients with COVID-19. Methods: A deep literature search was performed in the databases through August 21, 2020. Risk ratio (OR) and 95% confidence intervals (CIs) were pooled using analysis models. Results: Three studies including 2046 infected patients were precisely evaluated, and the results show that the elderly group has a higher risk of hypertension, diabetes, and cardiovascular disease than the younger patients. Their total white blood cells are higher than that of the younger patients, and their lymphocytes are relatively reduced compared with the younger patients. Conclusion: We comprehensively assessed the clinical characteristics of patients of different ages with COVID-19 and found that elder patients had a high risk of chronic cardiovascular and metabolism comorbidities. The characteristic clinical manifestations and laboratory examinations of elderly patients support their excessive inflammation and weak immune defenses against 2019-nCoV. All these findings provide important information for understanding the general clinical characterization of the aging immune defense against the virus and enhancing the public awareness of the prevention and treatment of elder patients in the COVID-19 pandemic.


Subject(s)
Aging/pathology , COVID-19/epidemiology , SARS-CoV-2/isolation & purification , Aged , COVID-19/virology , Humans , Prevalence , Risk Factors
20.
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
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