scholarly journals Aged BALB/c Mice as a Model for Increased Severity of Severe Acute Respiratory Syndrome in Elderly Humans

2005 ◽  
Vol 79 (9) ◽  
pp. 5833-5838 ◽  
Author(s):  
Anjeanette Roberts ◽  
Christopher Paddock ◽  
Leatrice Vogel ◽  
Emily Butler ◽  
Sherif Zaki ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Adverse Outcome ◽  
The Elderly ◽  
Advanced Age ◽  
Sars Coronavirus ◽  
Aged Mice ◽  
Age Related ◽  
Clinical Illness ◽  
Elderly Humans

ABSTRACT Advanced age has repeatedly been identified as an independent correlate of adverse outcome and a predictor of mortality in cases of severe acute respiratory syndrome (SARS). SARS-associated mortality may exceed 50% for persons aged 60 years or older. Heightened susceptibility of the elderly to severe SARS and the ability of SARS coronavirus to replicate in mice led us to examine whether aged mice might be susceptible to disease. We report here that viral replication in aged mice was associated with clinical illness and pneumonia, demonstrating an age-related susceptibility to SARS disease in animals that parallels the human experience.

Abstract 65: Restoration of Growth Differentiation Factor 11 Protects Against Stroke in Mice

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Anjali Chauhan ◽  
Jacob Hudobenko ◽  
Anthony Patrizz ◽  
Louise D McCullough
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
The Elderly ◽  
Vehicle Group ◽  
Peripheral Tissues ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Infarct Area ◽  
Age Related

Introduction: GDF 11 is a member of the transforming growth factor β superfamily. Loss of GDF11 occurs with aging and declining levels correlate with several detrimental age-associated phenotypes in both peripheral tissues and brain. Restoration of GDF11 enhances neurogenesis and cognitive function in aged mice. Brain expression of GDF11 has not been investigated after stroke. Stroke differentially affects the elderly. In this work we examined the role of GDF11 in aging, stroke and its potential utility as a neuroprotective agent. Methods: Male C57/BL6NCrl young (2-3 months) and aged (19-21) mice were used. Brain GDF11 expression was evaluated in young and aged mice by western blot. Focal ischemia was induced with a transient middle cerebral artery occlusion (MCAO). Mice were randomly assigned into two groups and were subjected to 90 min MCAO. Group 1 received vehicle (phosphate buffered saline) and group 2 was administered rGDF11 (100 ug/kg., ip) at the onset of ischemia. In additional experiments, the efficacy of delayed treatment (3 h after ischemia) with rGDF11 was tested. These mice were subjected to a 60 min MCAO. Mice were euthanized after 24 hours and 7 days respectively and brains were harvested to estimate infarct area. Results: A significant decrease in brain GDF11 levels was observed in aged mice as compared to young (p<0.05). Additionally, a significant decline in brain GDF11 expression was observed after stroke at 24 hours vs. sham groups (p<0.05). A significant decrease in cortical and hemispheric infarct area was observed in the rGDF11 group (cortical 48.73±1.05; hemisphere 49.68±3.58) as compared to vehicle group (60.54±4.88; 61.35±6.03), when GDF was administered at the time of ischemia. Delayed treatment with rGDF11 also reduced infarct at 7 days. Conclusions: Brain GDF11 levels decline with age and after stroke. Supplementation with rGDF11 ameliorates stroke induced injury in young mice at 24h and 7 days. These finding suggest potential role of GDF11 in age and stroke. Restoration of age-related loss of GDF may be a viable therapy for stroke.

scholarly journals Aging dampens the intestinal innate immune response during Clostridioides difficile infection and is associated with altered intestinal eosinophil mobilization

2020 ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Michael G. Dieterle ◽  
Kimberly C. Vendrov ◽  
Ingrid L. Bergin ◽  
Vincent B. Young
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Disease Severity ◽  
Advanced Age ◽  
Simultaneous Increase ◽  
Aged Mice ◽  
Age Related ◽  
Cellular Immune ◽  
The Impact ◽  
Young Mice

ABSTRACTClostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the impact of aging on the cellular immune response associated with C. difficile infection in the setting of advanced age remains to be well described. This study explores the effect of age on cellular immune responses in C. difficile infection as well as disease severity. Young adult mice (2-3 months old) and aged mice (22-28 months old) were rendered susceptible to C. difficile infection with cefoperazone and then infected with C. difficile strains of varying disease-causing potential. Aged mice infected with C. difficile develop more severe clinical disease, compared to young mice. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the cecum and colon of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice. Interestingly, while C. difficile infection in young mice was associated with a robust increase in cecal and colonic eosinophils, there was a complete lack of an intestinal eosinophil response in aged counterparts accompanied by a simultaneous increase in blood eosinophils with severe disease. These findings demonstrate that age-related alterations in immune responses are associated with significantly worse C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

scholarly journals Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging

2020 ◽  
Vol 117 (52) ◽  
pp. 33561-33569
Author(s):  
Megumi Inomata ◽  
Shuying Xu ◽  
Pallavi Chandra ◽  
Simin N. Meydani ◽  
Genzou Takemura ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Inflammatory Responses ◽  
The Elderly ◽  
Invasive Disease ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Murine Bone Marrow ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

scholarly journals COVID-19: when, along with aging, sex matters

2020 ◽  
Vol 6 (4) ◽  
Author(s):  
Virginia Boccardi ◽  
Patrizia Mecocci
Keyword(s):  
Innate Immunity ◽  
Severe Acute Respiratory Syndrome ◽  
Older Women ◽  
Steroid Hormones ◽  
Older Persons ◽  
Viral Infections ◽  
The Elderly ◽  
The Novel ◽  
Age Related ◽  
Patient Groups

Older persons are more susceptible to infection due to the age-related immunologic changes and the state of constitutive lowgrade inflammation. The rate of complications from the novel severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and its related coronavirus disease 2019 (COVID-19), is significantly higher in the elderly, with men as the most affected. It is known that women, in general, are less susceptible to viral infections complications thanks to three main differences in sex chromosomes, innate immunity, and steroid hormones. COVID-19 epidemiology in Italy further support that older women, even if frailer, may experience lower mortality than men, which extends the ‘male-female health-survival paradox’ to acutely ill patient groups.

scholarly journals Age-related exacerbation of hematopoietic organ damage induced by systemic hyper-inflammation in senescence-accelerated mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomonori Harada ◽  
Isao Tsuboi ◽  
Hirotsugu Hino ◽  
Miyuki Yuda ◽  
Yoko Hirabayashi ◽  
...  
Keyword(s):  
Stromal Cells ◽  
The Elderly ◽  
Organ Damage ◽  
Hematopoietic Organ ◽  
Aged Mice ◽  
Gm Csf ◽  
Expression Of Genes ◽  
Age Related ◽  
Genes Encoding ◽  
Positive Regulators

AbstractHemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyper-inflammatory disorder. The mortality of HLH is higher in the elderly than in young adults. Senescence-accelerated mice (SAMP1/TA-1) exhibit characteristic accelerated aging after 30 weeks of age, and HLH-like features, including hematopoietic organ damage, are seen after lipopolysaccharide (LPS) treatment. Thus, SAMP1/TA-1 is a useful model of hematological pathophysiology in the elderly with HLH. In this study, dosing of SAMP1/TA-1 mice with LPS revealed that the suppression of myelopoiesis and B-lymphopoiesis was more severe in aged mice than in young mice. The bone marrow (BM) expression of genes encoding positive regulators of myelopoiesis (G-CSF, GM-CSF, and IL-6) and of those encoding negative regulators of B cell lymphopoiesis (TNF-α) increased in both groups, while the expression of genes encoding positive-regulators of B cell lymphopoiesis (IL-7, SDF-1, and SCF) decreased. The expression of the GM-CSF-encoding transcript was lower in aged mice than in young animals. The production of GM-CSF by cultured stromal cells after LPS treatment was also lower in aged mice than in young mice. The accumulation of the TNF-α-encoding transcript and the depletion of the IL-7-encoding transcript were prolonged in aged mice compared to young animals. LPS dosing led to a prolonged increase in the proportion of BM M1 macrophages in aged mice compared to young animals. The expression of the gene encoding p16INK4a and the proportion of β-galactosidase- and phosphorylated ribosomal protein S6-positive cells were increased in cultured stromal cells from aged mice compared to those from young animals, while the proportion of Ki67-positive cells was decreased in stromal cells from aged mice. Thus, age-related deterioration of stromal cells probably causes the suppression of hematopoiesis in aged mice. This age-related latent organ dysfunction may be exacerbated in elderly people with HLH, resulting in poor prognosis.

scholarly journals Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain

Science ◽  
2020 ◽  
Vol 369 (6500) ◽  
pp. 167-173 ◽  
Author(s):  
Alana M. Horowitz ◽  
Xuelai Fan ◽  
Gregor Bieri ◽  
Lucas K. Smith ◽  
Cesar I. Sanchez-Diaz ◽  
...  
Keyword(s):  
Brain Aging ◽  
Plasma Concentrations ◽  
Signaling Cascades ◽  
Aged Mice ◽  
Beneficial Effects ◽  
Healthy Elderly ◽  
Age Related ◽  
Phospholipase D1 ◽  
Elderly Humans ◽  
Blood Factors

Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma concentrations of glycosylphosphatidylinositol (GPI)–specific phospholipase D1 (Gpld1), a GPI-degrading enzyme derived from liver, were found to increase after exercise and to correlate with improved cognitive function in aged mice, and concentrations of Gpld1 in blood were increased in active, healthy elderly humans. Increasing systemic concentrations of Gpld1 in aged mice ameliorated age-related regenerative and cognitive impairments by altering signaling cascades downstream of GPI-anchored substrate cleavage. We thus identify a liver-to-brain axis by which blood factors can transfer the benefits of exercise in old age.

scholarly journals Modulation of Bacterial Pathogenesis by Oppressive Aging Factors: Insights into Host-Pneumococcal Interaction Strategies

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Pooja Shivshankar
Keyword(s):  
Cellular Senescence ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
The Elderly ◽  
Receptor Expression ◽  
Chronic Obstructive ◽  
Related Phenomenon ◽  
Aged Mice ◽  
Inflammatory Status ◽  
Age Related

Streptococcus pneumonia, (Spn, the pneumococcus), is the leading cause of community-acquired pneumonia (CAP) and is responsible for 15–40% deaths in the elderly worldwide. A primed inflammatory status is a significant risk factor for the increased severity of infectious diseases among the elderly (≥65 years of age). Studies have shown that expression of host receptors that the pneumococci bind to invade the tissues are increased thereby increasing the susceptibility to pneumococcal challenge in aged mice. Cellular senescence, an age-related phenomenon that leads to cell cycle arrest may also contribute to increased inflammation in aged mice. Evidence of cellular senescence in aged lungs of humans and mice adds credits to the concept of inflammaging and enhanced bacterial ligands expression during aging. Furthermore, cell senescence has been shown to occur in age-associated lung pathologies such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) that may predispose the elderly to pathogenic assaults, including S. pneumoniae. This review highlights the aspects of: chronic inflammation in the aged population; contribution of cellular senescence to age-associated inflammation and their impact on host receptor expression; and, increased susceptibility of fibrosis and emphysematous lesions-bearing lungs to microbial infections.

scholarly journals LXR agonist Prevents Peripheral Neuropathy and modifies PNS immune cells in Aged Mice

2021 ◽  
Author(s):  
Chaitanya Gavini ◽  
Nadia Elshareif ◽  
Anand Germanwala ◽  
Gregory Aubert ◽  
Nigel Calcutt ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Immune Cell ◽  
The Elderly ◽  
Cholesterol Content ◽  
Nerve Fibers ◽  
Aged Mice ◽  
Diet Induced Obesity ◽  
Age Related ◽  
Potent Agonist ◽  
Progressive Disorder

Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities and increases the risk of injury. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist GW3965, alleviates pain in a diet-induced obesity model. Because cholesterol had also been linked to neuropathy during aging, we sought to test whether LXR activation may improve neuropathy and pain in aged mice by treating 21-month-old mice for 3 months with GW3965. Treatment resulted in a significant increase in nerve fibers of the sub-basal plexus, accompanied by a change in polarization, metabolism, and cholesterol content of macrophages in the sciatic nerve. These results suggest that activation of the LXR may block the progression of neuropathy associated with aging by modifying nerve-immune cell cholesterol, thereby providing new pathways to target in efforts to delay neuropathy during aging.

scholarly journals Genomic Analysis Reveals Age-Dependent Innate Immune Responses to Severe Acute Respiratory Syndrome Coronavirus

2008 ◽  
Vol 82 (19) ◽  
pp. 9465-9476 ◽  
Author(s):  
Tracey Baas ◽  
Anjeanette Roberts ◽  
Thomas H. Teal ◽  
Leatrice Vogel ◽  
Jun Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Host Response ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Host Responses ◽  
Aged Mice ◽  
Young Mice

ABSTRACT The relationship between immunosenescence and the host response to virus infection is poorly understood at the molecular level. Two different patterns of pulmonary host responses to virus were observed when gene expression profiles from severe acute respiratory syndrome coronavirus (SARS-CoV)-infected young mice that show minimal disease were compared to those from SARS-CoV-infected aged mice that develop pneumonitis. In young mice, genes related to cellular development, cell growth, and cell cycle were downregulated during peak viral replication, and these transcripts returned to basal levels as virus was cleared. In contrast, aged mice had a greater number of upregulated immune response and cell-to-cell signaling genes, and the expression of many genes was sustained even after viral clearance, suggesting an exacerbated host response to virus. Interestingly, in SARS-CoV-infected aged mice, a subset of genes, including Tnfa, Il6, Ccl2, Ccl3, Cxcl10, and Ifng, was induced in a biphasic pattern that correlated with peak viral replication and a subsequent influx of lymphocytes and severe histopathologic changes in the lungs. We provide insight into gene expression profiles and molecular signatures underlying immunosenescence in the context of the host response to viral infection.

scholarly journals Age-Related Impairment of Innate and Adaptive Immune Responses Following Intranasal Herpes Simplex Infection

2022 ◽  
Author(s):  
Ruchi Srivastava ◽  
Anshu Agrawal ◽  
Hawa Vahed ◽  
Lbachir BenMohamed
Keyword(s):  
Immune Response ◽  
Herpes Simplex ◽  
Immune Responses ◽  
The Elderly ◽  
Adaptive Immune Responses ◽  
Herpes Infection ◽  
Aged Mice ◽  
Adaptive Immune ◽  
Age Related ◽  
Hsv 1

Immune function declines with age, leading to an increased vulnerability to respiratory viral infections. The mechanisms by which aging negatively impacts the innate and adaptive immune system leading to enhanced susceptibility to infections remain to be fully elucidated. In the present study, we used a mouse model of intranasal infection with herpes simplex virus type 1 (HSV-1), a virus that can enter the lungs through the nasal route causing pneumonia, a serious health concern in the elderly. Following intranasal inoculation of young (6 weeks), adult (36 weeks), and aged (68 weeks) with HSV-1 (KOS strain) we: (i) compared the local and systemic innate and adaptive immune response to infection; and (ii) correlated the level and type of immune response to protection against HSV-1 infection. Compared to young and adult mice, aged mice displayed: (i) increased basal level activation of epithelial cells with a decreased expression of TLR3; (ii) increased activation of dendritic cells with increased expression of MHC-1, MHC-II and CD80/86; and (iii) decreased production of type-I interferons upon stimulation; (iv) a delay in cytokines and chemokines production in the lungs; and (v) an impairment in function (CD107 and IFN-g production) of HSV-specific CD8+ T cells. These impairment in innate and adaptive immune responses in aged mice following intranasal HSV-1 inoculation was associated with symptomatic herpes infection. The findings suggest an age-related impairment of both innate and adaptive immune responses which may exacerbate herpes infection and disease in the elderly.

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