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3.
Front Immunol ; 11: 579220, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193377

RESUMO

Old individuals are more susceptible to various infections due to immunological changes that occur during the aging process. These changes named collectively as "immunosenescence" include decreases in both the innate and adaptive immune responses in addition to the exacerbated production of inflammatory cytokines. This scenario of immunological dysfunction and its relationship with disease development in older people has been widely studied, especially in infections that can be fatal, such as influenza and, more recently, COVID-19. In the current scenario of SARS-CoV-2 infection, many mechanisms of disease pathogenesis in old individuals have been proposed. To better understand the dynamics of COVID-19 in this group, aspects related to immunological senescence must be well elucidated. In this article, we discuss the main mechanisms involved in immunosenescence and their possible correlations with the susceptibility of individuals of advanced age to SARS-CoV-2 infection and the more severe conditions of the disease.


Assuntos
Envelhecimento/imunologia , Imunossenescência , /fisiologia , /epidemiologia , Humanos , Pandemias , Fatores de Risco , /genética
4.
Exp Gerontol ; 142: 111147, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33171276

RESUMO

SARS-CoV-2 causes a severe pneumonia (COVID-19) that affects essentially elderly people. In COVID-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. Comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of COVID-19. Mitochondrial dysfunction is one of the hallmarks of aging and COVID-19 risk factors. Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. This review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of COVID-19. We suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in COVID-19 patients. Preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against COVID-19 severity.


Assuntos
Envelhecimento/imunologia , Mitocôndrias/fisiologia , Animais , /mortalidade , Síndrome da Liberação de Citocina/etiologia , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia
6.
Aging Cell ; 19(12): e13272, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33166035

RESUMO

The development of senescence in tissues of different organs and in the immune system are usually investigated independently of each other although during ageing, senescence in both cellular systems develop concurrently. Senescent T cells are highly inflammatory and secrete cytotoxic mediators and express natural killer cells receptors (NKR) that bypass their antigen specificity. Instead they recognize stress ligands that are induced by inflammation or infection of different cell types in tissues. In this article we discuss data on T cell senescence, how it is regulated and evidence for novel functional attributes of senescent T cells. We discuss an interactive loop between senescent T cells and senescent non-lymphoid cells and conclude that in situations of intense inflammation, senescent cells may damage healthy tissue. While the example for immunopathology induced by senescent cells that we highlight is cutaneous leishmaniasis, this situation of organ damage may apply to other infections, including COVID-19 and also rheumatoid arthritis, where ageing, inflammation and senescent cells are all part of the same equation.


Assuntos
Linfócitos T CD8-Positivos/citologia , Senescência Celular/fisiologia , Células Matadoras Naturais/imunologia , Leishmaniose Cutânea/imunologia , Receptores de Células Matadoras Naturais/imunologia , Envelhecimento/imunologia , Artrite Reumatoide/imunologia , Humanos , Leishmania braziliensis/imunologia , /imunologia
7.
Nat Metab ; 2(11): 1284-1304, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33199925

RESUMO

Decreased NAD+ levels have been shown to contribute to metabolic dysfunction during aging. NAD+ decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD+ homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38+ immune cells. Inflammation increases CD38 and decreases NAD+. In addition, senescent cells and their secreted signals promote accumulation of CD38+ cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD+ decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD+ through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD+.


Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Envelhecimento/metabolismo , Glicoproteínas de Membrana/metabolismo , NAD/biossíntese , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Envelhecimento/imunologia , Animais , Transplante de Medula Óssea , Senescência Celular , Células HEK293 , Humanos , Inflamação/imunologia , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mononucleotídeo de Nicotinamida/metabolismo , Fenótipo
8.
Virus Res ; 290: 198197, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33069815

RESUMO

The coronavirus disease-2019 (COVID-19) which caused by severe acute respiratory syndrome-related coronavirus (SARS-CoV-2), is a pandemic threat to global public health. It has a wide spectrum of clinical manifestations from mild to critical illness, the most serious of which is the complications of acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection appears mild in infants and children, however, in adults, it can lead to serious consequences. In this review, we highlighted the differences between the immune responses of the lung in children and adults, immune dysregulation and their possible role in clinical manifestations in COVID-19. There is a reduction in population of immunocompetent cells during aging and subsequently induced ineffective inflammation in the faces of some infections. Dysregulation in the immune system can lead to an unappropriated local and systemic immune responses and subsequently the rapid spread of the virus, leading to severe COVID-19 disease. Therefore, recognizing the differences in the immune responses of various hosts as well as to improve the immune system disorder should always be part of research and treatment protocols.


Assuntos
/imunologia , /patogenicidade , Fatores Etários , Envelhecimento/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade , Inflamação , Pulmão/imunologia , Pulmão/patologia , Fatores Sexuais
9.
Aging Cell ; 19(10): e13230, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33006233

RESUMO

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is known to preferentially target older subjects and those with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in all countries tested, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to antiviral approaches, by approaches that target the aging process.


Assuntos
Envelhecimento/imunologia , Infecções por Coronavirus/mortalidade , Pneumonia Viral/mortalidade , Fatores Etários , Idoso , Betacoronavirus , Feminino , Saúde Global , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/metabolismo , Fatores Sexuais
10.
Front Immunol ; 11: 573662, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123152

RESUMO

Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.


Assuntos
Senescência Celular/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Envelhecimento/imunologia , Betacoronavirus/imunologia , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Masculino , Monócitos/imunologia , Neutrófilos/imunologia , Obesidade/imunologia , Pandemias , Fatores de Risco , Linfócitos T/imunologia
13.
J Clin Invest ; 130(12): 6204-6213, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33085654

RESUMO

Human coronaviruses (hCoVs) cause severe respiratory illness in the elderly. Age-related impairments in innate immunity and suboptimal virus-specific T cell and antibody responses are believed to cause severe disease upon respiratory virus infections. This phenomenon has recently received increased attention, as elderly patients are at substantially elevated risk for severe COVID-19 disease and experience increased rates of mortality following SARS-CoV-2 infection compared with younger populations. However, the basis for age-related fatal pneumonia following pathogenic hCoVs is not well understood. In this Review, we provide an overview of our current understanding of hCoV-induced fatal pneumonia in the elderly. We describe host immune response to hCoV infections derived from studies of young and aged animal models and discuss the potential role of age-associated increases in sterile inflammation (inflammaging) and virus-induced dysregulated inflammation in causing age-related severe disease. We also highlight the existing gaps in our knowledge about virus replication and host immune responses to hCoV infection in young and aged individuals.


Assuntos
Envelhecimento/imunologia , Imunidade Inata , /imunologia , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Inflamação/imunologia , Inflamação/virologia , Fatores de Risco , Índice de Gravidade de Doença
14.
Mech Ageing Dev ; 192: 111363, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32987038

RESUMO

Neprilysin (NEP) is an integral membrane-bound metallopeptidase with a wide spectrum of substrates and physiological functions. It plays an important role in proteolytic processes in the kidney, cardiovascular regulation, immune response, cell proliferation, foetal development etc. It is an important neuropeptidase and amyloid-degrading enzyme which makes NEP a therapeutic target in Alzheimer's disease (AD). Moreover, it plays a preventive role in development of cancer, obesity and type-2 diabetes. Recently a role of NEP in COVID-19 pathogenesis has also been suggested. Despite intensive research into NEP structure and functions in different organisms, changes in its expression and regulation during brain development and ageing, especially in age-related pathologies, is still not fully understood. This prevents development of pharmacological treatments from various diseases in which NEP is implicated although recently a dual-acting drug sacubitril-valsartan (LCZ696) combining a NEP inhibitor and angiotensin receptor blocker has been approved for treatment of heart failure. Also, various natural compounds capable of upregulating NEP expression, including green tea (EGCG), have been proposed as a preventive medicine in prostate cancer and AD. This review summarizes the existing literature and our own research on the expression and activity of NEP in normal brain development, ageing and under pathological conditions.


Assuntos
Envelhecimento/imunologia , Doença de Alzheimer/imunologia , Diabetes Mellitus Tipo 2/imunologia , Regulação Enzimológica da Expressão Gênica/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias/imunologia , Neprilisina/imunologia , /imunologia , Envelhecimento/patologia , Doença de Alzheimer/patologia , Animais , Diabetes Mellitus Tipo 2/patologia , Humanos , Neoplasias/patologia
15.
Aging Cell ; 19(10): e13237, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32955770

RESUMO

SARS-CoV-2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID-19), a complex respiratory distress syndrome. Epidemiological data show that COVID-19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association between SARS-CoV-2 infection and the process of biological aging may provide a tractable avenue for therapy to prevent acute and long-term disease. Here, we discuss how cellular senescence-a state of stable growth arrest characterized by pro-inflammatory and pro-disease functions-can hypothetically be a contributor to COVID-19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity. First, we define why older COVID-19 patients are more likely to accumulate high levels of cellular senescence. Second, we describe how senescent cells can contribute to an uncontrolled SARS-CoV-2-mediated cytokine storm and an excessive inflammatory reaction during the early phase of the disease. Third, we discuss the various mechanisms by which senescent cells promote tissue damage leading to lung failure and multi-tissue dysfunctions. Fourth, we argue that a high senescence burst might negatively impact on vaccine efficacy. Measuring the burst of cellular senescence could hypothetically serve as a predictor of COVID-19 severity, and targeting senescence-associated mechanisms prior and after SARS-CoV-2 infection might have the potential to limit a number of severe damages and to improve the efficacy of vaccinations.


Assuntos
Envelhecimento/imunologia , Senescência Celular/imunologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Fatores Etários , Idoso , Betacoronavirus , Biomarcadores/análise , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Pneumonia Viral/mortalidade , Índice de Gravidade de Doença
16.
Nature ; 586(7831): 735-740, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32879487

RESUMO

Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-ß is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-ß. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-ß. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Imunidade Inata , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Idade de Início , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/imunologia , Envelhecimento/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/química , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Astrócitos/metabolismo , Domínio Catalítico , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Inflamação , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Presenilina-1/metabolismo , Proteínas de Ligação a RNA/genética , Risco , Regulação para Cima
18.
Zool Res ; 41(5): 503-516, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32772513

RESUMO

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.


Assuntos
Envelhecimento/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Macaca mulatta/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Fatores Etários , Envelhecimento/metabolismo , Animais , Betacoronavirus/fisiologia , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Inflamação/imunologia , Inflamação/veterinária , Inflamação/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta/virologia , Doenças dos Macacos/imunologia , Doenças dos Macacos/virologia , Pandemias/veterinária , Pneumonia Viral/veterinária , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/veterinária , Síndrome Respiratória Aguda Grave/virologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Carga Viral/imunologia , Carga Viral/veterinária , Replicação Viral/imunologia
19.
J Nutr Health Aging ; 24(7): 685-691, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32744561

RESUMO

A new coronavirus, called SARS-CoV-2, was identified in Wuhan, China, in December 2019. The SARS-CoV-2 spread very rapidly, causing a global pandemic, Coronavirus Disease 2019 (COVID-19). Older adults have higher peak of viral load and, especially those with comorbidities, had higher COVID-19-related fatality rates than younger adults. In this Perspective paper, we summarize current knowledge about SARS-CoV-2 and aging, in order to understand why older people are more affected by COVID-19. We discuss about the possibility that the so-called "immunosenescence" and "inflammaging" processes, already present in a fraction of frail older adults, could allow the immune escape of SARS-CoV-2 leading to COVID-19 serious complications. Finally, we propose to use geroscience approaches to the field of COVID-19.


Assuntos
Envelhecimento , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Geriatria , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Virologia , Idoso , Envelhecimento/imunologia , Envelhecimento/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Pandemias
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