Aging and obesity are high risk factors for several conditions and diseases. They are both associated with systemic inflammation and they are both ameliorated by a healthy life style, suggesting that ...they may share cellular and molecular pathways and underlying mechanisms. A close relationship between aging and obesity is also supported by the observation that the aging overweight/obese population is increasing worldwide, and mechanisms involved will be presented here. A focus of our work is to evaluate if obesity may be considered a good biomarker of accelerated aging of human antibody responses. We will summarize our published results showing the effects of obesity in accelerating age defects in the peripheral B cell pool and how these lead to dysfunctional humoral immunity.
The increase in the prevalence of obesity represents a worldwide phenomenon in all age groups and is pathologically and genetically correlated with several metabolic and cardiovascular diseases, ...representing the most frequent age-related diseases. Obesity superimposed on aging drastically increases chronic low-grade inflammation (inflammaging), which is an important link between obesity, insulin resistance, and age-associated diseases. Immune cells of both the innate and the adaptive immune systems infiltrate the adipose tissue (AT) and during obesity induce inflammatory responses associated with metabolic switches and changes in phenotypes and function of immune cell subsets. Obesity poses new health problems especially when it occurs in the context of other diseases, many of them frequently affect elderly subjects. An emerging problem is the decreased proportion of patients with obesity achieving clinical response to therapy. In this review, we will discuss the reciprocal influences of immune cell and AT inflammation in aging and age-associated diseases and the complex relationship of nutrient and energy-sensing homeostatic checkpoints, which contribute to shape the phenotype of the AT. We will specifically examine type-2 diabetes, rheumatoid arthritis, osteoarthritis, cognitive impairment, and dementia, where obesity plays a significant role, also in shaping some clinical aspects.
B Cell Immunosenescence Frasca, Daniela; Diaz, Alain; Romero, Maria ...
Annual review of cell and developmental biology,
10/2020, Volume:
36, Issue:
1
Journal Article
Peer reviewed
Open access
Innate and adaptive immune responses decline with age, leading to greater susceptibility to infectious diseases and reduced responses to vaccines. Diseases are more severe in old than in young ...individuals and have a greater impact on health outcomes such as morbidity, disability, and mortality. Aging is characterized by increased low-grade chronic inflammation, so-called inflammaging, that represents a link between changes in immune cells and a number of diseases and syndromes typical of old age. In this review we summarize current knowledge on age-associated changes in immune cells with special emphasis on B cells, which are more inflammatory and less responsive to infections and vaccines in the elderly. We highlight recent findings on factors and pathways contributing to inflammaging and how these lead to dysfunctional immune responses. We summarize recent published studies showing that adipose tissue, which increases in size with aging, contributes to inflammaging and dysregulated B cell function.
Major advances in preventing, delaying, or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching eight to nine ...decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T‐cell or B‐cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.
Aging of the immune system is characterized a profound change in the functionality of both innate and adaptive immune system, and accompanied by the onset of a chronic, low‐grade inflammatory status, and by a reduced capability to trigger an effective response to vaccine, which is typical of elderly people. N = Neutrophils; M = monocytes/macrophages; DC = dendritic cells; LC = Langerhans’ cells; NK = natural killer cells; T = T cells; B = B cells:
Aging is characterized by a progressive decline in the capacity of the immune system to fight influenza virus infection and to respond to vaccination. Among the several factors involved, in addition ...to increased frailty and high-risk conditions, the age-associated decrease in cellular and humoral immune responses plays a relevant role. This is in large part due to inflammaging, the chronic low-grade inflammatory status of the elderly, associated with intrinsic inflammation of the immune cells and decreased immune function.
Aging is usually associated with reduced influenza virus-specific and influenza vaccine-specific antibody responses but some elderly individuals with higher pre-exposure antibody titers, due to a previous infection or vaccination, have less probability to get infected. Examples of this exception are the elderly individuals infected during the 2009 pandemic season who made antibodies with broader epitope recognition and higher avidity than those made by younger individuals. Several studies have allowed the identification of B cell intrinsic defects accounting for sub-optimal antibody responses of elderly individuals. These defects include 1) reduced class switch recombination, responsible for the generation of a secondary response of class switched antibodies, 2) reduced de novo somatic hypermutation of the antibody variable region, 3) reduced binding and neutralization capacity, as well as binding specificity, of the secreted antibodies, 4) increased epigenetic modifications that are associated with lower antibody responses, 5) increased frequencies of inflammatory B cell subsets, and 6) shorter telomeres.
Although influenza vaccination represents the most effective way to prevent influenza infection, vaccines with greater immunogenicity are needed to improve the response of elderly individuals. Recent advances in technology have made possible a broad approach to better understand the age-associated changes in immune cells, needed to design tailored vaccines and effective therapeutic strategies that will be able to improve the immune response of vulnerable individuals.
Obesity negatively affects immune function and host defense mechanisms. Obesity is associated with chronic activation of the innate immune system and consequent local and systemic inflammation which ...contribute to pathologic conditions such as type-2 diabetes mellitus, cancer, psoriasis, atherosclerosis, and inflammatory bowel disease. Individuals with obesity have increased susceptibility to contract viral, bacterial, and fungal infections and respond sub-optimally to vaccination. In this review, we summarize research findings on the effects of obesity on immune responses to respiratory tract infections (RTI), focusing on
("pneumococcus") infection, which is a major cause of morbidity and mortality in the US, causing community-acquired infections such as pneumonia, otitis media and meningitis. We show that the risk of infection is higher in elderly individuals and also in individuals of certain ethnic groups, although in a few reports obesity has been associated with better survival of individuals admitted to hospital with pneumococcus infection, a phenomenon known as "obesity paradox." We discuss factors that are associated with increased risk of pneumococcal infection, such as recent infection with RTI, chronic medical conditions, and immunosuppressive medications.
In this study, we have compared frequencies, phenotype, function and metabolic requirements of B cells isolated from the breast and abdominal subcutaneous adipose tissue (AT) of women with obesity ...who underwent weight reduction surgeries. Results show that B cells from the abdominal AT are more inflammatory than those from the breast, characterized by higher frequencies of inflammatory B cell subsets and higher expression of RNA for inflammatory markers associated with senescence. Secretion of autoimmune antibodies is also higher in the abdominal AT as compared to the breast, and is associated with higher frequencies of autoimmune B cells with the membrane phenotype CD21lowCD95+ B cells expressing the transcription factor T-bet. Moreover, glucose uptake is higher in B cells from the abdominal AT as compared to the breast, thereby suggesting a better capacity to perform glycolysis, needed to support intrinsic B cell inflammation and autoimmune antibody secretion.
SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus-2), cause of COVID-19 (Coronavirus Disease of 2019), represents a significant risk to people living with pre-existing conditions associated ...with exacerbated inflammatory responses and consequent dysfunctional immunity. In this paper, we have evaluated the influence of obesity, a condition associated with chronic systemic inflammation, on the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. Our hypothesis is that obesity is associated with reduced amounts of specific IgG antibodies. Results have confirmed our hypothesis and have shown that SARS-CoV-2 IgG antibodies are negatively associated with Body Mass Index (BMI) in COVID-19 obese patients, as expected based on the known influence of obesity on humoral immunity. Antibodies in COVID-19 obese patients are also negatively associated with serum levels of pro-inflammatory and metabolic markers of inflammaging and pulmonary inflammation, such as SAA (serum amyloid A protein), CRP (C-reactive protein), and ferritin, but positively associated with NEFA (nonesterified fatty acids). These results altogether could help to identify an inflammatory signature with strong predictive value for immune dysfunction. Inflammatory markers identified may subsequently be targeted to improve humoral immunity in individuals with obesity and in individuals with other chronic inflammatory conditions.
The subset of pro-inflammatory B cells, called late memory, tissue-like or double negative (DN), accumulates in the blood of elderly individuals. Here we show that DN B cells do not proliferate and ...do not make antibodies to influenza antigens, but they secrete antibodies with autoimmune reactivity, in agreement with their membrane phenotype (CD95+CD21-CD11c+) and their spontaneous expression of the transcription factor T-bet. These cells also increase in the blood of individuals with obesity and autoimmune diseases, but causative mechanisms and signaling pathways involved are known only in part. In the present paper we compare frequencies and metabolic requirements of these cells in the blood of healthy individuals of different ages and in the blood and the subcutaneous adipose tissue (SAT) of individuals with obesity. Results show that DN B cells from young individuals have minimal metabolic requirements, DN B cells from elderly and obese individuals utilize higher amounts of glucose to perform autoimmune antibody production and enroll in aerobic glycolysis to support their function. DN B cells from the SAT have the highest metabolic requirements as they activate oxidative phosphorylation, aerobic glycolysis and fatty acid oxidation. DN B cells from the SAT also show the highest levels of ROS and the highest levels of phosphorylated AMPK (5'-AMP activated kinase) and Sestrin 1, both able to mitigate stress and cell death. This metabolic advantage drives DN B cell survival and function (secretion of autoimmune antibodies).
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