Inflammaging, Immunosenescence, and Anti-Inflammatory Medications Used in Psychiatry: A Brief Overview.

The immune system is central to brain health and longevity, yet with age, infection, injury, or chronic stress, the immune system can trigger persistent central nervous system inflammation that impairs brain functioning. This brief review investigates psychopharmacological treatments that have anti-inflammatory effects in the context of immune system dysregulation in the aging brain. [Journal of Psychosocial Nursing and Mental Health Services, 61(5), 7-10.].

COVID-19 and Brain Aging: What are the Implications of Immunosenescence?

The human lifespan is increasing, and mankind is aging. It is estimated that, until the year 2050, this population worldwide will reach 22% of the total world population. Along with aging, the human immunologic system changes, a process called immunosenescence or even inflammaging. The aging immune system increases mortality and morbidity in the elderly mainly because it loses its capacity to react against internal and external aggressions. There is a decrease in B and T lymphocytes and CD4+ lymphocytes lose the CD28 protein expression that is needed for costimulation, leading to reduced response to viral infections. This could be responsible for more deleterious consequences of coronavirus disease infection in the elderly. Besides that, the human brain ages, being more susceptible to damage and viral infections, such as COVID-19 infection. There are several pathways that could explain the susceptibility to the COVID-19 infection in the elderly brain, one of them is binding to ACE 2 receptors in cerebral cells through the spike protein. It has been reported that glial cells and neurons, in addition to endothelial and arterial smooth muscle cells in the brain, express the ACE 2 receptor, which would justify the neurological symptoms and consequences of the disease. This infection can have several clinical manifestations such as hemorrhagic stroke, delirium and long-term cognitive complaints, such as brain fog, polyneuropathies, short time memory complaints and insomnia. Although none of the studies could prove that there is a long-term neuronal damage, there are clinical sequelae that should be taken into account and more studies are necessary to know the consequences of the infection in the elderly brain.

Immunosenescence and inflamm-ageing in COVID-19.

The destructive effects of coronavirus disease 2019 (COVID-19) on the elderly and people with cardiovascular disease have been proven. New findings shed light on the role of aging pathways on life span and health age. New therapies that focus on aging-related pathways may positively impact the treatment of this acute respiratory infection. Using new therapies that boost the level of the immune system can support the elderly with co-morbidities against the acute form of COVID-19. This article discusses the effect of the aging immune system against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathways affecting this severity of infection.

Bibliometric and visualization analysis of global research trends on immunosenescence (1970-2021).

BACKGROUND: Immunosenescence, the aging of the immune system, leads to a decline in the body's adaptability to the environment and plays an important role in various diseases. Immunosenescence has been widely studied in recent years. However, to date, no relevant bibliometric analyses have been conducted. This study aimed to analyze the foundation and frontiers of immunosenescence research through bibliometric analysis. METHODS: Articles and reviews on immunosenescence from 1970 to 2021 were obtained from the Web of Science Core Collection. Countries, institutions, authors, journals, references, and keywords were analyzed and visualized using VOSviewer and CiteSpace. The R language and Microsoft Excel 365 were used for statistical analyses. RESULTS: In total, 3763 publications were included in the study. The global literature on immunosenescence research has increased from 1970 to 2021. The United States was the most productive country with 1409 papers and the highest H-index. Italy had the highest average number of citations per article (58.50). Among the top 10 institutions, 50 % were in the United States. The University of California was the most productive institution, with 159 articles. Kroemer G, Franceschi C, Goronzy JJ, Solana R, and Fulop T were among the top 10 most productive and co-cited authors. Experimental Gerontology (n = 170) published the most papers on immunosenescence. The analysis of keywords found that current research focuses on "inflammaging", "gut microbiota", "cellular senescence", and "COVID-19". CONCLUSIONS: Immunosenescence research has increased over the years, and future cooperation and interaction between countries and institutions must be expanded. The connection between inflammaging, gut microbiota, age-related diseases, and immunosenescence is a current research priority. Individualized treatment of immunosenescence, reducing its negative effects, and promoting healthy longevity will become an emerging research direction.

Signs of immunosenescence correlate with poor outcome of mRNA COVID-19 vaccination in older adults.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is effective in preventing COVID-19 hospitalization and fatal outcome. However, several studies indicated that there is reduced vaccine effectiveness among older individuals, which is correlated with their general health status1,2. How and to what extent age-related immunological defects are responsible for the suboptimal vaccine responses observed in older individuals receiving SARS-CoV-2 messenger RNA vaccine, is unclear and not fully investigated1,3-5. In this observational study, we investigated adaptive immune responses in adults of various ages (22-99 years old) receiving 2 doses of the BNT162b2 mRNA vaccine. Vaccine-induced Spike-specific antibody, and T and memory B cell responses decreased with increasing age. These responses positively correlated with the percentages of peripheral naïve CD4+ and CD8+ T cells and negatively with CD8+ T cells expressing signs of immunosenescence. Older adults displayed a preferred T cell response to the S2 region of the Spike protein, which is relatively conserved and a target for cross-reactive T cells induced by human 'common cold' coronaviruses. Memory T cell responses to influenza virus were not affected by age-related changes, nor the SARS-CoV-2-specific response induced by infection. Collectively, we identified signs of immunosenescence correlating with the outcome of vaccination against a new viral antigen to which older adults are immunologically naïve. This knowledge is important for the management of COVID-19 infections in older adults.

Immunosenescence in atherosclerosis: A role for chronic viral infections.

Immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, ROS generation and DNA damage which are associated with atherogenesis. Accumulating evidence shows that several DNA and RNA viruses are stimulators of immunosenescence and atherosclerosis in an interrelated network. DNA viruses such as CMV, EBV and HBV upregulate p16, p21 and p53 senescence-associated molecules; induce inflammaging, metabolic reprogramming of infected cells, replicative senescence and telomere shortening. RNA viruses such as HCV and HIV induce ROS generation, DNA damage, induction of senescence-associated secretory phenotype (SASP), metabolic reprogramming of infected cells, G1 cell cycle arrest, telomere shortening, as well as epigenetic modifications of DNA and histones. The newly emerged SARS-CoV-2 virus is also a potent inducer of cytokine storm and SASP. The spike protein of SARS-CoV-2 promotes senescence phenotype in endothelial cells by augmenting p16, p21, senescence-associated ß-galactosidase (SA-ß-Gal) and adhesion molecules expression. The impact of SARS-CoV-2 mega-inflammation on atherogenesis, however, remains to be investigated. In this review we focus on the common processes in immunosenescence and atherogenesis caused by chronic viral infections and discuss the current knowledge on this topic.

Immunosenescence and COVID-19.

Ageing is associated with modified function of both innate and adaptive immunity. It is believed that changes occurring in ageing immune system are responsible for increased severity and deadliness of COVID-19 in the elderly. Although supported by statistics and epidemiology, these finding do not compute at the mechanistic level as depending solely on chronological and biological ageing. The phenomena describing changes in the aging immune system are immunosenescence and inflammageing, which develop in time depending on challenges to the individual immune system (immunobiography). Thus, "richer" immunobiography (in addition to other factors, including genetic, epigenetics or metabolic) may adversely affect the reactivity to the SARS-CoV-2 not only at later decades of life, but also earlier, in young and middle-aged individuals. On the other hand, infection with SARS-CoV-2 is affecting the function of both innate and adaptive branches of the immune system, adding to the individual immunobiography. Summarizing, immunosenescence and inflammaging may aggravate, but also may be aggravated by SARS-CoV-2 infection.

Social environment as a modulator of immunosenescence.

Immune system aging, a process known as immunosenescence, involves a striking rearrangement affecting all immune cells, resulting in an increased rate of infections and a major incidence of autoimmune diseases and cancer. Nonetheless, differences in how individuals of the same chronological age carry out this immunosenescence establishment and thus the aging rate have been reported. In the context of neuroimmunoendocrine communication and its role in the response to stress situations, growing evidence suggests that social environments profoundly influence all physiological responses, especially those linked to immunity. Accordingly, negative contexts (loneliness in humans/social isolation in rodents) were associated with immune impairments and decreased lifespan. However, positive social environments have been correlated with adequate immunity and increased lifespan. Therefore, the social context in which an individual lives is proposed as a decisive modulator of the immunosenescence process and, consequently, of the rate of aging. In this review, the most important findings regarding how different social environments (negative and positive) modulate immunosenescence and therefore the aging rate, as well as the role of stress responses, hormesis, and resilience in these environments will be explained. Finally, several possible molecular mechanisms underlying the effects of negative and positive environments on immunosenescence will be suggested.

An immunologist's guide to immunosenescence and its treatment.

INTRODUCTION: Aging causes several changes in the immune system, although immune aging is strongly influenced by individual immunological history, as well as genetic and environmental factors leading to inter-individual variability. AREAS COVERED: We focused on the biological and clinical meaning of immunosenescence. SARS-CoV-2 and Yellow Fever vaccine have demonstrated the clinical relevance of immunosenescence, while inconsistent results, obtained from longitudinal studies aimed at looking for immune risk phenotypes, have revealed that immunosenescence is highly context-dependent. Large projects allowed the delineation of the drivers of immune system variance, including genetic and environmental factors, sex, smoking, and co-habitation. Therefore, it is difficult to identify the interventions that can be envisaged to maintain or improve immune function in older people. That suggests that drug treatment of immunosenescence should require personalized intervention. Regarding this, we discussed the role of changes in lifestyle as a potential therapeutic approach. EXPERT OPINION: Our review points out that age is only part of the problem of immunosenescence. Everyone ages differently because is unique in genetics and experience of life and this applies even more to the immune system (immunobiography). Finally, the review shows how appreciable results in the modification of immunosenescence biomarkers can be achieved with lifestyle modification.

How can Biology of Aging Explain the Severity of COVID-19 in Older Adults.

Aging has been identified as one of the most relevant risk factors for poor outcomes in COVID-19 infection. Since now, different mechanisms responsible for worse outcomes in the elderly have been proposed, which include the remodeling of immune system, the higher prevalence of malnutrition and sarcopenia, the increased burden of multimorbidity, and, to a lesser extent, the direct effects of age on the respiratory system and hormonal profile. It seems that the interplay between all these causes, rather than the individual pathophysiological mechanism, explains the increased severity of the disease with age.

Age-associated alterations in immune function and inflammation.

Immunosenescence is a term used to describe the age-related changes in the immune system. Immunosenescence is associated with complex alterations and dysregulation of immune function and inflammatory processes. Age-related changes in innate immune responses including alterations in chemotactic, phagocytic, and natural killing functions, impaired antigen presenting capacity, and dysregulated inflammatory response have been described. The most striking and best characterized feature of immunosenescence is the decline in both number and function of T cells. With age there is decreased proliferation, decreased number of antigen-naïve T cells, and increased number of antigen-experienced memory T cells. This decline in naïve T cell population is associated with impaired immunity and reduced response to new or mutated pathogens. While the absolute number of peripheral B cells appears constant with age, changes in B cell functions including reduced antibody production and response and cell memory have been described. However, the main alteration in cell-mediated function that has been reported across all species with aging is those observed in in T cell. These T cell mediated changes have been shown to contribute to increased susceptibility to infection and cancer in older adults. In addition to functional and phenotype alterations in immune cells, studies demonstrate that circulating concentrations of inflammatory mediators in older adults are higher than those of young. This low grade, chronic inflammatory state that occurs in the context of aging has been termed "inflammaging". This review will focus on age-related changes in the immune system including immunosenescence and inflammation as well as the functional consequences of these age-related alterations for the aged.

Immune system aging and the aging-related diseases in the COVID-19 era.

The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.

Antibody responses to COVID-19 vaccines in older adults.

Because of the senescence of the immune system, antibody response to the COVID-19 vaccines may differ from older to younger adults. The study aim compares the titers of SARS-CoV-2 IgG antibody of patients ≥60 years who received three doses of CoronaVac vaccine and those who received two doses of CoronaVac+1 dose of Pfizer-BioNTech after 1 month of the last vaccination. Patients ≥60 years who received the CoronaVac vaccine between March 1, 2021, and April 30, 2021, who did not have COVID-19 disease before the first dose of vaccination and were negative for COVID-19 antibodies, whose antibodies were tested before the third dose of vaccination, and who did not have any COVID-19 disease during the follow-up were included. The demographic characteristics and comorbidities of patients were recorded. An immunofluorescence assay (IFA) fast test and a chemiluminescent microparticle immunoassay (Abbott) were used to measure SARS-CoV-2 quantitative antibody levels at the first month after the third-dose vaccine. Totally 81 patients, 41 patients in third dose of the CoronaVac group (female:male 18:23, mean age 69.4 ± 8.5), and 40 patients in third dose of the Pfizer-BioNTech group (female:male 15:25, mean age 69.9 ± 9.1) were included. The patients' comorbidities in the groups were similar. The titers of IgG antibodies to SARS-CoV-2 measured according to both IFA and Abbott Kit at first month the third dose vaccination was significantly higher in the Pfizer-BioNTech group (p ≥ 0.001, p = 0.012, respectively). The results report that the formed immunity in the first month after the two doses of CoronaVac+1 dose Pfizer-BioNTech vaccine was higher than three doses of CoronaVac vaccine in older adults.

Innate Immune Responses of Vaccinees Determine Early Neutralizing Antibody Production After ChAdOx1nCoV-19 Vaccination.

Background: Innate immunity, armed with pattern recognition receptors including Toll-like receptors (TLR), is critical for immune cell activation and the connection to anti-microbial adaptive immunity. However, information regarding the impact of age on the innate immunity in response to SARS-CoV2 adenovirus vector vaccines and its association with specific immune responses remains scarce. Methods: Fifteen subjects between 25-35 years (the young group) and five subjects between 60-70 years (the older adult group) were enrolled before ChAdOx1 nCoV-19 (AZD1222) vaccination. We determined activation markers and cytokine production of monocyte, natural killer (NK) cells and B cells ex vivo stimulated with TLR agonist (poly (I:C) for TLR3; LPS for TLR4; imiquimod for TLR7; CpG for TLR9) before vaccination and 3-5 days after each jab with flow cytometry. Anti-SARS-CoV2 neutralization antibody titers (surrogate virus neutralization tests, sVNTs) were measured using serum collected 2 months after the first jab and one month after full vaccination. Results: The older adult vaccinees had weaker vaccine-induced sVNTs than young vaccinees after 1st jab (47.2±19.3% vs. 21.2±22.2%, p value<0.05), but this difference became insignificant after the 2nd jab. Imiquimod, LPS and CpG strongly induced CD86 expression in IgD+CD27- naïve and IgD-CD27+ memory B cells in the young group. In contrast, only the IgD+ CD27- naïve B cells responded to these TLR agonists in the older adult group. Imiquimode strongly induced the CD86 expression in CD14+ monocytes in the young group but not in the older adult group. After vaccination, the young group had significantly higher IFN-γ expression in CD3- CD56dim NK cells after the 1st jab, whilst the older adult group had significantly higher IFN-γ and granzyme B expression in CD56bright NK cells after the 2nd jab (all p value <0.05). The IFN-γ expression in CD56dim and CD56bright NK cells after the first vaccination and CD86 expression in CD14+ monocyte and IgD-CD27-double-negative B cells after LPS and imiquimod stimulation correlated with vaccine-induced antibody responses. Conclusions: The innate immune responses after the first vaccination correlated with the neutralizing antibody production. Older people may have defective innate immune responses by TLR stimulation and weak or delayed innate immune activation profile after vaccination compared with young people.

Aging-Related Impairments to M Cells in Peyer's Patches Coincide With Disturbances to Paneth Cells.

The decline in mucosal immunity during aging increases susceptibility, morbidity and mortality to infections acquired via the gastrointestinal and respiratory tracts in the elderly. We previously showed that this immunosenescence includes a reduction in the functional maturation of M cells in the follicle-associated epithelia (FAE) covering the Peyer's patches, diminishing the ability to sample of antigens and pathogens from the gut lumen. Here, co-expression analysis of mRNA-seq data sets revealed a general down-regulation of most FAE- and M cell-related genes in Peyer's patches from aged mice, including key transcription factors known to be essential for M cell differentiation. Conversely, expression of ACE2, the cellular receptor for SARS-Cov-2 virus, was increased in the aged FAE. This raises the possibility that the susceptibility of aged Peyer's patches to infection with the SARS-Cov-2 virus is increased. Expression of key Paneth cell-related genes was also reduced in the ileum of aged mice, consistent with the adverse effects of aging on their function. However, the increased expression of these genes in the villous epithelium of aged mice suggested a disturbed distribution of Paneth cells in the aged intestine. Aging effects on Paneth cells negatively impact on the regenerative ability of the gut epithelium and could indirectly impede M cell differentiation. Thus, restoring Paneth cell function may represent a novel means to improve M cell differentiation in the aging intestine and increase mucosal vaccination efficacy in the elderly.

Impaired Functional T-Cell Response to SARS-CoV-2 After Two Doses of BNT162b2 mRNA Vaccine in Older People.

Long-term care facility (LTCF) older residents display physiological alterations of cellular and humoral immunity that affect vaccine responses. Preliminary reports suggested a low early postvaccination antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of this study was to focus on the specific T-cell response. We quantified S1-specific IgG, neutralizing antibody titers, total specific IFNγ-secreting T cells by ELISpot, and functionality of CD4+- and CD8+-specific T cells by flow cytometry, after two doses of the BNT162b2 vaccine in younger and older people, with and without previous COVID-19 infection (hereafter referred to as COVID-19-recovered and COVID-19-naive subjects, respectively). Frailty, nutritional, and immunosenescence parameters were collected at baseline in COVID-19-naive older people. We analyzed the immune response in 129 young adults (median age 44.0 years) and 105 older residents living in a LCTF (median age 86.5 years), 3 months after the first injection. Humoral and cellular memory responses were dramatically impaired in the COVID-19-naive older (n = 54) compared with the COVID-19-naive younger adults (n = 121). Notably, older participants' neutralizing antibodies were 10 times lower than the younger's antibody titers (p < 0.0001) and LCTF residents also had an impaired functional T-cell response: the frequencies of IFNγ+ and IFNγ+IL-2+TNFα+ cells among specific CD4+ T cells, and the frequency of specific CD8+ T cells were lower in COVID-19-naive older participants than in COVID-19-naive young adults (p < 0.0001 and p = 0.0018, respectively). However, COVID-19-recovered older participants (n = 51) had greater antibody and T-cell responses, including IFNγ+ and IFNγ+IL-2+TNFα+-specific CD4+ T cells (p < 0.0001), as well as TNFα+-specific CD8+ T cells (p < 0.001), than COVID-19-naive older adults. We also observed that "inflammageing" and particularly high plasma levels of TNFα was associated to poor antibody response in the older participants. In conclusion, our results show that the COVID-19-naive older people had low counts and impaired specific CD4+ and CD8+ T cells, in addition to impaired antibody response, and that specific studies are warranted to assess the efficiency of SARS-CoV-2 mRNA-based vaccines, as in other immunocompromised subjects. Our study also shows that, despite their physiological alterations of immunity, vaccination is highly efficient in boosting the prior natural memory response in COVID-19-recovered older people.

[Immunosenescence, viral infections and nutrition: A narrative review of scientific available evidence]. / Inmunosenescencia, infecciones virales y nutrición: revisión narrativa de la evidencia científica disponible.

Aging of the immune system, or immunosenescence, alters the viral immune response in the elderly, especially when frailty exists. Research findings have demonstrated an imbalance in pro- and anti-inflammatory mechanisms, reduced production and diversification of T lymphocytes, and an alteration in immunovigilance and antibody synthesis. In this context, nutrition has a role in combating sarcopenia and frailty. Some food components that contribute to immune-competence are protein, vitamin D, n-3 fatty acids, antioxidant vitamins (vitamins C and E), zinc, selenium and iron. In times of a pandemic, nutritional recommendations for immune-competence in the elderly should be based on clinical studies. In this article, immunosenescence and its relationship to nutrition are addressed, including interventions studied in the context of the COVID-19 pandemic.

Aging-Related Cellular, Structural and Functional Changes in the Lymph Nodes: A Significant Component of Immunosenescence? An Overview.

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.

COVID-19 vaccines and vaccination program for aging adults.

OBJECTIVE: COVID-19 vaccines have developed quickly, and vaccination programs have started in most countries to fight the pandemic. The aging population is vulnerable to different diseases, also including the COVID-19. A high death rate of COVID-19 was noted from the vulnerable aging population. A present scenario regarding COVID-19 vaccines and vaccination program foraging adults had been discussed. MATERIALS AND METHODS: This paper reviews the current status and future projections till 2050 of the aging population worldwide. It also discusses the immunosenescence and inflammaging issues facing elderly adults and how it affects the vaccinations such as influenza, pneumococcal, and herpes zoster. RESULTS: This paper recommends clinical trials for all approved COVID-19 vaccines targeting the elderly adult population and to project a plan to develop a next-generation COVID-19 vaccine. CONCLUSIONS: The review has mapped the COVID-19 vaccination status from the developed and developing countries for the elderly population. Finally, strategies to vaccinate all elderly adults globally against COVID-19 to enhance longevity has been suggested.

Gross ways to live long: Parasitic worms as an anti-inflammaging therapy?

Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, probiotic therapies that restore 'old friend' microbes and helminths have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, which contributes to a range of age-related diseases, including cardiovascular disease, dementia, and cancer. Interestingly, Crowe et al., 2020 recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease?