The Impact of Immune System Aging on Infectious Diseases

“…to encompass nine common features, including genomic instability, telomere shortening attrition, epigenetic alteration, deregulation of nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, alteration of intercellular communication, and loss of proteostasis [5].”

“This was especially poignant in the wake of the COVID-19 pandemic, when the mortality rate was disproportionately high among the elderly [238].”

“Severe infections in the elderly can evolve into sepsis, a life-threatening event caused by host response failure, resulting in multiorgan collapse [215].”

“In addition, three other distinctive derangements, such as alteration of metabolic pathways, adaptation to stress, and, more importantly, chronic inflammation, have been added to the list [7].”

“It has also been considered a negative process because it leads to a type of inflammation called “inflammaging”, which defines a reduction in the capability to cope with a variety of stressors and a progressive increase in the pro-inflammatory status [16].”

“Although information regarding the numbers and performance of dendritic cells (DCs) is relatively scarce, the number of circulating conventional and plasmacytoid DCs appears to be reduced in frail, healthy elderly [35].”

“…of highly active antiretroviral therapy, which has prolonged the survival of these patients despite a persistent inflammation, fueled by high levels of IL-6 and TNF-α , interferon (IFN)- α , reduced production of IL-2 [116–118], as well as by a variable decrease in the number of TRECs [37,119,120].”

“Infected patients likely produce an increased number of intrahepatic senescent, not functional T cells [156,157], which may promote the development of hepatocellular cancer as these T cells would be unable to eliminate premalignant senescent hepatocytes [158].”

“These advances, which incorporate immunobiography information with clinical, immunological and omics data, could allow stratifying subgroups of subjects and to identify those markers that could lead to the rational development of vaccines specifically designed for older adults [253,254].”

“Dysregulation of the gut microbiota, more precisely the decrease in diversity of the microbiome associated with aging, appears also play a role in Clostridium difficile colitis, the major cause of gastrointestinal infections worldwide, occurring in up to 80% of cases in adults aged 65 [208,209].”

“Indeed, while the accumulation of pro-inflammatory factors and inflammaging were suggested as standing at the origin of most diseases of the elderly, age-related inflammation showed a closer correlation with longevity than any other parameters [22,23].”

“…of highly active antiretroviral therapy, which has prolonged the survival of these patients despite a persistent inflammation, fueled by high levels of IL-6 and TNF-α , interferon (IFN)- α , reduced production of IL-2 [116–118], as well as by a variable decrease in the number of TRECs [37,119,120].”

“Several senolytic clinical trials have been completed, are current, or are planned for the near future [259], which include those focusing on immunosenescence or inflammaging [260–262].”

“Aging female T cells produce This organ preserves the physiologic populations of white blood cells and platelets that, mobilized by pathogenic invaders in the blood, sustain a protective immune response [59]. more IL-10 [65], capable of neutralizing age-related inflammaging.”

“More generally, immunosenescence refers to a series of complex changes leading to altered innate and adaptive immune system functions which, overall, may result in a state of immunodeficiency [15].”

“Some investigations have used wild or pet store mice, which are maintained in hygienic conditions, which may recapitulate adult human immune challenges [90].”

“The progressive senescence of the immune system during adulthood occurs earlier than was previously appreciated, most likely because comparative analyses were performed between young subjects and very old people, thus missing the intermediate age [74,77].”

“This virus is recognized by pathogen recognition receptors, the Toll-like receptors, which undergo an age-related decline [169].”

“Th2 cells have been shown to increase with aging [224], playing a paradoxical role in sepsis, since they may also increase the production of pro-inflammatory cytokines during emergency myelogenesis, and concomitantly be potently immunosuppressive [225].”

“…function that contributes to the increased susceptibility of the elderly to infections and, possibly, autoimmune diseases and cancer” [12]; “the changes in the immune system associated with age” [13]; and “a gradual and subjective decline of the immune system and host defense mechanisms” [14].”

“Several signs of immunosenescence have been observed in the viral encephalitis caused by WNV [168], representing a worldwide health concern due to the prevalence, severity, and lack of efficient treatments for this disease.”

“A decline in the diversity of the TCR repertoire owing to thymic involution has been implicated as causing defective immune responses in the elderly [46].”

“The accumulation of terminally differentiated, apoptosis-resistant, CMV-specific CD8+ lymphocytes is believed to reduce the overall TCR repertoire diversity [149,150].”

“Cord blood cells show extreme individual variability, which flattens during the first weeks of life, including an initial short-lasting neutrophil expansion, and the increase in CD4+ and CD8+ lymphocytes and B cells occurring in all children [76].”

“Further, immunosenescence develops later and slower in women [68], and this has been associated with their longer life expectancy [69,70].”

“The occurrence of sepsis arising from a concurrent excess of inflammation and immunosuppression [220] may also induce solid organ impairment [221], as in the case of blood–brain barrier disruption, local myocardial ischemia, or infarction secondary to pre-existing coronaropathy.”

“Age-Associated Changes in the Immune Compartments Several age-related modifications affect the innate and adaptive immune system [26,27 In aging bone marrow, hematopoietic stem cells show reduced One of the most recent hypotheses on the meaning of immune system age-related changes is that these…”

“…higher monocyte activity [63], expression of myeloid cell-related genes [64], and a faster decline in the number and function of B and T cells [63]. females aged between 20 and 70, tested eight lymphocyte subpopulations, 3 million single nucleotide polymorphisms, and 560 genes of the immune…”

“Undoubtedly, a failure of innate immunity is also likely to play a role because of the decrease in macrophage functions [131,132], and of reduced uptake of opsonized bacteria by CD14+ monocytes [133].”

“…mediators, concomitantly with the adoption of lifestyle factors, including smoking, obesity, alcohol, lack of exercise, and exposure to ultraviolet radiation, are known to increase the risk for age-related multi-organ/system diseases (Figure 1) [15,19–22] and premature morbidity and mortality.”

“Additionally, the production of cytokines is not optimal for adaptive immune response priming [243].”

“The progressive senescence of the immune system during adulthood occurs earlier than was previously appreciated, most likely because comparative analyses were performed between young subjects and very old people, thus missing the intermediate age [74,77].”

“An pathological aging burdened by age-related diseases [25].”

“For instance, in the lungs, decreased respiratory muscle strength reduces lung compliance, and impaired muco-ciliary function leads to inefficient clearance of infectious organisms [101].”

“Telomere length measure, recognized as one of the most reliable biomarkers of aging [83], provides a rough estimate of the rate of the immunosenescence process and can hardly be regarded as clinically relevant [84].”

“…mice [135] reduced public CD8+ TCR αβ clonotypes and TCR αβ diversity [137] Influenza virus decrease in macrophage peritoneal phagocytic function [131,132] reduced uptake of bacteria by monocytes [133] decreased abundance, activity and migration of DCs [134] RSV low levels of serum neutralizing…”

“Although most individuals exposed to MTB manage to control tuberculosis (TB), which can remain in a latent form, approximately 5–10% of them develop an active disease [175].”

“These advances, which incorporate immunobiography information with clinical, immunological and omics data, could allow stratifying subgroups of subjects and to identify those markers that could lead to the rational development of vaccines specifically designed for older adults [253,254].”

“Also, intra-abdominal infections, such as cholecystitis, diverticulitis, appendicitis, abscesses, infectious endocarditis, bacterial meningitis, tuberculosis, and herpes zoster, have been reported to frequently occur in the elderly [113].”

“In addition, the virus can interfere with the type 1 IFN pathway and the production of pro-inflammatory cytokines [160].”

“Moreover, infections by new pathogens, such as West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19) pandemic, have shown heightened severity in the older population [99,100].”

“Similarly, IgA and IgM levels were found to be significantly lower in the elderly vaccinated against pneumonia [248–250], and antibodies against VZV are low in subjects ≥ 70 years old [251].”

“…and increase in CD56 − CD16+ NK cells percentage [146] lower number of naïve CD4+ and increased effector memory CD4+ and CD8+ T cells [148] reduced TCR repertoire diversity [151] EBV expansion of CD56-NK cells with reduced cytotoxic capacity and IFN-γ production [152] increase in…”

“Age-related alteration of the microbiota also leads to a decrease in the production of short-chain fatty acids, which may promote inflammation and cell vulnerability [207].”

“…and Gram-negative intestinal bacteria disequilibrium activation of DCs [205] release of pro-inflammatory cytokines, mainly IL-6 and IL-17 [206] senescent cellular markers in DCs [214] Gram-positive and Gram-negative induced sepsis expansion of myeloid-derived suppressor cells, inhibiting…”

“…of highly active antiretroviral therapy, which has prolonged the survival of these patients despite a persistent inflammation, fueled by high levels of IL-6 and TNF-α , interferon (IFN)- α , reduced production of IL-2 [116–118], as well as by a variable decrease in the number of TRECs [37,119,120].”

“Th2 cells have been shown to increase with aging [224], playing a paradoxical role in sepsis, since they may also increase the production of pro-inflammatory cytokines during emergency myelogenesis, and concomitantly be potently immunosuppressive [225].”

“Indeed, while the accumulation of pro-inflammatory factors and inflammaging were suggested as standing at the origin of most diseases of the elderly, age-related inflammation showed a closer correlation with longevity than any other parameters [22,23].”

“Although the output of new B cells, quantified by measuring K deleting recombinant excision circles (KRECs), remains conserved [49], with the peripheral number unchanged, aging is associated with a decline in the frequency of naïve B cells and in the percentage of switch memory B cells [50,51].”

“In addition, persistent infections result in a prolonged antigenic overload of the immune system, leading to host T-cell exhaustion [105] and the promotion and/or acceleration the progressive accumulation of cells with an immunosenescent phenotype [106], thus easing the development of a…”

“Similarly, the decreased function of the epithelial barriers of the skin, lungs, and gastrointestinal tract favors the pathogen invasiveness [102].”

“…Committee on Immunization Practices of Centers for Disease Control and Prevention recommends that adults over 65 years obtain immunization against herpes zoster virus, Streptococcus pneumoniae , influenza viruses [104], and more recently, RSV in those over 60 years [239], and SARS-CoV-2 [104].”

“Finally, vaccine-induced antibodies commonly show lower protective capacity [244], as suggested by the low production of antibodies in response to influenza vaccination in old rhesus macaques [246] and old individuals [247].”

“Vaccination that elicits immunological memory capable of protecting against subsequent infections is crucial in safeguarding the elderly, a population generally less responsive to both primary and booster challenges [134,236], and thus is less protected [237].”

“…these modifications are linked to the immune system response to permanent stress. self-renewal potential and increased skewing toward myelopoiesis [28], probably because of compromised Pax5 expression and Rag2 recombinase function and bone marrow niche alterations This novel vision considers…”

“The variation in cell composition, plasma proteins, and functional responses in aging through a system immunology approach has been possible due to the introduction of high-throughput “omics” technologies [93].”

“This provides unprecedented information on the human immune response following vaccinations, infections, autoimmunity, and tumors [94].”

“Age-Associated Changes in the Immune Compartments Several age-related modifications affect the innate and adaptive immune system [26,27 In aging bone marrow, hematopoietic stem cells show reduced One of the most recent hypotheses on the meaning of immune system age-related changes is that these…”

“Finally, vaccine-induced antibodies commonly show lower protective capacity [244], as suggested by the low production of antibodies in response to influenza vaccination in old rhesus macaques [246] and old individuals [247].”

“…senescent CD8+ CD28 − T cells [154] HCV high plasma levels of SASP proteins [155] increase in intrahepatic senescent, not functional T cells [156,157] HZV interferes with the type 1 IFN pathway and the production of pro-inflammatory cytokines [160] reduced frequency of virus-specific…”

“In-deed, as with many other aging-related diseases, the diagnosis of active TB is difficult because of non-specific symptoms, such as unexplained fever and weight loss, which are less pronounced in this population [177].”

“Since it can impact the functions of many organs and systems, it represents a major risk factor for the on-set and/or progression of a wide spectrum of aging-related disorders [1].”

“These features can only partly be explained by age-related comorbidities [217], which are related to multiple organ failure produced by an excessive inflammatory response [218].”

“Elderly people often have recurrent clinically mild RSV infections [138], which occasionally may cause altered airway resistance and the worsening of chronic obstructive lung disease [139], leading to serious or life-threatening pneumonia [140].”

“…can favor the appearance of autoreactive clones [66], as supported by epidemiological studies showing that about 80% of autoimmune diseases occur in females at earlier age [67]. factors are correlated with only a few changes in immune system genes, but these changes are extremely puissant [71].”

“…[68], women are A study, enrolling 500 males and 500 females aged between 20 and 70, tested eight lymphocyte subpopulations, 3 million single nucleotide polymorphisms, and 560 genes of the immune system before and after reported to be more sensitive to immunostimulating strategies [73].”

“In humans, senescent cells of various lineages accumulate at various body sites at different rates, from 2-to 20-fold, when comparing young (<35 years) to old (>65 years) healthy individuals [8].”

“Although all cell types can undergo senescence during aging, this process mainly affects fibroblasts, endothelial cells, chondrocytes, tenocytes, skin and immune cells [9–11].”

“In particular, senescent immune cells, by producing cytokines, chemokines, growth factors, proteases, and angiogenic factors, acquire the so-called “senescence-associated secretory phenotype” (SASP) [18].”

“The production of B lymphocytes, as well as of myeloid cells, is impaired in aged bone marrow [29].”

“Further, immunosenescence develops later and slower in women [68], and this has been associated with their longer life expectancy [69,70].”

“These cells have distinct phenotypes, gene expression profiles, special survival requirements, variations in B-cell receptor repertoires, and unique functions [52].”

“It is of interest that the accumulation of highly differentiated T cells and the significant reduction in naïve T cells are not observed in long-lived individuals [47], so centenarians show unexpectedly larger TCR repertoires [48].”

“Poor intestinal mucosal immunity represents a major factor leading to higher mortality from infections in aging [203] because it favors the changes in the human intestinal microbiota associated with inflammatory bowel diseases, irritable bowel syndrome, and metabolic disorders [204].”

“Aging appears to affect DCs, in terms of a decrease in number, activity, and migration, determining poorer viral clearance as well as clinical outcomes and susceptibility to complications, which have been correlated to the levels of circulating inflammatory cytokines [134].”

“…during HIV infection, the immunosenescence process is accelerated, resulting not only in an immunosuppressed state unable to contain HIV replication and spread, but also to a lower capacity to respond to new antigenic challenges favoring other infections and age-associated organ diseases [126].”

“In contrast, genetic The high humoral response observed in women can favor the appearance of autoreactive clones [66], as supported by epidemiological studies showing that about 80% of autoimmune diseases occur in females at earlier age [67]. factors are correlated with only a few changes in immune…”

“It is of interest that the accumulation of highly differentiated T cells and the significant reduction in naïve T cells are not observed in long-lived individuals [47], so centenarians show unexpectedly larger TCR repertoires [48].”

“The outcomes of sepsis are worst in older adults, with higher rates of mortality, organ dysfunction, cognitive deficiency, and permanent disabilities [216].”

“As a result, antibody affinity and diversity also decline, leading to impaired antibody responses [53].”

“…Klebsiella pneumoniae , Proteus mirabilis , Enterobacter species, Citrobacter species, and Pseudomonas aeruginosa , as well as Gram-positive bacteria, including group B Streptococcus , other streptococci, Staphylococcus aureus , coagulase-negative staphylococci, and Enterococcus species [195,196].”

“This receptor, potentially relevant for susceptibility to WNV, has been found in human DCs [170].”

“This acceleration is anticipated to be largely variable, being related to the variety of inducing environmental factors, type, intensity, duration, and temporal sequence of antigen exposure, the so called “exposome” [110], implying that that aging is an individual phenomenon.”

“…and autoantibody data were integrated with information on gut microbiota composition, routine clinical chemistry, and various clinical parameters [97]. multihierarchical or multiscale organization, the components at a lower scale are integrated with the functional units of the immediately higher…”

“In these patients, both antibody opsonic activities for all tested pneumococcal serotypes and phagocytic killing of pneumococci by neutrophils were significantly impaired [191].”

“…with worse health conditions [17]. and silencing of immune system genes occur through different “switches”, which partially Although detailed information is lacking regarding sex differences in immune performance, a number of advances have been made. percentages and types of immune players [72].”

“The interactions between MTB and the host immune system are complex and only partially clarified, but the concomitant overall senescence of both innate and adaptive immunity appears to play a major role [181–183].”

“…demonstrated moderate efficacy when used in clinical trials, next-generation senolytics (CAR-T cells, antibody drug conjugates or vaccines) targeting specific proteins selectively expressed during senescence and, based on new technical developments, can pave the way for preclinical research [263].”

“Similarly, IgA and IgM levels were found to be significantly lower in the elderly vaccinated against pneumonia [248–250], and antibodies against VZV are low in subjects ≥ 70 years old [251].”

“The number of circulating neutrophils does not significantly change [30], although the function of these cells may be compromised in aging, since activated neutrophils are more prone to apoptosis and deficient The prevalence of one of the conditions may result either in healthy longevity or…”

“…alter the mucosal landscape [195] aged bladder CXCL13+ macrophages may be responsible for inhibiting development of the adaptive immune responses [198] decreased macrophage phagocytosis [199] Gram-positive and Gram-negative intestinal bacteria disequilibrium activation of DCs [205] release of…”

“While natural killer (NK) cells significantly increase, with the majority of these cells being CD56dim, their proliferative ability declines with age [36].”

“CMV seropositive elderly donors have a decreased percentage of both CD16 − and CD16+ CD56bright NK cells, and an increase in the CD56 − CD16+ subset [146].”

“Other respiratory viruses, such as human metapneumovirus, human rhinovirus, and human parainfluenza virus, also lead to substantial morbidity and mortality in the elderly [144], but the impact of senescence and other factors modulating their severity in the elderly remain to be identified.”

“…phagocytic killing of neutrophils [191] changes in CD27+IgM+ B cells [194] increase in senescence markers (IL-1 α / β , TNF-α , IL-6, and CXCL1) [192] Escherichia coli and other bacteria inducing urinary tract infections high levels of pro-inflammatory cytokines (IL-6, IL-1 β , and TNF-α )…”

“…due to VZV infection, is also associated with an age-related decline in cell-mediated immunity against the virus, namely with the reduced frequency of virus-specific effector memory T cells [161], which appears to be the cause of the increased risk of post-herpetic neuralgia complications [162].”

“Data resulting from the measurement of thymic emigrants by flow cytometer [39–41] or TCR excision circles (TRECs) by real-time PCR [37,42–44] have demonstrated that the release of new T cells decreases progressively during aging.”

“…at the border between the follicular and marginal zones, become disorganized, leading to altered immune system cell localization, resulting in an improper antigen-presenting capacity [60,61]. epidemiological studies showing that about 80% of autoimmune diseases occur in females at earlier age [67].”

“Interestingly, patients who successfully eradicated Helicobacter pylori , another infection related to changes in the microbiota, had significantly lower histological markers of inflammation [210,211].”

“Similarly, IgA and IgM levels were found to be significantly lower in the elderly vaccinated against pneumonia [248–250], and antibodies against VZV are low in subjects ≥ 70 years old [251].”

“The data demonstrated that age preferentially Aging female T cells produce more IL-10 [65], capable of neutralizing age-related inflammaging. and macrophages, as well as multiple genes related to the immune system.”

“These conditions can be related to the incapacity, at any age, to preserve and/or restore an optimal “immune resilience” when inflammatory or antigenic stressors occur [269].”

“This disease is common in the elderly, and is associated with chronic diarrhea, malabsorption, weight loss, and secondary nutritional deficiencies [213].”

“…[135] reduced public CD8+ TCR αβ clonotypes and TCR αβ diversity [137] Influenza virus decrease in macrophage peritoneal phagocytic function [131,132] reduced uptake of bacteria by monocytes [133] decreased abundance, activity and migration of DCs [134] RSV low levels of serum neutralizing…”

“These data are in line with those obtained in mice, indicating that age induces an inflammatory pulmonary environment, turning the resident macrophages more prone to being infected by MTB [185].”

“With aging, a progressive increase in terminal effector memory T (TEMRA) cells occurs [86].”

“Although total white blood cell counts and lymphocyte counts have been the most studied biomarkers of adaptive immunity, they can further differentiate after their maturation in response to pathogens, so it is unclear when senescence is induced in these cells [82].”

“In particular, there are cell markers that are sensitive to the conditions in which they are collected, temperature, delay in processing, preservation method, duration of storage, and number of freeze–thaw cycles [256].”

“…of highly active antiretroviral therapy, which has prolonged the survival of these patients despite a persistent inflammation, fueled by high levels of IL-6 and TNF-α , interferon (IFN)- α , reduced production of IL-2 [116–118], as well as by a variable decrease in the number of TRECs [37,119,120].”

“While IL-6 serum concentrations in healthy individuals are undetectable or minimal, elevated levels have been reported, especially in advanced age, to be associated with disability and mortality; TNF-α age-related changes behave similarly [81].”

“Indeed, in this infection, an increase in Ag-experienced IFN-γ -producing CD4+ T cells has been described [234].”

“Dysregulation of the gut microbiota, more precisely the decrease in diversity of the microbiome associated with aging, appears also play a role in Clostridium difficile colitis, the major cause of gastrointestinal infections worldwide, occurring in up to 80% of cases in adults aged 65 [208,209].”

“Many of these improvements have been optimized for studies at the single cell level [95], especially to characterize immune system cells that are located in multiple sites, i.e., blood, primary and secondary lymphoid organs, respiratory and gastrointestinal tissues (lungs, intestine, pancreas, and…”

“…of the risk factors for poor outcomes in RSV infection found a strong link between immunosenescence and preexisting co-morbidities (cardiac, pulmonary, and immunocompromising conditions, diabetes, and renal disease), and living conditions (socioeconomic status and nursing home residence) [143].”

“…of bacteria by monocytes [133] decreased abundance, activity and migration of DCs [134] RSV low levels of serum neutralizing antibody and IFN-γ [141] RSV-specific effector memory T cells prevent symptomatic infection [142] CMV increased CD8+ CD244+ effector T cells [147] decreased…”

“For a discussion of the role of aging in response to severe acute respiratory syndrome coronavirus 2 infection, we recommend the reader refer to recent contributions [118,127,128].”

“Unfortunately, this longer life expectancy is associated with worse health conditions [17].”

“…antibody and IFN-γ [141] RSV-specific effector memory T cells prevent symptomatic infection [142] CMV increased CD8+ CD244+ effector T cells [147] decreased CD16-/CD16+CD56bright and increase in CD56 − CD16+ NK cells percentage [146] lower number of naïve CD4+ and increased effector memory…”

“Overall, TEMRA cells, characterized by a decline in proliferation potential, efficient cytotoxicity, pro-inflammatory activity, and high clonal expansion, are considered hallmarks of immunosenescence [87,88].”

“…[88] expansion of non-functional CD3-CD56-CD16+ NK cells [125] elevated KRECs in patients not needing therapy [121] decreased T-cell diversity [123] diminished CD8+ T-cell response in aged mice [135] reduced public CD8+ TCR αβ clonotypes and TCR αβ diversity [137] Influenza virus decrease in…”

“This was suggested mainly by a murine model performed in mice, in which Th2 function and anti-worm antibody production are compromised in old age [235].”

“An additional leading cause of infection-related mortality in the elderly is Streptococcus pneumoniae infection [190].”

“In addition, changes in the local production of adequate amounts of chemokines and cytokines were observed, which ensured an efficient immune response [57,58].”

“…and CD8+ T cells [148] reduced TCR repertoire diversity [151] EBV expansion of CD56-NK cells with reduced cytotoxic capacity and IFN-γ production [152] increase in terminally differentiated T cells and decrease in TCR repertoire diversity [153] expansion of viral-specific exhausted, senescent…”

“…and secondary lymphoid organs, respiratory and gastrointestinal tissues (lungs, intestine, pancreas, and liver), and barrier sites (skin and mucosal surfaces), where the composition, phenotype, function, and tissue-specific adaptations of different immune cell populations are known to differ [96].”

“Data resulting from the measurement of thymic emigrants by flow cytometer [39–41] or TCR excision circles (TRECs) by real-time PCR [37,42–44] have demonstrated that the release of new T cells decreases progressively during aging.”

“On the contrary, there are elderly people, in particular centenarians, who harbor a unique, highly functional immune system that has successfully adapted to a history of insults, allowing for exceptional longevity [268].”

“Poor intestinal mucosal immunity represents a major factor leading to higher mortality from infections in aging [203] because it favors the changes in the human intestinal microbiota associated with inflammatory bowel diseases, irritable bowel syndrome, and metabolic disorders [204].”

“…at the border between the follicular and marginal zones, become disorganized, leading to altered immune system cell localization, resulting in an improper antigen-presenting capacity [60,61]. epidemiological studies showing that about 80% of autoimmune diseases occur in females at earlier age [67].”

“Several senolytic clinical trials have been completed, are current, or are planned for the near future [259], which include those focusing on immunosenescence or inflammaging [260–262].”

“Converging literature recognizes IL-6 and TNF-α as relevant biomarkers for the aging innate immune system [80].”

“Overall, due the low adherence to treatment and poorer tolerance to TB drugs, anticipatory diagnosis in the elderly represents an important challenge [176].”

“Also, neutrophils, monocyte/macrophages, and DCs, the first barriers to this infection, show an age-related impairment [99].”

“Indeed, bacterial invasion leads to an increase in the secretion of inflammatory exosomes which, in turn, amplify immune senescence [214].”

“Finally, it must be remembered that impairments of the immune system resembling those induced by aging can have an iatrogenic origin; this is the case, for example, of disease-modifying therapies for multiple sclerosis [172].”

“Moreover, tetanus and diphtheria vaccines were also recommended, despite responses to these vaccines often being impaired in older individuals [240].”

“Although a diminished CD8+ T-cell immune response to influenza virus infection [135] has been demonstrated in the past in mice, only very recently has the role of CD8+ T cells been elucidated as a mechanism of respiratory viral infection severity in the elderly [136].”

“Finally, evidence has been gathered of an overall decline in mucosal immunity, especially in the gastrointestinal tracts of the elderly [62].”

“…the production of pro-inflammatory cytokines [160] reduced frequency of virus-specific effector memory T cells [161] increases in CD57+ NK cells [159] reduction in IFN-γ /IL-4 ratio and other pro-inflammatory, such as IL-17A, IL-2, TNF-α [187] reduction in regulatory T cells and polyfunctional…”

“Conclusively, our understanding of the relationship between aging and the onset of sepsis is incomplete and conflictual, as little or no association between age and inflammatory markers [226,227] or higher levels of these mediators among older septic patients [228] have been found.”

“One should remember that, to appreciate significant changes related to IS, long-term follow-up analyses should be performed, since a rather stable immune system cell composition is commonly observed in the short period of observation [79].”

“Vaccination that elicits immunological memory capable of protecting against subsequent infections is crucial in safeguarding the elderly, a population generally less responsive to both primary and booster challenges [134,236], and thus is less protected [237].”

“The interactions between MTB and the host immune system are complex and only partially clarified, but the concomitant overall senescence of both innate and adaptive immunity appears to play a major role [181–183].”

“Telomere length measure, recognized as one of the most reliable biomarkers of aging [83], provides a rough estimate of the rate of the immunosenescence process and can hardly be regarded as clinically relevant [84].”

“Unfortunately, large gaps exist between our understanding of the immune response to a natural influenza infection and vaccination, although immunity appears to be more robust and longer-lived in natural infections than following vaccinations [130].”

“Despite being extensively investigated, no conclusive data is available regarding how cytomegalovirus (CMV) infection influences the immune response in the elderly and how it can trigger an increase in pro-inflammatory cytokines, promoting inflammaging [145].”

“…differentiated T cells and decrease in TCR repertoire diversity [153] expansion of viral-specific exhausted, senescent CD8+ CD28 − T cells [154] HCV high plasma levels of SASP proteins [155] increase in intrahepatic senescent, not functional T cells [156,157] HZV interferes with the type…”

“The exact cause and significance of all these changes are not clear, but alterations to immune cell signaling may be one of prominent cause of malfunctioning immunity, as extensively discussed in Fulop et al. [54].”

“Infections from Escherichia coli are the most common cause of recurring UTIs that continue to be a burden on aging females [195].”

“Although the output of new B cells, quantified by measuring K deleting recombinant excision circles (KRECs), remains conserved [49], with the peripheral number unchanged, aging is associated with a decline in the frequency of naïve B cells and in the percentage of switch memory B cells [50,51].”

“Finally, it should be underlined that, despite the overall tuberculosis burden and rate of mortality in the elderly having declined in recent years [188], this pattern is expected to reverse, particularly for those aged ≥ 80 years [189].”

“A large body of information has been accumulated regarding the still ill-defined link between bacterial infections and immunosenescence [266], indicating that aging affects the functions of immune system cells, resulting in an increase in infection severity, and that chronic viral infections can…”

“…of human lung fibroblast cells by the measles virus generates cellular senescence, as documented by reduced cell proliferation, sa β -gal activity, increased expression of p53 and p21, as well as the induction of pro-inflammatory secretome with IL-8 or C-C motif chemokine ligand 5 expression [164].”

“…and regulatory T-cell productions [222] parasitic Leishmania expansion of senescent CD56+ CD57+ NK cells [231] expansion of CD57+ CD4+ lymphocytes [230] expansion of effector memory CD8+ T cells that re-express CD45RA marker [231] increased transcriptions of senescence-associated genes in the…”

“Mouse models have also been particularly informative in studies of aging [270], but they have not allowed us to establish to what extent these models faithfully recapitulate the mechanisms underlying immunosenescence processes in humans and their possible common effects in predisposing to…”

“In addition, a restriction on TCR repertoire diversity [45], both in memory CD4+ and CD8+ T cells, occurs [46].”

“…decreased T-cell diversity [123] diminished CD8+ T-cell response in aged mice [135] reduced public CD8+ TCR αβ clonotypes and TCR αβ diversity [137] Influenza virus decrease in macrophage peritoneal phagocytic function [131,132] reduced uptake of bacteria by monocytes [133] decreased…”

“As gut biodiversity decreases, potential pro-inflammatory microbes accumulate [205].”

“This is an important issue in view of the expected increase in population aging, leading to a higher incidence of herpes zoster cases in developed countries [163].”

“…bladder CXCL13+ macrophages may be responsible for inhibiting development of the adaptive immune responses [198] decreased macrophage phagocytosis [199] Gram-positive and Gram-negative intestinal bacteria disequilibrium activation of DCs [205] release of pro-inflammatory cytokines, mainly IL-6…”

“…and toxins, geographical location, seasons, the number of family members, composition of the microbiota, presence of co-infections, use of antibiotics, smoking, dietary intake, alcohol consumption, exercise, sleep patterns, and comorbidities of the host also play a role in vaccine response [241].”

“More recently, the issue of immune system variability has been addressed by a new approach, defined as “system immunology”, a branch of “systems biology” [91].”

“Furthermore, it must be remembered that some younger individuals show features consistent with a pro-inflammatory and early immunosenescence state, which may pre-dispose to an increased risk/severity of diseases [267].”

“Therefore, both chronic infection and the related immune response contribute to accelerating aging [109].”

“Interestingly, patients who successfully eradicated Helicobacter pylori , another infection related to changes in the microbiota, had significantly lower histological markers of inflammation [210,211].”

“…NK cells percentage [146] lower number of naïve CD4+ and increased effector memory CD4+ and CD8+ T cells [148] reduced TCR repertoire diversity [151] EBV expansion of CD56-NK cells with reduced cytotoxic capacity and IFN-γ production [152] increase in terminally differentiated T cells and…”

“…data were integrated with information on gut microbiota composition, routine clinical chemistry, and various clinical parameters [97]. multihierarchical or multiscale organization, the components at a lower scale are integrated with the functional units of the immediately higher scale [92].”

“One of the main and early investigated adaptive immune system impairments occurs as a result of thymic involution, such as loss of organ mass, disruption of architecture, enhancement of perivascular space, and increased adiposity, which fail to meet the demand for new T-cell output [37,38].”

“More informative is the quantification of TRECs and KRECs [43], which mirrors the capability to homeostatically replenish both lymphocyte pools.”

“…overload of the immune system, leading to host T-cell exhaustion [105] and the promotion and/or acceleration the progressive accumulation of cells with an immunosenescent phenotype [106], thus easing the development of a pro-inflammatory milieu that favors aging-related diseases [107,108].”

“…overload of the immune system, leading to host T-cell exhaustion [105] and the promotion and/or acceleration the progressive accumulation of cells with an immunosenescent phenotype [106], thus easing the development of a pro-inflammatory milieu that favors aging-related diseases [107,108].”

“Overall, TEMRA cells, characterized by a decline in proliferation potential, efficient cytotoxicity, pro-inflammatory activity, and high clonal expansion, are considered hallmarks of immunosenescence [87,88].”

“Conclusively, our understanding of the relationship between aging and the onset of sepsis is incomplete and conflictual, as little or no association between age and inflammatory markers [226,227] or higher levels of these mediators among older septic patients [228] have been found.”

“Finally, vaccine-induced antibodies commonly show lower protective capacity [244], as suggested by the low production of antibodies in response to influenza vaccination in old rhesus macaques [246] and old individuals [247].”

“…due to VZV infection, is also associated with an age-related decline in cell-mediated immunity against the virus, namely with the reduced frequency of virus-specific effector memory T cells [161], which appears to be the cause of the increased risk of post-herpetic neuralgia complications [162].”

“However, it is important to underline that the diagnosis and treatment of chronic diseases related to age place a significant burden on National Healthcare System budgets [265].”

“Antigen-specific T cells against EBV undergo an age-related increase in the expression of markers associated with a differentiated phenotype, including KLRG-1, an increase in terminally differentiated T cells, and a decrease in the TCR repertoire diversity [153].”

“The study demonstrates that the inter-individual variability of most immune system subpopulations starts before the age of 50 [78], well before the age of 60, conventionally established as the initiation of immunosenescence.”

“Similarly, parvoviruses induce the expression of a pro-inflammatory secretome, including IL-8, IL-6, and IL-1 β production [165]; dengue virus and Merkel cell polyomavirus elicit sa β -gal expression [166,167].”

“Patient-specific factors include immunosenescence, frailty, sarcopenia, cognitive dysfunction, multimorbidity, and polypharmacy [5].”

“This impairment manifests as a reduced ability to produce antibodies after vaccination or infection, making older individuals more susceptible to many infections, including influenza and pneumonia [206].”

“This functional impairment of the immune system reduces the effectiveness of responses to new pathogens, including opportunistic fungi [87].”

“Those cells significantly contribute to the inflammaging leading to the development of age-related diseases [141,142].”