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].”

“…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].”

“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].”

“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.”

“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].”

“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].”

“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].”

“…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].”

“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…”

“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].”

“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].”

“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].”

“…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…”

“…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].”

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

“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].”

“…[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].”

“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].”

“…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].”

“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].”

“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].”

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

“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].”

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

“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…”

“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].”

“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].”

“…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].”

“…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].”

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

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

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

“…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].”

“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.”

“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].”

“…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…”

“…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…”

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

“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].”

“…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].”

“…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].”

“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.”

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

“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.”

“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].”

“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].”

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

“…[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 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].”

“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].”

“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].”

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

“…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].”

“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 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…”

“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].”

“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].”

“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.”

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

“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].”

“…[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…”

“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].”

“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].”

“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].”

“…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].”

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

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

“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].”

“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.”

“…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…”

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

“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].”

“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].”

“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].”

“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].”

“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…”

“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].”

“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].”

“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…”

“…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…”

“…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].”

“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…”

“…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].”

“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].”

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

“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…”

“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].”

“…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].”

“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].”

“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].”

“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].”

“…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].”

“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.”

“…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].”

“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].”

“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].”

“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].”

“Alterations in monocyte percentage and phenotype increase with age, suggesting a potential link with the elderly’s specific susceptibility to developing active TB [186].”

“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].”

“A significant percentage of the elderly exhibit a tendency to express Th2 phenotypes and have been found to have low NK cell activity [218].”

“81 Preterm birth is correlated with myocardial remodeling and accelerated cardiovascular ageing later in life.”

“2012; Rea et al. 2018; Quiros-Roldan et al. 2024).”

“5,6 Also, sex -specific differences have been observed, with females showing higher numbers of total leukocytes, including higher proportions of T cells, B cells, and macrophages in tissues like the peritoneal and pleural cavities compared to males.”

“As a result, the immune system undergoes progressive weakening, with impaired T-and B-cell function and consequent compromise of both innate and adaptive immunity, and predisposes older adults to heightened vulnerability to HAIs [23].”

“Collectively, these factors significantly elevate the risk of MDR infections in older adults [25].”

“These innate and adaptive immune dysfunctions converge in the loss of “integrated immunocompetence”, a concept describing the immune system’s capacity to mount a coordinated and adaptive response to external stimuli [83].”

“This variation in prevalence across age groups suggests that older birds may have acquired immunity or benefit from better management practices, while younger birds are at higher risk due to incomplete immune development and greater susceptibility to infections (25).”

“Notably, women respond better to immunostimulating therapies, emphasizing the need for personalized health and vaccination strategies that consider sex-based immune variations [42].”

“…aging, immunological decline, and cumulative environmental exposures compromise skin barrier function, leading to increased incidence and severity of inflammatory skin diseases, infections, and malignancies, especially during periods of poor air quality or extreme weather events [88–90].”

“For decades, immunological aging research has focused predominantly on lymphocyte (especially T cell) intrinsic defects, declining efficacy, increased susceptibility to exhaustion, and impaired generation of new naive T cells by the aging thymus [24].”

“…are (older people, people with chronic illnesses, and people with weakened immune systems) and more complicated treatments (mechanical ventilation, indwelling catheters, organ transplantation) have changed the microbial battlefield, making hospitals perfect places for opportunistic infections [6].”

“…the finding that all isolates from older adults (≥ 60 years) were multidrug-resistant (MDR) highlights the need for targeted infection prevention interventions for high-risk populations, particularly elderly patients who may have prolonged antibiotic exposure due to chronic conditions [41,42].”

“A decrease in ciliary beat capacity and increased secretion of mucin have been reported in the literature [28–32].”

“Age is a major risk factor, with young adults potentially exhibiting hyperactive immune responses that trigger excessive inflammation and older adults experiencing immunosenescence, characterized by impaired viral clearance due to dysregulated immune responses [200–202].”

“Targeted healthcare interventions for this group, including regular screenings for infections and preventive care such as vaccinations, could help mitigate these risks [38].”

“Host-related factors, including age-related immune decline and prior exposure history, also play a significant role in shaping vaccine responses [6,38].”

“In older adults, neutrophils display reduced efficiency in chemotaxis, phagocytosis, and microbial killing [38,39].”

“Exhausted and terminally differentiated memory T cells frequently acquire resistance to apoptosis, allowing them to persist despite functional impairment [66–70].”

“Furthermore, declining immune function leads to the attenuated efficacy of cancer immunotherapy, markedly increased incidence and mortality of infectious diseases (such as influenza and pneumonia) [8,9], and elevated cardiovascular disease risk [10].”

“As a result, older adults display a reduced pool of naïve T cells for responding to novel antigens, while memory T cells become predominant [50–52].”

“The increasing burden with advancing age is consistent with prior literature, which highlights the greater vulnerability of older adults to infectious gastroenteritis due to age-related immunosenescence, comorbid conditions, and delayed healthcare-seeking behavior [22].”

“Aging is known to lead to a decline in immune function (immunosenescence), which may be an additional risk factor for IMD and its debilitating sequalae and consequences 58 .”

“What this study adds: ● Our study explored the clinical manifestations across different spectrums of ocular TB, including patients with proven infection (active disease) and those diagnosed solely based on IGRA positivity.”

“While in advanced age, reduced bone marrow hematopoietic potential manifests with reduced production of B cells (especially naive and switch memory B cells), increasing vulnerability to bacterial and viral infections [21].”

“The progressive systemic depletion of CD4 + T-lymphocytes caused by HIV infection directly translates to a profound impairment of mucosal immune surveillance in the female reproductive tract [38].”

“It may be due to the severe changes in hosts’ physiological imbalance and weakened immunity, which lead to susceptibility to fungal infections [78].”

“This pattern is consistent with their immature immune systems and limited adaptive immunity, which may reduce their ability to withstand acute and severe infections once disease occurs [40].”

“Collectively, these deficits compromise the overall effectiveness of the immune response and increase susceptibility to infections in the elderly [43].”

“Host-specific factors such as age-related immune decline, immunosuppression, and underlying comorbidities significantly influence the clinical trajectory and treatment outcomes of infections caused by antimicrobial-resistant pathogens [83–85].”

“The higher proportion of culture positives in elderly patients may be due to their weak immune system, which increases their susceptibility to infections, and, often, the presence of comorbidities [14].”

“Furthermore, as impaired innate and adaptive immune responses make the elderly more vulnerable to pathogens and decreases the effectiveness of many vaccines (28).”

“164–166 New research emphasizes the considerable role that imbalances in gut microbiota play in the processes associated with aging.”

“…to other family members ( p = 0.02), suggesting that occupational exposures and behavioural factors specific to this role, such as increased involvement in agricultural activities or greater exposure to contaminated environments, as mentioned above, may contribute to their increased risk [28, 29].”

“Advanced age is a risk factor not only for cryptococcal infection, but other infections as well due to immunosenescence from an aging immune system [12,13].”

“31 Several studies evaluating SSI risk factors are limited by single-center design, heterogeneous patient populations, and variations in wound classification systems.”

“…related signalling and senescence associated secretory phenotype (SASP) promote chronic low-grade inflammation (inflammaging) attenuating immune activity (Allameen et al., 2025; Kamroo et al., 2025; Mohapatra et al., 2023; Quiros-Roldan et al., 2024; Rea et al., 2018; Swanson et al., 2019).”

“Contrary to the expectation that infection accelerates physiological decline 24 , parasite exposure increased longevity in both sexes.”

“…respiratory infections accounted for the majority of cases among individuals over 55 years old, which is closely linked to age-related immune decline [22] and the higher prevalence of chronic respiratory diseases (e.g., Chronic Obstructive Pulmonary Disease (COPD), asthma) in this cohort [23].”

“However, related studies [40–42] revealed that age widely influenced the susceptibility to pathogen infections, and there were marked differences in susceptibility and immune responses across age groups.”

“The increase in middle-aged and older populations may be attributable to immunosenescence, which heightens infection risk [39].”

“Collaborative interlaboratory studies, such as those conducted under ISO standards for bacterial quantification, demonstrate how pooling resources and standardizing protocols can improve reproducibility and reliability across diverse settings (Quiros-Roldan et al., 2024).”

“This relationship may be attributed to the cumulative effects of chronic infections and the natural decline in immune function that occurs with aging [41].”

“Immunosenescence, the progressive decline in the immune system functions associated with aging, can favour – among other consequences – an increase of incidence and severity of infections [70, 71].”

“Oral carriage rates vary widely, ranging from 24 to 84% in healthy adults [108] and approximately 48% in denture wearers [109], with older adults being particularly vulnerable due to age ‑ related immune decline, chronic conditions, medications, or nutritional deficiencies [110].”

“Immune competence, inflammatory regulation, age, co-infections, metabolic status and environmental stress can affect disease severity (80).”

“In parallel, immunosenescence and inflammaging may increase susceptibility to viral and opportunistic infections and may amplify class-specific adverse effects, such as HZ with JAK inhibition and initiation-related conduction effects with S1P receptor modulators [37, 69, 81, 88, 89].”

“This may be particularly relevant for neuroinflammatory disease where long-term treatment may be required, and where patients may have age-related risks for metabolic comorbidities or vulnerability to infection [133,134].”

“Owners completed the Canine Dementia Scale (CADES 32 ) questionnaire along with others related to general health (study-specific), pain (LOAD, 37 CBPI 38 ), quality of life (adapted CORQ 39 , 40 ), sleep quality (Snore3.”

“Additional host factors contributing to increased risk among the elderly include reduced gastric acidity, impaired gut motility, and intestinal microbiome dysbiosis [ 10 , 11 ].”

“These processes collectively contribute to the chronic low-grade inflammatory state termed inflammageing , which substantially modifies host responses to acute inflammatory injury [14–21, 29, 30, 52, 53].”

“Other common age-related changes include declines in memory and information processing speed, as well as alterations in sexual, neurological, endocrine, cardiopulmonary, gastrointestinal, urinary [5,16], and immune system functions [17].”