An Association between Immunosenescence and CD4^+CD25^+ Regulatory T Cells: A Systematic Review

Objective Age-related increment of the prevalence of CD4^＋CD25^＋ regulatory T （Treg） cells were described controversially, and whether such changes explain immune dysfunction in the elderly is still unclear. The aim of this systematic review is to evaluate the role of the Tregs in immunosenescence. Methods Medline and manual searches were performed to identify all published epidemiological and animal studies investigating the efficacy of the association between immunosenescence and Treg cells. Results It was founded that the frequency, phenotypic characteristics, and number/function of Tregs were altered significantly with aging. Medical conditions in individuals with advanced ageas well as apoptosis intensity of Treg cells had an impact on the accumulation of Tregs which in turn could deteriorate cytotoxic activity of CD8＋ T and NK cells and production of IL-2. The range of immune cells that could be suppressed by Treg cells was quite wide and covered CD4^＋CD25^＋ T cells, NK cells, dendritic cells and even monocytes. These changes were observed both in humans and experimental animals. Besides, it was believed that frequency of Tregs increased with age and was accompanied by intensified suppressive activity for Tregs in patients, for example, with Alzheimer disease （AD） and Parkinson disease （PD）. The impaired condition of CD4＋ T cells, so-called immunosenescence, rendered transplant recipients less responsive to an allogeneic kidney graft, an effect that was limited to transplant recipients who were aged over 60 years. Conclusions Treg cells are associated with immunosenescence. All these changes contribute to the aging-related decline of immune responses and lead to the higher risk of immune-mediated diseases, cancer or infections in aged individuals.

Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection

Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus(HIV) disease progression, and functional T-cell responses in HIV-tuberculosis(HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB coinfection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis.

Impact of immunosenescence and inflammaging on the effects of immune checkpoint inhibitors

Immune checkpoint inhibitors(ICIs)are employed in immunotherapeutic applications for patients with weakened immune systems and can improve the ability of T cells to kill cancer cells.Although ICIs can potentially treat different types of cancers in various groups of patients,their effectiveness may differ among older individuals.The reason ICIs are less effective in older adults is not yet clearly understood,but age-related changes in the immune system,such as immunosenescence and inflammation,may play a role.Therefore,this review focuses on recent advances in understanding the effects of immunosenescence and inflammation on the efficacy of ICIs.

The role and research progress of MDSC in immune aging-related diseases

Myeloid-derived suppressor cells(MDSCs)are a group of heterogeneous immature cells with a strong immunosuppressive function in myeloid cells,which are impeded in the differentiation of myeloid cells under the pathological conditions of hypoxia,inflammation,infection,and cancer.As individuals age,there is a significant increase in myeloid-derived suppressor cells(MDSCs),which subsequently enhance the immunosuppressive functions of Tregs(regulatory T cells)and Bregs(regulatory B cells).Therefore,MDSC may be related to immune system remodeling,thereby preventing excessive lesions caused by aging.This indicates that MDSC could serve as a potent inducer of immune senescence.Immune senescence,characterized by immune dysfunction with aging,is closely linked to the onset of diseases like infections,pulmonary fibrosis,and tumors.To achieve the purpose of anti-aging by intervening in immune aging and slow down the occurrence and development of related diseases.Therefore,understanding the biological characteristics of MDSC and its role in immune aging is crucial for immunotherapy targeting MDSC.This article reviews the different roles of MDSC in immune aging and its relationship with pulmonary fibrosis,tumor and other related diseases to provide theoretical basis for more comprehensive targeted MDSC immunotherapy.

Noni(Morinda citrifolia L.) fruit juice delays immunosenescence in the lymphocytes in lymph nodes of old F344 rats

Objective： Aging is associated with the development of diseases because of immunosuppression and altered functioning of the neuroendocrine system. The medicinal properties of Morinda citrifolia L. have been widely exploited for the treatment of age-associated diseases. This study aims to investigate the in vitro and in vivo effects of noni（M. citrifolia） fruit juice（NFJ） on neuro-immunomodulation in the lymph node lymphocytes of F344 rats.Methods： Lymphocytes isolated from axillary and inguinal lymph nodes of young（3–4 months） and old（18–21 months） rats were treated in vitro with different concentrations（0.0001%, 0.01%, and 1%） of NFJ for a period of 24 h. In the in vivo study, old（16–17 months） male F344 rats were treated with 5 mL/kg body weight of 5%, 10% and 20% of NFJ, twice a day, by oral gavage, and lymph node lymphocytes were isolated after 60 d. Concanavalin A（Con A）-induced lymphocyte proliferation, interleukin-2（IL-2）and interferon-γ（IFN-γ） production and expression of intracellular markers, such as phosphoextracellular signal-regulated kinase（p-ERK1/2）, phospho-γ AMP response element-binding protein,phospho-protein kinase B（p-Akt）, phospho-tyrosine hydroxylase（p-TH）, phospho-nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor-α（p-IκB-α） and phospho-nuclear factor-κB（p-NF-κB p65 and p50） were examined in the lymphocytes of lymph nodes.Results： NFJ increased Con A-induced lymphocyte proliferation, IL-2 and IFN-γ production, and p-ERK1/2 expression both in vitro and in vivo. In in vivo NFJ-treated old rats, lymph node lymphocytes showed increased expression of p-TH and Akt, nitric oxide production and decreased expression of p-NF-κB p65 and p50.Conclusion： These results suggest that the immunostimulatory properties of NFJ are facilitated through intracellular signaling pathways involving ERK1/2, Akt and NF-κB.

The immunomodulatory effects of bone marrow-derived mesenchymal stem cells on lymphocyte in spleens of aging rats

Objective:To investigate the effects of bone marrow-derived mesenchymal stem cells(BMSCs)on the proliferation and secretion of IgM,IgG and IL-2 in spleen lymphocytes(L)of aging rats.Methods:BMSCs were isolated by the whole bone marrow adherence method and characterized.A rat model of aging was produced by daily subcutaneous injection of D-galactose into the back of the neck.Rat spleen lymphocyte isolate kit to isolate spleen lymphocytes from aging rats and young rats.In vitro,the co-culture system of BMSCs and aging rats lymphocytes was established,and under the induction of mitogen LPS and ConA,the proliferative activity of lymphocytes in each group was detected by CCK-8 assay,the levels of IgM and IgG in the culture supernatant of each group was detected by ELISA,and the IL-2 radioimmunoassay kits were used to detect the content of IL-2 in the supernatant of each group.Results:(1)The isolated adherent cells showed the characteristics of BMSCs,including spindle-shaped morphology,high expression of CD29,CD44,low expression of CD34 and CD45,and osteogenic/adipogenic ability.(2)Under LPS induction,lymphocyte proliferative activity and secretion of immunoglobulin IgG were reduced in the aging group compared with the young group,and co-culture with BMSCs reversed this trend.(3)Under ConA induction,the IL-2 content of BMSCs co-cultured with aging lymphocytes was higher than that of aging lymphocytes alone(P<0.0001);the IL-2 content of CsA co-cultured with aging lymphocytes was lower than that of aging lymphocytes alone(P<0.0001).Conclusion:BMSCs have immunomodulatory effects on the spleen lymphocytes of aging rats in vitro.

Increased vitamin D is associated with decline of naive, but accumulation of effector, CD8 T cells during early aging

Given the protective roles of 25-hydroxyvitamin D (25(OH)D or vitamin D) in musculoskeletal health and the potential beneficial effects of vitamin D supplementation in reducing the risk of various chronic diseases, intensive repletion of vitamin D has been widely advocated. Of note, CD8 T cells have the highest levels of the vitamin D receptor compared with other major immune cells. The effects of vitamin D on CD8 T cells during aging, however, remain unclear. This study determined the relationship between vitamin D levels and CD8 T cell status in 34 healthy female subjects (all >60 years old). The CD8 T-cell phenotype was defined by the surface expression of CD28 and CD95. The low-25(OH)D serum groups (≤30 ng/ml) had higher percentages of CD28+CD95–CD8+ (na?ve) T cells and lower percentages of CD28+CD95+CD8+ (effector) T cells. By contrast, subjects with high levels of 25(OH)D had very low percentages of na?ve CD8 T cells but very high percentages of effector CD8 T cells. There was a significant inverse correlation between 25(OH)D levels and the frequency of na?ve CD8 T cells. The results show that higher levels of vitamin D are correlated with decreased frequencies of na?ve CD8 T cells during early aging, suggesting that higher levels of 25(OH)D accelerate CD8 T cell senescence. These results warrant further evaluation of the effects of vitamin D supplementation in immune aging.

Common spices & yoga as incredible medicines for geriatric care during COVID-19

Geriatric care during coronavirus disease 2019 is a real concern for all countries whether it is developed or developing.Poor tolerability for conventional medicines,co-morbidities,weak immune system,high oxidative stress,arterial aging,psychological stress and somatization are few possible reasons for high vulnerability of elderly people for coronavirus disease 2019.Beside high vulnerability of elderly people other major lacunas like improper nurturing,health care services,delayed in providing emergency treatment facilities are also major concern.Therefore it is require to make them self dependent and self sufficient in taking care for themselves by providing information of simple household remedies and simple life style measures that can be adopted easily,tolerable,accessible,affordable and above all safe to use.The article discusses simple spices that can be use as medicines for the management of coronavirus disease 2019 related diseases along with depiction of simple yogic techniques that can be performed indoor to maintain physical activity.

Dietary Supplementation with Probiotic Strain Improves Immune-Health in Aged Mice

Ageing is associated with several anatomical and physiological changes of the organism, and the increase in global elderly population promotes the research to develop strategies to improve their quality of life. In this work, we characterized the immunological alterations naturally produced during aging in a mice model, and evaluated the effect of probiotic Lactobacillus (L.) rhamnosus CRL1505 administration on those immunological parameters. We demonstrated that L. rhamosus CRL1505 was able to improve peritoneal macrophages phagocytic activity, and the number of intestinal IgA+ cells in aged mice, reaching values of those parameters similar to young adult mice. The results of this work indicate that is plausible that the immunobiotic CRL1505 strain may find applications as a beneficial immunomodulator in aging to reinforce the intestinal and systemic immunity. The immune modulation in aging induced by L. rhamnosus CRL1505 could lead to the development of new strategies for functional foods specifically tailored for the elderly.

Immune‑Ageing Evaluation of Peripheral T and NK Lymphocyte Subsets in Chinese Healthy Adults

Ageing is often accompanied with a decline in immune system function,resulting in immune ageing.Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence.The change in immune phenotype is a key indication of the diseased or healthy status.However,the changes in lymphocyte number and phenotype brought about by ageing have not been comprehensively analysed.Here,we analysed T and natural killer(NK)cell subsets,the phenotype and cell differentiation states in 43,096 healthy individuals,aged 20–88 years,without known diseases.Thirty-six immune parameters were analysed and the reference ranges of these subsets were established in different age groups divided into 5-year intervals.The data were subjected to random forest machine learning for immune-ageing modelling and confirmed using the neural network analysis.Our initial analysis and machine modelling prediction showed that na.ve T cells decreased with ageing,whereas central memory T cells(Tcm)and effector memory T cells(Tem)increased cluster of differentiation(CD)28-associated T cells.This is the largest study to investigate the correlation between age and immune cell function in a Chinese population,and provides insightful differences,suggesting that healthy adults might be considerably influenced by age and sex.The age of a person's immune system might be different from their chronological age.Our immune-ageing modelling study is one of the largest studies to provide insights into‘immune-age’rather than‘biological-age’.Through machine learning,we identified immune factors influencing the most through ageing and built a model for immune-ageing prediction.Our research not only reveals the impact of age on immune parameter differences within the Chinese population,but also provides new insights for monitoring and preventing some diseases in clinical practice.

Sialic acid-mediated photochemotherapy enhances infiltration of CD8^(+)T cells from tumor-draining lymph nodes into tumors of immunosenescent mice

Immunoscenescence plays a key role in the initiation and development of tumors.Furthermore,immunoscenescence also impacts drug delivery and cancer therapeutic efficacy.To reduce the impact of immunosenescence on anti-tumor therapy,this experimental plan aimed to use neutrophils with tumor tropism properties to deliver sialic acid(SA)-modified liposomes into the tumor,kill tumor cells via SA-mediated photochemotherapy,enhance infiltration of neutrophils into the tumor,induce immunogenic death of tumor cells with chemotherapy,enhance infiltration of CD8^(+)T cells into the tumordraining lymph nodes and tumors of immunosenescent mice,and achieve SA-mediated photochemotherapy.We found that CD8^(+)T cell and neutrophil levels in 16-month-old mice were significantly lower than those in 2-and 8-month-old mice;16-month-old mice exhibited immunosenescence.The anti-tumor efficacy of SA-mediated non-photochemotherapy declined in 16-month-old mice,and tumors recurred after scabbing.SA-mediated photochemotherapy enhanced tumor infiltration by CD8^(+)T cells and neutrophils,induced crusting and regression of tumors in 8-month-old mice,inhibited metastasis and recurrence of tumors and eliminated the immunosenescence-induced decline in antitumor therapeutic efficacy in 16-month-old mice via the light-heat-chemical-immunity conversion.

Reference ranges and age-related changes of peripheral blood lymphocyte subsets in Chinese healthy adults

This study was performed to build region-specific reference ranges of peripheral blood lymphocyte subsets for Chinese healthy adults from the young to the elderly and analyze the trends of changes in lymphocyte subsets for evaluating the impact of age on the values.151 healthy adults aged 19-86 were recruited based on the SENIEUR protocol.Three sets of reference ranges were finally built applicable for the healthy young(19-44 years),middle-aged(45-64 years) and elder adults(≥65).Comparisons in parameters among the three cohorts showed that a statistically significant increase in CD16CD56+ NK cell was observed between the middle-aged and elder cohorts,whereas for the majority of the parameters,a significant decline was observed between the young and the middle-aged cohorts.Further results showed that inverse correlations were observed between the age and CD19+ B,CD3+ T,CD3+CD4+ T,CD4+CD45RA+CD62L+ nave T cell and CD4+CD28+/CD4+,while the positive one was identified between the age and the NK cell.These significant changes of the most of immune parameters provided evidence for immunosenescence.Notably,T cell activation markers of CD8+CD38+ and CD8+HLA-DR+ showed reverse trends of association with age,which provides a clue for further researches on the mechanisms underlying the paradoxical clinical presentation of the elder patients.

Changes of regulatory T cells and FoxP3 gene expression in the aging process and its relationship with lung tumors in humans and mice

Background Immunosuppressive regulatory T cells （Tregs） participate in tumor immune evasion and the number and suppressive function of Tregs change with the aging process, but it is not clear whether such change leads to a higher incidence of tumors in the elderly. To this end, we designed experiments to explore the changes of Tregs and the functional gene Forkhead box P3 （FoxP3） in the aging process and its relationship with lung tumors in humans and mice. Methods The percentage of CD4＋CD25＋CD127lowTregs and expression of FoxP3 mRNA were analyzed using flow cytometry （FCM） and real-time fluorescence-based quantitative polymerase chain reaction （FQ-PCR）. Markers were analyzed in the peripheral blood （PB） of 65 elderly patients （age 〉-65 years） with primary non-small cell lung cancer （NSCLC）, 20 younger patients （aged 〈55 years） with NSCLC, 30 elderly healthy individuals and 30 young healthy individuals. Furthermore, we set up the Lewis lung cancer model with C57BL/6 female mice. Thirty-six mice were divided into a young healthy group, a middle-aged healthy group, tumor group, and an elderly tumor group. The percentage an elderly healthy group, a young tumor group, a middle-aged of CD4＋CD25＋FoxP3＋ Tregs and the expression level of FoxP3 mRNA in splenocytes were determined in the six groups. Results The percentage of peripheral CD4＋CD25＋CD127low Tregs and the expression of FoxP3 mRNA were significantly increased in elderly patients with NSCLC comparing with the other groups and in elderly healthy individuals compared with young healthy individuals. Further analysis showed that the percentage of CD4＋CD25＋CD127lowTregs and the expression of FoxP3 mRNA were closely associated with tumor node metastasis （TNM） staging in elderly patients with NSCLC. In the mouse model, the percentage of CD4＋CD25＋FoxP3＋ Tregs and the expression of FoxP3 mRNA in splenocytes of the tumor groups were significantly higher than in the healthy groups, with the highest expression in the elderly tumor group. In the healthy groups, the elderly healthy mice had the highest percentage of Tregs and expression of FoxP3 mRNA. The elderly mice had larger and heavier tumors than did the young and middle aged mice. Conclusions The up-regulation of Tregs and the FoxP3 gene with aging may play an essential role in oncogenesis and development of lung tumors in an elderly population.

Characteristics of Lymphocyte Nuclear Factor-κB Signal Transduction Kinase Expression in Aging Process and Regulatory Effect of Epimedium Flavonoids

Objective：To study the characteristics of lymphocyte nuclear factor kappa B（NF-κB） signal transduction kinase-related molecular mRNA differential expressions at various month age segments in aging process and the intervening effect of Epimedium flavonoids（EF） on it.Methods：Sixty SD rats were divided into six groups,according to animals＇ age,i.e.,the 3 days（d） group,the 4 months（m） group,the 10 m group,the 18 m group,the 27 m group,and the 27 m＋EF group.RNA was extracted from separated splenic lymphocytes. Adopting NF-κB signal path functional genome oligonucleotide gene-chip（128 related genes）,the integral characteristics and differences of NF-κB signal transduction kinase-related mRNA expressions were determined, and the intervening effect of EF was examined.Results：The mean level of the NF-κB signal transduction kinase-related mRNA expressions in rats＇ splenic lymphocytes lowered with aging;the highest expression was presented at 3 d after birth,and then,it lowered gradually,with the lowest level at 18 m or 27 m.After EF intervention,the expression level was raised to the 10-18 m level in the aged rats.Conclusion：The changing rules of lymphocyte NF-κB-signal-transduction-kinase-related mRNA expressions in various stages of aging are helpful for selecting the well time for preventing and intervening aging,and will also give a hint to the molecular index for assessment of senility retarding researches.

Altered CD28 and CD95 mRNA expression in peripheral blood mononuclear cells from elderly patients with primary non-small cell lung cancer

Background The expression of the co-stimulatory molecule CD28 and death receptor CD95 on T cells, which change with age, are considered as important immunological parameters of immunosenescence. It is well established that CD28 and CD95 are associated with tumorgenesis and tumor progression, but the relationship between the age-related changes of these two immunological markers and cancer in the elderly is largely unknown. Methods The levels of CD28 and CD95 mRNA in peripheral blood mononuclear cells （PBMCs） from sixty-three elderly patients （aged 〉60 years） with primary non-small cell lung cancer （NSCLC） were analyzed by real-time fluorescence-based quantitative polymerase chain reaction （FQ-PCR）. In addition, twenty young patients （aged 〈60 years） with NSCLC, thirty elderly healthy donors and thirty young healthy donors were enrolled as controls. Results CD28 mRNA levels were significantly lower and CD95 mRNA levels were significantly higher in elderly patients with NSCLC than in the other groups. Similar results were found in elderly healthy donors comparing with young healthy donors. By Logistic regression analysis an increased risk of NSCLC was markedly associated with aging, down-regulation of CD28 mRNA and up-regulation of CD95 mRNA, and CD28 mRNA had an obvious negative correlation with the CD95 mRNA. In addition, the mRNA levels of CD28 and CD95 in the peripheral blood of the elderly patients was closely associated with the tumor node metastasis （TNM） stages, grade of cell differentiation and lymph node metastasis status, but not related to pathological types. Conclusions The results suggest a close relationship between T cell senescence and NSCLC tumour progress in the elderly, and that up-regulation of CD28 mRNA or down-regulation of CD95 mRNA in peripheral blood T cells may play an important role in inhibiting oncogenesis and development of primary NSCLC in the elderly.

Characterization of CD8＋CD57＋ T cells in patients wit acute myocardial infarction

Although T cells are known to be involved in the pathogenesis of coronary artery disease, it is unclear which subpopulation of T cells contributes to pathogenesis in acute myocardial infarction （MI）. We studied the immunological characteristics and clinical impact of CD8＋CD57＋ T cells in acute MI patients. The frequency of CD57＋ cells among CD8＋ T cells was examined in peripheral blood sampled the morning after acute MI events. Interestingly, the frequency of CD57＋ cells in the CD8＋ T-cell population correlated with cardiovascular mortality 6 months after acute MI. The immunological characteristics of CD8＋CD57＋ T cells were elucidated by surface immunophenotyping, intracellular cytokine staining and flow cytometry. Immunophenotyping revealed that the CD8＋CD57＋ T cells were activated, senescent T cells with pro-inflammatory and tissue homing properties. Because a high frequency of CD8＋CD57＋ T cells is associated with short-term cardiovascular mortality in acute MI patients, this specific subset of CD8＋ T cells might contribute to acute coronary events via their pro-inflammatory and high cytotoxic capacities. Identification of a pathogenic CD8＋ T-cell subset expressing CD57 may offer opportunities for the evaluation and management of acute MI.

The effects of Spirulina on anemia and immune function in senior citizens

Anemia and immunological dysfunction(i.e.immunosenescence)are commonly found in older subjects and nutritional approaches are sought to counteract these phenomena.Spirulina is a filamentous and multicellular bule-green alga capable of reducing inflammation and also manifesting antioxidant effects.We hypothesized that Spirulina may ameliorate anemia and immunosenescence in senior citizens with a history of anemia.We enrolled 40 volunteers of both sexes with an age of 50 years or older who had no history of major chronic diseases.Participants took a Spirulina supplementation for 12 weeks and were administered comprehensive dietary questionnaires to determine their nutritional regimen during the study.Complete cell count(CCC)and indoleamine 2,3-dioxygenase(IDO)enzyme activity,as a sign of immune function,were determined at baseline and weeks 6 and 12 of supplementation.Thirty study participants completed the entire study and the data obtained were analyzed.Over the 12-week study period,there was a steady increase in average values of mean corpuscular hemoglobin in subjects of both sexes.In addition,mean corpuscular volume and mean corpuscular hemoglobin concentration also increased in male participants.Older women appeared to benefit more rapidly from Spirulina supplements.Similarly,the majority of subjects manifested increased IDO activity and white blood cell count at 6 and 12 weeks of Spirulina supplementation.Spirulina may ameliorate anemia and immunosenescence in older subjects.We encourage large human studies to determine whether this safe supplement could prove beneficial in randomized clinical trials.

Senescent remodeling of the immune system and its contribution to the predisposition of the elderly to infections

Objective To review the senescent remodeling of the immune system with aging and its relevance to the increased susceptibility of the elderly to infectious diseases, along with an outlook on emerging immunological biomarkers. Data sources The data selected were from PubMed with relevant published articles in English or French from 1995 to the present. Searches were made using the terms immunosenescence and aging paired with the following： innate immunity, T-celr, B-cell, adaptive immunity and biomarkers. Articles were reviewed for additional citations and some information was gathered from web searches. Study selection Articles on aging of both the innate and adaptive immunity were reviewed, with special attention to the remodeling effect on the ability of the immune system to fight infectious diseases. Articles related to biomarkers of immunosenescence were selected with the goal of identifying immunological biomarkers predisposing the elderly to infections. Results Innate immunity is generally thought to be relatively well preserved or enhanced during aging compared with adaptive immunity which manifests more profound alterations. However, evidence, particularly in the last decade, reveals that both limbs of the immune system undergo profound remodeling with aging. Reported data on adaptive immunity is consistent and changes are well established but conflicting results about innate immunity were reported between in vivo and in vitro studies, as well as between murine and human studies. Epidemiological data suggests increased predisposition of the elderly to infections, but no compelling scientific evidence has directly linked senescent immune remodeling to this increased susceptibility. Recently, growing interest in identifying immunological biomarkers and defining immune risk phenotypes/profiles （IRP） has been expressed. Identification of biomarkers is in its early days and few potential biomarkers have been identified, with the Swedish having defined one IRP based on the adaptive immune response. Conclusions Aging does not necessarily lead to an unavoidable decline in immune functions. Instead, a complex remodeling occurs. Despite the lack of compelling scientific evidence, senescent immune remodeling surely is a significant contributing factor to the increased risk and severity of infections in the elderly. Although, no immunological biomarker has been formally linked to the increased risk of infections in the elderly, biomarkers remain a promising tool to predict the likelihood of healthy aging, the level of immune competence, and mortality risk in the elderly. Hence, more research is required to define healthy aging and identify immunological biomarkers.