• biomarkers
• human aging
• immune aging
• immunosenescence
• inflammaging

• Humans
• Aging/immunology
• Biomarkers/metabolism
• Animals
• Immune System/immunology
• Immunosenescence
• Neoplasms/immunology

• R01DK128435 NIH HHS
• PJT-186165 CIHR
• Buck Institute for Research on Aging Bioinformatics and Data Science Core
• 2R01NS100529-06A1 NINDS NIH HHS
• NNX16AE78G AM 000012 NASA
• 5P01AI153559-03 NIA NIH HHS
• 5P01AG066591-02 NIA NIH HHS
• 5U54AG075932-02 NIA NIH HHS
• 5P01 AG066591-03S1 NIA NIH HHS
• 1U01AG086214-01 NIA NIH HHS
• P01AG066591 NIA NIH HHS
• T32AG000266 NIA NIH HHS
• 1R03OD036497-01 National Institutes of Health Office of the Director
• National Institutes of Health
• Canadian Institutes of Health Research
• National Institute of Neurological Disorders and Stroke
• National Aeronautics and Space Administration
• National Institute on Aging

• Animals
• T-Lymphocytes, Regulatory/metabolism
• T-Lymphocytes, Regulatory/immunology
• Aging/immunology
• Aging/genetics
• Mice
• Lectins, C-Type/metabolism
• Lectins, C-Type/genetics
• Receptors, Immunologic/metabolism
• Receptors, Immunologic/genetics
• Mitochondria/metabolism
• Mitochondria/genetics
• Humans
• Cellular Senescence
• Mice, Inbred C57BL
• Male
• Female
• Flow Cytometry
• Single-Cell Analysis

• NutriSION-CM synergy grant Y2020/BIO-6350 Comunidad de Madrid
• NutriSION-CM synergy grant Y2020/BIO-6350; PIPF-2022/SAL-GL-25208 Comunidad de Madrid
• 101044248-LetTBe EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
• PID2022-141169OB-I00; PID2022-138295OB-I00 Ministry of Economy and Competitiveness | Consejo Superior de Investigaciones Científicas (Spanish National Research Council)
• PID2022-141169OB-I00; PID2022-138295OB-I00; FPU20/04066 Ministry of Economy and Competitiveness | Consejo Superior de Investigaciones Científicas (Spanish National Research Council)
• PID2022-141169OB-I00; PID2022-138295OB-I00; FPU19/02576 Ministry of Economy and Competitiveness | Consejo Superior de Investigaciones Científicas (Spanish National Research Council)

• 85
• CD8+CD56+T cells
• TIGIT
• Tregs
• aging
• the very old

• Medical Research Council

• Aging
• Autoimmunity
• Lacrimal gland
• MHC II presentation
• Regulatory T cells
• Sjögren disease

• R01 EY030447 NEI NIH HHS
• 221859/Z/20/Z Wellcome Trust
• CA125123 National Institutes of Health (US)
• EY-002520 NEI NIH HHS
• RR024574 National Institutes of Health (US)
• P30 CA125123 NCI NIH HHS
• PICT 2021-00109 Agencia Nacional de Promoción Científica y Tecnológica
• PICT 2020-00138 Agencia Nacional de Promoción Científica y Tecnológica
• P30CA125123 NCI NIH HHS
• R01EY030447 NEI NIH HHS
• R01EY035333 NEI NIH HHS
• EY007001 NEI NIH HHS
• P30 EY002520 NEI NIH HHS
• CPRIT-RP180672 CPRIT
• EY021725 NEI NIH HHS

• Humans
• Particulate Matter/adverse effects
• Giant Cell Arteritis/epidemiology
• Aged
• Female
• Male
• Environmental Exposure/adverse effects
• Aged, 80 and over
• Italy/epidemiology
• Middle Aged
• Cross-Over Studies
• Risk Factors
• Air Pollutants/adverse effects
• Bayes Theorem
• Time Factors
• Risk Assessment
• Air Pollution/adverse effects

• Aging
• CD4(+) T cells
• GIA
• Regulatory T cells
• Rheumatoid arthritis

• T-Lymphocytes, Regulatory/immunology
• Animals
• Arthritis, Rheumatoid/immunology
• Humans
• Aged
• Mice
• Male
• Middle Aged
• Aging/immunology
• Female
• Signal Transduction
• Adult
• Arthritis, Experimental/immunology
• Interferon Type I/immunology
• Interferon Type I/metabolism
• Oxygen Consumption
• Interferon-beta/immunology

• FOXP3
• Treg chemokine receptors
• Treg function
• Treg heterogeneity
• Treg markers
• Treg therapy
• regulatory T cells

• Humans
• T-Lymphocytes, Regulatory
• Autoimmune Diseases
• Phenotype
• Immune Tolerance
• Forkhead Transcription Factors/genetics

• Sächsische Landesbibliothek - Staats- und Universitätsbibliothek Dresden

• immunosenescence
• inflammation
• lymphocyte
• senescence
• thymus involution

• CI, confidential interval
• HR, hazard ratio
• ICD-10, International Classification of Disease, 10th revision
• SJS, Stevens–Johnson syndrome
• SKDB, Shizuoka Kokuho Database
• Stevens–Johnson syndrome
• TEN, toxic epidermal necrolysis
• claims database
• drug eruption
• pharmacoepidemiology
• population-based cohort study
• risk factor
• safety
• toxic epidermal necrolysis

• age
• colorectal cancer
• single-cell RNA sequencing
• tumor microenvironment

• Humans
• Colorectal Neoplasms/pathology
• Tumor Microenvironment/genetics
• T-Lymphocytes, Regulatory
• Sequence Analysis, RNA

• aging
• germinal center reaction
• pathogen-specific immune response
• regulatory T cells
• vaccination

• Aged
• Aged, 80 and over
• Aging
• Animals
• Antibodies, Viral
• Humans
• Mice
• T-Lymphocytes, Regulatory
• Vaccination/methods
• Vaccines

• Horizon 2020 Framework Programme
• Deutsche Forschungsgemeinschaft

An optimal immune response requires the appropriate interaction between the innate and the adaptive arms of the immune system as well as a proper balance of activation and regulation. After decades of life, the aging immune system is continuously exposed to immune stressors and inflammatory assaults that lead to immune senescence. In this review, we will discuss inflammaging in the elderly, specifically concentrating on IL-6 and IL-1b in the context of T lymphocytes, and how inflammation is related to mortality and morbidities, specifically cardiovascular disease and cancer. Although a number of studies suggests that the anti-inflammatory cytokine TGF-b is elevated in the elderly, heightened inflammation persists. Thus, the regulation of the immune response and the ability to return the immune system to homeostasis is also important. Therefore, we will discuss cellular alterations in aging, concentrating on senescent T cells and CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) in aging

• dysregulated tregs
• elderly
• immune senescence
• inflammaging
• inflammation
• t cell senescence

The immune system of centenarians remains active and young to prevent cancer and infections. Aging is associated with inflammaging, a persistent low-grade inflammatory state in which CD4⁺ T cells play a role. However, there are few studies that have been done on the CD4⁺ T cell subsets in centenarians. Herein, the changes in CD4⁺ T cell subsets were investigated in centenarians. It was found that with aging, the old adults had higher levels of proinflammatory cytokines and lower levels of anti-inflammatory cytokines in plasma. The levels of CRP, IL-12, TNF-α, IFN-γ, IL-6 and IL-10 were further increased in centenarians compared to old adults. While the levels of IL-17A, IL-1β, IL-23 and TGF-β in centenarians were closer to those in young adults. The total CD4⁺, CD8⁺, Th17 and Treg cells from peripheral blood mononuclear cells (PBMCs) were similar among the three groups. It was observed that the ratio of Th17/Treg cells was elevated in old adults compared to young adults. The ratio was not further elevated in centenarians but rather decreased. In addition, the ex vivo PBMCs differentiation assay showed that increased Th17 cells in centenarians tended to secrete fewer proinflammatory cytokines, while decreased Treg cells in centenarians were prone to secrete more anti-inflammatory cytokines. These observations suggested centenarians alleviated inflammaging by decreasing the ratio of Th17/Treg cells and changing them into anti-inflammatory secretory phenotypes, which provided a novel mechanism for anti-aging research.

• T helper 17 cell
• aging
• centenarians
• inflammaging
• regulatory T cell

• biomarkers
• future
• giant-cell arteritis
• imaging
• treatment

Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson’s disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2^+/−) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.

Aging has long been thought to be a major risk factor for various types of cancers. However, accumulating evidence indicates increased resistance of old animals to tumor growth. An in-depth understanding of how old individuals defend against tumor invasion requires further investigations.

We revealed age-associated alterations in tumor-infiltrating immune cells between young and old mice using single-cell RNA and coupled T cell receptor (TCR) sequencing analysis. Multiple bioinformatics methods were adopted to analyze the characteristics of the transcriptome between two groups. To explore the impacts of young and old CD8⁺ T cells on tumor growth, mice were treated with anti-CD8 antibody every 3 days starting 7 days after tumor inoculation. Flow cytometry was used to validate the differences indicated by sequencing analysis between young and old mice.

We found a higher proportion of cytotoxic CD8⁺ T cells, naturally occurring Tregs, conventional dendritic cell (DC), and M1-like macrophages in tumors of old mice compared with a higher percentage of exhausted CD8⁺ T cells, induced Tregs, plasmacytoid DC, and M2-like macrophages in young mice. Importantly, TCR diversity analysis showed that top 10 TCR clones consisted primarily of exhausted CD8⁺ T cells in young mice whereas top clones were predominantly cytotoxic CD8⁺ T cells in old mice. Old mice had more CD8⁺ T cells with a ‘progenitor’ and less ‘terminally’ exhausted phenotypes than young mice. Consistently, trajectory inference demonstrated that CD8⁺ T cells preferentially differentiated into cytotoxic cells in old mice in contrast to exhausted cells in young mice. Importantly, elimination of CD8⁺ T cells in old mice during tumor growth significantly accelerated tumor development. Moreover, senescent features were demonstrated in exhausted but not cytotoxic CD8⁺ T cells regardless of young and old mice.

Our data revealed that a significantly higher proportion of effector immune cells in old mice defends against tumor progression, providing insights into understanding the altered kinetics of cancer development and the differential response to immunotherapeutic modulation in elderly patients.

• CD8-positive T-lymphocytes
• cellular
• immunity
• immunotherapy
• lymphocytes
• tumor microenvironment
• tumor-infiltrating

• Aging
• Goblet cells
• Immune cells
• Lacrimal gland
• T regulatory t cells
• Tear film

• Aged
• Aging
• Dry Eye Syndromes
• Eye
• Humans
• Immune System
• Inflammation

• R01 EY030447 NEI NIH HHS
• P30 CA125123 NCI NIH HHS
• S10 RR024574 NCRR NIH HHS
• R01 EY026893 NEI NIH HHS
• S10 OD025251 NIH HHS
• P30 EY002520 NEI NIH HHS

• Autoimmune disease
• Cyclical immunomodulation
• Evolutionary medicine
• Evolutionary mismatch
• Immune tolerance
• Pregnancy compensation hypothesis

• cytomegalovirus
• elderly
• immunosenescence
• leprosy
• memory T cell
• skin lesions

Acquired immune responses mediated by CD4⁺ T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4⁺ T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4⁺ T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4⁺CD28^null effector T cells and a decline of CD4⁺CD25⁺CD62L⁺Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4⁺CD45RA⁺CD62L⁺ naïve T cells and a compensatory increase in the number of CD4⁺CD45RO⁺ memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16^Ink4a was increased while CD62L was decreased in CD4⁺CD28^null T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4⁺CD28⁺and CD4⁺CD28^null T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, Helicobactor pylori IgG and Chlamydia pneumonia IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4⁺ T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4⁺T cells, which may be responsible for the development of ACS.

• CD28null T cells
• CD4+ T cells
• acute coronary syndrome
• immunosenescence
• infection

• Candida
• Foxp3
• IL-1β
• Treg
• Treg17
• aging
• fungal infection
• senescence

• Aging
• Autoimmunity
• Cancer
• FOXP3
• Immune senescence
• Immune suppression
• Inflammaging
• Regulatory T cells
• T helper 17
• Treg

Mother-to-child transmission of HIV-1 occurs in a minority of HIV-infected mother-infant pairs, even without any interventions. The mechanisms that protect the majority of HIV-exposed infants from infection are unclear. T regulatory cells (Treg) have important immunomodulato-ry functions, but their role in the fetus as well as in mother-to-child transmission of HIV is under-studied.

We studied available cryopreserved peripheral blood mononuclear cells from HIV-exposed infants from the Breastfeeding, Antiretrovirals and Nutrition (BAN) Study cohort in Malawi: 64 in-fants were HIV-uninfected and 28 infants were HIV-infected at birth. We quantified the frequency of Treg cells (CD4+CD25+FoxP3+), and activated CD4+ and CD8+ T cells (CD38+ HLADR+) by flow cytometry at birth, 6 weeks and 6, 9 and 12 months of age. Descriptive statistics were performed to describe the distributions of these lymphocyte markers according to the HIV infection status; and Student’s t tests and Wilcoxon-Rank Sum tests were performed to compare HIV- infected and unin-fected infants.

T cell activation increased rapidly in the first 6 weeks of life, more pronounced on CD8+ T cells; a further increase in activation was observed at the time of weaning from breastfeeding at 6 months of age. In contrast, the frequency of Treg was stable over the first 6 weeks of life (median, 0.5%), slightly decreased between 6 weeks and 6 months (median at 6 months, 0.3%) and then slight-ly increased between 6 months (time of weaning) and 12 months of age (median, 0.45%). HIV-infected infants had significantly higher frequencies of activated T cells than uninfected infants (P < 0.01). At the time of birth, HIV-exposed uninfected infants had higher levels of Treg, compared to in-fants infected in utero, even though this did not reach statistical significance in this small sample size (P = 0.08).

This study provides initial evidence that Treg may play a role in preventing mother-to-child transmission of HIV, likely by suppressing immune activation in the fetus and infant, and needs to be substantiated in a larger study. Better characterization of the role of Treg in fetal and neonatal immunity may provide a valuable complementary approach to achieve eradication of mother-to-child transmission of HIV.

• HIV
• Treg
• infant
• mother-to-child transmission
• neonate
• regulatory T lymphocytes.

• Treg cells
• endometrial cancer
• endometrioid adenocarcinoma
• interleukin-10
• peripheral blood

• Aging
• Dry eye
• Lacrimal gland

Aging influences an organism’s entire physiology, affecting functions at the molecular, cellular, and systemic levels and increasing susceptibility to many major chronic diseases. The changes in the immune system that accompany human aging are very complex and are generally referred to as immunosenescence. The factors and mechanisms of immunosenescence are multiple and include, among others, defects in the bone marrow, thymic involution, and intrinsic defects in the formation, maturation, homeostasis, and migration of peripheral lymphocytes. Aging affects both the innate and adaptive arms of the immune system. The process of aging is commonly accompanied by low-grade inflammation thought to contribute to neuroinflammation and to many age-related diseases. Numerous attempts to define the role of chronic inflammation in aging have implicated chronic oxidative stress, mitochondrial damage, immunosenescence, epigenetic modifications, and other phenomena. Several lifestyle strategies, such as intervening to provide an adequate diet and physical and mental activity, have been shown to result in improved immune and neuroprotective functions, a decrease in oxidative stress and inflammation, and a potential increase in individual longevity. The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, holistic approach to determining the optimal nutritional and behavioral strategies that would maintain immune and other physiological systems in elderly people. In this chapter, we focus first on the age-related changes of the immune system. Further, we discuss possible deleterious influences of immunosenescence and low-grade inflammation (inflammaging) on neurodegenerative processes in the normally aging brain. Finally, we consider our current understanding of the modulatory potential of nutrition that may mediate anti-inflammatory effects and thus positively affect immunity and the aging brain.

• Animals
• Cytokines/metabolism
• Humans
• Immune System/physiology
• Immunosenescence
• Inflammation/pathology
• Lymphocytes/cytology

• aging
• bipolar
• confirmatory factor analysis
• neuroimmunology

• Aged
• Angiogenesis Inhibitors/therapeutic use
• Antineoplastic Agents/therapeutic use
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Clinical Trials as Topic
• Disease-Free Survival
• Humans
• Lung Neoplasms/drug therapy

• Foxn1
• aging
• atherosclerosis
• immune
• inflammatory
• mechanisms
• thymus

• Aging
• Cancer
• Immunity
• Immunotherapy

• Anti-CTLA-4
• Anti-PD-1
• Checkpoint inhibitors
• Immunotherapy
• Lung cancer
• Melanoma
• Older adults
• Renal cancer

• aging
• biological age
• biomarkers
• score
• senescence

• Aging/drug effects
• Aging/genetics
• Aging/metabolism
• Biomarkers/metabolism
• Cellular Senescence/drug effects
• Cellular Senescence/genetics
• Cytokines/metabolism
• Epigenesis, Genetic
• Gene-Environment Interaction
• Heart Function Tests
• Humans
• Kidney Function Tests
• Metformin/pharmacology
• Organ Specificity
• Respiratory Function Tests
• Telomere Homeostasis

• F32 HL129695 NHLBI NIH HHS
• K08 HL128867 NHLBI NIH HHS
• UL1 TR001422 NCATS NIH HHS

• CD4 T cells
• aging
• inflammation
• regulatory T cells
• senescence

A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4⁺ T cells characterized by loss of CD28 (“CD4⁺CD28⁻ T cells” or “CD4⁺CD28^null cells”) are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4⁺CD28⁻ T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1–2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4⁺CD28⁻ T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4⁺CD28⁻ phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association.

• CD4 T cells
• autoimmune diseases
• cardiovascular diseases
• chronic inflammatory disease
• cytotoxic T cells

• aging
• cancer
• immunity
• immunotherapy

• Asthma
• inflammation
• inner city
• sensitization
• sputum

• Adolescent
• Adult
• Age Factors
• Aged
• Aged, 80 and over
• Antiretroviral Therapy, Highly Active/methods
• CD4 Lymphocyte Count
• Comorbidity
• Female
• HIV Infections/diagnosis
• HIV Infections/drug therapy
• HIV Infections/mortality
• HIV Infections/physiopathology
• Humans
• Male
• Middle Aged
• Retrospective Studies
• Sex Factors
• Viral Load
• Young Adult