Featured article May 2023
Editor’s Pick: The effect of metformin on influenza vaccine responses in nondiabetic older adults: a pilot trial
Metformin has been used for many years to treat diabetes and is now attracting interest as a candidate anti-aging drug. One perceived problem of older adults is their poorer response to seasonal influenza vaccines. In this paper, the effects of 20 weeks of metformin treatment before vaccination was investigated in a double-blinded placebo-controlled study. Serum antibody titers were not increased by metformin but markers of T cell exhaustion were reduced, suggesting that T cell immunocompetence was increased. This pilot study in non-diabetic older adults illustrates the potential for repurposing drugs with extensively-established safety records to improve vaccine responsiveness in older adults.
by Dominique E. Martin, Andreia N. Cadar, Hunter Panier, Blake L. Torrance, George A. Kuchel & Jenna M. Bartley
Featured article March 2023
Editor's Pick: Composition of the infiltrating immune cells in the brain of healthy individuals: effect of aging
In several infectious, autoimmune and inflammatory conditions the central nervous system (CNS) is heavily infiltrated by immune cells, due to the breakdown of the blood-brain barrier. However, low numbers of immune cells are also present in the brain of healthy individuals, translocating across the blood-CSF barrier. In this study, 22 cell types, representative of natural and adaptive immune cells, were identified in 13 different brain regions of 55 subjects, donors without overt disease affecting the brain. The proportion of immune cells was determined by multiple gene signatures (WGS, WES and RNA-Seq) and analyzed by the cytometry tool CIBERSORTx, thus establishing the cell subtypes using levels of expression of 547 signature genes. The data show that macrophages M0 and resting memory CD4+ cells were the most abundant in all but one region (spinal cord where macrophages were less represented) and naïve CD4+ cells – but not naïve B cells - were consistently absent. The effect of aging was to increase the presence of innate immune cells (mainly monocytes) and decrease all adaptive immune cells (mainly CD8+ lymphocytes and follicular helper T cells, but also plasma cells, CD4+ cells and NK cells), in some cases in distinctive brain regions. This unique map of immune cells in the “normal” CNS is a useful guide to assess the changes observed in disease. The age associated changes in the composition of infiltrating immune cells are consistent with a role in tissue homeostasis and reflect similar changes described in peripheral immunosenescence.
by Tapio Nevalainen, Arttu Autio & Mikko Hurme
Featured article January 2023
Editor´s Pick: Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging
It is well known that naïve CD8+ T cell populations decline with age, and that effector memory (EM) CD8+ populations increase in their stead. Here, in a concise review, Shin and colleagues show that a further distinction based on IL-7 receptor alpha (Il-7Ra) levels is a promising avenue for developing biomarkers of immunosenescence. EM CD8+ T cells with low Il-7Ra increase with aging, and those with high IL-7Ra decrease. These differences are linked with many concomitant changes suggesting a functional importance: there are distinct methylation and gene expression profiles, links to influenza vaccine responsiveness (higher in those with low IL-7Ra), and links to mortality. Declining IL-7Ra has also been linked to decreases in chromatin accessibility with age. While more work certainly remains to be done - especially around the pathological versus adaptive nature of changes in IL-7Ra expression - this article shows that IL-7Ra is clearly emerging as a promising target as a biomarker of immune aging.
by Alan Cohen, Co-Guest Editor of the Topical Collection "Towards Biomarkers of Human Immunosenescence"
Featured article October 2022
Editors' pick: Aged microglia promote peripheral T-cell infiltration by reprogramming the microenvironment of neurogenic niches
In the past, the brain was considered an immune-privileged organ with physiological activities influenced by resident myeloid cells, the microglia. However, compelling evidence indicates that both circulatory innate and adaptive immune cells traffic into the brain under physiological conditions, without breaching the blood-brain barrier. Inside the brain, these migratory immune cells can control higher brain functions, including spatial learning and memory, anxiety, resilience to stress, and social behavior. Of note, brain ageing is associated with increased infiltration of T cells, for instance into the subventricular zone (SVZ). By secreting cytokines (IL-4, IFN-gamma, IL-17A), infiltrated T cells can attenuate neurogenesis and neuroplasticity, represented by cognitive decline. However, the mechanisms underlying age-related T-cell infiltration in the central nervous system remain elusive. Here, Zhang et al. established interaction networks among brain endothelial cells (BECs), microglia, and T cells by analyzing single-cell transcriptional profiles of cells from aged and young mice. Aged microglia shifted towards a pro-inflammatory and chemotactic state, priming BECs and recruiting peripheral T cells (CD8+) into the neurogenic niche. This study highlights the neuroimmune pathways involved in supporting brain homeostasis during normal ageing.
Featured article May 2022
Editors' pick: Longitudinal profiling of clonal hematopoiesis provides insight into clonal dynamics
Mutations accumulate in multiple tissues with age, but can be challenging to quantify. Blood is an easily accessible tissue in which clonal hematopoiesis can be documented. This is an age-related expansion of a mutant hematopoietic stem cell (HSC) arbitrarily defined as >2% of the blood cells. This phenomenon rarely occurs in younger people under 40, but is present in 10-20% of those over 70 and may even reach essentially 100% in the oldest old. It is clinically important because it is associated with an increased incidence of myeloid dysplasias that may become malignant, as well as cardiovascular disease. However, because of the complexity and cost of analytic methods such as whole-exome or genome sequencing, most investigations thus far have been cross-sectional, with all the limitations of such studies. However, Uddin et al. have now developed a new method to overcome this difficulty and present a longitudinal study tracking the nature and fate of clonal HSC expansions over a 16-year period covering late middle-age to old age. Such studies will provide important information on the clinical implications of differences in clonal mutational dynamics in diverse populations under different conditions.
Featured article March 2022
Editor's pick: Association between inflammatory cytokines and anti-SARS-CoV-2 antibodies in hospitalized patients with COVID-19
“Cytokine storm” describes an excessive cytokine/chemokine increase in the blood which is observed in some COVID-19 patients as a consequence of an overexuberant immune response. The authors asked whether a cytokine storm is associated with better or poorer anti-SARS-CoV-2 antibody production. They found that anti-SARS-CoV-2 IgG titers were significantly higher in severely ill patients than in moderately ill patients, but such a difference was not observed for IgM. High titers of early-stage IL-6, IL-8, and TNF-α (≤2 weeks after symptom onset) were positively correlated with high titers of late-stage IgG (≥5 weeks after symptom onset). Early responses resulting in elevated titers of cytokines such as IL-6 are thus associated with high titers of IgG antibodies against COVID-19.
Featured article February 2022
Editor's pick: Impaired JAK-STAT pathway signaling in leukocytes of the frail elderly
Why some older adults are more likely to become frail is an important question with many ramifications. This study asked whether frailty is associated with altered cytokine signaling through the JAK-STAT pathway and whether this reflected the individual´s chronic low-grade inflammatory status over the previous 20 years as assessed by CRP levels. Lower cytokine-induced pSTAT responsiveness correlated with higher frailty scores in both men and women, but the degree of dysfunctional pSTAT responses in frailer individuals differed between men and women, with lower IL-10-induced pSTAT3 responses in men related to both higher frailty scores and higher CRP levels over the past 20 years. These data add to the body of knowledge on sex differences in the manner in which resolution of low-grade inflammation, showing that defective regulatory pSTAT signaling is more pronounced in older men.
Featured article October 2021
Editors' pick: Differential immunogenicity of BNT162b2 or ChAdOx1 vaccines after extended-interval homologous dual vaccination in older people
A great deal of experience has now accumulated on the clinical efficacy of vaccines against Covid-19 but the important issue of the optimum length of time between first and booster vaccination in older adults was not immediately clear. This paper surveyed spike-specific antibody and T cell responses in people over 80 years of age after the second dose of either Pfizer/BioNTech BNT162b2 mRNA or AstraZeneca/Oxford ChAdOx1 adenovirus vaccine administered after an ‘extended interval’ of 8-12 weeks rather than the 4-week schedule originally stipulated. Importantly, results showed that both vaccines delivered in this manner elicited strong humoral immunity in older adults, but with antibody responses following BNT162b2 higher than after ChAdOx1, but T cell responses higher after the adenovirus-based vaccine.
Featured article August 2021
Editors' pick: Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma
Of the complex pathways regulating T cell production, development, activation, differentiation, efector function and ageing, miRs have recently gained prominence in the eyes of immunogerontologists. A prime mover in this respect is miR-181a, the expression of which is dynamically regulated during the T cell life cycle, from development in the thymus to differentiation and eventually aging in the periphery. In their review paper, “miR-181a-regulated pathways in T-cell differentiation and aging”, Kim, Ye, Weyand and Goronzy demystify the central function of this miR-181 family member, explaining the unique role of miR-181a in T cell development, T cell activation and antiviral T cell responses, the mechanisms causing its age-related decline and the potential of restoring its expression or targeting it to rejuvenate T cell responses in older people.
Featured article June 2021
Editors' pick: Functional conservation in genes and pathways linking ageing and immunity
The molecular basis of ageing and longevity is a subject of perennial interest, as is the “immunological theory of ageing” first proposed by Roy Walford in the 1960´s. This review paper scrutinizes the evidence for an intimate relationship between the immune system and organismal ageing, taking a very broad view of its genetic basis comparing humans, the mouse Mus musculus, the fruitfly Drosophila melanogaster, and the roundworm Caenorhabditis elegans. This survey revealed seven evolutionarily conserved signalling cascades, the insulin/TOR network, three MAPK (ERK, p38, JNK), JAK/STAT, TGF-β, and Nf-κB pathways that act pleiotropically and link immunity and lifespan across these species. Intrinsic functional conservation in these pathways between C. elegans, D. melanogaster, and mammals is proposed as a framework linking basic immune-ageing processes.
Featured article March 2021
Editors' pick: The effect on terminal ileum (TI) tissue resident memory T (TRM) cells
T cell changes with age in human have been examined almost exclusively in blood. Little is known whether these changes occur in tissues where most T cells reside. Using a human model of oral live attenuated typhoid vaccine, Ty21a, the authors investigated the effect of aging on terminal ileum (TI) tissue resident memory T (TRM) cells and found that that older volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to their younger adults. This study provides insights in the generation of local vaccine-specific responses in the older population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.
Featured article February 2021
Editors' pick: Aging and CMV discordance are associated with increased immune diversity between monozygotic twins
Dissecting the influence of genetics on immune parameters and their changes with age in humans is challenging. One of the few, albeit imperfect, approaches to this is to study monozygotic in comparison to dizygotic twins. This paper shows that not only aging but also discordance for infection with the persistent human herpesvirus Cytomegalovirus are associated with increased immune diversity, particularly in different T cell populations. This study used CyTOF to identify cell subset frequencies that were more or less strongly influenced by non-heritable factors already at middle-age, largely matching the data from older-aged cohorts and suggesting that divergence begins early on, with an increasingly lesser influence of genetics.
Featured article October 2020
Editors' pick: Genetic and environmental determinants of human TCR repertoire diversity
As people age and are increasingly exposed to internal and external immune challenges, the T cell antigen receptor repertoire changes to reflect memory of these challenges and the diversity of the repertoire decreases. The TCR recognizes antigens in association with HLA molecules. The HLA system is the most genetically polymorphic complex known, but its impact on the diversity of the TCR repertoire has remained unclear until now. This paper shows that TCR repertoire diversity is positively associated with polymorphism at HLA-I, but decreases with increasing age and cytomegalovirus infection, which shape the repertoire in healthy individuals. These observations reflect the mechanism responsible for the evolutionary advantage of HLA polymorphism, as long suspected but not documented until now.
Featured Article July/August 2020
Editors' pick: COVID-19: age, Interleukin-6, C-Reactive Protein, and lymphocytes as key clues from a multicentre retrospective study.
Correlations with age, male sex, high IL 6 and severity were confirmed in this multicenter retrospective study of demographic, clinical, laboratory and immunological features of 584 hospitalized COVID-19 patients in Spain. CD8 lymphopenia increased significantly as severity increased, as well as CD4 counts in men. B cells and NK cells showed similar trends. These Spanish patients were older and developed severe COVID-19 more frequently than previously reported cohorts mostly of Chinese patients, but the majority of risk factors appear similar. Intriguingly, however, the use of angiotensin-converting enzyme inhibitors was associated with a better prognosis, whereas angiotensin II receptor blocker use was associated with a more severe course.
Featured article June 2020
Editors' pick: Role of immune cells in the removal of deleterious senescent cells
Senescent cells accumulate and cause damage not only in ageing but also in response to environmental insults and, as recent data have documented, in the lungs of individuals infected with SARS-CoV-2, reflecting a potential pathogenic mechanism lasting well beyond acute respiratory syndrome. The ability of the immune system to clear such senescent cells and the deleterious effects of age on this important activity is considered in the paper by the group of Judy Campisi (Kale et al., Role of immune cells in the removal of deleterious senescent cells).
Featured article May 2020
Editors' pick: Effect of aging on the transcriptomic changes associated with the expression of the HERV-K (HML-2) provirus at 1q22
Up to one-tenth of the human genome consists of remnants of ancient retroviral infections (human endogenous retroviruses, HERV), some of which are expressed and may be associated with autoimmune or inflammatory disease. Their role in ageing, if any, is for the most part unknown. This study indicated that expression of one member of the HERV-K family (HML-2) was associated with enhanced neutrophil activity and pro-inflammatory status in nonagenarian relative to young women, as assessed by gene set enrichment analysis. This study sheds some light on the still-mysterious contribution of genomic “dark matter” to inflammageing and immunosenescence.
Featured article February 2020
Editors' pick: Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma
Despite the perceived negative health consequences of an ageing immune system, older cancer patients may actually respond better to checkpoint blockade immunotherapy. Wigand et al. looked at surgically-resected head and neck cancers and found that 70-90 year-old patients had significantly fewer regulatory T cells blocking the activity of CD8+ cytotoxic T cells (CTL) than younger patients, although both had equal amounts of CTL. This would make the elderly more likely to respond to the immune-boosting effects of immunotherapy.
Featured article January 2020
Editors' pick: Limited physical space in the human bone marrow
The attractive concept of limited "immunological space” whereby senescent and exhausted cells crowd out functional cells in older individuals has proven difficult to substantiate in humans where most studies are limited to peripheral blood. Naismith et al. now demonstrate that this “crowding effect” is observed in the rarely-studied human bone marrow environment and potentially results in lower titers of pathogen-specific antibodies in the blood, implying an important clinical relevance of this phenomenon.