Preventing metabolic syndrome (MetS) and frailty in older adults is crucial for healthy aging. The association between MetS and physical frailty is well-documented, with low-grade inflammation as potential explanation. However, the association between MetS and frailty as a multidimensional concept, and the association of low-grade inflammation with presence of MetS and frailty, is yet unclear. Therefore, we examined these associations low-grade inflammation in a large cohort of community-dwelling older adults.

Cognitive decline is a critical hallmark of brain aging. Although aging is a natural process, there is significant heterogeneity in cognition levels among individuals; however, the underlying mechanisms remain uncertain. In our study, we classified aged male Sprague‒Dawley rats into aged cognition-unimpaired (AU) group and aged cognition-impaired (AI) group by using an attentional set-shifting task. The transcriptome sequencing results of medial prefrontal cortex (mPFC) demonstrated significant differences in microglial activation and inflammatory response pathways between the two groups. Specifically, compared to AU rats, AI rats exhibited a greater presence of CD86-positive microglia and major histocompatibility complex class II (MHC-II)-positive microglia, along with elevated inflammatory molecules, in mPFC. Conversely, AI rats exhibited a reduction in the percentage of microglia expressing CD200R and the anti-inflammatory molecules Arg-1 and TGF-β. Additionally, peripheral blood analysis of AI rats demonstrated elevated levels of Th17 and Th1 cells, along with proinflammatory molecules; however, decreased levels of Treg cells, along with anti-inflammatory molecules, were observed in AI rats. Our research suggested that peripheral Th17/Treg cells and central microglial activation were associated with cognitive heterogeneity in aged rats. These findings may provide a new target for healthy aging.

Ageing is a major risk factor that contributes to increased mortality and morbidity rates during influenza A virus (IAV) infections. Macrophages are crucial players in the defense against viral infections and display impaired function during ageing. However, the impact of ageing on macrophage function in response to an IAV infection remains unclear and offers potential insight for underlying mechanisms. In this study, we investigated the immune response of young and aged human monocyte-derived macrophages to two different H1N1 IAV strains. Interestingly, macrophages of aged individuals showed a lower interferon response to IAV infection, resulting in increased viral load. Transcriptomic data revealed a reduced expression of stimulator of interferon genes (STING) in aged macrophages albeit the cGAS-STING pathway was upregulated. Our data clearly indicate the importance of STING signaling for interferon production by applying a THP-1 STING knockout model. Evaluation of mitochondrial function during IAV infection revealed the release of mitochondrial DNA to be the activator of cGAS-STING pathway. The subsequent induction of apoptosis was attenuated in aged macrophages due to decreased STING signaling. Our study provides new insights into molecular mechanisms underlying age-related immune impairment. To our best knowledge, we are the first to discover an age-dependent difference in gene expression of STING on a transcriptional level in human monocyte-derived macrophages possibly leading to a diminished interferon production.

MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.

Immunotherapy with checkpoint inhibition (ICI) is increasingly prescribed to older patients with cancer. High age, especially in combination with frailty, has been associated to immune senescence, which is the age-related decline in immune function, thereby possibly hindering ICI effectiveness. This cross-sectional study aimed to assess whether blood cell immune senescence markers are associated with age, frailty and response to anti-PD-1 treatment in older patients with metastatic melanoma.

Mast cells (MCs) are tissue resident cells of the immune system, mainly known for their role in allergy. However, mounting evidence indicates their involvement in the pathology of age-related diseases, such as Alzheimer's disease, Parkinson's disease, and cancer. MC numbers increase in aged tissues, but how ageing affects MCs is poorly understood.

In the last forty years, the number of people over 60 years of age has increased significantly owing to better nutrition and lower rates of infectious diseases in developing countries. Aging significantly impacts adipose tissue, which plays crucial role in hormone regulation and energy storage. This can lead to imbalances in glucose, and overall energy homeostasis within the body. Aging is irreversible phenomena and potentially causing lipid infiltration in other organs, leading to systemic inflammation, metabolic disorders. This review investigates various pathways contributing to aging-related defects in adipogenesis, such as changes in adipose tissue function and distribution. Polyphenols, a diverse group of natural compounds, can mitigate aging effects via free radicals, oxidative stress, inflammation, senescence, and age-related diseases. Polyphenols like resveratrol, quercetin and EGCG exhibit distinct mechanisms and regulate crucial pathways, such as the TGF-β, AMPK, Wnt, PPAR-γ, and C/EBP transcription factors, and influence epigenetic modifications, such as DNA methylation and histone modification. This review highlights the critical importance of understanding the intricate relationship between aging and adipogenesis for optimizing well-being with increasing age. These findings highlight the therapeutic potential of polyphenols like quercetin and resveratrol in enhancing adipose tissue function and promoting healthy aging.

Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood. Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance. Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and BiTEs, to tackle autoimmune-related conditions in aging and obesity.

Decline in immune function with age has been studied extensively, but approaches to immune restoration have been hampered by the lack of simple methods of identifying individuals whose immune system is in decline. Our approach has been to identify individuals whose immune decline has led to a loss of control of common latent viral infections and their consequent reactivation. Viruses excreted in urine were detected and quantified and we believe this approach could provide a 'surrogate marker' for identifying immune compromised individuals. Here we report the detection of human herpes virus (HHV) 5, 6a, 6b and 7 in the urine of healthy individuals over a wide age range and their correlation with T cell receptor excision circle (TREC) data. The results did not show a clear correlation between TREC values and the detection of individual specific viruses or viral load values when measured singly. However, a correlation was found between low TREC values and the detection of several different human herpes viruses in the urine in males. We present evidence suggesting that for males, the detection of three or more different human herpes viruses in the urine could identify individuals with declining immune function as evidenced by their significantly lower TREC levels.

Systemic inflammation significantly increases the risk of short- and long-term mortality in geriatric hospitalized patients. To predict mortality in older patients with various age-related diseases and infections, including COVID-19, inflammatory biomarkers such as the C-reactive protein (CRP) to albumin ratio (CAR), and related scores and indexes, i.e. Glasgow Prognostic Score (GPS), modified GPS (mGPS), and high sensitivity (hs)-mGPS, have been increasingly utilized. Despite their easy affordability and widespread availability, these biomarkers are predominantly assessed for clinical purposes rather than predictive applications, leading to their underutilization in hospitalized older patients. In this study, we investigated the association of CAR, GPS, mGPS, and hs-mGPS with short-term mortality in 3,206 geriatric hospitalized patients admitted for acute conditions, irrespective of admission diagnosis. We observed that unit increases of CAR, and the highest classes of GPS, mGPS, and hs-mGPS were significantly associated with a two- to threefold increased risk of death, even adjusting the risk for different confounding variables. Interestingly, a hs-mGPS of 2 showed the highest effect size. Furthermore, gender analysis indicated a stronger association between all CRP-albumin based parameters and mortality in men, underscoring the gender-specific relevance of inflammation-based circulating parameters in mortality prediction. In conclusion, scores based on serum CRP and albumin levels offer additional guidance for the stratification of in-hospital mortality risk in older patients by providing additional information on the degree of systemic inflammation.

Systemic lupus erythematosus (SLE) is an autoimmune disorder that commonly affects the skin, kidneys, joints, and various other systemic tissues, with its development intricately linked to the process of immunosenescence. Quercetin (QC), a phytochemical that occurs naturally, demonstrates many different biological capabilities, such as antibacterial, antioxidant, and anti-inflammatory activities. Our investigation found that QC effectively reduced kidney damage and relieved mesenteric lymph nodes (mLNs) swelling in MRL/lpr lupus mice. Moreover, QC has been found to decrease the number of senescent follicular helper T (Tfh) cells, a pivotal kind of T cells that contribute to the progression of SLE. In vitro, QC exhibited the capacity to modulate mRNA expression levels, with the downregulation of IL-6, IL21-AS1, IL-27, BCL6, and BCL2L12, and the upregulation of FOXP1 and BIM. This modulation resulted in the suppression of Tfh cells differentiation and the enhancement of apoptosis in senescent CD4 T cells. In addition, the HuProtTM Human Proteome Microarray revealed that QC can directly bind to BCL-2 protein and therefore promote the apoptosis of senescent CD4 T cell. As a result, our investigative elucidate the potent inhibitory action of QC on the ontogeny of Tfh cells, along with its capacity to abrogate the immunosenescent phenotype. This positions QC as a promising therapeutic strategy for treating SLE.

Older persons elicit heterogeneous antibody responses to vaccinations that generally are lower than those in younger, healthier individuals. As older age and certain comorbidities can influence these responses we aimed to identify health-related variables associated with antibody responses after repeated SARS-CoV-2 vaccinations and their persistence thereafter in SARS-CoV-2 infection-naïve and previously infected older persons.

We investigated the associations between IgM, IgG, IgA, and IgE levels and all-cause mortality risk in Chinese centenarians.

Previous research has indicated that extracellular vesicles (EVs) potentially play significant roles in multiple ageing phenotypes. This study uses a factorial experimental design to explore the interactions between circulating EVs and bone marrow-derived macrophages (BMDMs) isolated from young (7-12 weeks) and aged (70-90 weeks) mice.

The World Health Organization recognizes frailty and multimorbidity as major global health issues and underscores the need for effective interventions. Recent advances have identified interleukin-11 (IL-11), a pro-inflammatory cytokine, as a key player in modulating aging pathways (such as ERK, AMPK, mTOR and JAK-STAT3). Studies have shown that IL-11 inhibition can lead to improved health span and lifespan in animal models, with potential applications in humans. By targeting IL-11, researchers aim to mitigate age-related diseases, such as cancer, fibrosis, and multimorbidity, which pose significant healthcare challenges worldwide. IL-11 inhibition offers a promising strategy, with preclinical trials demonstrating its ability to regenerate renal cells, reduce hepatocyte death, and mitigate liver fibrosis. Further research is necessary to fully elucidate the mechanisms of IL-11 inhibition and its therapeutic potential. If successful, this approach could lead to the development of novel pharmacological interventions, promoting healthier aging and increasing human lifespan.

Historical survey confirms that, over the latter part of the 20 century, autoimmune-based diseases, including multiple sclerosis (MS), have shown a worldwide increase in incidence and prevalence. Analytical population studies have established that the exponential rise in MS is not solely due to improvements in diagnosis and healthcare but relates to an increase in autoimmune risk factors. Harmful environmental exposures, including non-communicable social determinants of health, anthropogens and indigenous or transmissible microbes, constitute a group of causal determinants that have been closely linked with the global rise in MS cases. Exposure to environmental stressors has profound effects on the adaptive arm of the immune system and, in particular, the associated intrinsic process of immune ageing or immunosenescence (ISC). Stressor-related disturbances to the dynamics of ISC include immune cell-linked untimely or premature (p) alterations and an accelerated replicative (ar) change. A recognised immune-associated feature of MS is pISC and current evidence supports the presence of an arISC during the disease. Moreover, collated data illustrates the immune-associated alterations that characterise pISC and arISC are inducible by environmental stressors strongly implicated in causing duplicate changes in adaptive immune cells during MS. The close relationship between exposure to environmental risk factors and the induction of pISC and arISC during MS offers a valid mechanism through which pro-immunosenescent stressors may act and contribute to the recorded increase in the global rate and number of new cases of the disease. Confirmation of alterations to the dynamics of ISC during MS provides a rational and valuable therapeutic target for the use of senolytic drugs to either prevent accumulation and enhance ablation of less efficient untimely senescent adaptive immune cells or decelerate the dysregulated process of replicative proliferation. A range of senotherapeutics are available including kinase and transcriptase inhibitors, rapalogs, flavanols and genetically-engineered T cells and the use of selective treatments to control emerging and unspecified aspects of pISC and arISC are discussed.

The immune system undergoes progressive functional remodeling from neonatal stages to old age. Therefore, understanding how aging shapes immune cell function is vital for precise treatment of patients at different life stages. Here, we constructed the first transcriptomic atlas of immune cells encompassing human lifespan, ranging from newborns to supercentenarians, and comprehensively examined gene expression signatures involving cell signaling, metabolism, differentiation, and functions in all cell types to investigate immune aging changes. By comparing immune cell composition among different age groups, HLA highly expressing NK cells and CD83 positive B cells were identified with high percentages exclusively in the teenager (Tg) group, whereas unknown_T cells were exclusively enriched in the supercentenarian (Sc) group. Notably, we found that the biological age (BA) of pediatric COVID-19 patients with multisystem inflammatory syndrome accelerated aging according to their chronological age (CA). Besides, we proved that inflammatory shift- myeloid abundance and signature correlate with the progression of complications in Kawasaki disease (KD). The shift- myeloid signature was also found to be associated with KD treatment resistance, and effective therapies improve treatment outcomes by reducing this signaling. Finally, based on those age-related immune cell compositions, we developed a novel BA prediction model PHARE ( https://xiazlab.org/phare/ ), which can apply to both scRNA-seq and bulk RNA-seq data. Using this model, we found patients with coronary artery disease (CAD) also exhibit accelerated aging compared to healthy individuals. Overall, our study revealed changes in immune cell proportions and function associated with aging, both in health and disease, and provided a novel tool for successfully capturing features that accelerate or delay aging.

The circulatory peripheral immune system is the most convenient approach for determining an individual's immune status. Due to various reasons, while previous studies have addressed the critical impact of age, most individual studies did not analyze immunosenescence in a systemic manner, which complicates the possibility of building a reference range for age-dependent immune profiles for effective immune monitoring. To address this gap, this study analyzed a group of healthy individuals to establish age-specific reference ranges of the healthy circulatory immune profile, and a systematic review and meta-analysis were conducted to validate the findings and create generalizable immune cell reference ranges.

The intestinal barrier encompasses physical and immunological components that act to compartmentalize luminal contents, such as bacteria and endotoxins, from the host. It has been proposed that an age-related decline of intestinal barrier function may allow for the passage of luminal contents into the bloodstream, triggering a low-grade systemic inflammation termed inflamm-aging. Although there is mounting evidence to support this hypothesis in model species, it is unclear if this phenomenon occurs in humans. In addition, despite being well-established that biological sex impacts aging physiology, its influence on intestinal barrier function and inflamm-aging has not been explored.