Search Results (370)

Background: Chemotherapy and radiation accelerate aging of multiple systems, including the immune and musculoskeletal systems. Resistance training may mitigate some of the late physiologic effects of cancer therapy. Methods: We developed a community-based pilot study of resistance training for long-term cancer survivors meeting criteria for pre-frailty or frailty (N = 8; 6 allogeneic hematopoietic cell transplant, 1 autologous hematopoietic transplant, 1 breast cancer survivor) and their caregivers (N = 8 healthy controls) consisting of a baseline assessment, 10 weeks of personalized resistance training at least once weekly as a group and as many additional times on an individual basis as their schedule allowed, and an end-of-study assessment to measure change in strength and body composition. Blood samples were collected at the start of the study and after the 10-week training program to assess changes in peripheral blood mononuclear cell DNA methylation patterns, gene expression measured by RNA sequencing, and stool microbiome analysis using metagenomics. The median number of resistance training sessions was 25 sessions. Results: Cancer survivors and controls both more than doubled their squat and press volume after 10 weeks. At baseline, cancer survivors exhibited a pro-inflammatory transcriptomic and epigenetic profile with elevated interferon signaling and reduced naïve T cell signatures compared to healthy controls, consistent with immune senescence. After 10 weeks of resistance training, these differences normalized, suggesting that exercise exerted anti-inflammatory and immune-restorative effects in cancer survivors at both gene expression and methylation levels. Ten fecal microbial pathways that were lower in relative abundance in patients compared with controls at baseline were no longer significantly different post-exercise. Conclusions: Our data suggest that in addition to beneficial changes in body composition, resistance training may exert an immune restorative effect in cancer survivors. Full article

Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state. In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds. Full article

Background: The pan-immune–inflammation (PIV) score is a hematological index derived from neutrophil, platelet, monocyte and lymphocyte counts. It has been demonstrated that it has high prognostic value in oncological patients. The aim of this study was to evaluate the association between PIV and 28-day mortality in elderly (≥65 years) critically ill patients admitted to the intensive care unit (ICU) with a diagnosis of sepsis. Methods: This single-centre retrospective study included 96 patients aged ≥65 years who were admitted to the ICU with a diagnosis of sepsis according to the Sepsis-3 criteria between 15 July 2024 and 15 July 2025. Patients were divided into low- and high-PIV groups based on the median PIV. Cox proportional hazards regression analysis and Kaplan–Meier survival analysis were performed. Results: The overall 28-day mortality rate was found to be 55.2% (n = 53). The median PIV was 866.58 (IQR: 497.34–1978.43). The PIV was shown not to be a significant predictor of 28-day mortality (AUC: 0.550; p = 0.400). No difference in survival was observed between the low- and high-PIV groups in the Kaplan–Meier analysis (log-rank p = 0.662). In multivariate Cox regression, high creatinine (HR: 2.683; p < 0.001), high calcium (HR: 2.312; p = 0.004), a low partial thromboplastin time (HR: 0.396; p = 0.005) and a requirement for vasopressors (HR: 2.225; p = 0.025) were identified as independent predictors of mortality. In the Kaplan–Meier analysis for 28-day survival, chronic obstructive pulmonary disease (p = 0.023) and chronic renal disease (p = 0.034) were found to be significantly associated with poorer survival. Conclusions: The PIV is unable to predict 28-day mortality in elderly critically ill patients diagnosed with sepsis. This finding suggests that immunosenescence and inflammaging reduce the predictive power of composite hematological indices. Markers of organ dysfunction, coagulopathy and hemodynamic instability remain more reliable prognostic indicators in geriatric patients with sepsis. Full article

Background: Muscle function determines overall health and is often impaired in metabolic syndrome and cancer, largely due to oxidative stress and inflammation. Olive mill wastewater (OMWW) is rich in bioactive polyphenols (e.g., hydroxytyrosol and verbascoside) that may hinder these potential pro-sarcopenic mechanisms, representing a potential nutraceutical to limit muscle health decline. Objective: To evaluate the effects of short-term supplementation with an OMWW-derived polyphenol extract (Oliphenolia^®, OMWW-OL) on muscle-related parameters and antioxidant biomarkers in adults at metabolic risk while maintaining dietary habits. Methods: This exploratory, hypothesis-driven secondary analysis was based on a single-arm longitudinal pilot study assessing patients at baseline (T0), after 30 days of supplementation (T1), and 30 days post-discontinuation (T2). Anthropometry, bioelectrical impedance, and biochemical assessments were performed. Results: Supplementation was associated with modest increases in skeletal muscle mass, muscle mass percentage, and wrist, arm, and calf circumferences. Fat mass decreased progressively, while total body water percentage and hydration status improved. Ferritin levels rose at T2, alongside increases in protein thiols (PSH) and Trolox equivalent antioxidant capacity (TEAC), suggesting improved iron status and reduced oxidative stress. Body weight and BMI decreased, as expected in a dietary intervention for metabolic syndrome, while muscle health showed a tendency toward improvement. Conclusions: Although the findings require cautious interpretation, short-term OMWW-OL supplementation was associated with modest but consistent directional changes in muscle-related and metabolic indicators in adults at metabolic risk. The results support hypothesis generation and highlight the need for larger studies to further explore the potential role of OMWW-OL in the context of cancer-associated sarcopenia. Full article

The progressive decline in immune function during aging, termed immunosenescence, is increasingly recognized as a critical driver of skeletal fragility and impaired bone regeneration. This age-associated phenomenon—driven by thymic involution, inflammaging, and the accumulation of senescent immune cells—disrupts bone homeostasis primarily through the establishment of a pro-inflammatory milieu, wherein senescence-associated secretory phenotype (SASP) factors directly reprogram the function and fate of mesenchymal stem cells, osteoblasts, osteoclasts, and chondrocytes. Clinically, this immune-driven disruption of the bone microenvironment manifests across a spectrum of age-related skeletal disorders—including osteoporosis and osteoarthritis as prototypes of systemic and local bone loss, respectively, as well as delayed fracture healing, intervertebral disc degeneration, and periodontitis as paradigms of impaired regenerative and defensive responses. Despite advances in osteoimmunology revealing bidirectional immune-bone interactions, the mechanistic links between senescent immune cells and bone pathophysiology remain incompletely defined, presenting a significant barrier to therapeutic innovation. Herein, we synthesize current evidence to elucidate how immunosenescence, through the dysfunction of both innate and adaptive immunity, progressively dismantles bone homeostasis. We critically evaluate current challenges in dissecting the relative contributions of immunological memory accumulation versus fundamental aging processes to skeletal decline. We identify key knowledge gaps and propose strategic research directions, including longitudinal human immunophenotyping studies and innovative organoid-immune aging models. Such approaches hold the potential to transform the therapeutic landscape of age-related skeletal diseases by enabling precision interventions that target specific immunosenescence pathways to rejuvenate the aging skeleton. Full article

Elderly psoriasis patients (≥65 years) demonstrate mainly preserved but substantially delayed therapeutic responses to IL-17 and IL-23 inhibitors, achieving lower PASI90 rates at early time-points with eventual “catch-up” by week 52, alongside increased adverse-event-driven discontinuation. This review synthesizes clinical efficacy data from real-world studies with emerging mechanistic evidence on immunosenescence and cellular senescence to propose the “Inflammatory Noise Floor” hypothesis. We postulate that senescent keratinocytes and fibroblasts constitutively secrete SASP cytokines (IL-6, IL-8, TNF-α) through pathways partially independent of IL-23/IL-17, potentially establishing a persistent baseline inflammation that IL-23/IL-17 blockade might not suppress. Concurrently, immunosenescence, characterized by CD8⁺CD28⁻ T-cell accumulation, exhaustion marker upregulation, and Treg dysfunction, is hypothesized to impair adaptive immune re-equilibration. This dual mechanism represents one plausible, albeit theoretical, explanatory framework for the temporal lag, PASI plateau effects, and infection risk observed in elderly patients. Optimizing outcomes in the elderly may require a pragmatic approach: accepting stable PASI 75-90 as a successful endpoint and prospectively validating extended assessment timelines. While a direct correlation remains to be proven, this framework identifies cellular and immunosenescence as potential targets for future senotherapeutic interventions. Full article

Rheumatoid arthritis (RA) has traditionally been managed after the onset of clinically apparent synovitis; however, accumulating evidence indicates that disease-related immune abnormalities precede clinical diagnosis by several years. This preclinical phase is characterized by systemic autoimmunity, early musculoskeletal symptoms, and subclinical inflammation in genetically and environmentally susceptible individuals. In this review, we summarize current concepts regarding the pathogenesis, risk stratification, and therapeutic interception of preclinical RA. Particular attention is given to the mucosal origin hypothesis and to the roles of immunosenescence, peripheral helper T cells, and fibroblast-like synoviocytes in early disease evolution. Recent advances in clinical, serological, and imaging-based risk stratification have improved the identification of individuals at high risk of progression to clinical RA, and emerging intervention trials have shown that selected therapies may delay disease onset or reduce early inflammatory burden. Although complete prevention of RA has not yet been achieved, these findings support a paradigm shift from the treatment of established RA toward earlier, risk-adapted intervention before irreversible joint damage occurs. Future efforts should focus on refining predictive biomarkers, optimizing the timing and intensity of intervention, and establishing safe, individualized preventive strategies. Full article

Background/Objectives: Immune aging has been associated with survival outcomes in patients with lung adenocarcinoma (LUAD), but its relevance within the tumor microenvironment (TME) remains unclear. Methods: Clinical, RNA-sequencing, and somatic mutation data from the TCGA LUAD cohort were analyzed. Immune aging score within the TME was quantified using a predefined blood-driven 121-gene immune aging signature (IAS-121), and patients were categorized into the lowest versus the highest IAS-121 tertiles. Immune cell composition in the TME was inferred using xCell. Overall survival (OS) was evaluated using Kaplan–Meier analysis, Cox proportional hazards models adjusted for age, sex, tumor stage, smoking status, and EGFR mutation status, and restricted cubic spline analysis to examine the dose–response relationship between IAS-121 and mortality risk. Sensitivity analyses comparing the highest versus lowest quartiles or higher than median versus lower than median of IAS-121 were performed. Two independent LUAD cohorts (GSE68465 and GSE50081) were employed for validation. Results: A total of 518 patients with LUAD from the TCGA cohort were analyzed. Restricted cubic spline analysis showed a linear association between IAS-121 and OS. Patients in the highest IAS-121 tertile showed significantly better survival than those in the lowest tertile in both the TCGA cohort (p < 0.001) and the external validation cohorts (p = 0.003). In multivariable-adjusted Cox models, the lowest IAS-121 tertile was associated with worse survival in TCGA (adjusted HR 1.87, 95% CI 1.20–2.92) and in the pooled external cohorts (adjusted HR 1.57, 95% CI 1.02–2.43). Subgroup analyses showed generally consistent associations across clinical strata. Tumors with higher IAS-121 exhibited lower CD8⁺ and CD4⁺ naïve T-cell enrichment but higher neutrophil infiltration. Conclusions: Immune aging within TME is associated with poorer survival in LUAD. Given this study is hypothesis-generating, further investigations integrating tissue- and blood-based measures of immune aging are warranted to clarify its clinical and biological implications. Full article

Background/Objectives: Influenza remains a primary cause of severe illness and death in adults over 60. In this group, immunosenescence and existing health conditions make infections more dangerous and traditional vaccines less effective. The MF59-adjuvanted vaccine was specifically designed to overcome these limitations by enhancing the body’s immune activation and antigen presentation. While the vaccine shows clear benefits, some recent concerns regarding vaccine safety have been raised without supporting scientific evidence. Therefore, this systematic review focuses on providing a comprehensive evaluation of its safety outcomes compared to standard vaccines. Methods: Following the PRISMA guidelines, a systematic review and meta-analysis were conducted; two researchers independently assessed the eligibility of the studies, and the risk of bias was assessed using RoB2 and ROBINS tools for randomized clinical trials and observational studies, respectively. Pooled risk estimates were calculated using a random-effects model. Results: Ten RCTs and three non-RCTs meeting the inclusion criteria were included. No significant differences were found for severe systemic outcomes: Guillain–Barré syndrome (RR 1.01, 95% CI 0.64–1.80) and encephalitis (RR 1.23, 95% CI 0.85–1.78). For other systemic adverse effects, there were no significant differences between adjuvanted and non-adjuvanted vaccines; only myalgia showed a small but significant increase with adjuvanted vaccines (RR 1.35, 95% CI 1.02–1.78) compared with non-adjuvanted vaccines. Conclusions: MF59-adjuvanted influenza vaccines have a favorable and well-characterized safety profile in adults aged 60 years and older. Adverse events are predominantly mild and transient, with no evidence of increased risk of serious or immune-mediated outcomes compared with non-adjuvanted vaccines. Full article

Background: The global demographic shift towards an aging population has driven a steady, exponential increase in the utilization of cardiac implantable electronic devices (CIEDs). Consequently, device-related infectious complications have emerged as a leading cause of morbidity and healthcare expenditure. Patients in their eighth decade of life—octogenarians (aged 80–90 years)—represent an exceptionally high-risk demographic due to the compounding factors of physiological frailty, immunosenescence, and complex multi-morbidity. Despite this growing demographic, their specific clinical presentations, microbiological profiles, and procedural outcomes following infection remain poorly defined in the current literature. This study aimed to comprehensively compare the clinical characteristics, pathogen distribution, and in-hospital outcomes of CIED infections in an octogenarian cohort against a younger patient population. Methods: We conducted a robust retrospective cohort analysis of 383 consecutive patients treated for confirmed CIED infections at one major tertiary referral center (Heidelberg University Hospital) between January 2002 and December 2022. The cohort was stratified by age into octogenarians (n = 76) and a younger control group (n = 307). We systematically extracted and compared data regarding baseline clinical presentation, chronic comorbidities, detailed microbiological cultures (pocket, blood, and extracted leads), and definitive in-hospital outcomes, primarily mortality and length of stay. Results: The octogenarian cohort exhibited a significantly heavier comorbidity burden, notably higher rates of coronary artery disease (51.3% vs. 29.6%, p < 0.001), systemic hypertension (55.3% vs. 38.1%, p = 0.007), and chronic obstructive pulmonary disease (7.9% vs. 1.6%, p = 0.003). Furthermore, therapeutic systemic anticoagulant use was substantially more prevalent in the elderly group (60.5% vs. 45.0%, p = 0.015). Octogenarians presented overwhelmingly with localized generator pocket infections (73.0% vs. 30.0%, p < 0.001) but paradoxically also demonstrated higher rates of systemic bacteremia and sepsis (26.3% vs. 15.0%, p = 0.019). Microbiological analysis revealed a unique pathogen profile, with Staphylococcus capitis found with significantly higher frequency in the generator pockets of the elderly cohort. Remarkably, despite possessing a higher average lead burden (2.1 vs. 1.2 leads) and extreme comorbidity profiles, octogenarians demonstrated no statistically significant differences in in-hospital mortality (3.9% vs. 4.2%, p = 1.000) or overall length of hospital stay (14.7 vs. 17.2 days, p = 0.386) when compared to the younger cohort. Conclusions: Octogenarians suffering from CIED infections display highly distinct clinical and microbiological profiles, characterized predominantly by elevated rates of localized pocket infections, specific opportunistic pathogens, and a severe underlying comorbidity burden. Crucially, our findings indicate that with the application of modern extraction and management protocols, advanced age alone does not intrinsically correlate with increased in-hospital mortality. Future prevention and perioperative management strategies tailored to this rapidly expanding demographic must heavily prioritize the mitigation of pocket-related complications, particularly considering the high prevalence of concurrent anticoagulation therapy. Full article

Purpose: Thymic involution, a hallmark of immune ageing, is associated with chronic low-grade inflammation (“inflammaging”) and has been implicated in age-associated inflammatory diseases, including atherosclerosis. This study aimed to evaluate the association between persistent thymus and coronary artery calcification based on the Agatston score. Materials and Methods: In an exploratory effort, we retrospectively analyzed 206 patients aged 40–64 years who underwent ECG-triggered thoracic CT between 2019 and 2024. Coronary artery calcifications were quantified on virtual non-contrast reconstructions using the Agatston score. Thymic tissue was graded on a five-point scale based on the extent of fatty replacement, with higher grades indicating greater thymic preservation. Results: The cohort included 126 men and 80 women. Complete fatty replacement of the thymus (Grade 0) was seen more often in men compared to women (51/126 vs. 18/80; p = 0.011). Linear regression analysis revealed a significant inverse association between thymus grade and coronary Agatston score (Beta (B) = −28.8 (95% CI −45.3 to −12.3); p = 0.001). After adjusting for age and sex, higher thymic grades remained significantly associated with lower coronary Agatston scores (B = −22.2 (95% CI: −41.7 to −2.6); p = 0.03). Further analysis with adjustments for cardiovascular risk factors was not performed. Conclusions: Residual thymic tissue was significantly inversely associated with coronary artery calcification, and this association persisted after adjustment for age and sex. These findings support the hypothetical concept that morphologically detectable thymic remnants may reflect interindividual differences in immune ageing and inflammaging that are associated with age-related inflammatory disease phenotypes. The results of this hypothesis-generating study give incentive to further investigate the nature and strength of these associations in prospective studies. Full article

Background: People living with HIV (PLWH) have a substantially increased risk of both AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs), which remain a major cause of morbidity despite effective antiretroviral therapy (ART); this review aims to integrate current epidemiological, molecular, and clinical evidence on HIV-associated oncogenesis. Methods: A structured literature search was conducted in PubMed (2000–2026) using predefined keywords, including “HIV”, “cancer”, “oncogenesis”, and “immune dysregulation”, with inclusion of original studies, systematic reviews, and meta-analyses meeting predefined quality criteria. Results: Available evidence indicates that HIV contributes to cancer development through both direct and indirect mechanisms: viral proteins such as Tat, Nef, and Vpr disrupt apoptosis, DNA repair, and cell cycle regulation, while chronic immune activation, persistent inflammation, and immunosuppression impair tumor immune surveillance and facilitate oncogenic viral co-infections, including Epstein–Barr virus, human papillomavirus, and human herpesvirus 8. Emerging pathways, such as epigenetic alterations, microRNA dysregulation, metabolic reprogramming, and the contribution of HIV reservoirs to pro-tumorigenic microenvironments, further modulate cancer risk. Conclusions: HIV may function as a cofactor that enhances the effects of oncogenic viruses by promoting viral persistence and immune dysregulation; while biologically plausible, direct evidence linking HIV to amplification of tumorigenesis in humans remains limited. Full article

Tissue repair is a finely organized process that progresses via a series of phases, including hemostasis, inflammation, proliferation, and remodeling, which are coordinated by immune–stromal interactions. Aging profoundly dysregulates these processes through mechanisms such as immunosenescence and inflammaging, cellular senescence, chronic inflammation, and extracellular matrix alterations, ultimately contributing to typical age-related progression. This review discusses the immune mechanisms that govern physiological tissue healing, as well as the age-related perturbations that lead to ulcerative and fibrotic diseases. It also highlights the potential application of extracellular vesicles (EVs), both mammalian and plant-derived, as a stable and low-immunogenicity mediator to modulate and re-establish repair homeostasis. Translational hurdles such as EV standardization, dosing, safety assessment, and manufacturing are critically discussed to promote their use in geroscience, regenerative medicine, and dermatology. Full article

Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood–brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases. Full article

Background: Obesity involves an excessive buildup of adipose tissue and is linked to chronic inflammation and oxidative stress, both of which contribute to immunosenescence. Obesity and aging share common features, including immune system impairment and oxidative and inflammatory states, suggesting that obesity may represent a model for accelerated immunosenescence. Objectives/Methods: The aim of this research was to evaluate in Zucker fatty (fa/fa) rats, a well-established genetic model of obesity, multiple immune function parameters (phagocytic activity, natural killer cell function, lymphocyte proliferation in response to mitogens, and cytokine profiles), as well as redox parameters (total antioxidant capacity, glutathione levels, activities of glutathione peroxidase and reductase, and xanthine oxidase activity) in peritoneal leukocytes, spleen, thymus, and liver at adult age (24 weeks). Comparisons were made with Zucker lean controls (fa/+), commonly used as standard controls, and Wistar rats as an independent control group. Results: Zucker fa/fa rats displayed significant physiological disorders, including increased body and organ weights, premature immunosenescence characterized by impaired innate and adaptive immune responses, reduced IL-2 and IL-10 secretion, elevated TNF-α production upon mitogen stimulation, and oxidative stress evidenced by redox imbalance in the spleen, thymus, and liver. Conclusions: These immune dysfunctions and oxidative imbalances are comparable to those observed during the aging process. Given that the immune parameters analyzed are considered indicators of health, aging rate, and longevity, our findings suggest that adult Zucker fa/fa rats could exhibit features of premature aging. Full article