Dual-target COX-2/5-LOX inhibitors are regarded as a rational strategy for the design of potent anti-inflammatory agents with favorable safety profiles. In this study, novel pyrazolo[1,5-a]pyrimidine derivatives were synthesized, developed, and screened for their ability to inhibit the cyclooxygenase-2 enzyme in vitro, with comparisons made to the established inhibitors Celecoxib and Meloxicam. Spectroscopic analyses confirmed the structure of the designed derivatives. The target prediction using AI was performed to identify potential targets that could be engaged through Swiss target prediction database. The SAR study was established by incorporating various substituents and nuclei into the pyrazolopyrimidine pharmacophore. The synthesized pyrazolopyrimidines exhibited IC50 values ranging from 53.32 ± 4.43 to 254.90 ± 6.45 nM, in comparison to Celecoxib (IC50 = 6.73 ± 5.69 nM) and Meloxicam (IC50 = 52.35 ± 6.66 nM). Notably, compound 5a was identified as the most active derivative, demonstrating an IC50 of 53.32 ± 4.43 nM. The three most prominent pyrazolopyrimidine derivatives, 3a, 5a, and 6a, were subsequently evaluated for their ability to inhibit the COX-1 and 5-LOX enzymes. Compounds 3a, 5a, and 6a demonstrated inhibitory activity against COX-1, with IC50 values of 476.45 ± 16.56, 757.51 ± 2.61, and 169.13 ± 5.77 nM, respectively. These derivatives 3a, 5a, and 6a showed significant selectivity index values of 7.91, 14.20, and 2.80, respectively, toward COX-2 rather than COX-1 in comparison to Meloxicam (SI = 0.75) and Celecoxib (SI = 2.35). Moreover, compound 5a exhibited 86 % inhibition compared to Zileuton's 88 %, while compounds 3a and 6a displayed inhibition rates of 84 % and 80 %, respectively, at a concentration of 100 μM. The most potent compound 5a, demonstrated the highest 5-LOX inhibitory activity, with IC50 of 2.292 ± 0.14 μM. The most promising pyrazolopyrimidine derivative 5a demonstrated a down-regulation of TNF-α and IL-6 gene expression by approximately 0.3826-fold and 0.2732-fold, respectively, when compared to Celecoxib, which induced reductions of 0.2320-fold and 0.2730-fold in these cytokines to promote apoptosis in RAW264.7 cells. Finally, in-silico ADME-T and docking simulations were conducted to predict the oral bioavailability, toxicity, and binding interactions with binding affinity.

Elevated neutrophil-to-lymphocyte ratio, a marker of inflammation, has been reported in adult and late-life depression. Vortioxetine has shown efficacy in treatment of late-life depression, yet little is known regarding its immunomodulatory role in clinical trials.

This is a post-hoc analysis of an eight-week randomized controlled trial. Depressed patients aged 65 or above were treated by vortioxetine, duloxetine or placebo. 321 patients that have taken blood tests at baseline and endpoint were included in the analysis. Neutrophil-to-lymphocyte ratio (NLR) was calculated using the absolute counts of each cell type. Cognitive performance was assessed by composite score of Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT) tasks, while depressive symptoms were assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) and Geriatric Depression Scale (GDS).

NLR levels decreased significantly in the entire analysis set (t(320) = 2.64, p = 0.008) and in the vortioxetine group (M = -0.186, t(105) = 2.070, p = 0.041, Cohen's d = 0.20), but not in the two other groups. This decrease was not significantly different compared to placebo (F(1, 213) = 0.420, p = 0.517). Furthermore, larger NLR changes in vortioxetine arm predicted significant cognitive improvement (β = -4.03, p = 0.03), specifically regarding the DSST correct symbols (β = -1.97, p = 0.04) and RAVLT delayed recall (β = -1.87, p = 0.02) tasks. Additionally, decreased NLR significantly predicted reduced GDS score (β = 1.82, p = 0.02), yet not MADRS score.

Vortioxetine treatment was associated with decreased NLR levels in late-life depression, and reductions in NLR predicted improvements in cognitive function and depressive symptoms, suggesting a potential link between inflammation and clinical outcomes.

As age increases, the immune function of elderly individuals gradually decreases, increasing their susceptibility to infectious diseases. Therefore, further research on common viral infections in the elderly population, especially severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses, is crucial for scientific progress. This review delves into the genetic structure, infection mechanisms, and impact of coinfections with these two viruses and provides a detailed analysis of the reasons for the increased susceptibility of elderly individuals to dual viral infections. We evaluated the clinical manifestations in elderly individuals following coinfections, including complications in the respiratory, gastrointestinal, nervous, and cardiovascular systems. Ultimately, we have summarized the current strategies for the prevention, diagnosis, and treatment of SARS-CoV-2 and influenza coinfections in older adults. Through these studies, we aim to reduce the risk of dual infections in elderly individuals and provide a scientific basis for the prevention, diagnosis, and treatment of age-related viral diseases, thereby improving their health status.

Non-operative spinal infections (NOSI) are caused by tuberculosis, brucella, and other specific bacteria. The etiology of the disease is insidious, the onset is slow and the diagnosis and treatment are difficult. Identifying the factors associated with spinal infection and early intervention can reduce the occurrence of the disease. At present, the research mainly focuses on the accurate diagnosis and treatment of spinal infection, and there are few studies on the prevention of spinal infection. The concept of "preventive treatment of diseases" in traditional Chinese medicine may help identify the causes and reduce the occurrence of NOSI.

To determine the association of age, bowel movements, and sleep patterns with NOSI.

Data of 69 NOSI patients and 84 healthy controls in a tertiary hospital from January 2019 to June 2024 were collected. Patients with NOSI had imaging evidence (magnetic resonance imaging) of spinal infections (including infections caused by tuberculosis, brucopathy, and other pathogens) and had no history of spinal surgery in the last 1 year were included in the analysis. Patients with spinal infection due to spinal surgery are excluded in the study. Data including age, sex, place of residence, sleeping status, and bowel movements were collected. SPSS22.0 was used for correlation analysis of all data.

The mean age of the NOSI group and the control group was 63.55 ± 14.635 years and 59.18 ± 17.111 years, respectively, without statistical difference (P = 0.096). There was also no statistically significant difference in gender between the two groups. In the NOSI group, 45 (65.22%) were over 60 years old, and 44 (63.77%) were rural residents. Compared with the control group, the NOSI group had more patients with sleep disorder and defecation disorder, accounting for 69.57% and 68.12%, respectively, with significant statistical difference (both P < 0.001). Regression analysis showed that defecation and sleep disorders were closely related to NOSI (both P < 0.001).

Most patients with NOSI are older and have sleep disorders and abnormal defecation.

The risk of infection in multiple myeloma patients is significant, due to immune dysfunction secondary to myeloma, immunosenescence and age-related comorbidities, given the elderly myeloma patient demographic. Newer treatments, despite providing unprecedented improvements in disease-control, have further elevated infection risk. This risk is so substantial that we are approaching a period where a subset of older myeloma patients may be more likely to die secondary to infectious complications imposed by redirected T-cell therapy rather than from myeloma. As a result, it is essential to provide myeloma patients with the appropriate prophylaxis and monitoring against infection. In this review, we discuss disease-related, patient-related and treatment-related reasons for the increased infection risk in myeloma patients, and how to both prevent and manage this risk through creating a dynamic, infection prevention plan that is personalised to the individual patient.

Inflammaging, defined as chronic low-grade inflammation associated with aging, is considered a key factor in many age-related diseases. Despite growing research, comprehensive assessments of trends and focuses on this field over the past 2 decades remain lacking.

To comprehensively analyze literature development trends, scientific priorities, and their evolution in the field of inflammaging from 2005 to 2024 using bibliometric analysis.

Academic literature on inflammaging was retrieved from the Web of Science Core Collection. CiteSpace software was used as the bibliometric tool to analyze annual publication trends, contributing countries/regions, leading research institutions, primary journals, and keyword co-occurrence, including clustering and burst analysis in this field.

The study included 1,800 eligible articles, demonstrating a consistent growth in research publications over the past 20 years. The United States and Italy were the principal contributors. The University of Bologna had the highest publication. Professor Claudio Franceschi has been a leading figure in this field. Journal analysis shows that research themes predominantly focus on molecular biology/immunology and medicine/clinical fields. Keyword analysis identifies major research hotspots as "inflammaging," "Crohn's disease," "periodontitis," "immunosenescence," "skeletal muscle," "gut microbiota," and "Parkinson's disease." Emerging term analysis indicates a shift from specific inflammatory diseases to broader aging and immune modulation studies.

This first systematic assessment of literature trends in the field of inflammaging from 2005 to 2024 reveals sustained academic growth and an increasingly deep research focus.

SARS-CoV-2, first identified in December 2019, caused a global pandemic, resulting in over 6.8 million deaths by March 2023. The elderly, or individuals over 65, accounted for the majority of COVID-19 deaths, with 81% of fatalities in the US in 2020 occurring in this group. Beyond mortality, aging populations are also at higher risk of long-term cardiovascular complications and acute respiratory distress syndrome (ARDS). Although these outcomes may be influenced by comorbidities common in the elderly, age has been found to be a standalone risk factor for severe COVID-19 infection. Therefore, investigating age-related factors in COVID-19 outcomes is crucial in protecting this vulnerable group. Of particular interest is the cytokine storm phenomenon, an excessive inflammatory response that contributes to severe COVID-19 symptoms, including ARDS and cardiovascular damage. Elevated levels of multiple cytokines are common in severe cases of COVID-19. We propose that changes that occur to cytokine profiles as we age may contribute to these aberrant inflammatory responses. This review specifically explored the interleukin class cytokines IL-1, IL-6, IL-17, and IL-23 and considered the potential of biologics targeting these cytokines to alleviate severe outcomes in both COVID-19 and aging individuals.

This study aimed to evaluate the impact of frailty and inflammation on all-cause mortality in patients with abdominal aortic aneurysm (AAA) who underwent endovascular aneurysm repair (EVAR), and key risk factors were also explored.

A retrospective analysis was conducted on 174 patients with AAA who underwent EVAR at Beijing Hospital between 2016 and 2024. Frailty was assessed using the modified five-item Frailty Index (mFI-5). Inflammation was quantified by the red cell distribution width-to-albumin ratio (RAR), a novel inflammatory marker. We examined the associations between frailty, preoperative risk factors, and mortality using Kaplan-Meier survival analysis and Cox proportional hazards models. Mediation analysis was performed to evaluate the role of RAR in the relationship between frailty and mortality.

Frailty was found to be an independent risk factor for all-cause mortality following EVAR (HR = 1.95, P = 0.048). Preoperative anemia (HR = 0.98, P = 0.032), elevated creatinine levels (HR = 1.01, P = 0.013), and prolonged operation time (HR = 1.01, P = 0.029) were also independent predictors of mortality. Kaplan-Meier survival analysis revealed significantly lower survival rates for frailty patients (P = 0.004). Additionally, RAR mediated 23.8% of the relationship between frailty and mortality (P = 0.012), underscoring its role as a key indicator of chronic inflammation.

Frailty and chronic inflammation, as measured by the innovative RAR marker, are significant contributors to mortality after EVAR. This study highlights the clinical utility of RAR in identifying high-risk AAA patients and its potential for guiding targeted preoperative interventions. Incorporating frailty assessments and inflammation monitoring into routine preoperative evaluations may improve patient outcomes by enabling personalized approaches such as nutritional optimization and inflammation control.

Mobility disability is a common condition affecting older adults, making walking and the performance of activities of daily living difficult. Frailty, cachexia and sarcopenia are related conditions that occur with advancing age and are characterized by a decline in muscle mass, strength, and functionality that negatively impacts health. Chronic low-grade inflammation is a significant factor in the onset and progression of these conditions. The toll-like receptors (TLRs) and the NLRP3 inflammasome are the pathways of signaling that regulate inflammation. These pathways can potentially be targeted therapeutically for frailty, cachexia and sarcopenia as research has shown that dysregulation of the TLR/NLRP3 inflammasome signaling pathways is linked to these conditions. Activation of TLRs with pathogen-associated molecular patterns (PAMPs or DAMPs) results in chronic inflammation and tissue damage by releasing pro-inflammatory cytokines. Additionally, NLRP3 inflammasome activation enhances the inflammatory response by promoting the production and release of interleukins (ILs), thus exacerbating the underlying inflammatory mechanisms. These pathways are activated in the advancement of disease in frail and sarcopenic individuals. Targeting these pathways may offer therapeutic options to reduce frailty, improve musculoskeletal resilience and prevent or reverse cachexia-associated muscle wasting. Modulating TLR/NLRP3 inflammasome pathways may also hold promise in slowing down the progression of sarcopenia, preserving muscle mass and enhancing overall functional ability in elderly people. The aim of this review is to investigate the signaling pathways of the TLR/NLRP3 inflammasome as a main target in frailty, cachexia and sarcopenia.

Immunity declines with age. This results in a higher risk of age-related diseases, diminished ability to respond to new infections and reduced response to vaccines. The causes of this immune dysfunction are cellular senescence, which occurs in both lymphoid and non-lymphoid tissue, and chronic, low-grade inflammation known as 'inflammageing'. In this Review article, we highlight how the processes of inflammation and senescence drive each other, leading to loss of immune function. To break this cycle, therapies are needed that target the interactions between the altered tissue environment and the immune system instead of targeting each component alone. We discuss the relative merits and drawbacks of therapies that are directed at eliminating senescent cells (senolytics) and those that inhibit inflammation (senomorphics) in the context of tissue niches. Furthermore, we discuss therapeutic strategies designed to directly boost immune cell function and improve immune surveillance in tissues.

As men get older, they often develop benign prostatic hyperplasia (BPH), an enlarged prostate that is not cancerous or dangerous. Although the etiology of BPH is unknown, increasing evidence indicates that the TGF-β signaling pathway might be a key player in its pathogenesis. TGF-β is a pleiotropic cytokine involved in proliferation, differentiation, and extracellular matrix re-modeling, which are all dysregulated in BPH. Cellular senescence is primarily initiated by TGF-β--induced, irreversible growth arrest and usually limits the prostate gland's hyperplastic growth. Moreover, senescent cells generate a Senescence-Associated Secretory Phenotype (SASP), which consists of numerous proinflammatory and profibrotic factors that can worsen disease ontogeny. In addition, TGF-β is among the most fibrogenic factors. At the same time, fibrosis involves a massive accumulation of extracellular matrix proteins, which can increase tissue stiffness and a loss of normal organ functions. TGF-β-mediated fibrosis in BPH changes the mechanical properties of the prostate and surrounding tissues to contribute to lower urinary tract symptoms. This review discusses the complicated molecular signaling of TGF-β underlying changes in cellular senescence and fibrosis during BPH concerning its therapeutic potential.

Community-acquired pneumonia (CAP) remains one of the leading respiratory diseases worldwide. With the aging of the global population, the morbidity, criticality and mortality rates of CAP in older adults remain high every year. Modulating the signaling pathways that cause the inflammatory response and improve the immune function of patients has become the focus of reducing inflammatory damage in the lungs, especially CAP in older adults. As an important factor that causes the inflammatory response of CAP and affects the immune status of the body, oxidative stress plays an important role in the occurrence, development and treatment of CAP. Furthermore, in older adults with CAP, oxidative stress is closely associated with immune senescence, sarcopenia, frailty, aging, multimorbidity, and polypharmacy. Therefore, multiple perspectives combined with the disease characteristics of older adults with CAP were reviewed to clarify the research progress and application value of modulating oxidative stress in older adults with CAP. Clearly, there is no doubt that targeted modulation of oxidative stress benefits CAP in older adults. However, many challenges and unknowns concerning how to modulate oxidative stress for further practical clinical applications exist, and more targeted research is needed. Moreover, the limitations and challenges of modulating oxidative stress are analyzed with the aim of providing references and ideas for future clinical treatment or further research in older adults with CAP.

The prognostic significance of dynamic changes in the albumin-to-C-reactive protein ratio (ACR) in elderly patients with community-acquired pneumonia (CAP) has not been fully elucidated. This study aims to evaluate the utility of ACR as a dynamic biomarker for predicting 28-day mortality and enhancing risk stratification in this high-risk population.

A retrospective cohort study was conducted on 437 elderly CAP patients (≥65 years). Serum albumin and C-reactive protein (CRP) levels were measured at admission (T0), 24 hours (T1), and 3 days (T2) post-admission. ACR was calculated for each time point, and its prognostic value was assessed using advanced statistical methods.

The 28-day mortality rate was 16.7%. ACR levels were consistently lower in non-survivors across all time points (P < 0.001). RCS analysis revealed a nonlinear relationship between ACR and mortality risk. Time-varying ROC analysis demonstrated that ACR consistently outperformed CRP in predicting mortality, with superior area under the curve (AUC) values at all time points. Random-effects modeling indicated minimal inter-individual variability in ACR (random effects variance: 0.030; standard deviation: 0.175). Time-varying Cox regression confirmed a strong negative association between dynamic ACR changes and mortality risk, with a C-statistic of 0.833 (P < 0.001).

Dynamic monitoring of ACR is a robust and clinically applicable tool for predicting short-term mortality in elderly CAP patients. By integrating markers of inflammation and nutritional status, ACR facilitates early identification of high-risk patients and supports personalized treatment strategies. These findings highlight the potential of ACR as a novel biomarker for improving clinical outcomes in this vulnerable population.

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.

Olive oil, the primary fat source in the Mediterranean diet (MedDiet), is rich in monounsaturated fatty acids (MUFA), especially oleic acid, which constitutes 70-80% of its composition. Extra-virgin olive oil (EVOO), produced by mechanically pressing olives, is the highest quality olive oil, with an intense flavor and acidity <1%. In contrast, refined olive oil (ROO), a blend of virgin and refined oils, contains fewer antioxidants and anti-inflammatory compounds. EVOO's health benefits stem largely from its MUFA content, which is linked to reduced risks of cardiovascular disease (CVD), neurodegenerative conditions, and certain cancers. Additionally, EVOO contains minor, but bioactive, components such as polyphenols, tocopherols, and phytosterols, contributing to its oxidative stability, sensory qualities, and health-promoting properties. These include polyphenols, like oleuropein, hydroxytyrosol, and tyrosol, which exhibit anti-inflammatory, cardioprotective, neuroprotective, and anticancer effects. Epidemiological studies suggest an inverse relationship between olive oil intake and CVD, with EVOO-enriched MedDiet interventions showing improved lipid profiles, reduced blood pressure, and lower cardiovascular event risk. The PREDIMED study highlights the significant role of EVOO in reducing cardiometabolic risk. This review explores the impact of EVOO's chemical components within the MedDiet framework on metabolic variables influencing cardiometabolic health.

In the subterranean rodent (Nanno)spalax galili, evolutionary adaptation to hypoxia is correlated with longevity and tumor resistance. Adapted gene-regulatory networks of Spalax might pinpoint strategies to maintain health in humans. Comparing liver, kidney and spleen transcriptome data from Spalax and rat at hypoxia and normoxia, we identified differentially expressed gene pathways common to multiple organs in both species. Body-wide interspecies differences affected processes like cell death, antioxidant defense, DNA repair, energy metabolism, immune response and angiogenesis, which may play a crucial role in Spalax's adaptation to environmental hypoxia. In all organs, transcription of genes for genome stability maintenance and DNA repair was elevated in Spalax versus rat, accompanied by lower expression of aerobic energy metabolism and proinflammatory genes. These transcriptomic changes might account for the extraordinary lifespan of Spalax and its cancer resistance. The identified gene networks present candidates for further investigating the molecular basis underlying the complex Spalax phenotype.

We aim to investigate cognitive phenotype distribution and MRI correlates across pediatric-, elderly-, and adult-onset MS patients as a function of disease duration.

In this cross-sectional study, we enrolled 1262 MS patients and 238 healthy controls, with neurological and cognitive assessments. A subset of 222 MS patients and 92 controls underwent 3T-MRI scan for brain atrophy and lesion analysis. Multinomial probabilistic models identified likelihood of belonging to cognitive phenotypes ("preserved-cognition," "mild verbal memory/semantic fluency," "mild multi-domain," "severe attention/executive," and "severe multi-domain") and experiencing MRI abnormalities based on disease duration and age at onset.

In all groups, the likelihood of "preserved-cognition" phenotype decreased, whereas "mild multi-domain" increased with longer disease duration. In pediatric- and adult-onset patients, the likelihood of "mild verbal memory/semantic fluency" phenotypes decreased with longer disease duration, and that of "severe multi-domain" increased with longer disease duration. Only in adult-onset patients, the likelihood of "severe executive/attention" phenotype increased with longer disease duration. All groups displayed escalating probabilities of cortical, thalamic, hippocampal, and deep gray matter atrophy over disease course. Compared to adult, pediatric-onset patients showed lower probability of experiencing thalamic atrophy with longer disease duration, while elderly-onset showed higher probability of experiencing cortical and hippocampal atrophy.

Age at MS onset significantly influences the distribution of cognitive phenotypes and the patterns of regional gray matter atrophy throughout the disease course.

Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.

Neuroinflammation represents a critical pathway in the brain for the clearance of foreign bodies and the maintenance of homeostasis. When the neuroinflammatory process is dysregulate, such as the over-activation of microglia, which results in the excessive accumulation of free oxygen and inflammatory factors in the brain, among other factors, it can lead to an imbalance in homeostasis and the development of various diseases. Recent research has indicated that the development of numerous neurodegenerative diseases is closely associated with neuroinflammation. The pathogenesis of neuroinflammation in the brain is intricate, involving alterations in numerous genes and proteins, as well as the activation and inhibition of signaling pathways. Furthermore, excessive inflammation can result in neuronal cell apoptosis, which can further exacerbate the extent of the disease. This article presents a summary of recent studies on the relationship between neuronal apoptosis caused by excessive neuroinflammation and neurodegenerative diseases. The aim is to identify the link between the two and to provide new ideas and targets for exploring the pathogenesis, as well as the prevention and treatment of neurodegenerative diseases.

Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was recognized by the 2024 Nobel Prize in Physiology or Medicine. Aging is not a gradual process that can be easily modeled and described. Instead, multiple temporal processes occur during aging, and they can lead to mosaic changes that are not uniform in pace. The rate of change depends on a combination of external and internal factors and can be boosted in accelerated aging. The rate can decrease in decelerated aging due to individual structural and functional reserves created by cognitive, physical training, or pharmacological interventions. Neuroaging can be caused by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle, and environmental factors, which are especially noticeable in space environments where adaptive changes can trigger aging-like processes. Numerous candidate molecular biomarkers specific to neuroaging need to be validated to develop diagnostics and countermeasures.

Cellular aging is a multifactorial and intricately regulated physiological process with profound implications. The interaction between cellular senescence and cancer is complex and multifaceted, senescence can both promote and inhibit tumor progression through various mechanisms. M6A methylation modification regulates the aging process of cells and tissues by modulating senescence-related genes. In this review, we comprehensively discuss the characteristics of cellular senescence, the signaling pathways regulating senescence, the biomarkers of senescence, and the mechanisms of anti-senescence drugs. Notably, this review also delves into the complex interactions between senescence and cancer, emphasizing the dual role of the senescent microenvironment in tumor initiation, progression, and treatment. Finally, we thoroughly explore the function and mechanism of m6A methylation modification in cellular senescence, revealing its critical role in regulating gene expression and maintaining cellular homeostasis. In conclusion, this review provides a comprehensive perspective on the molecular mechanisms and biological significance of cellular senescence and offers new insights for the development of anti-senescence strategies.

Inflammaging, a state of chronic, progressive low-grade inflammation during aging, is associated with several adverse clinical outcomes, including frailty, disability, and death. Chronic inflammation is a hallmark of aging and is linked to the pathogenesis of many aging-related diseases. Anti-inflammatory therapies are also increasingly being studied as potential anti-aging treatments, and clinical trials have shown benefits in selected aging-related diseases. Despite promising advances, significant gaps remain in defining, measuring, treating, and integrating inflammaging into clinical geroscience research. The Clin-STAR Inflammation Research Interest Group was formed by a group of transdisciplinary clinician-scientists with the goal of advancing inflammaging-related clinical research and improving patient-centered care for older adults. Here, we integrate insights from nine medical subspecialties to illustrate the widespread impact of inflammaging on diseases linked to aging, highlighting the extensive opportunities for targeted interventions. We then propose a transdisciplinary approach to enhance understanding and treatment of inflammaging that aims to improve comprehensive care for our aging patients.

Colostrum, the first fluid secreted by the mammary glands of mammalian mothers, contains essential nutrients for the health and survival of newborns. Bovine colostrum (BC) is notable for its high concentrations of bioactive components, such as immunoglobulins and lactoferrin. Despite dogs being the world's most popular companion animals, there is limited research on their immune systems compared to humans. This summary aims to consolidate published studies that explore the immune benefits of BC, focusing specifically on its implications for dogs.

Myocardial infarction (MI) is a prevalent cardiovascular disorder affecting individuals worldwide. There is a need to identify more effective therapeutic agents to minimize cardiomyocyte damage and enhance cardioprotection. Ginkgo biloba extract is extensively used to treat neurological disorders and peripheral vascular diseases. The aim of this study was to determine the protective effects and mechanisms of ginkgetin on postinfarction cardiomyocytes through bioinformatics and experimental validation.

Bioinformatics analysis was performed to predict the underlying biological mechanisms of ginkgetin in the treatment of MI. Next, we performed further validation through experiments. For in vivo studies, we used coronary ligation to construct an MI rat model. In vitro, oxygen and glucose deprivation (OGD) was performed to simulate ischemia in H9c2 cardiomyocytes.

Bioinformatics analysis revealed that the key targets of ginkgetin for MI treatment were MMP2, MMP9, and VEGFA. Immune infiltration analysis revealed that ginkgetin might be involved in immune regulation by acting on the TCR signaling pathway. The results of the GO enrichment analysis revealed that ginkgetin might protect the heart by acting on the cell membrane to alleviate the senescent apoptosis of cardiomyocytes after MI. In vivo studies revealed that ginkgetin ameliorated myocardial pathological damage and cardiac decompensation after MI. It also alleviated the inflammatory infiltration and senescent apoptosis of cardiomyocytes after MI. Additionally, ginkgetin can downregulate the activation signals of the TCR signaling pathway by dephosphorylating CD3 and CD28. In vitro studies revealed that ginkgetin attenuated elevated OGD-induced cytotoxicity, increased cell viability, and alleviated OGD-induced senescent apoptosis, thus protecting cardiomyocytes.

Ginkgetin inhibits postinfarction myocardial fibrosis and cardiomyocyte hypertrophy, scavenges oxygen free radicals, decreases postinfarction limbic cell inflammatory infiltration, suppresses activation of the inflammatory-immune pathway, and delays postinfarction peripheral cells from undergoing senescent apoptosis, thus protecting the heart.

Structural, functional, and molecular-level changes in the aging heart are influenced by a dynamic interplay between immune signaling and cellular metabolism that is referred to as immunometabolism. This review explores the crosstalk between cellular metabolic pathways including glycolysis, oxidative phosphorylation, fatty acid metabolism, and the immune processes that govern cardiac aging. With a rapidly aging population that coincides with increased cardiovascular risk and cancer incidence rates, understanding the immunometabolic underpinnings of cardiac aging provides a foundation for identifying therapeutic targets to mitigate cardiac dysfunction. Aging alters the immune environment of the heart by concomitantly driving the changes in immune cell metabolism, mitochondrial dysfunction, and redox signaling. Shifts in these metabolic pathways exacerbate inflammation and impair tissue repair, creating a vicious cycle that accelerates cardiac functional decline. Treatment with cancer therapy further complicates this landscape, as aging-associated immunometabolic disruptions augment the susceptibility to cardiotoxicity. The current review highlights therapeutic strategies that target the immunometabolic axis to alleviate cardiac aging pathologies. Interventions include modulating metabolic intermediates, improving mitochondrial function, and leveraging immune signaling pathways to restore cardiac health. Advances in immunometabolism thus hold significant potential for translating preclinical findings into therapies that improve the quality of life for the aging population and underscore the need for approaches that address the immunometabolic mechanisms of cardiac aging, providing a framework for future research.

Inflammaging refers to chronic, low-grade inflammation that becomes more common with age and plays a central role in the pathophysiology of various vascular diseases. Key inflammatory mediators involved in inflammaging contribute to endothelial dysfunction and accelerate the progression of atherosclerosis. In addition, specific pathological mechanisms and the role of inflammasomes have emerged as critical drivers of immune responses within the vasculature. A comprehensive understanding of these processes may lead to innovative treatment strategies that could significantly improve the management of age-related vascular diseases. Emerging therapeutic approaches, including cytokine inhibitors, senolytics, and specialized pro-resolving mediators, aim to counteract inflammaging and restore vascular health. This review seeks to provide an in-depth exploration of the molecular pathways underlying vascular inflammaging and highlight potential therapeutic interventions.

Eleven new ent-abietane diterpenoid lactones, designated euphjatrophanes H-R (1-11), were isolated from the whole plants of Euphorbia peplus, along with nine previously identified congeners (12-20). Their structures, including absolute configurations, were elucidated through a combination of NMR, HRESIMS, single-crystal X-ray diffraction, and calculations of ECD and DP4 + technologies. Notably, the absolute configurations of six compounds 1, 2, 4, 5, 6, and 7 were unambiguously determined by single-crystal X-ray diffraction analyses, conducted with Cu Kα radiation. The anti-inflammatory potential of all ent-abietane diterpenoid lactones was evaluated on macrophages. Compounds 6-9, 12-16 and 19 significantly suppressed nitric oxide production, while 10 μM of compounds 6, 9, 11 and 16 remarkably suppressed the mRNA expression of IL-6, IL-1β, and TNFα in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Notably, compound 6 demonstrated a dose-dependent inhibition of the levels of inflammatory mediators (IL-6, IL-1β, and TNFα). Furthermore, compound 6 effectively suppressed FOXO1 expression and reduced the phosphorylation level of NF-κB p65. These findings suggest that compound 6 might be a promising candidate for treating inflammation-related diseases.

Human peripheral blood mononuclear cells (PBMCs) have been largely utilized to assess the cytotoxic, immunomodulatory, and anti-inflammatory properties of both synthetic and natural compounds. Within the latter category, polyphenols from dietary sources have been extensively analyzed. PBMCs represent a feasible in vitro model to study polyphenol hallmarks and activity according to quantitative and qualitative differences in immune responses in individuals of different age. In this chapter, we propose a method for PBMC treatment with polyphenols and analysis designed on age-dependent qualitative and quantitative variability in immune cell performance.

Why and how do we age? This physiological phenomenon that we all experience remains a great mystery, largely unexplained even in this age of scientific and technological progress. Aging is a significant risk factor for numerous diseases, including cancer. However, underlying mechanisms responsible for this association remain to be elucidated. Recent findings have elucidated the significance of the accumulation of senescent cells and other inflammatory cells in organs and tissues with age, and their deleterious effects, such as the induction of inflammation in the microenvironment, as underlying factors contributing to organ dysfunction and disease development. Cellular senescence is a cellular phenomenon characterized by a permanent cessation of cell proliferation and secretion of several proinflammatory cytokines (senescence associated secretory phenotypes). Notably, the elimination of senescent cells from aging individuals has been demonstrated to alleviate age-related organ and tissue dysfunction, as well as various geriatric diseases. This review summarizes the molecular mechanisms by which senescent cells are induced and contribute to age-related diseases, as well as the technologies that ameliorate them.

Immunosenescence, the slow degradation of immune function over time that is a hallmark and driver of aging, makes older people much more likely to be killed by common infections (such as flu) than young adults, but it also contributes greatly to rates of chronic inflammation in later life. Such micro nutrients are crucial for modulating effective immune responses and their deficiencies have been associated with dysfunctional immunity in the elderly. In this review, we specifically focused on the contribution of major micro nutrients (Vitamins A, D and E, Vitamin C; Zinc and Selenium) as immunomodulators in ageing population especially related to inflame-ageing process including autoimmunity. This review will cover these hologenomic interactions, including how micro nutrients can modulate immune cell function and/or cytokine production to benefit their hosts with healthy mucous-associated immunity along with a sustainable immunologic homeostasis. For example, it points out the modulatory effects of vitamin D on both innate and adaptive immunity, with a specific focus on its ability to suppress pro-inflammatory cytokines synthesis while enhancing regulatory T-cell function. In the same context, also zinc is described as important nutrient for thymic function and T-cell differentiation but exhibits immunomodulatory functions by decreasing inflammation. In addition, the review will go over how micro nutrient deficiencies increase systemic chronic low-grade inflammation and, inflammaging as well as actually enhance autoimmune pathologies in old age. It assesses the potential role of additional targeted nutritional supplementation with micro nutrients to counteract these effects, promoting wider immune resilience in older adults. This review collates the current evidence and highlights the role of adequate micro nutrient intake on inflammation and autoimmunity during ageing, providing plausible origins for nutritional interventions to promote healthy immune aging.

The rise in global life expectancy has led to an increase in the older population, presenting significant challenges in managing infectious diseases. Aging affects the innate and adaptive immune systems, resulting in chronic low-grade inflammation (inflammaging) and immune function decline (immunosenescence). These changes would impair defense mechanisms, increase susceptibility to infections and reduce vaccine efficacy in older adults. Cellular senescence exacerbates these issues by releasing pro-inflammatory factors, further perpetuating chronic inflammation. Moreover, comorbidities, such as cardiovascular disease and diabetes, which are common in older adults, amplify immune dysfunction, while immunosuppressive medications further complicate responses to infections. This review explores the molecular and cellular mechanisms driving inflammaging and immunosenescence, focusing on genomic instability, telomere attrition, and mitochondrial dysfunction. Additionally, we discussed how aging-associated immune alterations influence responses to bacterial, viral, and parasitic infections and evaluated emerging antiaging strategies, aimed at mitigating these effects to improve health outcomes in the aging population.

Alzheimer's Disease (AD) is a progressive neurological disease associated with behavioral abnormalities, memory loss, and cognitive impairment that cause major causes of dementia in the elderly. The pathogenetic processes cause complex effects on brain function and AD progression. The proper protein homeostasis, or proteostasis, is critical for cell health. AD causes the buildup of misfolded proteins, particularly tau and amyloid-beta, to break down proteostasis, such aggregates are toxic to neurons and play a critical role in AD pathogenesis. The rise of cellular senescence is accompanied by aging, marked by irreversible cell cycle arrest and the release of pro-inflammatory proteins. Senescent cell build-up in the brains of AD patients exacerbates neuroinflammation and neuronal degeneration. These cells senescence-associated secretory phenotype (SASP) also disturbs the brain environment. When proteostasis failure and cellular senescence coalesce, a cycle is generated that compounds each other. While senescent cells contribute to proteostasis breakdown through inflammatory and degradative processes, misfolded proteins induce cellular stress and senescence. The principal aspects of the neurodegenerative processes in AD are the interaction of cellular senescence and proteostasis failure. This review explores the interconnected roles of proteostasis disruption and cellular senescence in the pathways leading to neurodegeneration in AD.

Age-associated sarcopenia decreases mobility and is promoted by cell senescence, inflammation, and fibrosis. The mitochondrial enzyme arginase-II (Arg-II) plays a causal role in aging and age-associated diseases. Therefore, we aim to explore the role of Arg-II in age-associated decline of physical activity and skeletal muscle aging in a mouse model. Young (4-6 months) and old (20-24 months) wild-type (wt) mice and mice deficient in arg-ii (arg-ii-/-) of both sexes are investigated. We demonstrate a decreased physical performance of old wt mice, which is partially prevented in arg-ii-/- animals, particularly in males. The improved phenotype of arg-ii-/- mice in aging is associated with reduced sarcopenia, cellular senescence, inflammation, and fibrosis, whereas age-associated decline of microvascular endothelial cell density, satellite cell numbers, and muscle fiber types in skeletal muscle is prevented in arg-ii-/- mice. Finally, we demonstrate an increased arg-ii gene expression level in aging skeletal muscle and found Arg-II protein expression in endothelial cells and fibroblasts, but not in skeletal muscle fibers, macrophages, and satellite cells. Our results suggest that increased Arg-II in non-skeletal muscle cells promotes age-associated sarcopenia, particularly in male mice.

This study compares the incidence, clinical features, microbial profiles, and outcomes of urinary tract infections (UTIs) in patients aged 65 years and older versus those younger than 65 years.

A longitudinal cohort of 1,123 patients was divided into Group A (≥65 years, n = 560) and Group B (<65 years, n = 563) and followed for 2 years. The study analyzed UTI incidence, clinical features, microbial profiles, and outcomes, including recurrence and antibiotic resistance.

Over 2 years, Group A had a significantly higher UTI incidence (38.0%) compared with Group B (12.8%) (P <0.0001). Complete recovery was less common in Group A (44.6%) than in Group B (70.83%), whereas recurrent UTIs and antibiotic resistance were more frequent in Group A (43.5% vs 22.2%, P <0.0001 and 11.7% vs 2.78%, P = 0.0017, respectively). Escherichia coli was the most prevalent pathogen in both groups, with Klebsiella and Pseudomonas species more common in recurrent UTIs, particularly in older patients. Risk factors for recurrent UTIs included advanced age, female sex, diabetes, immunosuppression, and renal stones.

These findings highlight the need for age-specific UTI prevention and management strategies that account for microbial resistance patterns and higher recurrence rates in older patients, addressing clinical and microbial challenges.

Sarcopenia is the gradual decrease in skeletal muscle mass, strength and function in elderly individuals. Gamma-aminobutyric acid (GABA) is a neurotransmitter naturally produced from glutamate by the enzyme glutamic acid decarboxylase. Age-related decline in GABA is linked to age-related motor and sensory decline and seems to affect sarcopenia, yet no detailed study has been conducted. In this study, we aimed to investigate the effect of GABA on improving sarcopenia by suppressing muscle protein degradation through supplementing decreased GABA in old mice.

GABA (10 or 30 mg/kg/day) was orally administered daily to young (3 months) and old (21-23 months) C57BL/6 mice for 7 weeks. The body weight and grip strength of the mice were measured weekly at the same time. After sacrificing the mice, the quadriceps and gastrocnemius muscles were excised from their hind limbs, and the spleen and serum were collected. Histological, biochemical and molecular analyses were conducted in various experiments.

The administration of GABA increased muscle strength (+41%, +70% compared to the aged mouse control group, GABA at doses of 10 or 30 mg/kg/day respectively, p < 0.05) and muscle mass (quadriceps: +28%, +46%; gastrocnemius: +12%, +19%, p < 0.05) in old mice. This increase was accompanied by a cross-sectional area (CSA) increase in the quadriceps and gastrocnemius muscle (p < 0.05). The administration of GABA increased IGF-1 levels in serum (p < 0.05), leading to the activation of muscle protein synthesis. We found that GABA inhibits sarcopenia by regulating muscle protein degradation through the activation of Akt/mTOR/FoxO3a signalling pathways. GABA also regulates inflammaging, which is a hallmark of age-related muscle atrophy. There was a significant increase in the F4/80 + CD11b + total macrophage ratio in gastrocnemius and spleen, especially the M1 macrophage ratio increased in old mice. However, GABA administration was effective in suppressing M1 macrophages (gastrocnemius: -40%, - 53%; spleen: -22%, -26%, p < 0.05). Pro-inflammatory cytokines such as TNF-α and IL-6, primarily secreted by M1 macrophages, are also decreased by treatment with GABA (TNF-α: -24%, -27%; IL-6: -45%, -59%, p < 0.05).

Together, this study demonstrates the importance of GABA in maintaining muscle and low-chronic inflammation during ageing. We suggest that GABA shows potential as a substance that can effectively address sarcopenia and enhance the overall lifespan and well-being of older individuals.

Background/Objectives: Charlson Comorbidity Index (CCI) is one of the most reliable indicators to assess the impact of multimorbidity on COVID-19-related outcomes. Moreover, the patient's clinical conditions are associated with SARS-CoV-2 outcomes. This study aimed to analyze the association between multimorbidity and COVID-19-related outcomes, evaluating whether the National Early Warning Score 2 (NEWS2) mediated these associations. Methods: Data were obtained through the platform "EPICLIN". We analyzed all patients who tested positive for COVID-19 after accessing the emergency department (ED) of San Luigi Gonzaga (Orbassano) and Molinette (Turin) hospitals from 1 March to 30 June 2020. Different outcomes were assessed: non-discharge from the ED, 30-day mortality, ICU admission/death among hospitalized patients, and length of hospitalization among surviving patients. Two subgroups of patients (<65 and 65+ years old) were analyzed using logistic regressions, Cox models, and mediation analyses. Results: There was a greater risk of not being discharged or dying among those who were younger and with CCI ≥ 2. Moreover, the higher the CCI, the longer the length of hospitalization. Considering older subjects, a greater CCI was associated with a higher risk of death. Regarding the mediation analyses, multimorbidity significantly impacted the hospitalization length and not being discharged in the younger population. Instead, in the older population, the NEWS2 played a mediation role. Conclusions: This research showed that multimorbidity is a risk factor for a worse prognosis of COVID-19. Moreover, there was a strong direct effect of CCI on not being discharged, and the NEWS2 was found to act as mediator in the association between multimorbidity and COVID-19-related outcomes.

Lung cancer (LC) remains one of the most prevalent and lethal malignancies globally, with a 5-year survival rate for advanced cases persistently below 10%. Despite the significant advancements in immunotherapy, a substantial proportion of patients with advanced LC fail to respond effectively to these treatments, highlighting an urgent need for novel immunotherapeutic targets. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has gained prominence as a potential target for improving LC immunotherapy due to its pivotal role in enhancing anti-tumor immune responses, augmenting tumor antigen presentation, and promoting T cell infiltration. However, emerging evidence also suggests that the cGAS-STING pathway may have pro-tumorigenic effects in the context of LC. This review aims to provide a comprehensive analysis of the cGAS-STING pathway, including its biological composition, activation mechanisms, and physiological functions, as well as its dual roles in LC and the current and emerging LC treatment strategies that target the pathway. By addressing these aspects, we intend to highlight the potential of the cGAS-STING pathway as a novel immunotherapeutic target, while also considering the challenges and future directions for its clinical application.

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.

Metabolic disorders and immunosenescence increase the risk of complications in people living with HIV (PLWH), affecting mortality and quality of life. However, their relationship remains unclear.

Participants were grouped by median TyG index, and logistic regression identified baseline independent factors of a high TyG index at Week 24. The association of the TyG index for hepatic steatosis was determined using ROC curves. We also explored correlations between the TyG index and aging markers, including CD4/CD8 ratio and CD8+ T cells and evaluated health-related quality of life (HRQoL).

A total of 203 PLWH were included in the study. We observed that PLWH in high TyG group tended to be older (P<0.001), have greater body weight (P<0.001), higher ALT levels (P=0.021), and increased low-density lipoprotein levels (P=0.001). ROC analysis revealed that TyG index was closely associated with hepatic steatosis at Week 52 (AUC=0.743) and Week 104 (AUC=0.728). Moreover, a higher TyG index was positively correlated with CD8+ T cell counts, while patients in the high TyG group had lower CD4/CD8 ratios at Week 52 and Week 104. Poorer mental health was observed in patients with CD8+ T cell counts ≥1000 and a high TyG index. Multivariate analysis further identified baseline older age (OR=1.108, P=0.002), elevated cholesterol (OR=3.407, P<0.001), and low HDL (OR=0.003, P<0.001) as factors associated with a high TyG index at Week 24.

The TyG index is closely linked to metabolic disorders and immunosenescence in PLWH. It offers a basis for personalized treatment strategies, improving physical and mental health and reducing complication risks.