OBJECTIVE: Senescent cells, inducing a senescence-associated secretory phenotype (SASP), lead to chronic inflammation in hard-to-heal wound tissue. However, eliminating senescent cells may impede normal wound healing due to their important role in the wound healing mechanism. Accordingly, we focused on wound exudates in hard-to-heal wounds, which contain many inflammation biomarkers consistent with SASP. Therefore, we hypothesized that senescent cells might be present in the exudates and induce chronic inflammation. This study investigated the relationship between gene expression associated with cellular senescence in exudates from pressure injuries and wound healing status.
METHODS: This retrospective cohort study involved patients treated by a pressure injury team. We collected viable cells from wound dressings and analyzed gene expression. Pearson\'s correlation coefficient was calculated between cellular senescence and SASP expression. The relationship between the gene expression of cellular senescence and the wound area reduction rate by the following week was examined using a mixed-effects model.
RESULTS: CDKN1A-related to cellular senescence-was expressed in 96.3 % of 54 samples, and CDKN1A expression and SASPs positively correlated (PLAU: r = 0.68 and TNF: r = 0.34). Low CDKN1A expression was statistically associated with a large wound area reduction rate (β = 0.83, p < 0.01).
CONCLUSIONS: Gene expression of both cellular senescence and SASP factor in wound dressings suggests the presence of cellular senescence. Senescent cells in wound dressings could be associated with delayed wound healing in the following week.

BACKGROUND: Ageing hallmarks, characterising features of cellular ageing, have a role in the pathophysiology of many age-related diseases. We examined whether obesity is associated with an increased risk of developing such hallmark-related diseases.
METHODS: In this multicohort study, we included people aged 38-72 years with data on weight, height, and waist circumference measured during a clinical examination at baseline between March 13, 2006, and Oct 1, 2010, from the UK Biobank with follow-up until Nov 12, 2021. To test reproducibility of the findings (replication analysis), we used data from people aged 40 years or older included in the Finnish Public Sector study and the Finnish Health and Social Support study who responded to the study surveys, had data on BMI, and were successfully linked to electronic health records from national registers up to Dec 31, 2016. Obesity and clinical characteristics were assessed at baseline. Via linkage to national health records, participants were followed up for 83 diseases related to nine ageing hallmarks (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication). Outcomes were the first instance of hallmark-related disease, in addition to co-occurrence of three or more hallmark-related diseases and mortality.
RESULTS: 496 530 adults (mean age 57·0 years [SD 8·1]) from the UK Biobank were included in the primary analysis, and 83 249 (mean age 48·2 years [6·4]) adults from the Finnish cohorts were included in the replication analysis. Median follow-up was 12·7 years (IQR 12·0-13·4) in the UK Biobank and 14·0 years (8·0-15·0) in the Finnish cohorts. After adjusting for demographic characteristics, lifestyle factors, and depression, UK Biobank participants with obesity (BMI ≥30·0 kg/m2) had a 1·40 (95% CI 1·38-1·41) times higher hazard ratio for the first hallmark-related disease than those with a healthy weight (BMI 18·5-24·9 kg/m2). The corresponding hazard ratios for three co-occurring diseases were 2·92 (95% CI 2·64-3·22) for deregulated nutrient sensing, 2·73 (2·46-3·02) for telomere attrition, 2·33 (2·10-2·60) for epigenetic alterations, 2·30 (2·14-2·48) for mitochondrial dysfunction, 2·23 (2·04-2·45) for stem cell exhaustion, 2·02 (1·89-2·16) for altered intercellular communication, 2·01 (1·89-2·15) for cellular senescence, 1·83 (1·67-2·00) for loss of proteostasis, and 1·39 (1·27-1·52) for genomic instability. These findings were replicated in the Finnish cohorts. In both studies, the associations between other risk factors (low education, unhealthy dietary factors [available only in the UK Biobank], smoking, high alcohol consumption, physical inactivity, and depression) and hallmark-related diseases were weaker than those with obesity. 45-60% of the excess mortality in people with obesity was attributable to hallmark-related diseases.
CONCLUSIONS: Obesity might have an important role in the development of diseases associated with cellular ageing. Tackling ageing mechanisms could potentially help to reduce the disease and mortality burden resulting from the obesity epidemic.
BACKGROUND: Wellcome Trust, UK Medical Research Council, US National Institute on Aging, Academy of Finland, and Finnish Foundation for Cardiovascular Research.
UNASSIGNED: For the German and Finnish translations of the abstract see Supplementary Materials section.

BACKGROUND: Osteoarthritis is a common degenerative joint disease that is highly prevalent in the elderly population. Along with the occurrence of sports injuries, osteoarthritis is gradually showing a younger trend. Osteoarthritis has many causative factors, and its pathogenesis is currently unknown. Cellular senescence is a stable form of cell cycle arrest exhibited by cells in response to external stimuli and plays a role in a variety of diseases. And it is only in the last decade or so that cellular senescence has gradually become cross-linked with osteoarthritis. However, there is no comprehensive bibliometric analysis in this field. The aim of this study is to present the current status and research hotspots of cellular senescence in the field of osteoarthritis, and to predict the future trends of cellular senescence in osteoarthritis research from a bibliometric perspective.
METHODS: This study included 298 records of cellular senescence associated with osteoarthritis from 2009 to 2023, with data from the Web of Science Core Collection database. CiteSpace, Scimago Graphica software, VOSviewer, and the R package \"bibliometrix\" software were used to analyze regions, institutions, journals, authors, and keywords to predict recent trends in cellular senescence related to osteoarthritis research.
RESULTS: The number of publications related to cellular senescence associated with osteoarthritis is increasing year by year. China and the United States contribute more than 70% of the publications and are the mainstay of research in this field. Central South University is the most active institution with the largest number of publications. International Journal of Molecular Sciences is the most popular journal in the field with the largest number of publications, while Osteoarthritis and Cartilage is the most cited journal. Loeser, Richard F. is not only the most prolific author, but also the most frequently cited author, contributing greatly to the field.
CONCLUSIONS: In the last decade or so, this is the first bibliometric study that systematically describes the current status and development trend of research on cellular senescence associated with osteoarthritis. The study comprehensively and systematically summarizes and concludes the research hotspots and development trends, providing valuable references for researchers in this field.

Recent research shows prominent effects of pregnancy and the parenthood transition on structural brain characteristics in humans. Here, we present a comprehensive study of how parental status and number of children born/fathered links to markers of brain and cellular ageing in 36,323 UK Biobank participants (age range 44.57-82.06 years; 52% female). To assess global effects of parenting on the brain, we trained a 3D convolutional neural network on T1-weighted magnetic resonance images, and estimated brain age in a held-out test set. To investigate regional specificity, we extracted cortical and subcortical volumes using FreeSurfer, and ran hierarchical clustering to group regional volumes based on covariance. Leukocyte telomere length (LTL) derived from DNA was used as a marker of cellular ageing. We employed linear regression models to assess relationships between number of children, brain age, regional brain volumes, and LTL, and included interaction terms to probe sex differences in associations. Lastly, we used the brain measures and LTL as features in binary classification models, to determine if markers of brain and cellular ageing could predict parental status. The results showed associations between a greater number of children born/fathered and younger brain age in both females and males, with stronger effects observed in females. Volume-based analyses showed maternal effects in striatal and limbic regions, which were not evident in fathers. We found no evidence for associations between number of children and LTL. Classification of parental status showed an Area under the ROC Curve (AUC) of 0.57 for the brain age model, while the models using regional brain volumes and LTL as predictors showed AUCs of 0.52. Our findings align with previous population-based studies of middle- and older-aged parents, revealing subtle but significant associations between parental experience and neuroimaging-based surrogate markers of brain health. The findings further corroborate results from longitudinal cohort studies following parents across pregnancy and postpartum, potentially indicating that the parenthood transition is associated with long-term influences on brain health.

Degenerative intervertebral disc disease (IVDD) is one of the main spinal surgery, conditions, which markedly increases the incidence of low back pain and deteriorates the patient\'s quality of life, and it imposes significant social and economic burdens. The molecular pathology of IVDD is highly complex and multilateral however still not ompletely understood. New findings indicate that IVDD is closely associated with inflammation, oxidative stress, cell injury and extracellular matrix metabolismdysregulation. Symptomatic management is the main therapeutic approach adopted for IVDD, but it fails to address the basic pathological changes and the causes of the disease. However, research is still focusing on molecular aspects in terms of gene expression, growth factors and cell signaling pathways in an attempt to identify specific molecular targets for IVDD treatment. The paper summarizes the most recent achievements in molecularunderstanding of the pathogenesis of IVDD and gives evidence-based recommendations for clinical practice.

UNASSIGNED: Chronic low-grade inflammation is widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. However, the additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers.
UNASSIGNED: In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned to either the rosuvastatin group (N=74) or the rosuvastatin/ezetimibe group (N=75). The immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples from baseline and post-12 weeks of medication.
UNASSIGNED: The fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Treg) significantly decreased after intervention in the rosuvastatin/ezetimibe group (-4.5 ± 14.1% and -1.2 ± 2.3%, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4% and 1.4 ± 1.5%, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, the fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339).
UNASSIGNED: We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells with rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, independent of improvements in lipid or HbA1c levels.

Blood-derived products, such as citrate platelet-rich plasma (CPRP) and hyperacute serum (HAS), are recognized for their rich growth factor content. When human dermal fibroblast (HDF) cells are exposed to combined mitogenic and DNA-damaging stimuli, it can lead to an increased burden of senescent cells and a modified senescence-associated secretory phenotype. In this study, the senescent state was comprehensively assessed through various methods, including phosphorylated histone H2AX (γH2AX) staining, p21 and p16 q-PCR, p21-western blot, growth curves, and senescence-associated ß-galactosidase staining. Two primary treatments with blood products were administered, one early (immediately after etoposide) and the other late (11 days after etoposide treatment). The effects of the blood product treatment were evaluated by measuring interleukin 6 and 8 (IL-6 and IL-8) levels, as well as collagen 1 (COL1) and p21 mRNA expression. Additionally, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays, cell size measurements, viability assays, and cell number calculations were conducted. The results revealed that cells treated with hyperacute serum in the early treatment phase exhibited the lowest observed IL-6 and IL-8 levels. In contrast, a clear inflammatory response for IL-8 was observed in cells treated with hyperacute serum and citrate platelet-rich plasma during the late treatment. Furthermore, an upregulation of COL1 expression was observed in the early treatment, while cells in the late treatment group remained unaffected. Notably, citrate platelet-rich plasma-treated cells showed a decrease in COL1 expression. Overall, the treatment with blood products appears to have slightly positive effects on skin rejuvenation.

OBJECTIVE: The aim of this experimental study is to investigate the correlation between the presence of senescent cells and the tumor size, the lymphovascular invasion (LVI), the invasion of rete testis (RTI), the preoperative tumor markers or pathological stage in patients who underwent orchiectomy for malignant purposes.
METHODS: This experimental study included patients with a history of radical orchiectomy performed from January 2011 to January 2019. The testicular tissue specimens underwent an immunohistopathological process for the detection of the presence of cellular senescence. Besides, the tumor size, the histopathological type, the pathological stage of the tumor and the presence of Lymphovascular (LVI) or rete testis (RTI) invasions were also recorded. Additionally, the preoperative serum levels of alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase were recorded. After the completion of immunohistochemical analysis, the rate of senescent cells in each specimen was also recorded.
RESULTS: The mean senescent cell rate was estimated to be 14.11±11.32% and 15.46±10.58% in patients with presence of LVI or absence of LVI, respectively (p=0.46). The mean senescent cell rate was calculated at 18.13±12.26% and 12.56±9.38% (p=0.096) in patients with presence of RTI or absence of RTI, respectively. The mean senescent cell rate in the pT1 group was calculated at 14.58 ± 9.82%, while in T2 and T3 groups the mean senescent cell rate was estimated to be 15.22 ± 12.03% and 15.35 ± 14.21%, respectively (p=0.98). A statistically significant correlation was detected between the senescence rate and the tumor size (Pearson score 0.40, p=0.027) and between the rate of senescent cells and the preoperative level of lactate dehydrogenase (LDH) (Pearson score -0.53, p=0.002).
CONCLUSIONS: The presence of cellular senescence was correlated with the extent of the testicular tumor in terms of tumor size as well as the preoperative level of the LDH serum marker.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 .

Cellular senescence is associated with a dysregulated inflammatory response, which is an important driver of the development of liver fibrosis (LF). This study aimed to investigate the effect of cellular senescence on LF and identify potential key biomarkers through bioinformatics analysis combined with validation experiments in vivo and in vitro.
The Gene Expression Omnibus (GEO) database and GeneCards database were used to download the LF dataset and the aging-related gene set, respectively. Functional enrichment analysis of differential genes was then performed using GO and KEGG. Hub genes were further screened using Cytoscape\'s cytoHubba. Diagnostic values for hub genes were evaluated with a receiver operating characteristic (ROC) curve. Next, CIBERSORTx was used to estimate immune cell types and ratios. Finally, in vivo and in vitro experiments validated the results of the bioinformatics analysis. Moreover, molecular docking was used to simulate drug-gene interactions.
A total of 44 aging-related differentially expressed genes (AgDEGs) were identified, and enrichment analysis showed that these genes were mainly enriched in inflammatory and immune responses. PPI network analysis identified 6 hub AgDEGs (STAT3, TNF, MMP9, CD44, TGFB1, and TIMP1), and ROC analysis showed that they all have good diagnostic value. Immune infiltration suggested that hub AgDEGs were significantly associated with M1 macrophages or other immune cells. Notably, STAT3 was positively correlated with α-SMA, COL1A1, IL-6 and IL-1β, and was mainly expressed in hepatocytes (HCs). Validation experiments showed that STAT3 expression was upregulated and cellular senescence was increased in LF mice. A co-culture system of HCs and hepatic stellate cells (HSCs) further revealed that inhibiting STAT3 reduced HCs senescence and suppressed HSCs activation. In addition, molecular docking revealed that STAT3 was a potential drug therapy target.
STAT3 may be involved in HCs senescence and promote HSCs activation, which in turn leads to the development of LF. Our findings suggest that STAT3 could be a potential biomarker for LF.