Senescence Markers Research Articles

Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells.

The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

The prospective association of cellular markers of biological aging with menopause in the Coronary Artery Risk Development in Young Adults Study.

Evidence from cross-sectional studies mainly among postmenopausal women suggests that biological aging is associated with reproductive senescence. We evaluated the prospective association of cellular markers of biological aging measured during the premenopausal period, and changes in these markers, with age at menopause. We studied 583 premenopausal women (39% Black) from the Coronary Artery Risk Development in Young Adults Study who had data on biological aging markers in 2000-2001 and reached menopause by 2020-2021. Linear regression models were used to evaluate the association of telomere length, mitochondrial DNA copy number, intrinsic or extrinsic epigenetic age acceleration, and PhenoAge or GrimAge acceleration with age at menopause. The mean age at baseline was 41.2 ± 3.3 years, with the mean age at menopause being 49.1 (median, 50) years. About one in five women had surgical menopause. In chronological age-adjusted models, only baseline GrimAge acceleration was associated with age at menopause; women whose epigenetic age was older than their chronological age reached menopause at 0.12 years (~6 weeks) earlier compared with women with equal epigenetic and chronological age (β = -0.123; 95% CI, -0.224 to -0.022; P = 0.018). However, this association was not statistically significant after adjustment for sociodemographic, behavior/lifestyle, and metabolic factors. Similar results were observed when changes in these biological aging markers were evaluated. The same associations were observed in analyses limited to women who reached natural menopause. Sociodemographic, behavior/lifestyle, and metabolic factors remain comparable, if not more robust predictors of the age at menopause compared with cellular measures of biological age.

Perceived age estimation from facial image and demographic data in young and middle-aged South Korean adults

Biological age is an indicator of whether an individual is experiencing rapid, slowing, or normal aging. Perceived age is highly correlated with biological age, which reflects health appraisal and is often used as a clinical marker of aging. Perceived age has been reported as an important indicator of biological age and general health status, not only in older adult populations but also in young and middle-aged adults. However, there is a lack of objective methods for quantifying perceived age in these younger age groups. Thus, this study aimed to propose a novel perceived age estimation algorithm to meet the need for an objective method to predict perceived age. This cross-sectional study included 609 healthy men and 1388 healthy women (29.02–57.91 years, average 44.4 years) from 2017 to 2019 using data from the Korean Medicine Daejeon Citizen Cohort Study. The proposed algorithm comprised two steps. First, the initial predicted perceived age was estimated from facial images using a convolutional neural network (CNN) ensemble model. Then, the final perceived age was estimated using regression from the chronological age, sex, BMI, and initial predicted perceived age obtained in the first step. Better performance results were obtained by model averaging and model stacking generated from various basic regression models. The averaging models of Lasso, XGBoost, and CatBoost showed a mean absolute error of 2.2944, indicating that this algorithm can be used as a screening method for general health status in the population.

Yoga-based lifestyle intervention for healthy ageing in older adults: a two-armed, waitlist randomized controlled trial with multiple primary outcomes.

Yoga-based clinical research has shown considerable promise in varied ageing-related health outcomes in older adults. However, robust frameworks have yet to be used in intervention research to endorse yoga as a healthy ageing intervention to test the multidimensional construct of healthy ageing. This was an assessor-masked, randomized controlled trial conducted among 258 sedentary, community-dwelling older adults aged 60-80years, randomly allocated to 26-week yoga-based intervention (YBI) (n = 132) or waitlist control (WLC) (n = 126). The effectiveness of YBI was assessed through two separate global statistical tests, generalized estimating equations and rank sum-based test, against a comprehensive healthy aging panel comprised of ten markers representing the domains of physiological and metabolic, cognitive, physical capability, psychological, and social well-being. The secondary outcomes were individual primary marker scores, Klotho, inflammatory markers, and auxiliary blood markers. We could establish the healthy aging effect of the 26-week YBI over WLC using two models of global statistical test (GEE, β = 0.29; 95% CI = 0.20 to 0.38, p < 0.001), and rank sum-based test (β = 0.28, 95% CI = 0.19 to 0.36, p < 0.001). There were also significant improvements in direction of benefit at individual levels of all the aging markers. Exploratory evaluation with adopted indices from contemporary clinical trials also validated the potential of YBI for healthy aging; HATICE adapted composite score (mean difference = - 0.18; 95% CI = - 0.26 to - 0.09, p < 0.001) and healthy ageing index (mean difference = - 0.33; 95% CI = - 0.63 to - 0.02, p = 0.03). The global effect of YBI across multiple ageing-related outcomes provides a proof of concept for further large-scale validation. The findings hold a great translational value given the accelerated pace of population aging across the globe. Trial registration: CTRI/2021/02/031373.

Butyrate modulates gut microbiota and anti-inflammatory response in attenuating cisplatin-induced kidney injury.

In our previous research, we reported that administering probiotics Lactobacillus reuteri and Clostridium butyricum (LCs) before cisplatin treatment effectively modifies structures of the gut microbiota and restore ecological balance and significantly increases butyrate levels, a process closely associated with reducing cisplatin-induced nephrotoxicity. This study aims to investigate further whether the elevation of metabolite butyrate in the gut, promoted by probiotics LCs, can effectively mitigate the nephrotoxic effects of cisplatin and the progression of renal senescence in rats. Results show that butyrate administration significantly improved kidney function and decreased renal fibrosis in a dose-dependent manner compared to the cisplatin group. Its effects were associated with reductions in inflammatory responses, evidenced by decreased levels of key inflammatory markers, including KIM-1, MPO, NOX2, F4/80, and TGF-β1, alongside increased production of the anti-inflammatory cytokine IL-10. Furthermore, the butyrate intervention ameliorated cisplatin-induced gut microbiota dysbiosis, preserving the structure and diversity of healthy microbial communities. Specifically, we observed a decrease in the abundance of Escherichia_Shigella and Blautia, alongside an increase in the abundance of the butyrate-producing genus Roseburia. Notably, Escherichia_Shigella exhibited a positive correlation with the pro-inflammatory factor MPO, while displaying a negative correlation with the anti-inflammatory cytokine IL-10. Butyrate also attenuated the cisplatin-induced expression of senescence markers p21 and p16 in kidney tissue. It alleviated the cisplatin-increased senescence-associated beta-galactosidase activity and reactive oxygen species production in SV40 MES-13 cells. These results indicate that butyrate, derived from the gut microbiota, may exert a protective effect against cisplatin-induced kidney damage by regulating microbiota balance and anti-inflammatory effects.

Broccoli Sprout Extract Suppresses Particulate-Matter-Induced Matrix-Metalloproteinase (MMP)-1 and Cyclooxygenase (COX)-2 Expression in Human Keratinocytes by Direct Targeting of p38 MAP Kinase

Background/Objectives: Particulate matter (PM) is an environmental pollutant that negatively affects human health, particularly skin health. In this study, we investigated the inhibitory effects of broccoli sprout extract (BSE) on PM-induced skin aging and inflammation in human keratinocytes. Methods: HaCaT keratinocytes were pretreated with BSE before exposure to PM. Cell viability was assessed using the MTT assay. The expression of skin aging and inflammation markers (MMP-1, COX-2, IL-6) was measured using Western blot, ELISA, and qRT-PCR. Reactive oxygen species levels were determined using the DCF-DA assay. Kinase assays and pull-down assays were conducted to investigate the interaction between BSE and p38α MAPK. Results: Our findings demonstrate that BSE effectively suppressed the expression of MMP-1, COX-2, and IL-6—critical skin aging and inflammation markers—by inhibiting p38 MAPK activity. BSE binds directly to p38α without competing with ATP, thereby selectively inhibiting its activity and downstream signaling pathways, including MSK1/2, AP-1, and NF-κB. Conclusions: These results suggest that BSE is a potential functional ingredient in skincare products to mitigate PM-induced skin damage.

White matter hyperintensities are independently associated with systemic vascular aging and cerebrovascular dysfunction.

In the Oxford Haemodynamic Adaptation to Reduce Pulsatility trial (OxHARP), sildenafil increased cerebrovascular reactivity but did not reduce cerebral pulsatility, a marker of vascular aging. This analysis of OxHARP tested whether these potentially causative mechanisms were independently associated with severity of white matter hyperintensities (WMH). To determine independence of the relationship between severity of white matter hyperintensities with both cerebral pulsatility and cerebrovascular reactivity in the same population. OxHARP was a double-blind, randomised, placebo-controlled, crossover trial of phosphodiesterase inhibitors in patients with mild-moderate WMH and previous minor cerebrovascular events. It determined effects on cerebrovascular pulsatility and reactivity on transcranial ultrasound, and reactivity on MRI. Associations were determined between baseline ultrasound measures, and averaged MRI measures across follow-up, with severity of WMH on clinical imaging (Fazekas or modified Blennow scores) and WMH volume in the MRI substudy, by ordinal and linear regression. In 75/75 patients (median 70 years, 78% male), cerebral pulsatility was associated with age (p<0.001) whereas reactivity on ultrasound was not (p=0.29). Severity of WMH in all participants was independently associated with decreased cerebrovascular reactivity and increased cerebral pulsatility (pulsatility p=0.016; reactivity p=0.03), with a trend to a synergistic interaction (p=0.075). Reactivity on ultrasound was still associated with WMH after further adjustment for age (p=0.017) but pulsatility was not (p=0.31). Volume of WMH in the MRI substudy was also independently associated with both markers on ultrasound (pulsatility p=0.005; reactivity p=0.029), and was associated with reduced cerebrovascular reactivity within WMH on MRI (p<0.0001). WMH are independently associated with cerebral pulsatility and reactivity, representing complementary potential disease mechanisms and treatment targets. clinicaltrials.org: https://classic.clinicaltrials.gov/ct2/show/NCT03855332.

Molecular Aspects of Loss of Y-linked Proteins and Their Potential Applications in Cell Biology

Loss of proteins linked to Y chromosome (LOY) is a biomarker in human that is typically found in male blood samples. In healthy males, its frequency often rises with age. Additionally, it has lately been linked to numerous illnesses, including cancer with significantly high prevalence. A healthy male development depends on the Y chromosome and associated proteins. The deletion of this chromosome’s proteins or even its LOY variant may have effects on the male body. These proteins serve purposes beyond those of the male reproductive system. Paternity testing, ancestry research, and sexual assault investigations are just a few of the forensic situations where Y-linked protein analyses are frequently used. Due to its connection to the aging process, LOY detection has the benefit of being a biological age biomarker. The possibility of using LOY as a biomarker brings to light the need to define the molecular process underlying its occurrence and its potential applications in both health and forensic studies. Humans frequently experience LOY, a non-physiological post-zygotic molecular change that mostly affects male blood cells[Forsberg, 2017; Forsberg et al., 2017]. It is a natural part of aging and has been related to a number of illnesses, including as Alzheimer’s, Autoimmune disorders, Schizophrenia, Cardiovascular problems, and different malignancies[Holmes et al., 1985;Persanietal., 2012; Dumanskiet al., 2016; Forsberg, 2017; Forsberg et al., 2017; Haitjemaet al., 2017;]. It is possible to think about LOY as a biological age marker and a biomarker that predicts male age-related disorders [Dumanskiet al., 2016].However, LOY analysis might obstruct the forensic examination of male samples while also being helpful in forensic investigations by offering important details.

Exposure to multiple metals and leukocyte telomere length in children and adolescents: The mediating effect of thyroid hormones

Exposure to metals has been related to alterations in leukocyte telomere length (LTL), an aging marker. However, the evidence regarding this relationship in children and adolescents, as well as the underlying mechanisms, remains unclear. Therefore, we aimed to explore the individual and mixture effects of metals on LTL in children and adolescents and to assess the mediating role of thyroid hormones and the modifying effect of a healthy lifestyle. In a cross-sectional study performed in Liuzhou, China, we assessed 5 serum thyroid hormones, 18 urinary metals, and LTL among 1050 children and adolescents aged 6–18 years. We employed multivariate linear regression and weighted quantile sum (WQS) regression to assess the associations of urinary metals with LTL in children and adolescents. Mediation analyses were conducted to explore the effects of thyroid hormones on these relationships. Urinary cobalt (Co), nickel (Ni), strontium (Sr), mercury (Hg), cadmium (Cd), and thallium (Tl) were related to a shorter LTL in children and adolescents. The WQS regression showed a 6.31% (95% CI: −8.76%, −3.79%) decrease in LTL per quartile increase in the WQS index, and identified Ni (23.3%), Sr (21.7%), and Tl (18.0%) as the major contributors. Mediation analyses showed that triiodothyronine (T3) mediated 14.8% and 8.1% of the associations of urinary Sr and Hg with LTL, respectively, and suppressed 9.3% of the association with urinary Co. Furthermore, the inverse associations of Sr, Cd, and Tl with LTL were attenuated among participants who adopted a healthy lifestyle. Our findings suggested that exposure to Co, Ni, Sr, Cd, Hg, Tl, and their mixture were related to a shorter LTL in children and adolescents, potentially mediated by thyroid hormones. Additionally, adopting a healthy lifestyle may alleviate these adverse effects.

Inhibition of the E3 ligase UBR5 stabilizes TERT and protects vascular organoids from oxidative stress

BackgroundExcessive oxidative stress is known to cause endothelial dysfunction and drive cardiovascular diseases (CVD). While telomerase reverse transcriptase (TERT) shows protective effects against oxidative stress in rodents and is associated to human flow-mediated dilation in CVD, its regulatory mechanisms in human vascular systems under pathological oxidative stress require further investigation.MethodsHuman induced pluripotent stem cells (hiPSCs) were used to create vascular organoids (VOs). These VOs and human umbilical vein endothelial cells (HUVECs) were subjected to oxidative stress through both hydrogen peroxide (H2O2) and oxidized low-density lipoprotein (oxLDL) models. The effects of TERT overexpression by inhibition of the ubiquitin protein ligase E3 component N-recognin 5 (UBR5) on reactive oxygen species (ROS)-induced vascular injury and cellular senescence were assessed using neovascular sprouting assays, senescence-associated β-galactosidase (SA-β-Gal) staining, and senescence-associated secretory phenotype (SASP) assays.ResultsROS significantly impaired VO development and endothelial progenitor cell (EPC) angiogenesis, evidenced by reduced neovascular sprouting and increased senescence markers, including elevated SA-β-Gal activity and SASP-related cytokine levels. Overexpression of TERT counteracted these effects, restoring VO development and EPC function. Immunoprecipitation-mass spectrometry identified UBR5 as a critical TERT regulator, facilitating its degradation. Inhibition of UBR5 stabilized TERT, improving VO angiogenic capacity, and reducing SA-β-Gal activity and SASP cytokine levels.ConclusionsInhibiting UBR5 stabilizes TERT, which preserves EPC angiogenic capacity, reduces VO impairment, and delays endothelial cell senescence under oxidative stress. These findings highlight the potential of targeting UBR5 to enhance vascular health in oxidative stress-related conditions.Graphical

Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) and its association with arterial stiffness in adolescents: Results from the EVA4YOU study.

To determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) among Western Austrian adolescents and its association with arterial stiffness as a marker of early vascular ageing. In the cross-sectional Early Vascular Ageing in the YOUth study, liver fat content was assessed by controlled attenuation parameter (CAP) using signals acquired by FibroScan (Echosense, Paris, France) in 14- to 19-year-old Austrian adolescents. Arterial stiffness was determined by carotid-femoral pulse wave velocity (cfPWV) and cardiovascular risk factors by a face-to-face interview, physical examination, and fasting blood analyses. Linear regression models and one-way analysis of variance were performed to analyze the association between liver fat content, MASLD and cfPWV. A total of 1292 study participants (65.2% female) aged 17.2 ± 1.3 years were included. MASLD was detected in 62 (4.8%) adolescents. CAP value showed a significant association with cfPWV in the unadjusted model (p < 0.001) but lost its significant influence in the multivariable model after adjusting for sex, age and cardiovascular risk criteria (increased BMI or waist circumference, impaired glucose metabolism, elevated blood pressure, elevated plasma triglycerides, and decreased HDL cholesterol; p = 0.540). In the analysis of variance, a significant increase in cfPWV was observed in adolescents with any of the five cardiovascular risk criteria for MASLD (p < 0.001), but not with the additional presence of steatotic liver disease (p = 0.291). In our adolescent cohort, liver fat content and MASLD were not found to be independent predictors for early vascular ageing. Nevertheless, the determination of liver fat content can be a useful tool to identify adolescents at high risk for cardiovascular disease and metabolic syndrome.

Blood based immune biomarkers associated with clinical frailty scale in older patients with melanoma receiving checkpoint inhibitor immunotherapy

IntroductionImmunotherapy with checkpoint inhibition (ICI) is increasingly prescribed to older patients with cancer. High age, especially in combination with frailty, has been associated to immune senescence, which is the age-related decline in immune function, thereby possibly hindering ICI effectiveness. This cross-sectional study aimed to assess whether blood cell immune senescence markers are associated with age, frailty and response to anti-PD-1 treatment in older patients with metastatic melanoma.MethodsIn a prospective observational study, sixty patients with stage IIIC or IV melanoma undergoing anti-PD1 treatment were categorized into young (< 65 years; n = 22), old (> 65 years) without frailty (n = 19), and old with frailty (n = 19). In-depth immune cell phenotyping was performed in baseline blood samples (prior to treatment) using multispectral flow cytometry and compared between groups and with immunotherapy treatment response. Antigen-presenting cell capacity was evaluated using mixed lymphocyte reaction and T cell proliferative potential was assessed using PHA proliferation assay.ResultsNo significant differences in treatment response rates were observed across age groups. Older patients, irrespective of frailty, showed lower levels of naïve CD8 + T cells, with the old and frail group also exhibiting reduced tissue-resident effector memory CD8 + T cells and CD8 + mucosal associated invariant T (MAIT) cells. These differences were not associated with treatment outcomes. T cell proliferation and antigen-presenting cell capacities did not differ across groups.ConclusionSeveral ageing and frailty associated changes were detected among circulating immune cells in blood but were not associated with response to immunotherapy in our study. While these findings suggest that the level of frailty and ageing may not necessarily preclude the efficacy of ICI therapy, further investigation is needed to fully understand the impact of frailty and ageing on immunotherapy.

Research on the Correlation Between Skin Elasticity Evaluation Parameters and Age

This study aims to explore the impact of aging on skin elasticity, a key biomechanical property that diminishes over time, using the Cutometer to assess viscoelastic parameters. Methods: Researchers analyzed 22 viscoelastic parameters from the facial skin of 60 women aged 18 to 70. Key Results: The findings indicate that relaxation phase parameters, particularly biological elasticity (R7), exhibited the strongest negative correlation with age (r = −0.62), signifying a notable decline in biological elasticity as women age. In contrast, maximum deformation during the first cycle (R0) and the total area under the upper curve after 10 cycles of deformation (F4) also showed significant negative correlations with age (r = −0.47, r = −0.48), suggesting that younger skin typically presents higher values. These correlations raise questions regarding practical applications, as the presence of moisturizers and emollients may alter the stratum corneum’s properties, thus impacting these measurements. Additionally, the ratio of delayed deformation to instantaneous deformation (R6) demonstrated a positive correlation with age (r = 0.49), indicating its potential as a marker for skin aging. Conclusions: This study highlights the critical role of relaxation phase parameters in accurately reflecting skin elasticity changes associated with aging. The results offer valuable insights for evaluating cosmetic efficacy, reinforcing the need for a nuanced understanding of how various parameters interact. These findings contribute to the ongoing development of more effective anti-aging treatments and products.

Comparative genome-wide association study of single- and multi-locus models with ontology analysis for enhancing Hanwoo cow reproductive traits.

The reproductive characteristics of Hanwoo play a significant role in farm profitability by decreasing the generation interval. This study analyzed 1015 primiparous and 916 multiparous cows using a genome-wide association study with both single-locus (GEMMA, GCTA) and multi-locus models (FarmCPU, BLINK). A significant marker for age at first service was identified across all methods. For age at first conception, GEMMA identified two markers, while FarmCPU and BLINK identified 14 and two markers, respectively. Regarding age at first calving, GEMMA identified two markers, and FarmCPU and BLINK found 15 and two markers, respectively. In multiparous cows, except for days open, one marker for gestation length and two markers for calving interval were identified in the multi-locus models (FarmCPU and BLINK). Additionally, one marker for the number of services per conception was identified using GEMMA. Key candidate genes included PLCB1 (maintaining pregnancy), MUC1 (fetal development), and ADCY5 (associated with fetal birth), while TXNL1 regulates embryo implantation timing. Gene ontology functions associated with embryo implantation and placental regulation were also confirmed (GO:0046875). Although the multi-locus models identified a greater number of markers and candidate genes, there was no overlap with the results from the single-locus models. The multi-locus models showed enhanced detection power, but slight inflation in test statistics (λ values) necessitates cautious interpretation to avoid false positives. Thus, a combination of both models is recommended to improve reproductive efficiency in cows, providing valuable insights into the genetic aspects of reproductive traits.

Proteomic Markers of Aging and Longevity: A Systematic Review

This article provides a systematic review of research conducted on the proteomic composition of blood as part of a complex biological age estimation. We performed a comprehensive analysis of 17 publicly available datasets and compiled an integral list of proteins. These proteins were sorted based on their detection probability using mass spectrometry in human plasma. We propose this list as a basis for creating a panel of peptides and quantifying the content of selected proteins in the format of a proteomic aging clock. The selected proteins are especially notable for their roles in inflammatory processes and lipid metabolism. Our findings suggest, for the first time, that proteins associated with systemic disorders, including those approved by the FDA for clinical use, could serve as potential markers of aging.

Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk.

Anti-aging effect of extracellular vesicles from mesenchymal stromal cells on senescence-induced chondrocytes in osteoarthritis.

Age is the most important risk factor for degenerative diseases such as osteoarthritis (OA). It is associated with the accumulation of senescent cells in joint tissues that contribute to the pathogenesis of OA, in particular through the release of senescence-associated secretory phenotype (SASP) factors. Mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) are promising treatments for OA. However, the senoprotective effects of MSC-derived EVs in OA have been poorly investigated. Here, we used EVs from human adipose tissue-derived MSCs (ASC-EVs) in two models of inflammaging (IL1β)- and DNA damage (etoposide)-induced senescence in OA chondrocytes. We showed that the addition of ASC-EVs was effective in reducing senescence parameters, including the number of SA-β-Gal-positive cells, the accumulation of γH2AX foci in nuclei and the secretion of SASP factors. In addition, ASC-EVs demonstrated therapeutic efficacy when injected into a murine model of OA. Several markers of senescence, inflammation and oxidative stress were decreased shortly after injection likely explaining the therapeutic efficacy. In conclusion, ASC-EVs exert a senoprotective function both in vitro, in two models of induced senescence in OA chondrocytes and, in vivo, in the murine model of collagenase-induced OA.

Elocalcitol mitigates high-fat diet-induced microglial senescence via miR-146a modulation

BackgroundMicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence.ResultsWild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo’s therapeutic efficacy on miR-146a.ConclusionElocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence.

Causal associations between telomere length and pulmonary arterial hypertension: A two-sample Mendelian randomization study

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by elevated pulmonary artery pressure, leading to right heart failure, and mortality. The role of telomere length, a marker of biological aging, in PAH remains unclear. We utilized summary-level data from genome-wide association studies for various measures of telomere length and PAH. Single nucleotide polymorphisms associated with telomere length at a genome-wide significance level were used as instrumental variables. The inverse variance weighted method was the primary analysis, with sensitivity analyses including the weighted median and Mendelian randomization-Egger regression. The odds ratios and 95% confidence intervals (CI) were calculated to estimate the causal effect of telomere length on PAH risk. The Mendelian randomization analyses revealed no significant causal association between overall telomere length and PAH (odds ratios per standard deviation increase = 1.229, 95% CI: 0.469–3.222, P = .676). Similar null findings were observed for granulocyte, lymphocyte, naive T-cell, memory T-cell, B-cell, and natural killer-cell telomere lengths. Sensitivity analyses confirmed the robustness of the results, with no evidence of horizontal pleiotropy or significant influence of individual single nucleotide polymorphisms on the overall estimates. This Mendelian randomization study didn’t support a causal association between telomere length and PAH.

Mapping lateral stratigraphy at Palaeolithic surface sites: A case study from Dhofar, Oman

Open-air accumulations of chipped stone debris are a common feature in arid landscapes, yet despite their prevalence, such archives are often dismissed as uninformative or unreliable. In the canyonlands of Dhofar, southern Oman, lithic surface scatters are nearly ubiquitous, including extensive, multi-component workshops associated with chert outcrops. These sites typically display chronologically diagnostic features that correspond to distinct taphonomic states, which in turn appear linked to spatial distribution, with more heavily weathered artifacts often found farther from the chert outcrops. We propose that post-depositional modifications and spatial distributions of chipped stone artifacts reflect site formation processes and, under certain conditions, may provide relative chronological information when absolute dating methods are unavailable. Our study tests this hypothesis by mapping artifact distribution and lithic taphonomy across a series of surface sites in southern Oman, spanning the Lower, Middle, and Upper/Late Palaeolithic periods. The results largely support our model, offering valuable insights into surface site formation and technological change over time. While these findings serve as broad predictive markers for age, their applicability for analyzing finer-scale assemblage variability remains to be determined. Future taphonomic recording systems should aim to quantify surface modifications to enhance replicability for such studies.