Experimental gerontology最新文献

{"title":"Mediating role of thyroid dysfunction in the relationship between insomnia and osteoporosis: A Mendelian randomization analysis","authors":"Lei Wu ,&nbsp;Hengheng Zhang ,&nbsp;Yongwen Li ,&nbsp;Jinxin Tang ,&nbsp;Dengwen wang ,&nbsp;Linrong Zhu","doi":"10.1016/j.exger.2025.112842","DOIUrl":"10.1016/j.exger.2025.112842","url":null,"abstract":"<div><h3>Background</h3><div>Insomnia and osteoporosis are both prevalent conditions with rising incidence. Observational studies have suggested that insomnia may lead to thyroid dysfunction, which in turn contributes to osteoporosis. However, the interplay among these three conditions remains unexamined. This study aimed to investigate the causal association between insomnia and osteoporosis, while also analyzing whether thyroid dysfunction mediates this relationship.</div></div><div><h3>Method</h3><div>A two-sample Mendelian randomization approach was applied to examine the genetic association between insomnia and osteoporosis. Mediator MR was subsequently used to assess the intermediary role of thyroid dysfunction. The inverse variance weighting method served as the primary analytical strategy. Heterogeneity was evaluated using MR-Egger's intercept, Cochran's Q test, and leave-one-out analysis. The MR-PRESSO test was conducted to assess horizontal pleiotropy. To ensure robustness, FDR correction was applied.</div></div><div><h3>Results</h3><div>A genetic association between insomnia and osteoporosis was observed (IVW: OR = 1.004, <em>p</em> = 0.007). Insomnia showed a genetic link with hypothyroidism (IVW: OR = 1.010, <em>p</em> = 0.00075), but not with hyperthyroidism, Hashimoto's thyroiditis, or Graves' disease (<em>p</em> &gt; 0.05). Mediator MR revealed that hypothyroidism accounted for 6.29 % (6.27 %–6.31 %) of the effect of insomnia on osteoporosis.</div></div><div><h3>Conclusion</h3><div>This study supports a causal link between insomnia and osteoporosis. Hypothyroidism plays a mediating role in this pathway. Targeting hypothyroidism may lower the risk of osteoporosis associated with insomnia.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112842"},"PeriodicalIF":4.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Good sleep quality predicts a lower risk of osteoporosis in older adults: Evidence from the English longitudinal study of ageing","authors":"Mixue Guo ,&nbsp;Mengyuan Cai ,&nbsp;Huqiang Dong ,&nbsp;Hongli Wan ,&nbsp;Zongren Zhao ,&nbsp;Luming Wei ,&nbsp;Qixin Chen","doi":"10.1016/j.exger.2025.112844","DOIUrl":"10.1016/j.exger.2025.112844","url":null,"abstract":"<div><h3>Background</h3><div>Osteoporosis is an increasingly prevalent public health concern in ageing populations. While traditional risk factors such as ageing, hormonal status, and physical inactivity are well-recognized, the role of sleep quality in osteoporosis risk remains understudied. This study aimed to investigate the prospective association between sleep quality and the risk of developing osteoporosis among older adults.</div></div><div><h3>Methods</h3><div>We conducted a prospective cohort study using data from the English Longitudinal Study of Ageing (ELSA). A total of 5958 osteoporosis-free participants aged ≥50 years were recruited at wave 4 (2008–2009) and followed up across waves 5 to 8 (2016–2017), with a maximum follow-up of 8 years. Sleep quality was assessed using a validated four-item questionnaire (score range: 4–16), and categorized as good (4 ≤ score ≤ 7), intermediate (8 ≤ score ≤ 11), and poor (12 ≤ score ≤ 16) sleep quality groups. Incident osteoporosis was identified via self-reported physician diagnosis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs), adjusting for demographic, socioeconomic, lifestyle, and health-related covariates including sleep duration.</div></div><div><h3>Results</h3><div>During the 8-year follow-up, 319 participants (5.36 %) developed osteoporosis. Compared to those with poor sleep quality, the risk of osteoporosis was significantly lower in the intermediate (adjusted HR = 0.64, 95 % CI: 0.49–0.85) and good sleep quality groups (adjusted HR = 0.54, 95 % CI: 0.39–0.73). A significant dose–response relationship was observed (P for trend &lt;0.001). These associations remained robust among participants with normal sleep duration (6–9 h). Subgroup analyses revealed that the associations were particularly significant in adults aged 60–80 years, those who were married or cohabiting, and individuals with hypertension, even after Bonferroni correction.</div></div><div><h3>Conclusions</h3><div>Higher sleep quality was significantly associated with a reduced risk of osteoporosis among older adults. These findings suggest that sleep quality may be a potentially modifiable behavioral factor related to osteoporosis risk, warranting further investigation in future longitudinal and interventional studies.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112844"},"PeriodicalIF":3.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between dietary inflammatory index and endometriosis in the US population: A cross-sectional study","authors":"Yan Chen ,&nbsp;Meng Yu ,&nbsp;Shan Hu ,&nbsp;Donghui Yu ,&nbsp;Ying Zhao","doi":"10.1016/j.exger.2025.112846","DOIUrl":"10.1016/j.exger.2025.112846","url":null,"abstract":"<div><h3>Background</h3><div>Endometriosis is a chronic inflammatory disorder affecting reproductive-aged women. The Dietary Inflammatory Index (DII), a measure of diet-related inflammation, has been implicated in various inflammatory diseases, but its role in endometriosis remains unclear.</div></div><div><h3>Methods</h3><div>This cross-sectional study analyzed 4149 women from the NHANES 2001–2006, including 287 with endometriosis. DII scores were derived from dietary data and categorized into quartiles. Logistic regression models were used to assess the association between DII and endometriosis, adjusting for confounders. Restricted cubic splines (RCS) were applied to explore non-linear trends, and subgroup analyses evaluated effect modifications. LASSO regression identified key predictors, and a nomogram was developed for risk prediction.</div></div><div><h3>Results</h3><div>Women with endometriosis had higher DII scores than those without (1.69 ± 1.76 vs. 1.48 ± 1.74, <em>P</em> = 0.044). In fully adjusted models, the odds of endometriosis increased with higher DII quartiles (Q4 vs. Q1: OR1.40, 95 % CI: 1.02–1.98, <em>P</em> for trend &lt; 0.001). While non-linear trends were not statistically significant (<em>P</em>-non-linear = 0.128), RCS analysis suggested a steeper risk increase at higher DII levels. Subgroup analyses indicated stronger associations among older women, those with higher BMI, and smokers. The nomogram achieved moderate predictive performance (AUC: 66.6 %, 95 % CI: 63.7–69.5 %).</div></div><div><h3>Conclusion</h3><div>Higher DII scores are associated with increased odds of endometriosis. Dietary interventions targeting inflammation may offer a novel approach to managing endometriosis.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112846"},"PeriodicalIF":4.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparison of internal fixation and artificial hip replacement in elderly hip fracture and analysis of factors of postoperative stroke occurrence","authors":"Shengcheng Yao ,&nbsp;Yingnan Zhang ,&nbsp;Yuan Wang ,&nbsp;Fang Pei ,&nbsp;Kaijin Guo ,&nbsp;Bin Deng","doi":"10.1016/j.exger.2025.112845","DOIUrl":"10.1016/j.exger.2025.112845","url":null,"abstract":"<div><h3>Objective</h3><div>This study is designed to assess the effect of internal fixation (IF) versus artificial hip replacement (AHR) on stroke during and after hip fracture.</div></div><div><h3>Methods</h3><div>A total of 120 elderly patients with hip fractures who were treated in our hospital were retrospectively analyzed and divided into an IF group and an AHR group according to the surgical method. Comparisons were made between patients of two groups in general data, intraoperative and postoperative general conditions, hip function scores, and hip joint excellence rate. According to whether or not patients have had a postoperative stroke, they were classified into the occurrence and non-occurrence groups in order to analyze the influence of single factor and multivariate analysis on the postoperative hip fracture of the elderly patients.</div></div><div><h3>Results</h3><div>All patients were followed up for 12 months postoperatively. In contrast to the IF group, the AHR group showed better intraoperative and postoperative conditions, higher Harris function score, higher hip joint excellent rate, and lower incidence of postoperative stroke (all <em>P</em> &lt; 0.05). In 120 cases of patients, 18 cases of postoperative stroke occurred, with the incidence rate of 15.00 %. The results of the multivariate analysis reflected that the risk factors for postoperative stroke during hospitalization for hip fracture included advanced age, ASA III and above, long-term anticoagulant medication, and IF surgery (all OR &gt; 1, <em>P</em> &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>Compared with IF, giving AHR treatment to elderly hip fracture patients can considerably optimize the surgical indicators, improve the hip function of elderly patients, and provide better postoperative recovery.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112845"},"PeriodicalIF":4.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Remazolam affects the phenotype and function of astrocytes to improve traumatic brain injury by regulating the Cx43” [Experimental Gerontology (2024) 189:112404]","authors":"Jing Xia ,&nbsp;Yang Tan ,&nbsp;Congli Mao ,&nbsp;Wenting Shen ,&nbsp;Ying Zhao","doi":"10.1016/j.exger.2025.112841","DOIUrl":"10.1016/j.exger.2025.112841","url":null,"abstract":"","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112841"},"PeriodicalIF":4.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144700742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of unstable resistance training combined with high-definition transcranial direct current stimulation on proprioception, balance and fall risks in the elderly: a randomized controlled trial study","authors":"Di Peng ,&nbsp;Shengnian Zhang ,&nbsp;Yu Zhang ,&nbsp;Han Wu ,&nbsp;Xu Zou ,&nbsp;Guanyue Zhang ,&nbsp;Yuan Ma ,&nbsp;Tongxin Ma ,&nbsp;Lejun Wang","doi":"10.1016/j.exger.2025.112843","DOIUrl":"10.1016/j.exger.2025.112843","url":null,"abstract":"<div><h3>Objective</h3><div>This study examined the combined effects of unstable resistance training (URT) and high-definition transcranial direct current stimulation (tDCS) on proprioception, balance, and fall risk in community-dwelling older adults, targeting both central neural drive and peripheral neuromuscular adaptations.</div></div><div><h3>Method</h3><div>Ninety older adults (mean age 66.2 ± 3.3 years) were recruited and randomly assigned to five groups: (1) URT + a-tDCS, (2) URT + s-tDCS, (3) URT, (4) stable resistance training (SRT) and (5) a health education control group (HALE). All participants underwent an 8-week intervention (three sessions per week, 30 min per session). Participants in the URT + a-tDCS group received 2 mA stimulation for 20 min concurrently with URT sessions. Assessments of ankle proprioception, balance and fall risk were conducted at baseline and post-intervention.</div></div><div><h3>Result</h3><div>Eight weeks of URT + a-tDCS significantly improved proprioception at dorsiflexion and plantarflexion, compared with URT + s-tDCS, URT, SRT and baseline (<em>P</em> &lt; 0.05). URT + s-tDCS and URT enhanced proprioception at plantarflexion than baseline (<em>P</em> = 0.033; <em>P</em> = 0.021). Balance measurements (i.e. COP displacement, COP ellipse area and sway velocity index) under stable and unstable surfaces were significantly improved after URT + a-tDCS, compared with other three training modalities and baseline. The fall-risk declined significantly after URT + a-tDCS compared with HALE and baseline (<em>P</em> &lt; 0.05). The change in sway velocity index was positively related to the change in proprioception at plantarflexion after 8-week URT intervention (<em>R</em>^<em>2</em> = 0.378, <em>P</em> = 0.015).</div></div><div><h3>Conclusion</h3><div>The combined URT and a-tDCS intervention demonstrated synergistic effects, producing statistically significant improvements in proprioceptive acuity and balance parameters among older adults. This integrated intervention offers a promising approach to fall prevention and highlights the importance of targeting both central and peripheral mechanisms in rehabilitation strategies.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112843"},"PeriodicalIF":3.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single nucleotide polymorphism SULT2A1 rs4149448 and genetic risk score as biomarkers of frailty and progression of chronic kidney disease","authors":"Hellen Christina Neves Rodrigues ,&nbsp;Alexandre Siqueira Guedes Coelho ,&nbsp;Ana Tereza Vaz de Souza Freitas ,&nbsp;Maria do Rosário Gondim Peixoto ,&nbsp;Maria Aderuza Horst ,&nbsp;Nara Aline Costa","doi":"10.1016/j.exger.2025.112836","DOIUrl":"10.1016/j.exger.2025.112836","url":null,"abstract":"<div><h3>Background</h3><div>Frailty is a multifactorial condition highly prevalent in patients with chronic kidney disease (CKD), increasing with disease progression. Identifying genetic determinants associated with frailty may aid in risk stratification. We aimed to identify whether single nucleotide polymorphisms (SNPs), individually or combined into a genetic risk score (GRS), are associated with the frailty phenotype and adverse clinical outcomes in CKD patients.</div></div><div><h3>Methods</h3><div>This is a longitudinal study that evaluated patients with CKD 3b-5 non-dialysis dependent [69 (57–72) years; 59,1 % men; body mass index, 27.2 ± 5.3 kg/m²]. Clinical, anthropometric, and biochemical variables, including 25(OH)D concentration, were evaluated. Eight SNPs associated with low vitamin D levels were genotyped using qPCR. The genetic risk score (GRS) was calculated by summing the number of risk alleles for vitamin D deficiency across the SNPs, resulting in values ranging from 0 to 16. Frailty was assessed using the physical frailty phenotype. The outcomes considered were non-elective hospitalization and changes in CKD stage.</div></div><div><h3>Results</h3><div>Around 36 % of patients were frail, and 68 % had 25(OH)D levels below 20 ng/mL and were considered deficient. The higher GRS [9 (7–10) versus 6 (5–7); <em>p</em> = 0.034] occurred in patients who developed CKD progression. After the adjusted logistic regression analysis, the <em>SULT2A1</em> genotype of rs4149448 was associated with a greater chance of frailty (OR: 8.8 IC95% 1.048–74.733; <em>p</em> = 0.045).</div></div><div><h3>Conclusion</h3><div>Specific genetic variants, including a higher GRS and the SNP <em>SULT2A1</em> rs4149448 genotype, were associated with CKD progression and frailty, suggesting their potential role in risk stratification.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112836"},"PeriodicalIF":3.9,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144686600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fall history and risk of incident stroke in middle-aged and older adults with possible sarcopenia: A longitudinal cohort study based on CHARLS","authors":"Peiling Ke ,&nbsp;Da Chen ,&nbsp;Linjie Su","doi":"10.1016/j.exger.2025.112835","DOIUrl":"10.1016/j.exger.2025.112835","url":null,"abstract":"<div><h3>Background</h3><div>Possible sarcopenia (PS) was defined per AWGS 2019 criteria as reduced muscle strength or physical performance without low muscle mass. PS and falls are prevalent in aging populations, yet their combined impact on long-term stroke risk remains underexplored, particularly in Asian cohorts. This study investigates the association between fall history and incident stroke among middle-aged and older Chinese adults with PS.</div></div><div><h3>Methods</h3><div>Using longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS, 2015–2018), we analyzed 4605 participants with PS (mean age: 64.8 years). Fall history was assessed by self-reported response to “Have you fallen in the past two years?” Stroke was physician-diagnosed via self-report. Multivariable-adjusted logistic regression models evaluated stroke risk, adjusting for demographics, comorbidities (hypertension, diabetes), and biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hs-CRP]). Subgroup and sensitivity analyses assessed robustness.</div></div><div><h3>Results</h3><div>Stroke incidence was 9.3 % among fallers and 6.7 % among non-fallers, with a <em>P</em>-value of 0.036. Participants with fall history exhibited a 37 % higher risk of incident stroke compared to non-fallers (adjusted OR: 1.37, 95 % CI: 1.02–1.84). The association remained consistent across age, sex, BMI, and most comorbidity subgroups, except for dyslipidemia (interaction <em>P</em> = 0.022). Sensitivity analyses, including multiple imputation for missing data, exclusion of adults &gt;80 years, and removal of hip fracture cases, consistently confirmed the robustness of the findings.</div></div><div><h3>Conclusion</h3><div>Fall history independently predicts stroke risk in individuals with PS, highlighting the potential of fall prevention to reduce stroke burden in this population. This study provides novel evidence of a prolonged stroke risk trajectory in Asian PS cohorts, complementing Western studies focused on short-term post-fall risks. The study has several limitations. Self-reported falls may introduce recall bias and lack mechanistic details. Unmeasured confounders such as diet and medication use constrain causal interpretation. Data constraints prevented differentiation between stroke subtypes.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112835"},"PeriodicalIF":3.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144654333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Involvement of the tryptophan-kynurenine pathway in the pathogenesis of autoimmune diseases","authors":"A-Yuan Chen ,&nbsp;Ying-Jie Zhao ,&nbsp;Yue-Ye Wang ,&nbsp;Wei Wei ,&nbsp;Wei Hu ,&nbsp;Yan Chang","doi":"10.1016/j.exger.2025.112837","DOIUrl":"10.1016/j.exger.2025.112837","url":null,"abstract":"<div><div>The kynurenine pathway (KP), a major metabolic pathway for L-tryptophan (Trp) in mammals, plays a multifaceted role in various physiological processes, including neural activity, immune system regulation, and the maintenance of intestinal homeostasis. The functional connection between the KP and immune system is supported by robust evidence, including disease-associated alterations in KP metabolite concentrations and enzyme activities that correlate with immune function changes. Imbalances in the KP can be detrimental, as excessive production of pro- or anti-inflammatory metabolites may promote autoimmunity or impair pathogen defense. To date, KP enzymes and metabolites have been extensively studied as both promoters and therapeutic targets in a wide array of autoimmune diseases (AID). Pharmacological modulation of the KP represents a promising therapeutic strategy, as it can regulate immune responses and attenuate disease progression in AID. However, the precise cellular and molecular mechanisms by which the KP contributes to AID pathogenesis remain incompletely understood. This review explores the complex mechanisms through which KP enzymes and metabolites regulate inflammatory immune responses in AID, and highlights potential therapeutic targets for drug development.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112837"},"PeriodicalIF":3.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF3 as a molecular nexus linking ferroptosis regulation to sarcopenia pathogenesis via PI3K/Akt pathway activation","authors":"Zhi Chen ,&nbsp;Dingxiang Hu ,&nbsp;Chengjian Wu ,&nbsp;Zhengru Wu ,&nbsp;Jiajun Lin ,&nbsp;Wenge Liu","doi":"10.1016/j.exger.2025.112830","DOIUrl":"10.1016/j.exger.2025.112830","url":null,"abstract":"<div><h3>Purpose</h3><div>Sarcopenia, characterized by progressive skeletal muscle loss and weakness, has unclear pathogenesis and lacks targeted therapies. Emerging evidence implicates ferroptosis in sarcopenia progression, though its regulatory mechanisms remain undefined. This study investigates the ferroptosis-sarcopenia interplay, identifies core regulators and elucidates their molecular basis.</div></div><div><h3>Methods</h3><div>The experimental design combined in vivo and in vitro approaches using SAMP8 mice and C2C12 myoblast. Sarcopenia phenotypes were systematically characterized through functional assessments of mice, histomorphological analysis of gastrocnemius muscle, and quantification of iron deposition. Bioinformatics cross-analysis was performed by intersecting the sarcopenia-related gene expression dataset (GSE175495) with ferroptosis-associated genes from the FerrDb database, identifying ATF3 as a hub gene. Validation was conducted through Western blot (WB) and quantitative real-time PCR (qPCR). For mechanistic exploration, ferroptosis was induced in C2C12 cells using ferric ammonium citrate (FAC, 500 μM, 48 h), followed by lentivirus-mediated ATF3 overexpression. The regulatory role of ATF3 in ferroptosis was assessed via reactive oxygen species (ROS) assay, malondialdehyde (MDA) quantification, and FerroOrange fluorescent probe for intracellular iron detection. Transcriptome sequencing of ATF3-dysregulated cell lines was performed, and GO/ KEGG enrichment analyses were applied to identify critical signaling pathways. Functional validation was further conducted using pathway-specific inhibitors.</div></div><div><h3>Results</h3><div>Aged SAMP8 mice exhibited hallmark sarcopenia characteristics including 31 % reduction in grip strength, 42 % decrease in muscle fiber cross-sectional area, and 2.1-fold elevation in intramuscular iron content. Molecular analysis revealed age-dependent downregulation of ATF3 expression (57 % protein decrease, 63 % mRNA reduction). ATF3 overexpression in C2C12 cells significantly attenuated ferroptosis, evidenced by 45–52 % reductions in ROS/MDA levels and reversal of atrophy-related protein expression. Transcriptomic profiling identified 773 differentially expressed genes functionally enriched in PI3K/Akt signaling, with ATF3 overexpression inducing 3.2-fold activation of p-Akt. Crucially, pharmacological PI3K inhibition completely abolished ATF3-mediated ferroptosis suppression, establishing pathway dependency.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that ATF3 serves as a critical molecular nexus linking ferroptosis regulation to sarcopenia pathogenesis through PI3K/Akt pathway activation.</div></div>","PeriodicalId":94003,"journal":{"name":"Experimental gerontology","volume":"209 ","pages":"Article 112830"},"PeriodicalIF":3.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}