The Journals of Gerontology Series A: Biological Sciences and Medical Sciences最新文献

{"title":"Extracellular Vesicles and Epigenetic Aging Clocks in Tissue Aging: An Exosome-Focused Conceptual Framework with a Focus on Skin","authors":"Zeynep Yaren Dinçer, Kaan Zikşahna, Murat Ihlamur","doi":"10.1093/gerona/glag183","DOIUrl":"https://doi.org/10.1093/gerona/glag183","url":null,"abstract":"Tissue aging is a multifactorial process characterized by cellular senescence, disrupted intercellular communication, and epigenetic alterations, with skin providing a clinically accessible and biologically informative model system. Exosomes and other extracellular vesicles (EVs) are increasingly recognized as mediators of aging-related signalling, whereas DNA methylation–based aging clocks offer quantitative measures of biological age. In this narrative review, we examine the potential interplay between EV/exosome biology and epigenetic aging clocks across tissue-aging contexts, while using skin aging as a primary focus and illustrative model. We review evidence from studies of keratinocytes, dermal fibroblasts, mesenchymal stromal cells, and aging-associated EV cargo, distinguishing studies with direct DNA methylation age readouts from those reporting indirect epigenetic effects. Current evidence indicates that EVs/exosomes from aged or senescent cells may disseminate pro-aging and inflammatory signals, whereas vesicles from young or regenerative sources may support repair and tissue homeostasis. Nevertheless, direct evidence that EVs alter skin epigenetic clock measures remains scarce. In particular, direct experimental evidence demonstrating that aged-cell-derived EVs or exosomes alter DNA methylation clock readings in human keratinocytes or dermal fibroblasts is currently lacking. We propose that skin serves as a useful model for investigating how extracellular signalling interfaces with epigenetic aging dynamics. Therefore, the proposed exosomal–epigenetic clock feedback-loop framework should be interpreted as a hypothesis-generating conceptual model rather than as a validated mechanistic pathway.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148461863","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":"Urinary Metabolic Age from High-Resolution NMR Reveals Longitudinal Aging Patterns.","authors":"Karen Friederike Gauß,Nele Friedrich,Ann-Kristin Henning,Johannes Hertel,Hans Jörgen Grabe,Henry Völzke,Matthias Nauck,Astrid Petersmann","doi":"10.1093/gerona/glag180","DOIUrl":"https://doi.org/10.1093/gerona/glag180","url":null,"abstract":"Biological age captures inter-individual heterogeneity in aging process arising from genetic and environmental influences. Metabolites, as the end-products of metabolism, integrate these factors and are therefore well suited for biological age estimation. Urinary metabolomics, in particular, provides a non-invasive and information-rich matrix for assessing systemic metabolic states. We applied different machine learning techniques to develop a biological age score from high-resolution 1H nuclear magnetic resonance (NMR) metabolites measured in urine samples from a large population-based cohort. The derived metabolic age score was applied to evaluate longitudinal trajectories over more than a decade. Cross-sectional associations with age-related clinical phenotypes were examined, and prospective analyses assessed associations with incident diseases and all-cause mortality. Metabolic age progression over time varied between individuals, underscoring inter-individual heterogeneity in metabolic aging. In cross-sectional analyses, the metabolic age score showed biologically plausible associations with a range of age-related clinical phenotypes. Furthermore, metabolic age was predictive of multiple diseases and all-cause mortality independent of chronological age. Our findings highlight the utility of urinary metabolomics as a robust, non-invasive approach for biological age assessment. The characterization of long-term metabolic age trajectories provides novel insight into inter-individual differences in aging and establishes urinary metabolic age as a promising tool for risk stratification and aging research.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429065","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":"Metabolomic signatures and causal effects of circulating metabolites on age-related cataract","authors":"Xing-Xuan Dong, Shi-Yi Gong, Jia-Yan Kai, Dan-Lin Li, Dan-Ning Hu, Chaofu Ke, Chen-Wei Pan","doi":"10.1093/gerona/glag182","DOIUrl":"https://doi.org/10.1093/gerona/glag182","url":null,"abstract":"Background Age-related cataract (ARC) is a leading cause of visual impairment and blindness among older adults, yet effective pharmacological options remain limited. This study aimed to identify candidate circulating metabolic biomarkers and pathways associated with ARC risk. Methods Genetic data for blood metabolites and ARC were derived from three metabolite genome-wide association studies (GWASs) and FinnGen. Mendelian randomization (MR) analyses assessed associations between 121 metabolites and ARC. UK Biobank cohort analyses evaluated whether MR-identified associations were observed in longitudinal real-world data. Bioinformatics and molecular docking analyses were used to explore potential mechanistic pathways and applicability. Results MR analyses identified protective associations of 1,5-anhydroglucitol (odds ratio (OR) = 0.60, 95% confidence interval (CI) = 0.43-0.82), triglycerides in low-density lipoprotein (LDL) (OR = 0.95, 95% CI = 0.92-0.98), linoleic acid (OR = 0.92, 95% CI = 0.88-0.97), and polyunsaturated fatty acids (PUFAs) (OR = 0.93, 95% CI = 0.89-0.97) with ARC. In cohort analysis, linoleic acid (hazard ratio (HR) = 0.96, 95% CI = 0.94-0.98) and PUFAs (HR = 0.96, 95% CI = 0.94-0.98) were associated with a lower incident ARC risk, whereas triglycerides in LDL was not significant overall, although an inverse association was observed in participants aged ≥ 60 years (HR = 0.97, 95% CI = 0.95-0.99). Bioinformatics analyses identified candidate genes and pathways, and docking suggested potential interactions between linoleic acid and candidate proteins. Conclusions Linoleic acid and PUFAs showed consistent inverse associations with ARC. Further experimental studies are needed to validate their biological relevance and clinical utility.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148432072","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":"Heterogeneity in Aging: Exploring Grip Strength Variability in Population-Based Age-Sex Cohorts","authors":"Richard H Fortinsky, Lisa C Barry, Katherine Zavez, Chia-Ling Kuo, Shangshu Zhao, Ofer Harel, George A Kuchel","doi":"10.1093/gerona/glag181","DOIUrl":"https://doi.org/10.1093/gerona/glag181","url":null,"abstract":"Background Heterogeneity in aging refers to the increased variability in individual characteristics that occurs with age. Little is known about sex differences in heterogeneity in aging trends, or about longitudinal patterns of heterogeneity within age groups. Methods We used grip strength, a well-recognized measure of physical function, to explore patterns of variance in population-based age-sex groups cross-sectionally and longitudinally. We constructed a cohort from the UK Biobank database consisting of individuals aged 40-69 at first grip strength assessment and with a recorded follow-up grip strength assessment (N = 73,134; 52% female; assessment-reassessment interval, 4-18 years). In females and males separately, we compared, with and without covariates: (1) patterns of grip strength variance across successively older five-year age groups at initial assessment; (2) differences in grip strength variance between first and second assessments within the same age groups; (3) differences in grip strength variance between assessments when intervals were <10 years or ≥ 10 years. Results Cross-sectional results revealed that, for females, grip strength variance did not differ significantly between pairs of successively older age groups; for males, grip strength variance decreased across successively older age groups. Longitudinal results showed that, for females, grip strength variance remained stable over time, whereas for males grip strength variance increased over time within nearly all age group cohorts. Covariates attenuated but did not eliminate these trends. Conclusions Heterogeneity in grip strength with aging operates differently in females and males, and patterns of heterogeneity for males are strikingly different depending on whether age is explored cross-sectionally or longitudinally.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"39 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415944","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":"Sleep Disturbance, Physical Frailty, and Risk of Cognitive Impairment and Dementia in Older Adults with Subjective Cognitive Decline: A 10-Year Longitudinal Study","authors":"Jing Huang, Qian-Li Xue, Sarah L Szanton, Adam P Spira, Nalaka S Gooneratne, Katie L Stone, Junxin Li","doi":"10.1093/gerona/glag178","DOIUrl":"https://doi.org/10.1093/gerona/glag178","url":null,"abstract":"Background Subjective cognitive decline (SCD), a self-perceived decline in cognition without objective impairment, may represent an intermediate stage before clinical cognitive impairment develops. Sleep disturbance and physical frailty may reflect broader aging-related vulnerability and contribute to further cognitive progression in SCD. This study examined individual associations of sleep disturbance and physical frailty with 10-year incidence of cognitive impairment and dementia among older adults with SCD and explored whether physical frailty moderated the associations between sleep disturbance and cognitive outcomes. Methods Data were drawn from six waves of the Health and Retirement Study (HRS; 2010–2020). Independent analyses of sleep included 3,014 individuals with SCD at baseline, and frailty analyses used a subsample of 1,141 with frailty data. Sleep disturbance was assessed using a modified Jenkins Sleep Scale, and physical prefrailty/frailty was defined by the Fried frailty phenotype. Incident cognitive impairment and dementia were identified using validated HRS cognitive cutoffs. Discrete-time survival models adjusted for socio-demographics and health-related covariates. Results Sleep disturbance was not independently associated with incident cognitive impairment or dementia in fully adjusted models. Baseline physical prefrailty/frailty was significantly associated with increased odds of incident cognitive impairment (OR = 1.44, 95% CI: 1.15–1.80) and dementia (OR = 1.89, 95% CI: 1.23–2.93). Exploratory analyses suggested possible variation in the association between sleep disturbance and incident cognitive impairment by frailty status, but this finding should be interpreted cautiously. Conclusions Physical prefrailty/frailty is a significant factor of cognitive impairment in older adults with SCD, while the effect of sleep disturbance may vary by frailty status.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415561","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":"Differential Associations of Oral Health with Early- and Late-Onset Dementia: A Prospective Analysis of the UK Biobank","authors":"Yunrui Liu, Xiang Qi, Huabin Luo, Ruotong Liu, Zhijing Xu, Bei Wu","doi":"10.1093/gerona/glag179","DOIUrl":"https://doi.org/10.1093/gerona/glag179","url":null,"abstract":"Background Poor oral health is a modifiable risk factor for dementia, but whether the associations differ by age at onset and are modified by genetic susceptibility remains unclear. Methods In this prospective cohort study of 364,231 dementia-free UK Biobank participants, we examined associations between oral health indicators and incident early- and late-onset dementia (EOD and LOD). Genetic susceptibility was assessed using polygenic risk score (PRS) and apolipoprotein E (APOE) ε4 status. Multivariable Cox proportional hazards models evaluated independent and joint associations. Results Over a median follow-up of 13.6 years, 359 participants developed EOD and 6,668 developed LOD. Oral health indicators were not consistently associated with EOD. In contrast, painful gums (hazard ratio [HR], 1.24; 95% CI, 1.09–1.40), toothache (HR, 1.17; 95% CI, 1.04–1.33), denture use (HR, 1.18; 95% CI, 1.12–1.25), and a higher number of oral health conditions (HR, 1.08; 95% CI, 1.05–1.12) were consistently associated with increased LOD risk. Joint analyses demonstrated dose–response patterns for LOD, with the highest risks among individuals with both poor oral health and elevated genetic susceptibility. Conclusions Poor oral health was associated primarily with LOD, particularly among individuals with elevated genetic susceptibility.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"220 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148415560","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":"Physical activity fragmentation and functional decline among older adults: Findings from the National Health and Aging Trends Study.","authors":"Nicholas R Lamoureux,Joey M Saavedra,Brian Downer,Jennifer A Schrack,Amal A Wanigatunga","doi":"10.1093/gerona/glag177","DOIUrl":"https://doi.org/10.1093/gerona/glag177","url":null,"abstract":"BACKGROUNDPhysical activity fragmentation is associated with poor physical function in older adulthood, but the relationship between changes in physical activity fragmentation with concurrent and future changes in physical function are unclear, and this information is important for guiding clinical decision making. We therefore characterized this relationship in a nationally representative sample of older adults.METHODSData were drawn from a subset of the National Health and Aging Trends Study. Activity fragmentation was defined as the probability of transitioning from an active to a sedentary bout, captured using wrist-worn actigraphy, while function was assessed using the Short Physical Performance Battery (SPPB). The association between physical activity fragmentation with any instance of longitudinal decline in SPPB was evaluated using multivariable logistic regression.RESULTSThe sample included 531 participants aged ≥70 years (55.4% female). Among those with baseline SPPB ≤ 6, higher baseline activity fragmentation was associated with lower baseline function overall, and with a 1-year future decline in function (adjusted OR: 1.32; 95% CI: 1.01-1.72 per 10% higher baseline fragmentation). A 1-year increase in fragmentation was associated with a greater likelihood of experiencing a concurrent decline in SPPB, particularly among those with baseline SPPB = 7-10 (OR: 2.21; 95% CI: 1.17-4.17). The 1-year change in activity fragmentation was not associated with declines in SPPB the following year.CONCLUSIONSPhysical activity fragmentation may represent a digital biomarker, rather than an antecedent, of changes in physical function, highlighting the potential utility of accelerometry for identifying at-risk phenotypes likely to benefit from early interventions.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408564","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":"Life-course metabolic vulnerability and chronic kidney disease risk after early-life famine exposure in Middle-aged and older chinese adults.","authors":"Da Xu,Zhujie Ran,Yaoda Hu,Qiaolu Cheng,Jing Nai,Xingming Chen,Qiong Ou,Yawen Liu,Tan Xu,Yuhong Zhao,Bo Qu,Zhen Song,Ji Tu,Qing Wang,Zhili Chen,Zichao Wang,Mengwei Zhang,Huijing He,Guangliang Shan","doi":"10.1093/gerona/glag175","DOIUrl":"https://doi.org/10.1093/gerona/glag175","url":null,"abstract":"BACKGROUNDEarly-life undernutrition may increase susceptibility to chronic kidney disease (CKD), but whether adult metabolic burden modifies this association remains unclear. We examined early-life famine exposure and CKD among middle-aged and older Chinese adults using two complementary national cohorts.METHODSWe analyzed 7,238 participants from the 2023 to 2024 China National Health Survey (CNHS) and 8,273 from the China Health and Retirement Longitudinal Study (CHARLS). In CNHS, famine exposure was defined by birth cohort and prefecture-level cohort size shrinkage index, with age-balanced non-famine births as the reference group. Prevalent CKD was evaluated using Firth logistic regression and difference-in-differences models, including joint associations with adult meat consumption. In CHARLS, self-reported famine severity, waist circumference trajectories, and incident CKD were evaluated using Cox models.RESULTSIn CNHS, the famine-CKD association increased with regional famine intensity, with an interaction odds ratio of 1.04 per unit increase in cohort size shrinkage index (95% confidence interval, 1.01-1.07). Severe famine exposure combined with frequent meat consumption was associated with higher odds of prevalent CKD (odds ratio, 2.09; 95% confidence interval, 1.16-3.76). In CHARLS, severe famine exposure combined with a high-stable waist circumference trajectory showed the highest risk of incident CKD (hazard ratio, 1.75; 95% confidence interval, 1.05-2.91), with an increasing trend across famine severity mainly in this trajectory group. Cumulative diabetes partly mediated this association.CONCLUSIONSEarly-life famine exposure was associated with higher CKD risk, particularly among individuals with unfavorable adult metabolic profiles, supporting life-course metabolic vulnerability in CKD risk stratification.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393649","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":"Global prevalence, trends, and dose-response associations of polypharmacy in older adults.","authors":"Fangyuan Tian,Zhaoyan Chen,Ying Zhang,Hongyu Cai,Xuehua Wan,Fei Zhou,Zhen Zhou","doi":"10.1093/gerona/glag176","DOIUrl":"https://doi.org/10.1093/gerona/glag176","url":null,"abstract":"BACKGROUNDPolypharmacy is common in older adults with comorbidities. This study aims to estimate its global prevalence, temporal trends, and dose-response associations with adverse health outcomes.METHODSPubMed, Embase, The Cochrane Library, Web of Science and Scopus were searched from inception to June 30, 2025. Random-effects meta-analyses were used to pool prevalence estimates of polypharmacy based on mixed thresholds and relative risks. Study quality was assessed using Hoy's method. Hazard ratios (HRs) from individual studies were synthesised using random-effects dose-response meta-analysis in studies that provided sufficient quantitative exposure information.RESULTSA total of 545 studies, providing 565 prevalence estimates, were included, comprising 16,620,414 older adults from 56 countries worldwide. The pooled global prevalence of polypharmacy was 50.4% (95% confidence interval [CI]: 48.2-52.7%; 95% prediction interval: 6.8-93.5%). It demonstrated a significant increasing temporal trend in polypharmacy prevalence over calendar years. Compared with non-polypharmacy, polypharmacy was associated with a significantly higher risk of multiple adverse outcomes. Dose-response meta-analyses showed a monotonic increase in risk with each additional medication for mortality (HR: 1.05, 95%CI: 1.03-1.06, P＜0.001), emergency (HR: 1.02, 95%CI: 1.02-1.03, P＜0.001), and hospital admission (HR: 1.04, 95%CI: 1.02-1.07, P＜0.001). Outcome-specific thresholds ranged from 4.55 to 5.46 medications. A pooled estimate of approximately five medications was obtained as a descriptive summary across outcomes.CONCLUSIONPolypharmacy affects approximately half of older adults worldwide and has increased steadily over time. It is associated with an increased risk of multiple adverse health outcomes, with risks increasing progressively as medication burden rises.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393601","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":"Global Burden and Temporal Prediction of Intestinal Obstruction (1990-2021) and the Relationship with Blood Metabolites: An Integrated Analysis of GBD and Mendelian Randomization.","authors":"Zhujiang Dai,Xiangyu Zhang,Zhebin Hua,Yaosheng Wang,Hui Zhang,Xingwang Hu,Peng Du,Weimin Xu","doi":"10.1093/gerona/glag171","DOIUrl":"https://doi.org/10.1093/gerona/glag171","url":null,"abstract":"BACKGROUNDIntestinal obstruction (IO) poses a significant challenge to healthcare systems, particularly in aging societies. This study systematically evaluated the global burden of IO from 1990 to 2021, predicted trends through 2044, and explored potential metabolic risk factors.METHODSBased on the Global Burden of Disease (GBD) 2021 statistics, we analyzed incidence, mortality, and disability-adjusted life years (DALYs) across 204 countries. Trends were quantified using estimated annual percentage changes (EAPC), while frontier and decomposition analyses assessed the impact of population aging. Future trends were projected using age-period-cohort (APC) models. Additionally, a two-sample Mendelian Randomization (MR) analysis was conducted to investigate the relationship between metabolites and IO.RESULTSGlobally, the age-standardized incidence rate (ASIR) showed a slight upward trend, rising from 185.57 to 191.92 per 100,000 between 1990 and 2021 (EAPC: 0.09), whereas the age-standardized mortality rate (ASMR) declined (EAPC: -1.03). Notably, high-SDI regions(e.g., the United States, the United Kingdom) exhibited rising DALYs, largely driven by population aging. Projections indicate that by 2044, the ASMR will further decrease to 2.20 (females) and 3.11 (males) per 100,000. The MR analysis identified 13 genetically predicted circulating metabolites associated with IO susceptibility, providing hypothesis-generating metabolic signals that warrant further validation.CONCLUSIONSWhile IO mortality has decreased globally, the absolute burden of IO remains substantial in the context of rapid population aging. Future health policies should focus on resource allocation and surgical care for older adults. The identified metabolic signals may provide candidate avenues for future early screening and prevention research in geriatric care.","PeriodicalId":22892,"journal":{"name":"The Journals of Gerontology Series A: Biological Sciences and Medical Sciences","volume":"267 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393602","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}