GeroScience最新文献

{"title":"Correlations between white matter hyperintensities, magnetic resonance imaging findings, and cognition in the oldest old: a multimodal cross-sectional study.","authors":"Ryo Ueda, Ryo Shikimoto, Jinichi Hirano, Takashi Sasaki, Yukiko Abe, Masaru Mimura, Yasumichi Arai","doi":"10.1007/s11357-026-02295-8","DOIUrl":"https://doi.org/10.1007/s11357-026-02295-8","url":null,"abstract":"<p><p>Small vessel disease and brain atrophy are linked to cognition in later life, but whether these associations persist in the oldest old is unclear, as lesion burden and survivorship may change effect sizes. We analyzed 249 adults aged 89-94 years from the Kawasaki Aging and Wellbeing Project. White matter hyperintensities (WMHs) were segmented on fluid-attenuated inversion recovery; gray and white matter volumes were derived from T1-weighted magnetic resonance imaging; and peak width of skeletonized mean diffusivity (PSMD) indexed diffuse white matter damage. Global cognition was assessed with the Mini-Mental State Examination (MMSE). Robust multivariable regression related MMSE to age, education, sex, apolipoprotein E ε4 status, WMH burden, volumetric measures, PSMD, and a PSMD × education interaction. Voxel-wise lesion-symptom mapping and tract-based spatial statistics evaluated tract-level effects. Older age and higher WMH burden were associated with lower MMSE, whereas higher education was associated with higher MMSE. PSMD showed no independent main effect after covariate adjustment. An exploratory PSMD × education interaction was nominally significant in the primary model but attenuated in sensitivity analyses. Exploratory spatial analyses suggested that WMHs in the inferior fronto-occipital fasciculus (IFOF) and inferior longitudinal fasciculus, as well as higher axial diffusivity in the left IFOF, were associated with lower MMSE. Overall, the principal contribution of this study is confirmatory evidence, in a rare oldest-old cohort, that WMH burden and education remain associated with global cognition; spatial and interaction findings are hypothesis-generating and should not be interpreted as confirmatory evidence of tract-specific mechanisms.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between dietary patterns and CAIDE-predicted dementia risk: A 20-year cohort of the Korean Genome and Epidemiology study.","authors":"Ji-Eun Youn, Seok-Jae Heo, Yae-Ji Lee, Tae-Hwa Han, Yu-Jin Kwon, Ji-Won Lee","doi":"10.1007/s11357-026-02288-7","DOIUrl":"https://doi.org/10.1007/s11357-026-02288-7","url":null,"abstract":"<p><p>This study examined associations between dietary habits and the risk of developing Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE)-predicted late-life dementia risk in Korean adults. A total of 5,042 participants aged 40-69 years were included. We assessed associations between dietary patterns-the Mediterranean diet, Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, Korean Healthy Eating Index (KHEI), and Empirical Dietary Inflammatory Index (EDII)-and CAIDE-predicted high risk of dementia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, and cumulative incidence was assessed using Kaplan-Meier analysis. Longitudinal trajectories of CAIDE scores over a 10-year period were analyzed using linear mixed-effects models. During follow-up of 15.83 years, 30.9% progressed to CAIDE-predicted high risk of dementia. The highest tertile of the Mediterranean diet, MIND diet, and KHEI were associated with lower cumulative incidence (P = .008, P < .001, and P < .001) and reduced risk of progression to CAIDE-predicted high risk of dementia (HR 0.78, 95% CI 0.67-0.90, HR 0.80, 95% CI 0.69-0.93, and HR 0.80, 95% CI 0.70-0.91, respectively) along with lower CAIDE score (P < .001, P < .001, P = .002). Conversely, the highest EDII tertile showed the highest cumulative incidence (P < .001), an increased risk of progression to CAIDE-predicted high risk of dementia (HR 1.15, 95% CI 1.01-1.32), and elevated CAIDE scores (P < .001). Greater adherence to the Mediterranean diet, MIND diet, and KHEI, and lower consumption of pro-inflammatory diets were associated with a lower risk of high CAIDE-predicted late-life dementia and slower accumulation of risk factors.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency-specific photobiomodulation at theta and gamma enhances cognitive networks and mitigates age-related decline.","authors":"Natalia Arias, Lucía Rodríguez-Fernández, Candela Zorzo, Verónica Peña León, Laura Mañas Cordero, Alba Gutiérrez-Menéndez, Juan A Martínez, Jorge L Arias","doi":"10.1007/s11357-026-02278-9","DOIUrl":"https://doi.org/10.1007/s11357-026-02278-9","url":null,"abstract":"<p><p>Photobiomodulation (PBM) is a non-invasive strategy to enhance cognitive function, yet the effects of stimulation frequency remain unclear. We applied pulsed 810 nm PBM at 5 Hz or 40 Hz to the frontal cortex of adult rats, and 40 Hz PBM to aged rats. In young adults, both stimulation frequencies enhanced cognitive flexibility, and in aged rats 40 Hz PBM improved learning speed. In terms of brain changes, we studied cytochrome c oxidase (CCO) activity, c-Fos expression and protein levels. We observed a decrease in the prefrontal CCO activity in adults, and an increase in prefrontal c-Fos expression, both with 40 Hz. Regarding protein levels in young rats, 5 Hz PBM reduced pERK expression in the hippocampus and p38 in the prefrontal cortex, while regulating interleukins and cytokines in these regions. Additionally, 5 Hz upregulated Synapsin-I expression in both the prefrontal cortex and hippocampus, and increased PSD-95 levels selectively in the hippocampus, highlighting its role in synaptic plasticity and memory consolidation. Notably, 5 Hz also increased GFAP expression in both regions, and selectively upregulated NF-κB expression. 40 Hz PBM reduced pERK expression in the hippocampus and p38 in the prefrontal cortex, also modulating interleukins and cytokines in these areas. Additionally, 40 Hz increased p38 expression in the hippocampus and reduced p53 and BAX levels in the prefrontal cortex. Also, 40 Hz upregulated Synapsin-I in both regions and increased PSD-95 expression in both the prefrontal cortex and hippocampus. As observed with 5 Hz, 40 Hz also elevated GFAP expression in both regions. In aged rats, PBM reduced Iba-1 in prefrontal cortex and hippocampus, enhanced NeuN in prefrontal cortex, and decreased p38 and BCL-2 in the hippocampus. Collectively, these results demonstrate frequency-dependent modulation of neuroinflammation, synaptic plasticity, and apoptosis, while highlighting the beneficial effects of 40 Hz PBM in aged subjects, supporting PBM as a targeted approach to improve cognitive function across the lifespan.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of psychosocial factors with cardiovascular health in aging: insights from the Inlife-Aging Project.","authors":"Iván H Martín-Costa, Laura Martínez-Sánchez, Verónica Mihaiescu-Ion, Sonia Ortega-Gómez, Javier S Morales, José L Andrey-Guerrero, María J Pedrosa-Martínez, Eulalio Valmisa, José D Santotoribio, David Jiménez-Pavón, Ana Carbonell-Baeza","doi":"10.1007/s11357-026-02262-3","DOIUrl":"https://doi.org/10.1007/s11357-026-02262-3","url":null,"abstract":"<p><p>Life's Essential 8 (LE8) provides a multidimensional framework to assess cardiovascular health (CVH) in aging populations. The objective of this study was to describe LE8 component scores and their variation by age, sex, and psychosocial factors in middle-aged and older adults from Cádiz, Spain. Cross-sectional data were analyzed from 495 adults aged 50-79 years (59.4% women; 34.7% ≥ 65 years). LE8 scores were calculated following American Heart Association guidelines. Group comparisons used t-tests, ANOVA, and chi-square tests to explore differences across demographic and psychosocial variables. Age- and sex-adjusted linear regressions were fitted for CVH, health behaviors (HB), and health factors (HF). Most participants showed moderate CVH, HB, and HF scores (76.6%; 53.1%; 62.2%). Diet quality had the lowest mean (40.8 ± 31.7), while physical activity and sleep health were the highest (88.3 ± 30.6 and 85.0 ± 22.2). Middle-aged adults presented higher CVH and HF scores (mean differences [MD]: 2.5 ± 0.3; 7.8 ± 1.5), whereas older adults scored better in HB (MD: 2.8 ± 1.4). Women exhibited higher CVH, HB, and HF scores than men (MD: 3.6 ± 0.3; 2.8 ± 0.4; 4.4 ± 0.4), with middle-aged women showing the most favorable CVH profile (73.0 ± 10.5) and older men the least favorable (66.4 ± 11.0). Higher self-rated health (β = 0.240; R2 = 0.096) and educational attainment (β = 0.235; R2 = 0.090) were the strongest correlates of CVH (both P < 0.001). LE8 scoring revealed an intermediate CVH profile, with disparities by age, sex, and psychosocial context. Middle-aged women showed the most favorable profiles, while self-rated health and educational attainment emerged as key psychosocial markers for CVH assessment.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of gait speed, grip strength, depressive symptoms, and their combinations with fracture risk in older adults.","authors":"Temam Beshir Raru, Julie A Pasco, Mojtaba Lotfaliany, Shiva Ganjali, Robyn L Woods, Anna Barker, Suzanne G Orchard, Joanne Ryan, Alice J Owen, Michael Berk, Mohammadreza Mohebbi","doi":"10.1007/s11357-026-02271-2","DOIUrl":"https://doi.org/10.1007/s11357-026-02271-2","url":null,"abstract":"<p><p>Gait speed, grip strength, and depression are common and often coexist in older adults, and their interaction may provide a comprehensive understanding of fracture risk. This study examined the individual and combined associations of slow gait, weak grip, and depressive symptoms with the risk of fractures in older adults. Sixteen thousand three hundred fifty-seven Australian participants aged ≥ 70 years from the ASPirin in Reducing Events in the Elderly (ASPREE) trial were included. Sub-distribution hazard ratios (sHR) and 95% confidence intervals (CI) were estimated using a multivariable-adjusted Fine-Gray model, accounting for death as a competing risk. The sHR for any fractures was 17% higher among participants with slow gait and 23% higher among those with depressive symptoms, while weak grip was not significantly associated. The co-occurrence of slow gait and weak grip was associated with a 23% higher risk of any fracture (sHR = 1.23; 95% CI 1.04-1.46). Slow gait combined with depressive symptoms was associated with a 46% higher risk of any fracture and a 64% higher risk of MOF (sHR = 1.46; 95% CI 1.06-2.01; sHR = 1.64; 95% CI 1.03-2.61, respectively). Weak grip combined with depressive symptoms was associated with a 47% higher risk of any fracture and a 57% higher risk of MOF (sHR = 1.47; 95% CI 1.08-2.00; sHR = 1.57; 95% CI 1.01-2.47, respectively). These associations were stronger among males and those with diabetes. The combination of slow gait with either weak grip or depressive symptoms was more strongly associated with fracture risk than each factor individually. These findings underscore the importance of incorporating physical function and mental health assessments in clinical evaluations of older adults.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZNRF2-mediated CD-M6PR degradation and lysosomal dysfunction aggravate cellular senescence and aging.","authors":"Tingting Zhao, Weitong Xu, Fangfang Wang, Honghan Chen, Hui Gong, Yu Yang, Ning Huang, Ming Yang, Jian Zhang, Chuhui Gong, Xiaoli Huang, Ying Li, Cuiying Zhang, Hengyi Xiao","doi":"10.1007/s11357-026-02253-4","DOIUrl":"https://doi.org/10.1007/s11357-026-02253-4","url":null,"abstract":"<p><p>Lysosomal dysfunction is a hallmark of cellular senescence, yet the mechanisms governing lysosomal protein trafficking remain incompletely understood. Here, we show that CD-M6PR, a principal receptor for lysosomal enzyme transport, is markedly reduced in senescent fibroblasts and in aged mice and humans, and that its loss correlates with the severity of autolysosomal impairment. Mechanistically, the reduction of CD-M6PR in senescent cells mainly stems from the accelerated proteasome-mediated degradation. Utilizing structural predictions and experimental validation, we identified the E3 ubiquitin ligase ZNRF2 as a critical mediator of CD-M6PR's rapid degradation in senescent cells, facilitated by ZNRF2's elevated expression in these cells. We further link stress-induced mTORC1 activation to increased ZNRF2 expression, which in turn reduces CD-M6PR protein levels, impairs lysosomal enzyme trafficking, and compromises autolysosomal function, thereby exacerbating cellular senescence. Collectively, these data define a previously unrecognized mTORC1-ZNRF2-CD-M6PR axis and reveal a novel mechanism by which aberrant mTORC1 signaling promotes lysosomal dysfunction and senescence, with potential implications for therapeutic targeting of age-related pathologies.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low genetic risk for coronary artery disease underlies multigenerational longevity and healthy aging.","authors":"Pedro Sant' Anna Barbosa Ferreira, Stella Trompet, Eline Slagboom, Joris Deelen, Marian Beekman, Niels van den Berg","doi":"10.1007/s11357-026-02272-1","DOIUrl":"https://doi.org/10.1007/s11357-026-02272-1","url":null,"abstract":"<p><p>Aging is a major risk factor for chronic diseases. Unlike the general population, members of long-lived families maintain exceptional health as they age, with over 10 years delayed onset of their first chronic disease. We therefore hypothesize that one of the key features explaining healthy survival up to high ages (longevity) is the absence of chronic disease risk alleles. We investigated this hypothesis in the Leiden Longevity Study, a cohort with data from more than 420 long-lived families in three generations and the Leiden 85-plus study. To analyze our data, we constructed a set of polygenic scores (PGS) covering the top diseases causing most deaths in the Netherlands. We showed that having an increasing number of long-lived ancestors is additively associated with lower genetic risk for coronary artery disease (CAD). Using accelerated failure time modelling, we further showed that a lower PGS for CAD explains up to 20% of the delay in cardiovascular disease incidence in descendants of long-lived families. Finally, we constructed a novel cholesterol-metabolism-PGS, based on gene-annotation enrichment analysis, that predicted time to all-cause mortality in two independent 90 + study populations. Our findings demonstrate that the absence of chronic disease risk alleles is one key feature linked to longevity and that alleles linked to cholesterol metabolism are a key component in healthy aging trajectories.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy revealed as a targetable vulnerability in senescent cells by cell painting phenotypic profiling: a mechanistic study of MCOPPB and related compounds.","authors":"Matthew Lacey, Lucie Beresova, Alzbeta Srovnalova, Pavlo Polishchuk, Michal Sala, Zdenek Skrott, Marian Hajduch, Petr Dzubak, Jiri Bartek, Anna Siskova, Martin Loffelmann, Radim Nencka, Martin Mistrik","doi":"10.1007/s11357-026-02258-z","DOIUrl":"https://doi.org/10.1007/s11357-026-02258-z","url":null,"abstract":"<p><p>Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting-based morphological profiling, we identified a distinct cluster of senolytic compounds comprised of both known and novel autophagy inhibitors, including AZ191, bafilomycin A1, chloroquine, daurisoline, dauricine, MCOPPB, and its derivative MS1108. These compounds selectively eliminated senescent cells by disrupting autophagic flux. Our findings reveal senescent cell dependence on autophagy as an essential survival mechanism, define the existence of a mechanistically distinct class of senolytics acting through autophagy inhibition, and demonstrate the predictive value of Cell Painting in aging-related drug discovery. Our results provide new insights into senescent cell vulnerability and expand the therapeutic landscape for aging-related pathologies by highlighting autophagy as a targetable dependency.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term cerebrovascular effects of cyclophosphamide and vincristine: endothelial senescence, impaired DNA repair signaling, and blood-brain barrier dysfunction.","authors":"Dorina Nagy, Kiana Vali Kordestan, Roland Patai, Rafal Gulej, Siva Sai Chandragiri, Raghavendra Y Nagaraja, Santny Shanmugarama, Shoba Ekambaram, Evelyn Brunner, Rebeka Kristof, Mark Nagykaldi, Parikshat Sirpal, Andriy Yabluchanskiy, Karl E Balsara, Rene Y McNall, Zoltan Ungvari, Anna Csiszar","doi":"10.1007/s11357-026-02270-3","DOIUrl":"https://doi.org/10.1007/s11357-026-02270-3","url":null,"abstract":"<p><p>Chemotherapy-related cognitive impairment is increasingly recognized as a long-term consequence of cancer treatment, yet the contribution of the cerebrovascular system remains poorly defined. In this study, we investigated the long-term effects of clinically relevant treatment regimens with cyclophosphamide (CP) and vincristine (VIN) on cerebrovascular cellular senescence, associated molecular signatures, and downstream functional outcomes, including disruption of blood-brain barrier (BBB) integrity in a mouse model. Our results showed that CP induces a persistent cerebrovascular endothelial phenotype characterized by increased cellular senescence, upregulation of mRNA expression of DNA damage checkpoint regulators, and concomitant downregulation of key DNA repair genes. BBB integrity was preserved after CP treatment for larger molecular tracers (40 kDa and 3 kDa) but exhibited increased permeability to small tracers (0.3 kDa), measured by in vivo two-photon microscopy, indicating a subtle yet persistent disruption of barrier function. In contrast, VIN elicited a markedly attenuated and heterogeneous transcriptional response and did not produce detectable BBB impairment, underscoring agent-specific cerebrovascular effects of chemotherapy. Collectively, these findings suggest that chemotherapy induces a persistent cerebrovascular injury phenotype with features resembling vascular aging and reduced vascular resilience, providing a potential mechanistic link between systemic cancer therapy and long-term adverse effects on brain health.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory protein epigenetic scores (EpiScores) and cognitive function in the longitudinal Swedish adoption/twin study of aging (SATSA).","authors":"Kazuyuki Ishihara, Sara Hägg, Thaís Lopes De Oliveira","doi":"10.1007/s11357-026-02274-z","DOIUrl":"https://doi.org/10.1007/s11357-026-02274-z","url":null,"abstract":"<p><p>Protein epigenetic scores (EpiScores) are DNA methylation (DNAm)-based proxies for circulating protein levels and may provide insights into inflammation-cognition relationships. Although some EpiScores have been linked to cognitive decline, it remains unclear whether these proxies show similar associations in other cohorts, and whether their effects vary across distinct cognitive domains. We aimed to evaluate the associations between inflammatory proteins EpiScores and cognitive functions including specific domains in the Swedish Adoption/Twin Study of Aging (SATSA) cohort. We analyzed 1332 repeated measurements from 520 SATSA participants across up to six testing waves (1992-2014). Inflammatory protein EpiScores (N = 27) were generated using previously published CpG site-specific weights. Outcomes were a global cognitive function (GCF) score and four specific cognitive domains (verbal ability, spatial ability, memory, and perceptual speed). We applied marginal linear models within the generalized estimating equations (GEE) framework to estimate population-averaged longitudinal associations, controlling the false discovery rate (FDR) using the Benjamini-Hochberg (BH) procedure (q < 0.05 considered significant). Two EpiScores-C-X-C motif chemokine ligand 9 (CXCL9) and vascular cell adhesion molecule 1 (VCAM1)-showed significant positive associations with GCF. In domain-specific outcomes, VCAM1 demonstrated a positive association with spatial ability, whereas C-X-C motif chemokine ligand 11 (CXCL11) had a negative association with verbal ability. These associations were broadly consistent across multiple sensitivity analyses. Inflammation-related DNAm signatures of certain proteins were associated with cognitive performance in SATSA samples. Moreover, the associations differ by cognitive domain. Future longitudinal studies are warranted to clarify the causal implications of these EpiScore-cognition associations and to explore population differences in DNAm patterns.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}