GeroScience最新文献

{"title":"Early cerebral hypoperfusion promotes spatially biased tau pathology in tau-seeded PS19 mice.","authors":"Shuai Zhao, Xinyi Zhang, Siyan Zhong, Kaicheng Li, Yaping Yan, Baorong Zhang, Yanxing Chen","doi":"10.1007/s11357-026-02587-z","DOIUrl":"https://doi.org/10.1007/s11357-026-02587-z","url":null,"abstract":"<p><p>Growing evidence has demonstrated a significant association between reduced cerebral blood flow and Alzheimer's disease (AD)-related cognitive impairment. Chronic cerebral hypoperfusion (CCH) has been reported to exacerbate tau hyperphosphorylation and behavioral deficits in rodents, but whether CCH promotes tau pathology at the initial stage of tauopathy remains unclear. Here we show, using a tau-seeded PS19 mouse model with unilateral common carotid artery occlusion, that early CCH exacerbates spatially biased tau pathology, inducing ipsilateral enrichment of insoluble tau in the hippocampus and, in the cortex, an ipsilateral increase that was dependent on the presence of tau seeds. Early CCH also induces myelin loss in the cortex and dorsal fornix, although no synergistic interaction was detected between tau seeds and CCH. Additionally, early CCH promotes microglial activation and IL-1β elevation, and increases hippocampal neuronal loss. In the Morris water maze, early CCH-exposed mice display a marginal trend toward reduced spatial memory performance that did not reach statistical significance. These findings indicate that early CCH facilitates tau pathology and neuroinflammation at the early stage of tauopathy, with only a marginal trend toward early cognitive changes, providing experimental evidence that vascular hypoperfusion may act as a disease modifier in the initial phase of tau pathology, with potential implications for early detection and therapeutic targeting of vascular contributions to tauopathies.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149180985","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":"Regional oxygen extraction fraction is higher in older adults with type 2 diabetes and obesity: associations with cognition and metabolic markers.","authors":"Mohamad N Elsharydah, Yousif Al-Khoury, Sharvinee Ragunatha Rao, Jeff Schaffert, Anujit Saha, Jack Kaufman, Ali Rezaei, Jennine Leary, Alison Jin, Jaime P Almandoz, Claudine J Gauthier, Binu P Thomas","doi":"10.1007/s11357-026-02590-4","DOIUrl":"10.1007/s11357-026-02590-4","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) and obesity are highly prevalent among older adults and associated with increased Alzheimer's disease and related dementia (ADRD) risk, but underlying mechanisms linking T2D and obesity to cognitive impairment remain partially understood. Quantitative susceptibility mapping (QSM)-derived oxygen extraction fraction (OEF) provides a noninvasive MRI-based marker of cerebral metabolism and may capture early alterations in brain physiology. In this single-center, cross-sectional pilot study, we examined QSM-derived OEF in older adults with T2D + obesity (N = 14) and age- and sex-matched controls (N = 18) and evaluated associations with blood markers and cognitive performance. Whole-brain OEF was higher in participants with T2D + obesity (29.5% vs 27.3%; p = 0.019), with higher OEF observed across all examined lobar regions (p < 0.05). The T2D + obesity group demonstrated lower Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Attention (p = 0.035) and Global Cognition (p = 0.022) indices and lower Delis-Kaplan Executive Function System (D-KEFS) Color-Word Switching (p = 0.001) scores. Whole-brain OEF was positively associated with leptin (p = 0.018) and negatively associated with HDL (p = 0.030). Higher regional OEF significantly correlated with lower cognitive performance, particularly D-KEFS (r = -0.40 to -0.62) and RBANS Attention (r = -0.36 to -0.41). This is the first study to support a potential link between altered cerebral oxygen extraction, metabolic dysfunction, and cognitive performance in older adults with T2D and obesity. Larger, longitudinal studies are needed to confirm these associations and determine their relevance to cognitive decline and ADRD risk.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181051","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":"Inhibition of soluble epoxide hydrolase rescues cognitive deficits by preserving neurovascular integrity and attenuating glial and neuropathology in diabetic-related dementia.","authors":"Xing Fang, Jane J Border, Huawei Zhang, Gilbert C Morgan, Andrew Gregory, Yvan Hanscom-Trofy, Rui Dong, Jun Yang, Sung Hee Hwang, Christophe Morisseau, Bruce D Hammock, Fan Fan, Richard J Roman","doi":"10.1007/s11357-026-02591-3","DOIUrl":"10.1007/s11357-026-02591-3","url":null,"abstract":"<p><p>Diabetes mellitus (DM) is a major risk factor contributing to the development of Alzheimer's disease-related dementias (ADRD). While one of the early symptoms of both Alzheimer's disease (AD) and DM-related ADRD is a reduction in cerebral blood flow, the underlying biological mechanisms driving this decline remain to be fully elucidated. Genome-wide association studies have linked AD/ADRD to single-nucleotide polymorphisms in the gene encoding soluble epoxide hydrolase (sEH), an enzyme we previously reported to be upregulated in the brains of an AD rat model. Our previous studies also demonstrated that chronic sEH inhibition with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) preserves hippocampal-dependent spatial learning and memory and improves cerebral hemodynamics in both AD and DM-ADRD models. In the present study, we found that chronic TPPU treatment (1 mg/kg/day) reduced sEH expression in the brain, improved cortical-based non-spatial recognition memory involving both cortical and hippocampal networks, and reduced anxiety in DM-ADRD rats. TPPU improved brain perfusion and normalized impaired whisker-evoked functional hyperemia, an effect associated with increased Kir2.1 expression and neurovascular coupling in cerebral capillaries. Furthermore, TPPU increased tight junction protein expression (ZO-1 and OCLN), mitigated capillary rarefaction, and suppressed astrocyte and microglial activation in DM-ADRD rats. At the cellular level, TPPU attenuated hippocampal neurodegeneration, restored the expression of synaptic proteins (PSD95 and SY38), and reduced levels of proinflammatory chemokines, including MCP-1, RANTES, and MIP-1α, in the hippocampus of DM-ADRD rats. In conclusion, TPPU preserves cognitive function in DM-ADRD by mitigating cerebrovascular dysfunction, neuroinflammation and gliosis, thereby preserving synaptic integrity and neuronal survival, and represents a promising therapeutic strategy for DM-ADRD.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181085","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":"Reduced structural connectivity in age-related hearing loss aligns with the sensory deprivation theory.","authors":"Jordi H C Boons, Alberto De Luca, Gertjan Dingemanse, Elisabeth J Vinke, Bernd Kremer, Meike W Vernooij, André Goedegebure","doi":"10.1007/s11357-026-02589-x","DOIUrl":"https://doi.org/10.1007/s11357-026-02589-x","url":null,"abstract":"<p><p>Age-related hearing loss (ARHL) may contribute to cognitive decline through structural degeneration and brain reorganization, as posited by the sensory deprivation theory. These processes can be characterized by topological changes, such as strengthening and weakening of structural connections between brain regions. Stronger connections are more relevant to reorganization, as reorganization is thought to support speech processing by recruiting additional brain networks as a compensatory mechanism. We investigated connectivity changes associated with ARHL to improve the understanding of the sensory deprivation theory. Similar to the lateralization of speech processing, we hypothesized that structural reorganization associated with ARHL would be most evident in the left hemisphere. We assessed whole-brain structural connectivity using 1.5 Tesla diffusion-weighted MRI and structural T1 images in 2402 participants (median age = 66.1 years, females = 54.7%) from the population-based Rotterdam Study. Pure-tone audiometry was performed, and pure-tone averages (PTAs), for different frequency ranges including PTA_low (250-1000 Hz) and PTA_all (250-8000 Hz), were determined for the better-hearing ear to reflect ARHL. ARHL was primarily associated with weaker connections involving frontal and subcortical gray matter regions. Contrary to our hypothesis, no lateralization in the connectivity alterations was observed. PTA_low and PTA_all yielded the strongest associations, likely driven by low-frequency hearing thresholds. Adjusting for cardiovascular risk factors attenuated associations, especially for PTA_low. In conclusion, the findings contradict the hypothesized compensatory structural reorganization expected from the neural effects of sensory deprivation. While the observed weaker connectivity aligns with the sensory deprivation theory, the results also suggest cardiovascular health as a common risk factor.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168118","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":"Bone marrow myeloid skewing and preserved immunoregulation in hip osteoarthritis of elderly patients","authors":"Ada Tushe,Eleonora Binatti,Elisa Belluzzi,Assunta Pozzuoli,Samuela Francescato,Barbara Buldini,Carlo Biz,Pietro Ruggieri,Susanna Mandruzzato","doi":"10.1007/s11357-026-02578-0","DOIUrl":"https://doi.org/10.1007/s11357-026-02578-0","url":null,"abstract":"Abstract Osteoarthritis (OA) is increasingly recognized as a disease involving low-grade inflammation and immune remodeling, yet the contribution of the bone marrow (BM) myeloid compartment to hip OA remains poorly defined. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunoregulatory activity and potential roles in inflammatory bone disease. Here, we investigated ex vivo BM myeloid composition and the functional properties of BM-MDSCs in elderly patients with hip OA compared with patients undergoing surgery for proximal femoral fracture. BM aspirates from both cohorts were analyzed by flow cytometry and cultured with G-CSF and GM-CSF to induce BM-MDSCs. Despite the lower mean age of the hip osteoarthritis cohort, these patients showed a significantly higher proportion of BM myeloid cells than fracture patients, whereas lymphoid cell frequencies were not significantly different. Analysis of myeloid maturation stages revealed enrichment of CD11b⁺/CD16 low metamyelocyte-like cells in hip OA samples both ex vivo and after cytokine-driven expansion. Functional assays demonstrated that inhibition of activated T cell proliferation was confined to the most immature myeloid fraction, which displayed promyelocyte-like features. This suppressive activity was preserved in both hip OA and fracture cohorts, with no significant difference between groups. These findings indicate that hip OA is associated with BM myeloid skewing and selective enrichment of myeloid subsets reassembling metamyelocytes-like cells, while maintaining conserved immunoregulatory function. The BM may represent an active immunological compartment linked to the balance between chronic inflammation and immune regulation in hip OA.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"10 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149150031","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":"Balance control is more affected in older than younger adults by repeated visual perturbations during walking","authors":"Yaqi Li,Eugénie Lambrecht,Sjoerd M. Bruijn,Jaap H. van Dieën","doi":"10.1007/s11357-026-02573-5","DOIUrl":"https://doi.org/10.1007/s11357-026-02573-5","url":null,"abstract":"Abstract Sensory degradation with aging can impair balance control, partly by disrupting visual contributions to self-motion estimation. We investigated age-related differences in center of mass (CoM) trajectories controlling in the frontal plane during exposure to repeated visual perturbations in walking. We hypothesized that the older adults would show larger responses to visual perturbations and less adaptation to repeated visual perturbation exposure. We applied three visual perturbations to 14 healthy older (age = 75.0 ± 2.4) and 16 younger adults (age = 23.4 ± 3.9) walking on a treadmill: fixating a stationary target with the background moving to the right (MB), tracking a target moving rightward over a stationary background with head rotation (MT-HR), and tracking a moving target with eye movement only (MT-EM). CoM position deviations due to the visual perturbations were assessed. Over the whole trial, the older adults did not show larger CoM position variability than the younger during visual perturbation walking, which was contrary to our hypothesis. During visual perturbation epochs, both age groups deviated in the same direction except MB. In MB, the older adults deviated to an opposite direction after a few perturbation repetitions. Moreover, in MT-HR and MT-EM, the older adults deviated earlier than the younger adults and they deviated more in the MT-HR condition. This indicates that older adults exhibit reduced ability to accurately estimate self-motion through correction by other sensory modalities when exposed to visual perturbations. Over repeated perturbations, the older adults showed decreased CoM deviations in MT-EM, which suggests that they still maintain the capacity to downweight visual information after repeated exposure.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"248 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149150032","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":"Brain care score and retinal health: structural and metabolic insights from the UK Biobank.","authors":"Jun Yu, Yuzhou Zhang, Yue Lan Gao, Mary Ho, Ka Wai Kam, Bo Gong, Alvin L Young, Chi Pui Pang, Clement C Tham, Jason C Yam, Li Jia Chen","doi":"10.1007/s11357-026-02579-z","DOIUrl":"https://doi.org/10.1007/s11357-026-02579-z","url":null,"abstract":"<p><p>The retina is an extension of the central nervous system and a recognized indicator of systemic health, yet the link between the brain care score (BCS) and retinal health remains unclear. In this study, we aimed to assess the associations of BCS with retinal layer thickness and retinal biological age and to evaluate potential metabolic mediation for retinal thickness. A total of 28,657 UK Biobank participants with optical coherence tomography (OCT) imaging at baseline were included, of whom 14,656 had metabolomic data. We constructed a 19-point BCS incorporating physical, lifestyle, and social-emotional domains, with higher scores indicating better brain care. Eight retinal layers and overall macular thickness were assessed. Retinal aging was evaluated using the OCT age gap, defined as the difference between the retinal age predicted by a support vector machine model trained on OCT-derived structural metrics and chronological age. Using multivariable linear regression, higher BCS was associated with thicker neuroretinal layers, photoreceptor layers, and overall macular thickness. Exploratory indirect-effect analyses identified candidate metabolic patterns primarily involving lipid, unsaturated fatty acid, and branched-chain amino acid pathways. Furthermore, each 5-unit increase in BCS was associated with a reduced retinal age gap. Our study identified associations between higher BCS and thicker neuroretinal and photoreceptor layers, as well as a reduced OCT age gap. These findings link a higher BCS to more favorable retinal structural phenotypes and identify candidate metabolic patterns for further investigation.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136352","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":"A conserved post-maturity imbalance between housekeeping and integrative genome activity in aging.","authors":"Lev Salnikov, Saveli Goldberg, Eugene Pinsky","doi":"10.1007/s11357-026-02575-3","DOIUrl":"https://doi.org/10.1007/s11357-026-02575-3","url":null,"abstract":"<p><p>Aging biology still lacks a fully mechanistic explanation for why functional decline accelerates after sexual maturity in the absence of a single initiating pathology. Here, we integrate cross-species epigenetic, transcriptomic, and proteomic datasets to test whether aging is associated with a post-maturity imbalance between two genome partitions: housekeeping genes (HG), which encode the cellular maintenance infrastructure, and integrative genes (IntG), which support specialized tissue functions. We emphasize HG because this compartment defines the basal capacity for repair, proteostasis, biosynthesis, and cell-autonomous survival; changes in HG output may therefore help distinguish candidate upstream regulatory changes from downstream damage signatures. Across datasets, we observe a consistent divergence after sexual maturity: the HG compartment loses transcriptional share in low-renewal tissues, whereas IntG promoter methylation becomes progressively more dispersed, with methylation-mRNA Spearman correlations of rho = -0.15 to -0.28 (five tissues, p < 0.05 FDR) and modest mRNA-protein concordance (rho = 0.204, p < 0.001, n = 6,449), indicating partial post-transcriptional decoupling. These associations are compatible with the continued action of an ontogenetic regulatory program that shifts genome activity toward specialized function at the expense of maintenance. This interpretation is consistent with hyperfunction/developmental theories, while reframing the hyperfunctional state as a possible downstream consequence of asymmetric developmental regulation. Although causality remains to be tested experimentally, the convergence of multi-omics evidence supports a testable model in which restoring HG/IntG regulatory balance may represent a future experimental direction for modulating age-related decline, rather than a translational implication supported by the current data.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136424","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":"Mitochondrial dysfunction and inflammaging: a mechanistic bridge between bioenergetic failure and senescence.","authors":"Salvatore Nesci, Cristina Algieri","doi":"10.1007/s11357-026-02588-y","DOIUrl":"https://doi.org/10.1007/s11357-026-02588-y","url":null,"abstract":"<p><p>Ageing is characterized by a progressive decline in mitochondrial integrity that extends beyond impaired energy production to include redox imbalance, defective quality control, altered organelle dynamics, and persistent inflammatory signalling. This review examines mitochondrial dysfunction as a mechanistic bridge linking bioenergetic failure to cellular senescence and inflammaging, two central features of biological ageing. We discuss how impaired oxidative phosphorylation, loss of mitochondrial membrane potential, increased electron leak, and excessive reactive oxygen species progressively damage mitochondrial DNA, proteins, and lipids, thereby amplifying organelle dysfunction and compromising cellular homeostasis. Particular emphasis is placed on the threshold effect of mitochondrial DNA mutations, whose age-dependent clonal expansion can drive respiratory chain deficiency in vulnerable tissues. We further analyze mitochondria as signalling platforms that integrate regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, and as sources of mitochondrial damage-associated molecular patterns promoting sterile inflammation. Finally, we highlight mitochondrial dysfunction-associated senescence as a central process through which persistent mitochondrial stress reshapes the senescence-associated secretory phenotype and reinforces inflammaging. Overall, the evidence supports a model in which dysfunctional mitochondria act as both initiators and amplifiers of senescence and inflammation, contributing to tissue degeneration and age-related functional decline. Understanding these interconnected mechanisms may help identify therapeutic strategies targeting mitochondrial bioenergetics, inflammatory signalling, and senescent cell burden in ageing.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147966","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 community toilet deprivation and depression among older adults in India: a multilevel analysis of the Longitudinal Aging Study in India from 2017-2018","authors":"Anoop Jain,Rockli Kim,S. V. Subramanian","doi":"10.1007/s11357-026-02537-9","DOIUrl":"https://doi.org/10.1007/s11357-026-02537-9","url":null,"abstract":"","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"5 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092030","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}