Aging and Disease最新文献

{"title":"Accelerated Epigenetic Aging in Diabetes: Socio-Biological Pathways of Health Inequity.","authors":"Su Yon Jung","doi":"10.14336/AD.2026.0553","DOIUrl":"https://doi.org/10.14336/AD.2026.0553","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is an aging-related disease with greater incidence in older African Americans (AAs) than whites, but studies on racial disparity in epigenetic aging pathways are scarce; specifically, socio-biological aging processes are not well characterized. We investigated biological aging acceleration (aging accel) with development of T2DM and additionally, insulin resistance (IR) of nondiabetic women at baseline in cross-section. We estimated the extent to which social adversity explained AAs' greater aging accel and, together with accelerated aging, mediated their greater burden of glucometabolic outcomes. Clinical and social determinants of health (SDOH) variables and genome-wide DNA methylation data were extracted from the Women's Health Initiative with > 1,500 postmenopausal non-diabetic women. Diabetic outcome was followed for a mean of 19 years, and baseline IR was measured using fasting serum samples. Aging accel metrics were calculated with Levine's clock, and mediation effects of SDOH and aging accel was estimated via Multiple Mediation analyses. Greater aging accel was observed in T2DM, albeit with only univariate significance and IR and in AAs rather than whites. SDOH was associated with greater aging accel, but its impact on greater accelerated aging in AAs varied and in combination, was minimal. Although aging accel has greater influence than SDOH on the racial difference in glucometabolic outcomes, these parameters jointly mediated to only a limited extent T2DM/IR pathways by race. Our mediation findings are exploratory and hypothesis-generating and thus, our results warrant validation studies to better understand socio-glucometabolic pathways shared by epigenetic aging processes and to inform early risk stratification among at-risk older women for disease prevention and reduced racial health inequity.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148710995","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":"Metformin: A Promising Candidate for Slowing the Progression of Cardiovascular Aging.","authors":"Yan Miao, Wenting Wang, Ye Liu, Shumai Zhu, Ye Li, Xuehong Zheng, Dongye Zhuo, Jiaxin Hua, Lihan Zhu, Jing Zhang, Wenli Gu, Lin Zhang, Jun Zhang, Xiang Gu, Yuanzheng Ye, Fang Wang, Peng Yu, Xiao Liu","doi":"10.14336/AD.2025.1308","DOIUrl":"https://doi.org/10.14336/AD.2025.1308","url":null,"abstract":"<p><p>Cardiovascular aging, characterized by endothelial dysfunction, arterial stiffening, and myocardial remodeling, is a major contributor to the development of age-related cardiovascular disease. Metformin, a first-line therapy for type 2 diabetes, has attracted interest as a promising geroprotective agent due to its ability to target several fundamental aging pathways. Mechanism: Beyond glucose-lowering effects, metformin may confer cardiovascular benefits through activation of AMP-activated protein kinase and inhibition of mitochondrial complex I. Preclinical work suggests these pathways enhance mitochondrial biogenesis, reduce oxidative stress, promote autophagy, and suppress chronic inflammation. Furthermore, metformin has been reported to modulate epigenetic clocks and support genomic stability, potentially mitigating several hallmarks of aging. Clinical Evidence: Although preclinical evidence is substantial, clinical findings remain heterogeneous. Observational studies and trials like UKPDS suggest cardiovascular benefits, whereas randomized controlled trials (RCTs) such as TAYSIDE, GIPS-III, REMOVAL and GOMET yielded inconsistent results for both clinical and surrogate cardiovascular endpoints. Result interpretations are often limited by relatively small sample sizes and short follow-up durations. Sex Differences and Limitations: Emerging evidence suggests sexual dimorphism in metformin responses, potentially influenced by hormonal status and pharmacokinetics. Additional challenges include the hormetic dose-response, the heterogeneity and frailty of older populations, and the absence of validated aging-specific cardiovascular endpoints. Metformin remains a promising candidate to mitigate cardiovascular aging. However, definitive conclusions regarding its efficacy in non-diabetic older adults will require large-scale, long-term RCTs incorporating aging-related biomarkers and stratification according to sex and metabolic status.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711053","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":"Glymphatic System Function and Cognition: Converging Evidence from DTI-ALPS Imaging - A Narrative Review.","authors":"Anna B Marcinkowska, Małgorzata Grzywińska, Paweł J Winklewski","doi":"10.14336/AD.2026.0511","DOIUrl":"https://doi.org/10.14336/AD.2026.0511","url":null,"abstract":"<p><p>The glymphatic system, a brain-wide perivascular network mediating cerebrospinal fluid-interstitial fluid exchange, has emerged as a candidate determinant of cognitive health through its role in clearing metabolic waste, neurotoxic proteins, and neuroactive metabolites. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index provides a non-invasive means to assess glymphatic activity in vivo, yet no synthesis has consolidated what this marker captures, how reliably it predicts cognitive outcomes, and what pathways may account for observed associations. This narrative review, informed by selected principles from the PRISMA 2020 framework but not constituting a formal systematic review, synthesizes evidence linking DTI-ALPS to domain-specific cognitive performance in healthy aging and neurological disease, encompassing the Alzheimer's disease continuum, cerebral small vessel disease, Parkinson's disease, multiple sclerosis, stroke, and HIV-associated neurocognitive disorder. Lower DTI-ALPS values were consistently associated with worse cognitive performance. The strongest associations were observed for memory and global cognition, followed by executive functions and processing speed; evidence for language and visuospatial abilities was less consistent. Longitudinal data indicate that DTI-ALPS decline may precede detectable amyloid pathology, positioning this index as a candidate early prognostic marker. Three mechanistic pathways are discussed: disruption of sleep-dependent waste clearance; compromise of gray matter integrity through neurotoxic metabolite accumulation; and facilitation of amyloid-β and tau pathology via impaired perivascular protein clearance. Limitations include the indirect nature of DTI-ALPS as a clearance measure, predominance of cross-sectional designs, small samples, and absence of sex-stratified analyses despite known hormonal modulation of glymphatic function. Longitudinal studies, randomized trials of glymphatic-targeting interventions, and acquisition protocol standardization represent priority directions for future research.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711031","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":"Immune Thrombocytopenia in Older Adults: Age-Related and Disease-Specific Alterations in Platelets.","authors":"Elena Monzón Manzano, Carmen Herrero Carrasco, Paula Acuña, Lucía Del Pino Molina, Elena G Arias-Salgado, Ana Mendoza, Rick Kapur, Leendert Porcelijn, Mónica Martín Salces, María Isabel Rivas Pollmar, Eduardo López-Granados, Víctor Jiménez Yuste, Mercedes Gasior Kabat, Raquel Ramírez Martín, Nora Butta, María Teresa Álvarez Román","doi":"10.14336/AD.2026.0663","DOIUrl":"https://doi.org/10.14336/AD.2026.0663","url":null,"abstract":"<p><p>Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with a higher incidence among older adults. Aging per se alters platelet characteristics, including reduced reactivity and increased caspase activity, changes also observed in ITP. The aim of this study was to assess the impact of aging on the hemostatic characteristics of patients with ITP and its potential contribution to the increased burden of the disease. Additionally, the study sought to identify characteristics of the disease itself, independent of age. Patients with ITP over 65 years of age (ITP>65) and patients aged 65 or under (ITP≤65) were included, as well as age-matched healthy controls (HC). Basal P-selectin exposure was higher in the ITP≤65 than in the HC≤65 group but no difference was observed between the ITP>65 and HC>65 groups. This may be due to the synergistic effect of disease and aging, because P-selectin exposure was higher in the HC>65 group than in the HC≤65 group. The ITP>65 patients exhibited reduced platelet responsiveness to agonists and increased caspase-3/7 activity compared with the ITP≤65 patients. Their clots were more resistant to lysis, likely due to elevated plasma levels of circulating cell-free DNA (cfDNA) and plasminogen activator inhibitor-1 (PAI-1). Comparisons between the ITP≤65 and HC≤65 groups as well as the ITP>65 and HC>65 groups revealed ITP-specific features, such as reduced sialic acid residues due to elevated neuraminidase-1 (NEU1) exposure. These findings showed that age-related changes in haemostasis can overlap with disease-specific features, highlighting the need for age-stratified approaches.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148711009","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 C. elegans-to-Mouse Discovery Framework for Prioritizing Sarcopenia Interventions.","authors":"Yejin Cho, Hyo-Deok Seo, Chang Hwa Jung, Jiyun Ahn, Jeong-Hoon Hahm","doi":"10.14336/AD.2026.0758","DOIUrl":"https://doi.org/10.14336/AD.2026.0758","url":null,"abstract":"<p><p>Sarcopenia is a manifestation of musculoskeletal aging, yet no approved therapy is available. A major challenge is not the lack of potential interventions, but the difficulty of efficiently identifying which candidates should advance to aged-mammal validation. Sarcopenia is driven by multiple biological processes, including mitochondrial dysfunction, impaired proteostasis, redox dysregulation, inflammaging, and altered nutrient sensing. Consequently, candidate interventions encompass not only conventional drug candidates but also natural products, dietary compounds, food-derived metabolites, and multi-component formulations. This diversity creates a candidate space that is difficult to systematically evaluate using aged-mouse models alone. Here, we propose a C. elegans-to-mouse discovery framework for sarcopenia intervention development. C. elegans enables rapid organism-level assessment of locomotor function, muscle integrity, toxicity, genetic dependency, and conserved aging mechanisms within a single in vivo system. These features allow large candidate pools, including diverse compounds, doses, and combinations, to be screened and prioritized before resource-intensive mammalian studies. Within this framework, preservation of age-related function serves as the primary selection criterion, whereas conserved biological mechanisms provide additional support for candidate advancement. Mitochondrial quality control, redox resilience, proteostasis, and gut-muscle communication are discussed as representative domains that facilitate cross-species interpretation. Examples including urolithin A, norharmane, and spermidine illustrate how worm-based functional screening can be integrated with mechanistic evidence and aged-mouse validation. Collectively, this review proposes a practical framework that integrates function-centered screening with conserved mechanistic interpretation to improve early-stage prioritization of sarcopenia interventions. This framework provides a conceptual strategy for accelerating the discovery of function-preserving therapeutics for skeletal muscle aging.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597696","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":"Hepatic FoxO3 Supports Metabolic Resilience, Attenuates Age-Associated Obesity and Metabolic Dysfunction, and Mitigates Diet-Induced Steatohepatitis.","authors":"Toshimitsu Komatsu, Seongjoon Park, Sangeun Kim, Hiroko Hayashi, Isao Shimokawa","doi":"10.14336/AD.2026.0477","DOIUrl":"https://doi.org/10.14336/AD.2026.0477","url":null,"abstract":"<p><p>Forkhead box O3 (FoxO3) is implicated in aging and metabolic regulation; however, its roles in the local and systemic control of aging remain incompletely understood. In this study, we characterized the effects of hepatocyte-specific Foxo3 deletion on hepatic metabolic and whole-body energy homeostasis during aging, and the susceptibility of mice to metabolic disease. Male hepatocyte-specific Foxo3 knockout (h-Foxo3^-/-) mice developed moderate obesity and higher plasma insulin levels by middle age, despite no difference in food intake compared with wild-type mice. Indirect calorimetry revealed lower energy expenditure relative to body weight, a higher respiratory quotient, and less fatty acid oxidation, indicating a shift toward carbohydrate-dependent energy metabolism. Adipose tissue exhibited inflammatory cell infiltration and high expression of inflammatory and senescence markers, consistent with systemic insulin resistance. Although these findings suggested that hepatokine signaling regulates systemic metabolism, there was limited direct evidence for FoxO3-dependent hepatokine secretion. RNA-sequencing analysis suggested that fatty acid processing and xenobiotic and detoxification pathways were suppressed in h-Foxo3^-/- liver and that gluconeogenic and proinflammatory programs were activated. h-Foxo3^-/- mice exhibited hepatic steatosis and an increase in the oxidized glutathione concentration when consuming a regular diet, and those consuming a fat-, fructose-, and cholesterol-rich diet, which induces steatohepatitis, showed more severe fibrosis than controls. Collectively, these findings suggest that hepatic FoxO3 is a key regulator coordinating hepatic lipid processing, xenobiotic metabolism and detoxification, susceptibility to metabolic disorders, and systemic metabolic flexibility. Thus, hepatic FoxO3 contributes to the maintenance of metabolic resilience during aging.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597384","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":"Cognitive Impairment after Aneurysmal Subarachnoid Hemorrhage: Temporal Patterns and Electrophysiological Risk Stratification.","authors":"Kun Yang, Peng Liu, Oxana Semyachkina-Glushkovskaya, Mingchang Li, Yuxiang Yan, Hongqi Zhang","doi":"10.14336/AD.2026.10505","DOIUrl":"https://doi.org/10.14336/AD.2026.10505","url":null,"abstract":"<p><p>Cognitive impairment (CI) after aneurysmal subarachnoid hemorrhage (aSAH) is common, but its temporal course and prediction using multimodal data remain unclear. This prospective cohort study assessed time to first-detected CI among survivors eligible for follow-up cognitive testing. CI was defined as an education-adjusted Montreal Cognitive Assessment score <26 at 7 to 24 months after admission. A sensitivity endpoint using MoCA <23 was also examined. First-detected CI-free survival was compared between patients with aSAH and those with unruptured intracranial aneurysms (UIAs). Within the aSAH cohort, six prediction schemes were tested, including core clinical variables alone and clinical variables plus baseline cognition, plasma biomarkers, event-related potentials (ERPs), MRI, or CSF markers. Patients with aSAH had lower 24-month first-detected CI-free survival than patients with UIA, 43.7% vs. 71.4%, with an 8.1-month loss in restricted mean survival time, 95% CI 6.2 to 9.6. They also had a higher hazard of first-detected CI, HR 7.21, 95% CI 3.59 to 14.49. Among the six prediction schemes, only the ERP CP2 pair model met all prespecified performance criteria. In temporal internal validation, this model achieved an AUROC of 0.928 and a Brier score of 0.103. Incremental value was greatest in patients aged ≥60 years and those with Fisher grade 3 to 4. aSAH was associated with earlier CI and substantial loss of CI-free time compared with UIA. An ERP-based model showed the most stable internally validated performance, especially in older patients and those with greater hemorrhagic burden. External multicenter validation is needed before clinical use.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597345","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":"Targeting the Microbiota-Butyrate-BHB Axis As a Potential Metabolic Therapeutic Strategy for Alzheimer's Disease.","authors":"Vijay Kumar, Sinae Jang, Yebeen Choi, Sujin Kim, Yunkwon Nam, MyeongHeon You, Minho Moon","doi":"10.14336/AD.2026.0606","DOIUrl":"https://doi.org/10.14336/AD.2026.0606","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is increasingly linked to metabolic and microbial dysregulations, with butyrate and β-hydroxybutyrate (BHB) identified as key modulators. BHB is a ketone body primarily produced by the liver during periods of low glucose availability, and BHB levels are reduced in the AD brain and peripheral blood. Butyrate, a microbiota-derived short-chain fatty acid, is also reduced in the peripheral blood in association with gut microbiota dysbiosis. The reduction of butyrate and BHB, together with gut microbiota dysbiosis, is commonly observed in AD patients and correlates with cognitive decline and AD-related pathologies. Reduced levels of butyrate and BHB may impair energy metabolism, exacerbating amyloid-beta (Aβ) and tau pathologies. In contrast, preliminary evidence from interventional and ketogenic studies suggests that increasing butyrate and BHB levels may attenuate AD-related pathologies, such as Aβ and tau abnormalities, while improving cognitive function. Emerging evidence suggests that both butyrate and BHB can cross the blood-brain barrier (BBB), suppressing oxidative stress and pro-inflammatory cytokines and potentially mitigating Aβ aggregation and tau hyperphosphorylation. Accordingly, therapeutic strategies targeting the microbiota-butyrate-BHB axis represent a promising and biologically plausible approach that warrants further rigorous clinical investigation for the prevention and treatment of AD. This review comprehensively examines the roles of butyrate and BHB in ameliorating key AD-related pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Additionally, the review explores the bidirectional association between butyrate/BHB and gut dysbiosis in AD, including how dysbiosis reduces butyrate/BHB levels while elevating them may reverse dysbiosis and improve gut-brain axis function. Collectively, these findings suggest that butyrate and BHB emerge as promising candidates for potential novel adjunctive therapies for AD, although supporting human evidence remains preliminary and heterogeneous.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597540","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":"Glial Scar Stiffness Affects NSCs Differentiated Direction via Piezo1 Post-Stroke.","authors":"Shengju Wu, Yuanyue Song, Yangqianbo Yao, Ze Liu, Yaohui Tang, Wanlu Li, Guo-Yuan Yang, Zhijun Zhang","doi":"10.14336/AD.2026.0347","DOIUrl":"https://doi.org/10.14336/AD.2026.0347","url":null,"abstract":"<p><p>Following ischemic stroke, the progressive formation and mechanical stiffening of the glial scar pose a critical microenvironmental barrier to neural regeneration. However, how this dynamic stiffness influences the fate of neural stem cells (NSCs) remains unclear. To address this, this study aimed to elucidate the mechanotransduction mechanism regulating NSCs differentiation post-stroke. Specifically, thirty male C57BL/6J mice underwent distal middle cerebral artery occlusion to establish a focal cerebral ischemia model. We combined in vivo transplantation of NSCs into distal middle cerebral artery occlusion mouse stroke models and in vitro culture on polyacrylamide hydrogels mimicking scar stiffness. Furthermore, transcriptomic analysis and functional validation through Piezo1 knockdown were employed. Mechanistic insights were explored by examining calcium influx and the Notch signaling pathway. We found that increased substrate stiffness potently inhibited neuronal differentiation and neurite outgrowth. Importantly, Piezo1 was identified as a key mechanosensitive regulator and its knockdown severely diminished both the neuronal differentiated direction and the NSCs proliferation. Mechanistically, Piezo1-mediated calcium influx modulated Notch signaling, forming a stiffness-sensing axis that coordinates the differentiation gene network. Overall, these findings identify aberrant mechanosensing as an important contributing factor of neurogenesis and highlight Piezo1 as a potential therapeutic target for enhancing neural repair.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597328","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":"Intestinal Organoids from Alzheimer's Disease Transgenic Mice Reveal Structural and Molecular Gut Pathology.","authors":"K Matisse Gilson, Alfredo Fernandez Higueras, Winston M Walters, Juliana Sanchez-Molano, Vania W Almeida, Zane Zeier, W Dalton Dietrich, Helen M Bramlett, Nadine A Kerr","doi":"10.14336/AD.2026.0233","DOIUrl":"10.14336/AD.2026.0233","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common form of dementia, and early alterations in the gut may contribute to disease progression. The current study focused on generating intestinal organoids from 3xTg-AD transgenic and Wild Type (WT) mice to investigate the role of the gut-brain axis in AD. Intestinal organoid cultures were produced through isolation of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5+) crypt cells from 4-5-month-old or 1-year-old intestinal tissue. Transmission electron microscopy (TEM) analysis of aged 3xTg organoids demonstrated evidence of impaired gut epithelial viability compared to WT controls. In aged 3xTg organoids, enlarged intercellular spaces, disrupted cell adhesions, diminished tight junction complexes, cellular debris, and amyloid-like fibrils were prominent findings. Immunostaining also demonstrated decreased E-Cadherin and ZO1 expression, along with increased cellular and luminal Aβ in aged 3xTg organoids compared to young 3xTg and WT organoids and p-tau protein accumulation in aged 3xTg organoids compared to all other experimental groups. In the aged 3xTg cohort, increased immunoreactivity of inflammasome components, including IL-1β, ASC, and GSDMD, implicated pyroptosis as a potential mechanism of cell death. These results support the hypothesis that familial AD pathology includes pronounced effects on gut organoid viability, junctional integrity, and abnormal protein accumulation within the intestinal epithelium. This study provides early evidence of gut organoid abnormalities occurring independently of alterations in the AD brain. These findings suggest that the gut epithelium may warrant further investigation as a potential target for future therapeutic strategies in AD.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597433","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}