Aging Cell最新文献

{"title":"Enhanced C/EBPα Function Extends Healthspan and Lifespan in the African Turquoise Killifish","authors":"Christine Müller,&nbsp;Joscha S. Muck,&nbsp;Kirill Ustyantsev,&nbsp;Gertrud Kortman,&nbsp;Josephine Hartung,&nbsp;Eugene Berezikov,&nbsp;Cornelis F. Calkhoven","doi":"10.1111/acel.70211","DOIUrl":"10.1111/acel.70211","url":null,"abstract":"<p>The transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) regulates cell differentiation, proliferation, and function in various tissues, including the liver, adipose tissue, skin, lung, and hematopoietic system. Studies in rats, mice, humans, and chickens have shown that CEBPA mRNA undergoes alternative translation initiation, producing three C/EBPα isoforms. Two of these isoforms act as full-length transcription factors with N-terminal transactivation domains and a C-terminal dimerization and DNA-binding domain. The third isoform is an N-terminally truncated variant, translated from a downstream AUG codon. It competes with full-length isoforms for DNA binding, thereby antagonizing their activity. Expression of the truncated C/EBPα isoform depends on the initial translation of a short upstream open reading frame (uORF) in the CEBPA mRNA and subsequent re-initiation at a downstream AUG codon, a process stimulated by mTORC1 signaling. We investigated whether the ortholog of the CEBPA gene in the evolutionarily distant, short-lived African turquoise killifish (<i>Nothobranchius furzeri</i>) is regulated by similar mechanisms. Our findings reveal that the uORF-mediated regulation of C/EBPα isoform expression is conserved in killifish. Disruption of the uORF selectively eliminates the truncated isoform, leading to unrestrained activity of the full-length C/EBPα isoforms. This genetic modification significantly extended both the median and maximum lifespan and improved the healthspan of male <i>N. furzeri</i>. Furthermore, comparative transcriptome analysis revealed an upregulation of genes and pathways that are associated with healthspan and lifespan regulation in other species. These results highlight a conserved mechanism of <i>CEBPA</i> gene regulation across species and its potential role in modulating the lifespan and aging phenotypes.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repeated Withdrawal of a GLPR Agonist Induces Hyperleptinemia and Deteriorates Metabolic Health in Obese Aging UM-HET3 Mice","authors":"Nisi Jiang,&nbsp;Jiyuan Yin,&nbsp;Noah Lawrence,&nbsp;Jieyi Meng,&nbsp;Laurence T. Maeyens,&nbsp;Ziying Xu,&nbsp;Xin Li,&nbsp;Mbolle Ekane,&nbsp;Ariana Chaudhary,&nbsp;Pengju Cao,&nbsp;Guannan Li,&nbsp;Carolina Solis-Herrera,&nbsp;Yi Zhu,&nbsp;Shangang Zhao","doi":"10.1111/acel.70210","DOIUrl":"10.1111/acel.70210","url":null,"abstract":"<p>GLP-1-based therapy is highly effective in combating aging-associated metabolic diseases. However, the metabolic effects of frequent withdrawal from this therapy in aged, obese mice have not been previously studied. In this study, aged obese UM-HET3 mice were assigned to three groups: Group 1 received no liraglutide treatment (Lira OFF); Group 2 underwent 3 cycles of treatment followed by withdrawal (Lira ON/OFF); and Group 3 remained on continuous treatment (Lira ON). As expected, mice in Group 3 showed reduced body weight and food intake, along with improved metabolic health. In contrast, mice in Group 2 developed hyperleptinemia and visceral fat expansion, leading to impaired metabolic health. Importantly, although these mice regained their fat mass after each treatment cycle, they failed to restore lean mass, an unfavorable shift in body composition that may increase vulnerability to aging-related sarcopenia. These findings suggest that continuous GLP-1-based therapy is necessary to sustain metabolic benefits, while intermittent use may promote age-associated sarcopenia and metabolic decline.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70210","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Clocks as Biomarkers for Bone Aging: Evidence From a Twin Study","authors":"Mette Soerensen,&nbsp;Florence Figeac,&nbsp;Kaare Christensen,&nbsp;Moustapha Kassem","doi":"10.1111/acel.70204","DOIUrl":"10.1111/acel.70204","url":null,"abstract":"<p>Osteoporosis is driven by skeletal aging and increases the risk of fragility fractures. Skeletal aging is influenced by epigenetic mechanisms; however, the link to the epigenetic clocks, that is, the suggested biomarkers of biological aging intensively studied within aging research, remains largely unexplored. We investigated the association of eight epigenetic clocks—Horvath, IEAA, Hannum, EEAA, PhenoAge, GrimAge, DunedinPoAm, DunedinPACE—and methylation-based telomere length (mTL) measured at intake (1997, 2007, or 2008–11) with register-based incident fracture and osteoporosis diagnoses in 310 (Discovery cohort), and 777 (Replication cohort) twins, derived from nationwide population-based surveys (end-of-follow-up: 2022). For the 288 youngest twins, bone mineral density (BMD), and bone turnover markers C-terminal telopeptide (CTX) and amino pro-collagen type 1 N-terminal propeptide (P1NP) were available. Analyses were conducted at both the individual and twin-pair levels, reducing genetic and environmental confounding. A consistent pattern emerged: increased epigenetic age, faster pace of aging, and shorter mTL associated with a higher risk of fractures, or osteoporosis. Notably, DunedinPoAm, DuninPACE, and GrimAge demonstrated the most robust associations. DuninPACE displayed the largest effects; hazard ratios ranging from 1.29 to 3.17, reflecting a 29%–217% increased hazard for diagnosis pr. one standard deviation increase in DuninPACE. The same directions of effects were seen for decreasing CTX and P1NP levels, suggesting bone remodeling impairment for individuals with higher biological age. Lastly, sex- and age-specific analysis of BMD indicated the same direction of effect for DunedinPoAm, and GrimAge in older females. These findings suggest that epigenetic clocks may serve as biomarkers for bone aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70204","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary Citrate Restores Age-Related Endothelial Cell Mitochondrial Dysfunction and Alleviates Atherosclerosis","authors":"Ya Zhao,&nbsp;Jia-Yu Qiu,&nbsp;Fang Wu,&nbsp;Xue-Ting Gong,&nbsp;Wei-Xin Lv,&nbsp;Jian-Kun Liu,&nbsp;Jia-Yi Dong,&nbsp;Xue-Er Li,&nbsp;An-Dong Wu,&nbsp;Jing-Jing Duan,&nbsp;Yang Xiang,&nbsp;Xiao-Li Tian","doi":"10.1111/acel.70213","DOIUrl":"10.1111/acel.70213","url":null,"abstract":"<p>Vascular aging increases the susceptibility to cardio-cerebrovascular conditions, such as atherosclerotic diseases and hypertension, the leading causes of global disability and mortality. Dietary citrate extends the lifespan of <i>Drosophila melanogaster</i> and <i>Caenorhabditis elegans</i> as well as improves the memory of mice injured by a high-fat diet (HFD); whether it alleviates vascular aging and age-related vascular diseases; however, remains unknown. Here, we showed that dietary supplementation of citrate delayed vascular aging, as evidenced by maintaining the integrity of elastic fibers and decreasing the level of the aging-related marker, CDKN1A (p21). Functionally, citrate improved the sensitivity to endothelial-dependent vasodilators and lowered blood pressure, and in HFD-fed <i>ApoE</i>^{<i>−/−</i>} mice, it reduced the size of atherosclerotic plaques, decreased the necrotic core area and vulnerability index in aortic root plaques. Additionally, citrate decreased the frailty index, increased bone density, and improved maximal grip strength and balance speed in both aged and HFD-fed <i>ApoE</i>^{<i>−/−</i>} mice. Mechanistically, we showed that citrate exposure delayed human umbilical vein endothelial cell senescence with a decreased percentage of cells stained with senescence-associated β-galactosidase and p21 levels. Moreover, citrate activated AMPK-related pathways and reversed senescence-related mitochondrial dysfunction in basal respiration, maximal respiration, and ATP production and reduced the production of reactive oxygen species (ROS). The citrate-promoted beneficial effects were abolished due to inactivated AMPK and the increased mitochondrial ROS. Thus, we demonstrate that dietary citrate delays vascular aging and alleviates age-related vascular diseases by improving mitochondrial function via activation of AMPK-related pathways. Citrate may have potential clinical implications for interventions against vascular aging and age-related vascular diseases.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APOE4 Exacerbates Alzheimer-Like Pathologies and Cognitive Deficits Induced by Blood-Derived Aβ in a Mouse Model","authors":"Zhong-Yuan Yu,&nbsp;Xiao-Yu Liu,&nbsp;Qiong-Yan Li,&nbsp;Jin-Mei Tuo,&nbsp;Qi Tan,&nbsp;Zhi-Hao Liu,&nbsp;Zi-Yu Yuan,&nbsp;Ru Zeng,&nbsp;Yang Zhao,&nbsp;Jiang-Hui Li,&nbsp;Yu-Di Bai,&nbsp;Gui-Hua Zeng,&nbsp;Dong-Wan Chen,&nbsp;Xian-Le Bu,&nbsp;Wang-Sheng Jin,&nbsp;Yan-Jiang Wang","doi":"10.1111/acel.70205","DOIUrl":"10.1111/acel.70205","url":null,"abstract":"<p>Apolipoprotein E4 (APOE4) is a significant risk for both familial Alzheimer's disease (AD) and sporadic AD with elusive mechanisms. Previous studies mainly focused on the role of APOE4 in familial AD, with less attention to sporadic AD. Our previous study demonstrated that blood cell-derived amyloid-β (Aβ) can enter the brain and induce AD-like pathologies, providing a novel animal model to study sporadic AD to a certain extent. The impacts of APOE4 on Alzheimer-like pathologies and cognitive deficits induced by blood-derived Aβ remain unknown. In the present study, we found that APOE4 prompted the entry of blood Aβ into the brain. APOE4 recipient mice showed impaired integrity of the blood–brain barrier and higher Aβ levels in the brain after transplantation of bone marrow cells from APP/PS1•APOE4 mice. In addition, we observed that the APOE4 recipient mice displayed aggravated tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits at the age of 12 months. Our study demonstrates that APOE4 is capable of facilitating the entry of blood-derived Aβ into the brain and enhancing the AD-like pathologies triggered by blood-derived Aβ. Our findings provide a possible way by which APOE4 elevates the risk of sporadic AD.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply","authors":"Zhihua Huang,&nbsp;Xinxin Liu,&nbsp;Xiaojia Zhou,&nbsp;Keyu Chen,&nbsp;Honglin Diao,&nbsp;Mingyue Wang,&nbsp;Jianlei Wei,&nbsp;Zeping Li,&nbsp;Yang Yang,&nbsp;Zebin Mao,&nbsp;Wenhua Yu","doi":"10.1111/acel.70203","DOIUrl":"10.1111/acel.70203","url":null,"abstract":"<p>The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS), rendering them uniquely dependent on exogenous asparagine (Asn). This vulnerability was exploited through combined treatment with L-asparaginase (ASNase) and autophagy inhibitors, which synergistically deplete Asn via complementary mechanisms: ASNase degrades extracellular Asn pools, while autophagy inhibition blocks intracellular protein recycling as an alternative Asn source. This dual approach induced selective synthetic lethality across multiple SNC types in vitro. In aged mice, the combination therapy significantly reduced SNC burden in diverse tissues, improved physiological function, and attenuated progression of age-related conditions including osteoporosis, atherosclerosis, and non-alcoholic fatty liver disease. Our findings establish concurrent targeting of extracellular and intracellular Asn supplies as a potent, selective senolytic strategy with broad therapeutic potential for age-related disorders.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell Fluorescence Imaging Reveals Heterogeneity in Senescence Biomarkers and Identifies Rapamycin-Responsive Sub-Populations","authors":"Vijayraghavan Seshadri,&nbsp;Charmaine Chng,&nbsp;Joel Tyler,&nbsp;Cestarangga Adikerta,&nbsp;Kaveh Baghaei,&nbsp;Yan Wang,&nbsp;Nuri Gueven,&nbsp;Sharon Ricardo,&nbsp;Iman Azimi","doi":"10.1111/acel.70209","DOIUrl":"10.1111/acel.70209","url":null,"abstract":"<p>Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-βgal), EdU incorporation, p21 and p16, are used to identify senescent cells, no single biomarker universally defines cellular senescence and current methods often fail to address heterogeneity in biomarker expression levels. This study leverages single-cell fluorescence imaging to assess multiple senescence markers including SA-βgal enzymatic activity, p21 and IL-6 expression and nuclear and cell area in chemotherapy-induced (mitomycin C) and oxidative stress-induced (D-galactose) senescence models in human fibroblasts. Our findings reveal significant heterogeneity in SA-βgal activity and distinct sub-populations within senescent cells. Nuclear and cell area measurements emerged as robust indicators of cellular senescence, displaying similar variability across individual cells. Importantly, we identified specific nuclear area sub-populations that strongly correlate with IL-6 expression levels, demonstrating a relationship between the heterogeneous expression of senescence biomarkers and the SASP. To address this heterogeneity, we introduced an induction threshold method to more accurately quantify the percentage of cells expressing senescence biomarkers. Furthermore, in both senescence models, we observed that rapamycin, a well-known senomorphic agent, selectively targets specific biomarker-expressing sub-populations. This study underscores the value of assessing cellular heterogeneity in senescence research and provides an improved approach for analysing senescence markers in diverse cellular contexts.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR65 Functions as a Key Factor of Bone Aging and a Novel Therapeutic Target for Osteoporosis","authors":"Kun Zhang,&nbsp;Yehua Li,&nbsp;Yi Ren,&nbsp;Yifan He,&nbsp;Jiajun Wang,&nbsp;Xiaoxiu Li,&nbsp;Kefei Guo,&nbsp;Yi Yang,&nbsp;Zhemin Shi,&nbsp;Lina Zheng,&nbsp;Wei Hong","doi":"10.1111/acel.70212","DOIUrl":"10.1111/acel.70212","url":null,"abstract":"<p>Osteoporosis (OP) is a metabolic bone disease, characterized by loss of bone mass and destruction of bone microstructure, which has a high incidence of disability. Identification of the key factors of pathogenesis is essential for diagnosis and therapy. In this study, we have identified the proton-sensing receptor GPR65, which is specifically expressed in osteoclasts and is significantly down-expressed in osteoclast differentiation, aging, ovariectomy (OVX)-, and tail suspension (TS)-induced osteoporotic bone tissue. In vivo experiments confirmed that knockout of GPR65 exacerbates bone loss and OP induced by TS, OVX, and aging. In vitro experiments demonstrated that silencing GPR65 or application of either endogenous or exogenous antagonist of GPR65 promotes osteoclast differentiation, whereas overexpression of GPR65 or application of either endogenous or exogenous agonist inhibits osteoclast differentiation, and knockout of Gpr65 mitigates this effect. Mechanistic studies revealed that GPR65 inhibits osteoclast differentiation by binding to Gαq, activating GSK3β, and suppressing its phosphorylation, thereby inhibiting the nuclear translocation of NFATc1 that mediates osteoclast differentiation. Furthermore, application of GPR65 agonist alleviated OVX-induced OP in vivo, indicating GPR65 as a novel therapeutic target for bone aging and OP.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Normal Ageing Impacts the Extent and Diversity of Neural Plasticity Induced in the Mouse Brain With Repetitive Transcranial Magnetic Stimulation","authors":"Rebecca C. S. Ong,&nbsp;Alexander D. Tang","doi":"10.1111/acel.70206","DOIUrl":"10.1111/acel.70206","url":null,"abstract":"<p>Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain, and where these changes occur in the brain are unknown. Furthermore, it is not known why different rTMS protocols induce different changes in the aged brain, or why rTMS is less effective in older adults compared to younger adults. Using spatial transcriptomics, we uncovered that rTMS primarily acts on genes related to synaptic plasticity in both cortical and subcortical circuits in aged mice, but the specific changes were dependent on the brain region and even down to individual cortical layers in the motor and somatosensory cortices. Comparing our results from aged mice to young adult mice revealed that rTMS acts on a larger variety of neural plasticity mechanisms in the young adult brain, and that rTMS was less effective at altering gene expression related to neural plasticity in the aged brain, but this varied between brain regions and the protocol of rTMS applied. These findings provide a comprehensive map of the mechanisms altered by rTMS across the aged brain and highlight the need to consider the effect of ageing when optimising rTMS protocols for older populations.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70206","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Plasma Metabolomic Profile and Machine Learning-Based Brain Age","authors":"Yang Li,&nbsp;Jiao Wang,&nbsp;Yuyang Miao,&nbsp;Michelle M. Dunk,&nbsp;Yan Liu,&nbsp;Zhongze Fang,&nbsp;Qiang Zhang,&nbsp;Weili Xu","doi":"10.1111/acel.70208","DOIUrl":"10.1111/acel.70208","url":null,"abstract":"<p>Metabolomics has been associated with cognitive decline and dementia, but the relationship between metabolites and brain aging remains unclear. We aimed to investigate the associations of metabolomics with brain age assessed by neuroimaging and to explore whether these relationships vary according to apolipoprotein E (<i>APOE</i>) ε4. This study included 17,770 chronic brain disorder-free participants aged 40–69 years from UK Biobank who underwent neuroimaging scans an average of 9 years after baseline. A total of 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Brain age was estimated using LASSO regression and 1079 brain MRI phenotypes and brain age gap (BAG; i.e., brain age minus chronological age) was calculated. Data were analyzed using linear regression. We identified 64 and 77 metabolites associated with brain age and BAG, respectively, of which 55 overlapped. Lipids (including cholesterol, cholesteryl esters, free cholesterol, phospholipids, and total lipids) in S/M-HDL, as well as phospholipids and triglycerides as a percentage of total lipids in different-density lipoproteins, were associated with larger BAG. The percentages of cholesterol, cholesteryl esters, and free cholesterol to total lipids in VLDL, LDL, and HDL of different particle sizes were associated with smaller BAG. The associations of LA/FA, omega-6/FA, SFA/FA, and phospholipids to total lipids in L-HDL with brain age were consistent across <i>APOE</i> ε4 carriers and non-carriers (all <i>p</i> for interaction &gt; 0.05). Plasma metabolites show remarkably widespread associations with brain aging regardless of <i>APOE</i> ε4 genetic risk. Metabolic profiles could serve as an early indicator of accelerated brain aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}