Pub Date : 2026-01-23DOI: 10.1007/s11357-025-02094-7
Hai-Yan Hou,Ping Wang,Sheng-Ju Guo,Hui-Jie Li
The lateral prefrontal cortex (LPFC) plays a pivotal role in executive functions and exhibits a hierarchical rostro-caudal organization critical for higher-order cognition. Using connectome gradient mapping of resting-state fMRI data across young, middle-aged, and older adults (N = 478), we found preserved global gradient structure but significant compression of the principal gradient in older adults relative to middle-aged adults, particularly in dorsolateral (DLPFC) and frontopolar (FPC) regions. This reduced functional differentiation corresponded to lower spatial separation between LPFC subdivisions. Meta-analytic decoding linked these changes to attenuated engagement of executive functions. Crucially, in an independent cohort of older adults (N = 99), individuals with better executive function exhibited greater gradient range and variation at the global level, along with higher gradient values in the DLPFC and ventrolateral prefrontal cortex (VLPFC) and lower values in the premotor cortex at the regional level. These findings suggest that age-related disruption of LPFC gradient organization may reflect neural dedifferentiation and is closely related to executive decline. Gradient compression in the LPFC may serve as a novel biomarker of cognitive aging, offering insights into the hierarchical reorganization of brain networks in late life.
{"title":"Hierarchical disruption of lateral prefrontal cortex gradients in cognitive aging.","authors":"Hai-Yan Hou,Ping Wang,Sheng-Ju Guo,Hui-Jie Li","doi":"10.1007/s11357-025-02094-7","DOIUrl":"https://doi.org/10.1007/s11357-025-02094-7","url":null,"abstract":"The lateral prefrontal cortex (LPFC) plays a pivotal role in executive functions and exhibits a hierarchical rostro-caudal organization critical for higher-order cognition. Using connectome gradient mapping of resting-state fMRI data across young, middle-aged, and older adults (N = 478), we found preserved global gradient structure but significant compression of the principal gradient in older adults relative to middle-aged adults, particularly in dorsolateral (DLPFC) and frontopolar (FPC) regions. This reduced functional differentiation corresponded to lower spatial separation between LPFC subdivisions. Meta-analytic decoding linked these changes to attenuated engagement of executive functions. Crucially, in an independent cohort of older adults (N = 99), individuals with better executive function exhibited greater gradient range and variation at the global level, along with higher gradient values in the DLPFC and ventrolateral prefrontal cortex (VLPFC) and lower values in the premotor cortex at the regional level. These findings suggest that age-related disruption of LPFC gradient organization may reflect neural dedifferentiation and is closely related to executive decline. Gradient compression in the LPFC may serve as a novel biomarker of cognitive aging, offering insights into the hierarchical reorganization of brain networks in late life.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"275 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021602","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}
Pub Date : 2026-01-22DOI: 10.1007/s11357-025-02085-8
Danmeng Lily Li,Allison M Hodge,Joanne Ryan,Melissa C Southey,Graham G Giles,Roger L Milne,Pierre-Antoine Dugué
Several methylation-based surrogate markers of C-reactive protein (mCRP) have been proposed and used to assess the risk of age-related phenotypes and construct novel ageing markers. We aimed to (i) assess the variance in plasma CRP explained by several mCRP markers; (ii) compare their associations with three health-related traits: mortality, body mass index (BMI), and PCGrimAge; and (iii) assess the stability of CRP and mCRP over a decade. Blood samples were collected from 947 participants in the Melbourne Collaborative Cohort Study at baseline (1990-1994) and wave 2 (2003-2007). High-sensitivity CRP was measured in plasma samples. Five mCRP markers were calculated: mCRP-Ligthart, mCRP-Wielscher, mCRP-EpiScore, mCRP-GrimAge2, and mCRP-Hillary. Intraclass correlation coefficients (ICCs) were calculated to assess the stability of CRP/mCRP between baseline and wave 2. Associations of wave 2 CRP/mCRP with mortality (Ndeaths = 319) were assessed using Cox models and linear regression for BMI and age-adjusted PCGrimAge. mCRP explained 6.0% (mCRP-Wielscher) to 16.8% (mCRP-GrimAge2) of the variance in plasma CRP. The ICCs for CRP and mCRP markers were similar, ranging from 0.44 (mCRP-GrimAge2) to 0.63 (mCRP-Wielscher). Compared with CRP, mCRP had stronger associations with PCGrimAge, whereas for mortality and BMI, the associations were similar or weaker for mCRP. Associations between mCRP and mortality were greatly attenuated after adjusting for PCGrimAge but less so after adjusting for CRP. The association of CRP with mortality remained strong after adjusting for mCRP. Our study validated mCRP markers and clarified the role of CRP and mCRP in ageing, which may inform the use and development of ageing biomarkers.
{"title":"DNA methylation-based surrogate markers of C-reactive protein and their associations with health-related traits.","authors":"Danmeng Lily Li,Allison M Hodge,Joanne Ryan,Melissa C Southey,Graham G Giles,Roger L Milne,Pierre-Antoine Dugué","doi":"10.1007/s11357-025-02085-8","DOIUrl":"https://doi.org/10.1007/s11357-025-02085-8","url":null,"abstract":"Several methylation-based surrogate markers of C-reactive protein (mCRP) have been proposed and used to assess the risk of age-related phenotypes and construct novel ageing markers. We aimed to (i) assess the variance in plasma CRP explained by several mCRP markers; (ii) compare their associations with three health-related traits: mortality, body mass index (BMI), and PCGrimAge; and (iii) assess the stability of CRP and mCRP over a decade. Blood samples were collected from 947 participants in the Melbourne Collaborative Cohort Study at baseline (1990-1994) and wave 2 (2003-2007). High-sensitivity CRP was measured in plasma samples. Five mCRP markers were calculated: mCRP-Ligthart, mCRP-Wielscher, mCRP-EpiScore, mCRP-GrimAge2, and mCRP-Hillary. Intraclass correlation coefficients (ICCs) were calculated to assess the stability of CRP/mCRP between baseline and wave 2. Associations of wave 2 CRP/mCRP with mortality (Ndeaths = 319) were assessed using Cox models and linear regression for BMI and age-adjusted PCGrimAge. mCRP explained 6.0% (mCRP-Wielscher) to 16.8% (mCRP-GrimAge2) of the variance in plasma CRP. The ICCs for CRP and mCRP markers were similar, ranging from 0.44 (mCRP-GrimAge2) to 0.63 (mCRP-Wielscher). Compared with CRP, mCRP had stronger associations with PCGrimAge, whereas for mortality and BMI, the associations were similar or weaker for mCRP. Associations between mCRP and mortality were greatly attenuated after adjusting for PCGrimAge but less so after adjusting for CRP. The association of CRP with mortality remained strong after adjusting for mCRP. Our study validated mCRP markers and clarified the role of CRP and mCRP in ageing, which may inform the use and development of ageing biomarkers.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"30 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021352","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}
Pub Date : 2026-01-21DOI: 10.1007/s11357-026-02108-y
Jorge Quarleri,M Victoria Delpino
{"title":"Is the emerging influenza A(H3N2) K subclade a specific threat for older adults?","authors":"Jorge Quarleri,M Victoria Delpino","doi":"10.1007/s11357-026-02108-y","DOIUrl":"https://doi.org/10.1007/s11357-026-02108-y","url":null,"abstract":"","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"49 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005228","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}
Cerebral small vessel disease (CSVD) significantly contributes to cognitive decline and poses potential risk factors for both dementia and acute cerebrovascular events. Tai Chi has been recognized as an effective mind-body intervention for enhancing cognitive function and promoting neural plasticity. However, the neurobiological mechanisms that underlie how Tai Chi exercises affect cognitive improvement in patients with CSVD remain unclear. We recruited 51 patients with CSVD, randomly assigning them to either a 24-week Tai Chi exercise group (n = 26) or a health education control group (n = 25). We collected and analyzed data on neuropsychological assessments, plasma homocysteine levels, and brain structural and functional connectivity (SC and FC). Additionally, we employed network-based statistics along with correlational and mediation effect analyses to analyze the intervention process. Patients in the intervention group demonstrated a significant improvement in cognitive function. Furthermore, they demonstrated an increased FC pattern in the frontal-parietal-occipital regions, along with a significant rise of structural-functional coupling within the frontal network and a reduction in the occipital network. The enhanced structural-functional coupling in the frontal network partially mediated the reduction in homocysteine levels and the improvement in cognitive function.
{"title":"Tai Chi modulating multimodal connectivity patterns and cognitive function in cerebral small vessel disease.","authors":"Xiaoyong Zhong,Zhongpeng Dai,Liuxi Chu,Hongliang Zhou,Wanqing Lin,Bin Chen","doi":"10.1007/s11357-026-02106-0","DOIUrl":"https://doi.org/10.1007/s11357-026-02106-0","url":null,"abstract":"Cerebral small vessel disease (CSVD) significantly contributes to cognitive decline and poses potential risk factors for both dementia and acute cerebrovascular events. Tai Chi has been recognized as an effective mind-body intervention for enhancing cognitive function and promoting neural plasticity. However, the neurobiological mechanisms that underlie how Tai Chi exercises affect cognitive improvement in patients with CSVD remain unclear. We recruited 51 patients with CSVD, randomly assigning them to either a 24-week Tai Chi exercise group (n = 26) or a health education control group (n = 25). We collected and analyzed data on neuropsychological assessments, plasma homocysteine levels, and brain structural and functional connectivity (SC and FC). Additionally, we employed network-based statistics along with correlational and mediation effect analyses to analyze the intervention process. Patients in the intervention group demonstrated a significant improvement in cognitive function. Furthermore, they demonstrated an increased FC pattern in the frontal-parietal-occipital regions, along with a significant rise of structural-functional coupling within the frontal network and a reduction in the occipital network. The enhanced structural-functional coupling in the frontal network partially mediated the reduction in homocysteine levels and the improvement in cognitive function.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"35 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015154","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}
Pub Date : 2026-01-19DOI: 10.1007/s11357-025-02047-0
Nicholas A Carlini,Bradley A Ruple,Helya Rostamkhani,Huihui Shi,J Alan Maschek,Brady E Hanson,Namakkal Soorappan Rajasekaran,Russell S Richardson,Micah J Drummond,Ryan M Broxterman,Joel D Trinity
Aging changes the lipidome and mitochondrial function in a sex-dependent manner, yet their associations remain poorly understood. Twenty-four younger (7M/17F) and forty-three older (21M/22F) adults underwent blood draws and skeletal muscle biopsies for this cross-sectional investigation. Plasma lipidomic profiling was performed via liquid chromatography-tandem mass spectrometry, while peak mitochondrial O2 utilization (OXPHOS) and hydrogen peroxide (H2O2) emission were assessed using high-resolution respirometry. Plasma lipidomic analysis annotated 535 lipid species across 28 different lipid classes. Lipid-age associations were identified in four lipid classes for both sexes with twelve lipid classes demonstrating sex-specific associations, including triglycerides (TG), carnitines (CAR), and fatty acids (FA). For lipid-OXPHOS interactions, the primary lipid class and species associated with higher OXPHOS exclusively in males were ceramides (CER) and dimethyl cholesterol esters (dimethyl-CE), while TG were the primary lipid species associated with impaired OXPHOS in females. For lipid-H2O2 interactions, the primary lipid class and species associated with higher H2O2 were methyl desmosteryl esters (methyl-DE), methyl cholesterol esters (methyl-CE), FA and TG in males whereas females exhibited 10 (CE, SM, LPC, dihexosylceramides (Hex2Cer), LPE, PI, HexCer, LPI, CAR, and hexosyl-N-acetylneuraminyl-ceramides (Hex2NeuAcCer)) lipid classes associated exclusively with H2O2 emission. These findings establish novel age- and sex-specific relationships between age-related changes in plasma lipids and skeletal muscle mitochondrial function, revealing distinct lipid signatures for respiration and H2O2 emission in males and females.
衰老以性别依赖的方式改变脂质组和线粒体功能，但它们之间的关联仍然知之甚少。24名年轻人（7米/17层）和43名老年人（21米/22层）接受了抽血和骨骼肌活检。通过液相色谱-串联质谱法进行血浆脂质组学分析，同时使用高分辨率呼吸仪评估线粒体O2利用率（OXPHOS）和过氧化氢（H2O2）排放峰值。血浆脂质组学分析注释了28个不同脂类的535种脂质。在两性的四类脂质中发现了脂质年龄相关性，其中有十二类脂质显示出性别特异性相关性，包括甘油三酯（TG）、肉碱（CAR）和脂肪酸（FA）。在脂质-OXPHOS相互作用中，仅在男性中与较高OXPHOS相关的主要脂类和种类是神经酰胺（CER）和二甲基胆固醇酯（dimethyl- ce），而在女性中与OXPHOS受损相关的主要脂类是TG。对于脂质-H2O2相互作用，与较高H2O2相关的主要脂类和种类是雄性的甲基去氨酯（甲基- de）、甲基胆固醇酯（甲基-CE）、FA和TG，而雌性则表现出10种（CE、SM、LPC、二己基神经酰胺（Hex2Cer）、LPE、PI、HexCer、LPI、CAR和己基- n -乙酰神经酰胺（Hex2NeuAcCer））脂类，它们只与H2O2排放相关。这些发现在年龄相关的血浆脂质变化和骨骼肌线粒体功能之间建立了新的年龄和性别特异性关系，揭示了男性和女性呼吸和H2O2排放的不同脂质特征。
{"title":"Age and sex shape plasma lipid associations to skeletal muscle mitochondrial respiration and H2O2 emission.","authors":"Nicholas A Carlini,Bradley A Ruple,Helya Rostamkhani,Huihui Shi,J Alan Maschek,Brady E Hanson,Namakkal Soorappan Rajasekaran,Russell S Richardson,Micah J Drummond,Ryan M Broxterman,Joel D Trinity","doi":"10.1007/s11357-025-02047-0","DOIUrl":"https://doi.org/10.1007/s11357-025-02047-0","url":null,"abstract":"Aging changes the lipidome and mitochondrial function in a sex-dependent manner, yet their associations remain poorly understood. Twenty-four younger (7M/17F) and forty-three older (21M/22F) adults underwent blood draws and skeletal muscle biopsies for this cross-sectional investigation. Plasma lipidomic profiling was performed via liquid chromatography-tandem mass spectrometry, while peak mitochondrial O2 utilization (OXPHOS) and hydrogen peroxide (H2O2) emission were assessed using high-resolution respirometry. Plasma lipidomic analysis annotated 535 lipid species across 28 different lipid classes. Lipid-age associations were identified in four lipid classes for both sexes with twelve lipid classes demonstrating sex-specific associations, including triglycerides (TG), carnitines (CAR), and fatty acids (FA). For lipid-OXPHOS interactions, the primary lipid class and species associated with higher OXPHOS exclusively in males were ceramides (CER) and dimethyl cholesterol esters (dimethyl-CE), while TG were the primary lipid species associated with impaired OXPHOS in females. For lipid-H2O2 interactions, the primary lipid class and species associated with higher H2O2 were methyl desmosteryl esters (methyl-DE), methyl cholesterol esters (methyl-CE), FA and TG in males whereas females exhibited 10 (CE, SM, LPC, dihexosylceramides (Hex2Cer), LPE, PI, HexCer, LPI, CAR, and hexosyl-N-acetylneuraminyl-ceramides (Hex2NeuAcCer)) lipid classes associated exclusively with H2O2 emission. These findings establish novel age- and sex-specific relationships between age-related changes in plasma lipids and skeletal muscle mitochondrial function, revealing distinct lipid signatures for respiration and H2O2 emission in males and females.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"22 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994947","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}
The interaction between nuclear (nDNA) and mitochondrial DNA (mtDNA) methylation is not well known in the healthy population. The D-loop methylation level of the Olympic champions (N = 58) was significantly lower than that of non-champions (N = 32) (~ 36% unadjusted mean difference p = 0.016, sex and age adjusted p = 0.017). Interestingly, the robust linear analysis revealed that biological sex is a significant factor in mtDNA D-loop methylation (estimate = 1.521, p = 0.033). On the other hand, we cannot find relationships between the methylation levels of mtDNA and nuclear DNA, suggesting distinct regulation of the methylation/demethylation process of mtDNA and nuclear DNA. DNA methylation-based aging clocks showed a significant relationship with the levels of Klotho, irisin, and its receptor (irisin receptor integrin alpha-V), as well as with epigenetic regulators such as ten-eleven translocation enzyme 2, which were measured using enzyme-linked immunosorbent assay. Therefore, the data suggest a complex regulatory process of epigenetic aging and raise the possibility that D-loop methylation may have functional relevance in health, which remains to be explored.
{"title":"Epigenetic insights of Olympic champions: nuclear and mitochondrial DNA methylation and regulators of aging.","authors":"Timea Teglas,Ferenc Torma,Zoltan Bori,Dora Aczel,Gergely Babszky,Takuji Kawamura,Mitsuru Higuchi,Gu Yaodong,Muhammad Lee,Steve Horvath,Zsolt Radak","doi":"10.1007/s11357-025-02092-9","DOIUrl":"https://doi.org/10.1007/s11357-025-02092-9","url":null,"abstract":"The interaction between nuclear (nDNA) and mitochondrial DNA (mtDNA) methylation is not well known in the healthy population. The D-loop methylation level of the Olympic champions (N = 58) was significantly lower than that of non-champions (N = 32) (~ 36% unadjusted mean difference p = 0.016, sex and age adjusted p = 0.017). Interestingly, the robust linear analysis revealed that biological sex is a significant factor in mtDNA D-loop methylation (estimate = 1.521, p = 0.033). On the other hand, we cannot find relationships between the methylation levels of mtDNA and nuclear DNA, suggesting distinct regulation of the methylation/demethylation process of mtDNA and nuclear DNA. DNA methylation-based aging clocks showed a significant relationship with the levels of Klotho, irisin, and its receptor (irisin receptor integrin alpha-V), as well as with epigenetic regulators such as ten-eleven translocation enzyme 2, which were measured using enzyme-linked immunosorbent assay. Therefore, the data suggest a complex regulatory process of epigenetic aging and raise the possibility that D-loop methylation may have functional relevance in health, which remains to be explored.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"29 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993036","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}
Pub Date : 2026-01-17DOI: 10.1007/s11357-025-02076-9
Menno Van Damme,Sanne Stegen,Bram Steenwinckel,Helene Schroé,Gustavo A Reyes Del Paso,Matias M Pulopulos,Rudi De Raedt,Marie-Anne Vanderhasselt,Wim Derave,Femke Ongenae,Jan Boone,Wim Van Criekinge,Ernst R Rietzschel,Tim De Meyer
Epigenetic clocks are emerging as promising biomarkers of biological aging, yet their sensitivity to short-term interventions remains unclear. This pilot study investigates whether the GrimAge clock can capture the effects of a 6-month cycling-based endurance exercise training intervention, with cardiorespiratory fitness (VO2 max) and body composition as primary outcomes. We enrolled 42 adults aged 35-65, of whom 38 completed the study and 33 adhered to the protocol (> 66% adherence). Participants demonstrated significant improvements in VO2 max (+ 20%, P < 0.001) and body composition (P < 0.001). High-quality epigenetic data preprocessing yielded highly reproducible GrimAge estimates (< 2 months measurement error), which strongly correlated with chronological age (R2 = 0.86, P < 0.001). On average, GrimAge decreased by 7.44 months relative to the expected trajectory (P = 0.012), reflecting improvements in VO2 max (R2 = 0.27, P = 0.002) but not body composition changes. Notably, GrimAge changes strongly correlated with fluctuations in leukocyte composition, particularly neutrophil fraction (R2 = 0.74, P < 0.001). Adjusting for leukocyte composition improved consistency in GrimAge changes, aligning them with additional intervention outcomes and explaining up to 81% of variance. These findings demonstrate that GrimAge is responsive to short-term endurance training, serving as a meaningful biomarker of improved cardiorespiratory fitness, while also capturing immune system variability. This study supports the use of GrimAge in evaluating longevity interventions and highlights the importance of accounting for leukocyte composition in epigenetic aging research.
表观遗传时钟正在成为生物衰老的有前途的生物标志物，但它们对短期干预的敏感性尚不清楚。本初步研究以心肺功能（最大摄氧量）和身体成分为主要指标，调查GrimAge时钟是否能捕捉6个月周期耐力运动训练干预的效果。我们招募了42名年龄在35-65岁之间的成年人，其中38人完成了研究，33人遵守了方案（bbb66%的依从性）。参与者的最大摄氧量（+ 20%,P < 0.001）和身体成分（P < 0.001）均有显著改善。高质量的表观遗传数据预处理产生了高度可重复的GrimAge估计（< 2个月测量误差），其与实足年龄密切相关（R2 = 0.86, P < 0.001）。平均而言，GrimAge相对于预期轨迹减少了7.44个月（P = 0.012），反映了最大摄氧量的改善（R2 = 0.27, P = 0.002），但没有反映身体成分的变化。值得注意的是，GrimAge变化与白细胞组成，特别是中性粒细胞部分的波动密切相关（R2 = 0.74, P < 0.001）。调整白细胞组成提高了GrimAge变化的一致性，使其与其他干预结果一致，并解释了高达81%的差异。这些发现表明GrimAge对短期耐力训练有反应，作为改善心肺健康的有意义的生物标志物，同时也捕获免疫系统变异性。这项研究支持使用GrimAge来评估长寿干预措施，并强调了在表观遗传衰老研究中考虑白细胞组成的重要性。
{"title":"Epigenetic age deceleration reflects exercise-induced cardiorespiratory fitness improvements.","authors":"Menno Van Damme,Sanne Stegen,Bram Steenwinckel,Helene Schroé,Gustavo A Reyes Del Paso,Matias M Pulopulos,Rudi De Raedt,Marie-Anne Vanderhasselt,Wim Derave,Femke Ongenae,Jan Boone,Wim Van Criekinge,Ernst R Rietzschel,Tim De Meyer","doi":"10.1007/s11357-025-02076-9","DOIUrl":"https://doi.org/10.1007/s11357-025-02076-9","url":null,"abstract":"Epigenetic clocks are emerging as promising biomarkers of biological aging, yet their sensitivity to short-term interventions remains unclear. This pilot study investigates whether the GrimAge clock can capture the effects of a 6-month cycling-based endurance exercise training intervention, with cardiorespiratory fitness (VO2 max) and body composition as primary outcomes. We enrolled 42 adults aged 35-65, of whom 38 completed the study and 33 adhered to the protocol (> 66% adherence). Participants demonstrated significant improvements in VO2 max (+ 20%, P < 0.001) and body composition (P < 0.001). High-quality epigenetic data preprocessing yielded highly reproducible GrimAge estimates (< 2 months measurement error), which strongly correlated with chronological age (R2 = 0.86, P < 0.001). On average, GrimAge decreased by 7.44 months relative to the expected trajectory (P = 0.012), reflecting improvements in VO2 max (R2 = 0.27, P = 0.002) but not body composition changes. Notably, GrimAge changes strongly correlated with fluctuations in leukocyte composition, particularly neutrophil fraction (R2 = 0.74, P < 0.001). Adjusting for leukocyte composition improved consistency in GrimAge changes, aligning them with additional intervention outcomes and explaining up to 81% of variance. These findings demonstrate that GrimAge is responsive to short-term endurance training, serving as a meaningful biomarker of improved cardiorespiratory fitness, while also capturing immune system variability. This study supports the use of GrimAge in evaluating longevity interventions and highlights the importance of accounting for leukocyte composition in epigenetic aging research.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"56 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145993035","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}
Pub Date : 2026-01-16DOI: 10.1007/s11357-025-02078-7
Sagar Vyavahare,Ford Berger,Shelton G Swint,Bharati Mendhe,Mansi Shukla,Ian Duchesne,Roger Zhong,Marion A Cooley,Meghan E McGee-Lawrence,Carlos M Isales,Jessica M Hoffman,Sadanand Fulzele
Aging is associated with alterations in endogenous tryptophan (TRP) metabolism that contributes to musculoskeletal decline. In this study, we investigated the effects of the microbiota-derived TRP metabolite, indole-3-propionic acid (IPA), on musculoskeletal health in aged mice and lifespan in Drosophila melanogaster. Aged C57BL/6 mice received IPA (20 mg/kg, subcutaneous, three times per week for 12 weeks), while Drosophila were maintained on food supplemented with IPA (100 µM) throughout their lifespan. Our findings revealed that IPA-treated aged mice exhibited enhanced muscle function (grip strength and hang time). Histological and bone microCT analyses revealed no changes in muscle fiber size but enhanced bone microarchitecture. Furthermore, molecular studies have elucidated that IPA treatment prevents oxidative stress and reduces senescence, indicating improved cellular survival. Our Drosophila melanogaster longevity analysis revealed a significant extension of lifespan, but lifespan effects were genotype- and sex-specific. Collectively, our findings identify IPA as a promising microbiota-derived metabolite that improves musculoskeletal health and promotes longevity, highlighting its potential as a therapeutic intervention for age-related decline in function.
{"title":"Microbiota-derived indole-3-propionic acid extends lifespan in Drosophila and improves muscle and bone health in mice.","authors":"Sagar Vyavahare,Ford Berger,Shelton G Swint,Bharati Mendhe,Mansi Shukla,Ian Duchesne,Roger Zhong,Marion A Cooley,Meghan E McGee-Lawrence,Carlos M Isales,Jessica M Hoffman,Sadanand Fulzele","doi":"10.1007/s11357-025-02078-7","DOIUrl":"https://doi.org/10.1007/s11357-025-02078-7","url":null,"abstract":"Aging is associated with alterations in endogenous tryptophan (TRP) metabolism that contributes to musculoskeletal decline. In this study, we investigated the effects of the microbiota-derived TRP metabolite, indole-3-propionic acid (IPA), on musculoskeletal health in aged mice and lifespan in Drosophila melanogaster. Aged C57BL/6 mice received IPA (20 mg/kg, subcutaneous, three times per week for 12 weeks), while Drosophila were maintained on food supplemented with IPA (100 µM) throughout their lifespan. Our findings revealed that IPA-treated aged mice exhibited enhanced muscle function (grip strength and hang time). Histological and bone microCT analyses revealed no changes in muscle fiber size but enhanced bone microarchitecture. Furthermore, molecular studies have elucidated that IPA treatment prevents oxidative stress and reduces senescence, indicating improved cellular survival. Our Drosophila melanogaster longevity analysis revealed a significant extension of lifespan, but lifespan effects were genotype- and sex-specific. Collectively, our findings identify IPA as a promising microbiota-derived metabolite that improves musculoskeletal health and promotes longevity, highlighting its potential as a therapeutic intervention for age-related decline in function.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"29 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971849","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}
Metacontrol, the ability to adapt cognitive control to task demands, declines with age and is thought to be reflected in aperiodic and periodic neural dynamics. Given that anodal transcranial direct current stimulation (atDCS) can modulate cortical excitability via membrane potential shifts, we tested whether atDCS alters the neurophysiological signatures of metacontrol in younger and older adults. In a mixed design, younger and older participants performed a Go/Nogo task under both atDCS and sham stimulation conditions; resting-state EEG data were also acquired. Aperiodic activity was analyzed using the FOOOF algorithm, and periodic activity was examined through time-frequency analysis. Behaviorally, younger adults showed higher accuracy and faster responses than older adults, but no significant stimulation effects emerged in either group. Results showed that, compared to sham, aperiodic activity (FOOOF exponent) increased after atDCS, particularly in older adults, indicating a steepening of the EEG spectrum and thus increased inhibitory tone in the aging process. However, resting-state aperiodic activity did not predict stimulation-induced effects within either group. In the periodic domain, we found no evidence that atDCS modulated task-related theta or alpha power. Moreover, exploratory analyses revealed no significant associations between atDCS-induced changes in the aperiodic exponent and oscillatory power. This dissociation indicates that, under the present conditions, the periodic and aperiodic components of the EEG signal reflect distinct and likely independent neurophysiological responses to neuromodulation. Targeting metacontrol mechanisms through neuromodulation may, with further validation, open new avenues for supporting cognitive health in older adults.
{"title":"Metacontrol-related aperiodic and periodic neural activity in cognitive aging: enhancing the neural signal-to-noise ratio through anodal transcranial direct current stimulation.","authors":"Yu Pi,Qinfei Zhang,Shuhui Lyu,Christian Beste,Lorenza Colzato,Bernhard Hommel","doi":"10.1007/s11357-025-02077-8","DOIUrl":"https://doi.org/10.1007/s11357-025-02077-8","url":null,"abstract":"Metacontrol, the ability to adapt cognitive control to task demands, declines with age and is thought to be reflected in aperiodic and periodic neural dynamics. Given that anodal transcranial direct current stimulation (atDCS) can modulate cortical excitability via membrane potential shifts, we tested whether atDCS alters the neurophysiological signatures of metacontrol in younger and older adults. In a mixed design, younger and older participants performed a Go/Nogo task under both atDCS and sham stimulation conditions; resting-state EEG data were also acquired. Aperiodic activity was analyzed using the FOOOF algorithm, and periodic activity was examined through time-frequency analysis. Behaviorally, younger adults showed higher accuracy and faster responses than older adults, but no significant stimulation effects emerged in either group. Results showed that, compared to sham, aperiodic activity (FOOOF exponent) increased after atDCS, particularly in older adults, indicating a steepening of the EEG spectrum and thus increased inhibitory tone in the aging process. However, resting-state aperiodic activity did not predict stimulation-induced effects within either group. In the periodic domain, we found no evidence that atDCS modulated task-related theta or alpha power. Moreover, exploratory analyses revealed no significant associations between atDCS-induced changes in the aperiodic exponent and oscillatory power. This dissociation indicates that, under the present conditions, the periodic and aperiodic components of the EEG signal reflect distinct and likely independent neurophysiological responses to neuromodulation. Targeting metacontrol mechanisms through neuromodulation may, with further validation, open new avenues for supporting cognitive health in older adults.","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":"4 1","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986575","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}
Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation may drive structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.
{"title":"Lipid-laden endothelial cells exhibit a transcriptomic signature linked to blood-brain barrier dysfunction, metabolic reprogramming, and increased inflammation in the aging brain.","authors":"Sarah Otu-Boakye, Duraipandy Natarajan, Bhuvana Plakkot, Ilakiya Raghavendiran, Paulina Hoppa, Tamas Kiss, Madhan Subramanian, Priya Balasubramanian","doi":"10.1007/s11357-025-01986-y","DOIUrl":"10.1007/s11357-025-01986-y","url":null,"abstract":"<p><p>Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation may drive structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.</p>","PeriodicalId":12730,"journal":{"name":"GeroScience","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989201","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}
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