Aging Cell最新文献

{"title":"Enhanced Microglial Engulfment of Dopaminergic Synapses Induces Parkinson's Disease-Related Executive Dysfunction in an Acute LPC Infusion Targeting the mPFC.","authors":"Yehao Liu, Rui Chen, Chunyan Mu, Junjie Diao, Yurong Guo, Xiaoyu Yao, Shijie Shi, Mengying Wang, Zhi Zhang, Xiaoling Qin, Chuanxi Tang","doi":"10.1111/acel.70003","DOIUrl":"https://doi.org/10.1111/acel.70003","url":null,"abstract":"<p><p>The dysfunction of the dopaminergic projection from the ventral tegmental area (VTA) to the medial prefrontal cortex (mPFC) is believed to play a key role in the pathophysiology of Parkinson's disease (PD) accompanied by executive dysfunction (EDF). In this study, we identified an abnormal increase in lysophosphatidylcholine (LPC) levels in PD patients, which closely correlates with the severity of cognitive impairment. LPC disrupts the miR-2885/TDP-43 signaling pathway in microglia, driving dopaminergic presynaptic engulfment. In LPC-exposed mice, microglial activation via miR-2885/TDP-43/p65 signaling led to inflammatory cytokine and complement release, marking dopaminergic synapses for phagocytosis with a \"PS/C1q\" signal. Following the inhibition of LPC-induced microglial activation through chemogenetic methods, we observed a significant reduction in the phagocytosis of dopaminergic synapses, resulting in improved executive function. The miR-2885 disrupted LPC-induced dopaminergic phagocytosis and alleviated EDF. Furthermore, the accumulation of excessive TDP-43 due to the loss of miR-2885 promoted the engulfment of dopaminergic synapses by facilitating the entry of p65 into the nucleus. Inhibiting TDP-43 levels effectively mitigated LPC-induced EDF. Additionally, supplementing dopamine receptor agonists enhanced the excitability of regional glutamatergic neurons, leading to improved executive function. In summary, LPC exposure in the mPFC impairs microglial regulation, leading to dopaminergic synaptic loss and underactivity of glutamatergic neurons. These changes drive the development of executive dysfunction in PD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70003"},"PeriodicalIF":8.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptional Heterogeneity and Differential Response of Rod Photoreceptor Pathway Uncovered by Single-Cell RNA Sequencing of the Aging Mouse Retina.","authors":"Laura Campello, Matthew J Brooks, Benjamin R Fadl, Hyo Sub Choi, Soumitra Pal, Anand Swaroop","doi":"10.1111/acel.70001","DOIUrl":"https://doi.org/10.1111/acel.70001","url":null,"abstract":"<p><p>Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in the retina, the light-sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are still poorly understood, highlighting the need to identify biomarkers for better prognosis and alleviation of aging-associated vision impairment. Here, we investigate dynamics of transcriptional dysregulation in the retina and identify affected pathways within distinct retinal cell types. Using an optimized protocol for single-cell RNA sequencing of mouse retinas at 3, 12, 18, and 24 months, we detect a progressive increase in the number of differentially expressed genes across all retinal cell types. The extent and direction of expression changes varies, with photoreceptor, bipolar, and Müller cells showing the maximum number of differentially expressed genes at all age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations of rod photoreceptors and bipolar cells, distributed across distinct areas of the retina. Our findings provide a plausible molecular explanation for enhanced susceptibility of rod cells to aging and correlate with the observed loss of scotopic sensitivity in elderly individuals.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70001"},"PeriodicalIF":8.0,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Healthy Aging Metabolomic and Proteomic Signatures Across Multiple Physiological Compartments.","authors":"R Moaddel, J Candia, C Ubaida-Mohien, T Tanaka, A Z Moore, M Zhu, G Fantoni, S Church, J D'Agostino, J Fan, N Shehadeh, S De, E Lehrmann, M Kaileh, E Simonsick, R Sen, J M Egan, L Ferrucci","doi":"10.1111/acel.70014","DOIUrl":"https://doi.org/10.1111/acel.70014","url":null,"abstract":"<p><p>The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to recognize that aging pervasively affects the whole body. The simultaneous modeling of hundreds of metabolites and proteins across multiple compartments may provide a more detailed picture of healthy aging and point to differences between chronological and biological aging. Herein, we report proteomic analyses of plasma and urine collected in healthy men and women, age 22-92 years. Using these data, we developed a series of metabolomic and proteomic predictors of chronological age for plasma, urine, and skeletal muscle. We then defined a biological aging score, which measures the departure between an individual's predicted age and the expected predicted age for that individual based on the full cohort. We show that these predictors are significantly and independently related to clinical phenotypes important for aging, such as inflammation, iron deficiency anemia, muscle mass, and renal and hepatic functions. Despite a different set of selected biomarkers in each compartment, the different scores reflect a similar degree of deviation from healthy aging in single individuals, thus allowing identification of subjects with significant accelerated or decelerated biological aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70014"},"PeriodicalIF":8.0,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling Alveolar Fibroblast and Activated Myofibroblast Heterogeneity and Differentiation Trajectories During Lung Fibrosis Development and Resolution in Young and Old Mice.","authors":"Arun Lingampally, Marin Truchi, Xianrong Shi, Yuqing Zhou, Esmeralda Vasquez-Pacheco, Georgios-Dimitrios Panagiotidis, Stefan Hadzic, Janine Koepke, Ana Ivonne Vazquez-Armendariz, Susanne Herold, Christos Samakovlis, Hector A Cabrera-Fuentes, Xuran Chu, Werner Seeger, Jin-San Zhang, Elie El Agha, Bernard Mari, Saverio Bellusci, Chengshui Chen","doi":"10.1111/acel.14503","DOIUrl":"https://doi.org/10.1111/acel.14503","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is an age-associated disease characterized by the irreversible accumulation of excessive extracellular matrix components by activated myofibroblasts (aMYFs). Following bleomycin administration in young mice, fibrosis formation associated with efficient resolution takes place limiting the clinical relevance of this model for IPF. In this study, we used aged mice in combination with bleomycin administration to trigger enhanced fibrosis formation and delayed resolution as a more relevant model for IPF. Alveolosphere assays were carried out to compare the alveolar resident mesenchymal niche activity for AT2 stem cells in young versus old mice. Lineage tracing of the Acta2+ aMYFs in old mice exposed to bleomycin followed by scRNAseq of the lineage-traced cells isolated during fibrosis formation and resolution was performed to delineate the heterogeneity of aMYFs during fibrosis formation and their fate during resolution. Integration of previously published similar scRNAseq results using young mice was carried out. Our results show that alveolar resident mesenchymal cells from old mice display decreased supporting activity for AT2 stem cells. Our findings suggest that the cellular and molecular mechanisms underlying the aMYFs formation and differentiation towards the Lipofibroblast phenotype are mostly conserved between young and old mice. In addition to persistent fibrotic signaling in aMYF from old mice during resolution, we also identified differences linked to interleukin signaling in old versus young alveolar fibroblast populations before and during bleomycin injury. Importantly, our work confirms the relevance of a subcluster of aMYFs in old mice that is potentially relevant for future management of IPF.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14503"},"PeriodicalIF":8.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Negative Effect of Gst-35 on the Health Span of Caenorhabditis elegans Through Lysosomal Dysfunction via the Pmk-1 and Skr Genes.","authors":"Yehui Gao, Xinyun Zhang, Congmin Wei, Hongru Lin, Mengchen Wu, Botian Ma, Jinyun Jiang, Shan Li, Hongbing Wang","doi":"10.1111/acel.70016","DOIUrl":"https://doi.org/10.1111/acel.70016","url":null,"abstract":"<p><p>As global life expectancy increases, the focus has shifted from merely extending lifespan to promoting healthy aging. GSTA1, GSTA2, and GSTA3 (GSTA1-3), members of the alpha class of glutathione S-transferases, are involved in diverse biological processes, including metabolism and immune regulation, highlighting their potential influence on human health span and lifespan. In this study, we employed Caenorhabditis elegans as a model organism to investigate the role of gst-35, an ortholog of mammalian GSTA1-3, in healthy aging. Our results demonstrated that gst-35 overexpression has detrimental effects on multiple physiological functions in nematodes. Specifically, gst-35 overexpression significantly reduced lifespan, impaired development and growth, and substantially diminished reproductive capacity, physical fitness, and stress resistance. In contrast, gst-35 knockout partially enhanced physical fitness and stress resistance. Comprehensive RNA-sequencing transcriptome analysis revealed that gst-35 overexpression disrupted metabolic homeostasis and induced lysosomal dysfunction. These effects were mediated through the activation of the pmk-1 signaling pathway and suppression of skr genes, which collectively impaired healthy aging processes. These findings illuminate the complex role of gst-35 in aging and provide valuable insights into the molecular mechanisms underlying healthy aging, offering potential targets for interventions aimed at promoting health span.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70016"},"PeriodicalIF":8.0,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and Pharmacological Inhibition of Metabotropic Glutamate Receptor Signalling Extends Lifespan in Drosophila.","authors":"Cui Guan, Abigail Otchere, Mihails Laskovs, Irene Papatheodorou, Cathy Slack","doi":"10.1111/acel.14500","DOIUrl":"https://doi.org/10.1111/acel.14500","url":null,"abstract":"<p><p>Invertebrate models have been instrumental in advancing our understanding of the molecular mechanisms of ageing. The isolation of single gene mutations that both extend lifespan and improve age-related health have identified potential targets for therapeutic intervention to alleviate age-related morbidity. Here, we find that genetic loss of function of the G protein-coupled metabotropic glutamate receptor (DmGluRA) in Drosophila extends the lifespan of female flies. This longevity phenotype was accompanied by lower basal levels of oxidative stress and improved stress tolerance, and differences in early-life behavioural markers. Gene expression changes in DmGluRA mutants identified reduced ribosome biogenesis, a hallmark of longevity, as a key process altered in these animals. We further show that the pro-longevity effects of reduced DmGluRA signalling are dependent on the fly homologue of Fragile X Mental Retardation Protein (FMRP), an important regulator of ribosomal protein translation. Importantly, we can recapitulate lifespan extension using a specific pharmacological inhibitor of mGluR activity. Hence, our study identifies metabotropic glutamate receptors as potential targets for age-related therapeutics.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14500"},"PeriodicalIF":8.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic Hevin/SPARCL-1 Regulates Cognitive Decline in Pathological and Normal Brain Aging.","authors":"Felipe Cabral-Miranda, Ana Paula Bergamo Araujo, Danilo Bilches Medinas, Flávia Carvalho Alcantara Gomes","doi":"10.1111/acel.14493","DOIUrl":"https://doi.org/10.1111/acel.14493","url":null,"abstract":"<p><p>Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of Aβ plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression. In conclusion, our results propose astrocytic Hevin as a potential therapeutic target for age-associated cognitive decline.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14493"},"PeriodicalIF":8.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduction of DNA Topoisomerase Top2 Reprograms the Epigenetic Landscape and Extends Health and Life Span Across Species.","authors":"Man Zhu, Meng Ma, Lunan Luo, Feiyang Li, Jiashun Zheng, Yan Pan, Lu Yang, Ying Xiao, Ziyan Wang, Bo Xian, Yi Zheng, Hao Li, Jing Yang","doi":"10.1111/acel.70010","DOIUrl":"https://doi.org/10.1111/acel.70010","url":null,"abstract":"<p><p>DNA topoisomerases are essential molecular machines that manage DNA topology in the cell and play important roles in DNA replication and transcription. We found that knocking down the enzyme topoisomerase Top2 or its mammalian homolog TOP2B increases the lifespan of S. cerevisiae, C. elegans, and mice. TOP2B reduction also extends the health span of mice and alleviates the pathologies of aging in multiple tissues. At the cellular/molecular level, TOP2B reduction alleviates the major hallmarks of aging, including senescence, DNA damage, and deregulated nutrient sensing. We observed that TOP2B reduction changes the epigenetic landscape of various tissues in old mice toward that of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 reduction confers pro-longevity effect across species possibly through a conserved mechanism and may be a promising strategy for longevity intervention.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70010"},"PeriodicalIF":8.0,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Citrate Supplementation Mitigates Age-Associated Pathologic Intervertebral Disc Calcification in LG/J Mice.","authors":"Olivia K Ottone, Jorge J Mundo, Boahen N Kwakye, Amber Slaweski, John A Collins, Qinglin Wu, Margery A Connelly, Fatemeh Niaziorimi, Koen van de Wetering, Makarand V Risbud","doi":"10.1111/acel.14504","DOIUrl":"10.1111/acel.14504","url":null,"abstract":"<p><p>Despite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. We investigated the efficacy of long-term oral K₃Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K₃Citrate reduced the incidence of disc calcification without affecting the vertebral bone structure, knee calcification, plasma chemistry, or locomotion in LG/J mice. Notably, a positive effect on grip strength was evident in treated mice. FTIR spectroscopy of the persisting calcified nodules indicated K₃Citrate did not alter the mineral composition. Mechanistically, activation of an endochondral differentiation in the cartilaginous endplates and nucleus pulposus (NP) compartment contributed to LG/J disc calcification. Importantly, K₃Citrate reduced calcification incidence by Ca²⁺ chelation throughout the disc while exhibiting a differential effect on NP and endplate cell differentiation. In the NP compartment, K₃Citrate reduced the NP cell acquisition of a hypertrophic chondrocytic fate, but the pathologic endochondral program was unimpacted in the endplates. Overall, this study for the first time shows the therapeutic potential of oral K₃Citrate as a systemic intervention strategy to ameliorate disc calcification.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14504"},"PeriodicalIF":8.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures.","authors":"Fang Yu, Changhan Chen, Wuping Liu, Zhixiang Zhao, Yuhua Fan, Zhenjiang Li, Weilun Huang, Tingting Xie, Cheng Luo, Zhouzhou Yao, Qi Guo, Zhiyu Yang, Juan Liu, Yujin Zhang, Rodney E Kellems, Jian Xia, Ji Li, Yang Xia","doi":"10.1111/acel.14482","DOIUrl":"https://doi.org/10.1111/acel.14482","url":null,"abstract":"<p><p>Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that \"rejuvenation molecules\" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward Rapoport-Luebering Shunt to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals. As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function. Overall, we identified that youthful erythrocyte function and metabolism enable longevity individuals to better counteract peripheral tissue hypoxia, inflammation, and oxidative stress, thus maintaining healthspan.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14482"},"PeriodicalIF":8.0,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}