Aging Cell最新文献

{"title":"Senescence landscape in the liver following sepsis and senolytics as potential therapeutics.","authors":"Rupa Lavarti, Lun Cai, Tatiana Alvarez‐Diaz, Thalia Medina‐Rodriguez, Sergei Bombin, Raghavan Pillai Raju","doi":"10.1111/acel.14354","DOIUrl":"10.1111/acel.14354","url":null,"abstract":"<p><p>Senescence, caused by cell-cycle arrest, is a hallmark of aging. Senescence has also been described in embryogenesis, wound healing, and acute injuries. Sepsis is characterized by a dysregulated host response to infection, leading to organ dysfunction and mortality. Most of the pathophysiology of human sepsis is recapitulated in the mouse model of polymicrobial sepsis, developed by cecal ligation and puncture (CLP). In this report, we demonstrate a rapid onset of cellular senescence in the liver of mice subjected to CLP-induced sepsis, characterized by the upregulation of p21, p53, and other senescence markers, including SA-βgal. Using RNAscope, confocal microscopy, and flow cytometry, we further confirm the emergence of p21-expressing senescence phenotype in the liver 24 h after sepsis induction. Senescence was observed in several cell types in the liver, including hepatocytes, endothelial cells, and macrophages. We determined the landscape of senescence phenotype in murine sepsis by single-cell sequencing, which further ascertained that this cell fate is not confined to any particular cell type but displays a heterogeneous distribution. Furthermore, we observed a significant reduction in mortality following sepsis when mice were treated with senolytics, a combination of dasatinib and quercetin, before the CLP surgery. Our experiments unequivocally demonstrated a rapid development of cellular senescence with sepsis and, for the first time, described the senescence landscape in the sepsis liver and the possible role of senescent cells in the worsening outcome following sepsis.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14354"},"PeriodicalIF":8.0,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491457","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":"Cellular senescence contributes to spontaneous repair of the rat meniscus.","authors":"Yusuke Aimono, Kentaro Endo, Ichiro Sekiya","doi":"10.1111/acel.14385","DOIUrl":"https://doi.org/10.1111/acel.14385","url":null,"abstract":"<p><p>Cellular senescence, traditionally associated with aging and chronic diseases, has recently been identified as a potential facilitator of tissue regeneration via a senescence-associated secretory phenotype (SASP). In rodents, the meniscus is known to regenerate spontaneously from the surrounding synovium, but the mechanism, and especially its relationship to cellular senescence, remains unclear. This study investigated the contribution of cellular senescence to spontaneous repair of the rat meniscus. We created a rat partial medial meniscectomy (pMx) model to evaluate time-course changes in regenerative tissue. Immunohistochemistry revealed marked increases in p16 expression and senescence-associated beta-galactosidase (SA-β-gal) activity in the regenerating tissue at the early phase after pMx surgery. RNA sequencing of regenerating tissues identified the upregulation of genes related to aging, extracellular matrix organization, and cell proliferation. Fluorescence staining identified high expression of SOX9, a master regulator of cartilage/meniscus development, adjacent to p16-positive cells. In vitro investigations of the effect of SASP factors on synovial fibroblasts (SFs) demonstrated that conditioned medium from senescent SFs stimulated the proliferation and chondrogenic differentiation of normal SFs. In vivo histological evaluation to determine whether selective elimination of senescent cells with a senolytic drug (ABT-263) retarded spontaneous repair of meniscus in vivo confirmed that ABT-263 decreased the meniscus score and expression of SOX9, aggrecan, and type 1 collagen. Our findings indicate that transient senescent cell accumulation and SASP in regenerating tissues beneficially contribute to spontaneous repair of the rat meniscus. Further research into the molecular mechanism will provide a novel strategy for meniscus regeneration based on cellular senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14385"},"PeriodicalIF":8.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491453","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":"Suppressing DUSP16 overexpression induced by ELK1 promotes neural progenitor cell differentiation in mouse models of Alzheimer's disease.","authors":"Huimin Zhao, Yao Mu, Anqi Liang, Jie Wei, Sixian Lai, Xin Li, Peipei Chen, Hao Li, Hua He, Xiaoquan Liu, Haochen Liu","doi":"10.1111/acel.14372","DOIUrl":"https://doi.org/10.1111/acel.14372","url":null,"abstract":"<p><p>Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen-activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual-specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by stimulating neural progenitor cell (NPC) differentiation in AD mice remains unclear. Our study demonstrates an association between DUSP16 SNPs and clinical progression in individuals with mild cognitive impairment (MCI). Besides, increased DUSP16 expression was detected in both 3xTg and SAMP8 mouse models of AD, accompanied by NPC neural differentiation impairments. By silencing DUSP16, the induction of neural differentiation, synaptic transmission, and cognitive benefits were observed in both AD mice. Furthermore, DUSP16 was involved in the process of NPC differentiation through regulating c-Jun N-terminal kinase (JNK) phosphorylation and SOX2 expression. Moreover, ETS transcription factor (ELK1) was involved in the DUSP16 transcription, which resulted in the upregulation of DUSP16 at the state of AD. Our data uncovers a potential regulatory role for DUSP16 in adult hippocampal neurogenesis (AHN) and provides a possibility to find a novel strategy for AD intervention.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14372"},"PeriodicalIF":8.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453921","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":"Vascular inflammaging: Endothelial CEACAM1 expression is upregulated by TNF-α via independent activation of NF-κB and β-catenin signaling.","authors":"Lisa Götz, Uwe Rueckschloss, Andreas Reimer, Heike Bömmel, Andreas Beilhack, Süleyman Ergün, Florian Kleefeldt","doi":"10.1111/acel.14384","DOIUrl":"https://doi.org/10.1111/acel.14384","url":null,"abstract":"<p><p>Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro-inflammatory cytokine TNF-α. CEACAM1 is critical for aging-associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF-α in detail. Using wildtype (WT) and TNF-α knockout (Tnf^-/-) mice, we confirmed that the aging-related upregulation of endothelial CEACAM1 critically depends on TNF-α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF-α time-dependently upregulated CEACAM1 in vitro. In pharmacological experiments, we identified an early NF-κB- and a delayed β-catenin-mediated response. Involvement of β-catenin was further substantiated by siRNA-mediated knockdown of the β-catenin-targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co-immunoprecipitation analysis revealed release of β-catenin from adherens junctions by TNF-α. Finally, TNF-α activated Akt kinase by increasing its Ser⁴⁷³ phosphorylation. Consequently, Akt kinase facilitated β-catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser⁹ and by increased phosphorylation of β-catenin at Ser⁵⁵² that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging-related, inflammation-mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14384"},"PeriodicalIF":8.0,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453925","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":"Angiopoietin-2 reverses endothelial cell dysfunction in progeria vasculature.","authors":"Sahar Vakili, Elizabeth K Izydore, Leonhard Losert, Wayne A Cabral, Urraca L Tavarez, Kevin Shores, Huijing Xue, Michael R Erdos, George A Truskey, Francis S Collins, Kan Cao","doi":"10.1111/acel.14375","DOIUrl":"https://doi.org/10.1111/acel.14375","url":null,"abstract":"<p><p>Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, resulting in a toxic form of lamin A called progerin. Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients. Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD). Endothelial cell-cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology. However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction. An antibody array screening of healthy and HGPS patient EC secretomes identified Angiopoietin-2 (Ang2) as a down-regulated signaling molecule in HGPS ECs. A similar down-regulation of Ang2 mRNA and protein was detected in the aortas from an HGPS mouse model. Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation. Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells. Lastly, by utilizing adenine base editor (ABE)-corrected HGPS ECs and progerin-expressing HUVECs, we demonstrated a negative correlation between progerin and Ang2 expression. Lastly, our results indicated that Ang2 exerts its beneficial effect in ECs through Tie2 receptor binding, activating an Akt-mediated pathway. Together, these results provide molecular insights into EC dysfunction in HGPS and suggest that Ang2 treatment has potential therapeutic effects in HGPS-related CVD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14375"},"PeriodicalIF":8.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453913","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":"Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes.","authors":"Steven K Malin, Daniel J Battillo, Michal S Beeri, Maja Mustapic, Francheska Delgado-Peraza, Dimitrios Kapogiannis","doi":"10.1111/acel.14369","DOIUrl":"https://doi.org/10.1111/acel.14369","url":null,"abstract":"<p><p>Adults with prediabetes are at risk for Alzheimer's Disease and Related Dementia (ADRD). While exercise may lower ADRD risk, the exact mechanism is unclear. We tested the hypothesis that short-term exercise would raise neuronal insulin signaling and pro-BDNF in neuronal extracellular vesicles (nEVs) in prediabetes. Twenty-one older adults (18F, 60.0 ± 8.6 yrs.; BMI: 33.5 ± 1.1 kg/m²) with prediabetes (ADA criteria; 75 g OGTT) were randomized to 12 supervised work-matched continuous (n = 13, 70% HR_peak) or interval (n = 8, 90% HR_peak and 50% HR_peak for 3 min each) sessions over 2-wks for 60 min/d. Aerobic fitness (VO₂peak) and body weight were assessed. After an overnight fast, whole-body glucose tolerance (total area under the curve, tAUC) and insulin sensitivity (SIis) were determined from a 120 min 75 g OGTT. nEVs were acquired from 0 and 60 min time-points of the OGTT, and levels of insulin signaling proteins (i.e., p-IRS-1, total-/p-Akt, pERK1/2, pJNK1/2, and pp38) and pro-BNDF were measured. OGTT stimulatory effects were calculated from protein differences (i.e., OGTT 60-0 min). Adults were collapsed into a single group as exercise intensity did not affect nEV outcomes. Exercise raised VO₂peak (+1.4 ± 2.0 mL/kg/min, p = 0.008) and insulin sensitivity (p = 0.01) as well as decreased weight (-0.4 ± 0.9 kg, p = 0.04) and whole-body glucose tAUC_120min (p = 0.02). Training lowered 0-min pro-BDNF (704.1 ± 1019.0 vs. 414.5 ± 533.5, p = 0.04) and increased OGTT-stimulated tAkt (-51.8 ± 147.2 vs. 95 ± 204.5 a.u., p = 0.01), which was paralleled by reduced pAkt/tAkt at 60 min of the OGTT (1.3 ± 0.2 vs. 1.2 ± 0.1 a.u., p = 0.04). Thus, 2 weeks of exercise altered neuronal insulin signaling responses to glucose ingestion and lowered pro-BNDF among adults with prediabetes, thereby potentially lowering ADRD risk.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14369"},"PeriodicalIF":8.0,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453924","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":"Multiple outcomes of the germline p16^INK4a mutation affecting senescence and immunity in human skin.","authors":"Priya Subramanian, Souraya Sayegh, Phatthamon Laphanuwat, Oliver P Devine, Carlos Henrique Fantecelle, Justyna Sikora, Emma S Chambers, Sophia N Karagiannis, Daniel C O Gomes, Anjana Kulkarni, Malcolm H A Rustin, Katie E Lacy, Arne N Akbar","doi":"10.1111/acel.14373","DOIUrl":"https://doi.org/10.1111/acel.14373","url":null,"abstract":"<p><p>The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16^INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16^INK4a but express higher levels of the DNA-damage protein 𝛾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence-related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14373"},"PeriodicalIF":8.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453918","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":"Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia.","authors":"Nathalie Launay, Maria Espinosa-Alcantud, Edgard Verdura, Gorka Fernández-Eulate, Jon Ondaro, Pablo Iruzubieta, Maria Marsal, Agatha Schlüter, Montserrat Ruiz, Stephane Fourcade, Agustí Rodríguez-Palmero, Miren Zulaica, Andone Sistiaga, Garazi Labayru, Pablo Loza-Alvarez, Alejandro Vaquero, Adolfo Lopez de Munain, Aurora Pujol","doi":"10.1111/acel.14355","DOIUrl":"https://doi.org/10.1111/acel.14355","url":null,"abstract":"<p><p>Senescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH-mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14355"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453912","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":"Hippocampal Nogo66-NgR1 signaling activation restricts postsynaptic assembly in aged mice with postoperative neurocognitive disorders.","authors":"Min Jia, Gui-Zhou Li, Jiang Chen, Xiao-Hui Tang, Yan-Yu Zang, Guo-Lin Yang, Yun Stone Shi, Daqing Ma, Mu-Huo Ji, Jian-Jun Yang","doi":"10.1111/acel.14366","DOIUrl":"https://doi.org/10.1111/acel.14366","url":null,"abstract":"<p><p>Postoperative neurocognitive disorders (pNCD) are a common neurological complication, especially in elderly following anesthesia and surgery. Yet, the underlying mechanisms of pNCD remain elusive. This study aimed to investigate the molecular mechanisms that compromise synaptic metaplasticity in pNCD development with a focus on the involvement of Nogo-66 receptor 1 (NgR1) in the pathogenesis of pNCD in aged mice. Aged mice subjected to anesthesia and laparotomy surgery exhibited anxiety-like behavior and contextual fear memory impairment. Moreover, the procedure significantly increased NogoA and NgR1 expressions, particularly in the hippocampal CA1 and CA3 regions. This increase led to the depolymerization of F-actin, attributed to the activation of the RhoA-GTPase, resulting in a reduction of dendritic spines and changes in their morphology. Additionally, these changes hindered the efficient postsynaptic delivery of the subunit GluA1 and GluA2 of AMPA receptors (AMPARs), consequently diminishing excitatory neurotransmission in the hippocampus. Importantly, administering the competitive NgR1 antagonist peptide NEP1-40 (Nogo-A extracellular peptide residues 1-40 amino acids of Nogo-66) and Fasudil (a Rho-kinase inhibitor) effectively mitigated synaptic impairments and reversed neurocognitive deficits in aged mice following anesthesia and surgery. Our work indicates that high hippocampal Nogo66-NgR1 signaling disrupts postsynaptic AMPA receptor surface delivery due to F-actin depolymerization in the pathophysiology of pNCD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14366"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453915","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":"Ketogenic β-hydroxybutyrate regulates β-hydroxybutyrylation of TCA cycle-associated enzymes and attenuates disease-associated pathologies in Alzheimer's mice.","authors":"Wanhong Han, Bingchang Zhang, Wenpeng Zhao, Wentao Zhao, Jiawei He, Xiansheng Qiu, Liang Zhang, Xiuyan Wang, Yong Wang, Hanwen Lu, Yaya Zhang, Yuanyuan Xie, Yanyan Geng, Wujie Zhao, Qionghui Huang, Yun-Wu Zhang, Zhanxiang Wang","doi":"10.1111/acel.14368","DOIUrl":"https://doi.org/10.1111/acel.14368","url":null,"abstract":"<p><p>Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification that has recently been found to regulate protein functions. However, whether and how protein Kbhb modification participates in Alzheimer's disease (AD) remains unknown. Herein, we carried out 4D label-free β-hydroxybutylation quantitative proteomics using brain samples of 8-month-old and 2-month-old APP/PS1 AD model mice and wild-type (WT) controls. We identified a series of tricarboxylic acid (TCA) cycle-associated enzymes including citrate synthase (CS) and succinate-CoA ligase subunit alpha (SUCLG1), whose Kbhb modifications were decreased in APP/PS1 mice at pathological stages. Sodium β-hydroxybutyrate (Na-β-OHB) treatment markedly increased Kbhb modifications of CS and SUCLG1 and their enzymatic activities, leading to elevated ATP production. We further found that Kbhb modifications at lysine 393 site in CS and at lysine 81 site in SUCLG1 were crucial for their enzymatic activities. Finally, we found that β-OHB levels were decreased in the brain of APP/PS1 mice at pathological stages. While ketogenic diet not only significantly increased β-OHB levels, Kbhb modifications and enzymatic activities of CS and SUCLG1, and ATP production, but also dramatically attenuated β-amyloid plaque pathologies and microgliosis in APP/PS1 mice. Together, our findings indicate the importance of protein Kbhb modification for maintaining normal TCA cycle and ATP production and provide a novel molecular mechanism underlying the beneficial effects of ketogenic diet on energy metabolism and AD intervention.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14368"},"PeriodicalIF":8.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453916","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}