Aging Cell最新文献_第10页

Telomerase reverse transcriptase gene knock-in unleashes enhanced longevity and accelerated damage repair in mice. 端粒酶逆转录酶基因敲入可以延长小鼠寿命，加速损伤修复。

IF 8 1区医学

Aging Cell Pub Date : 2024-12-11 DOI: 10.1111/acel.14445

Tian-Yi Zhu, Po Hu, Yu-Hui Mi, Jun-Li Zhang, An-Na Xu, Ming-Tong Gao, Ying-Ying Zhang, San-Bing Shen, Guang-Ming Yang, Yang Pan

{"title":"Telomerase reverse transcriptase gene knock-in unleashes enhanced longevity and accelerated damage repair in mice.","authors":"Tian-Yi Zhu, Po Hu, Yu-Hui Mi, Jun-Li Zhang, An-Na Xu, Ming-Tong Gao, Ying-Ying Zhang, San-Bing Shen, Guang-Ming Yang, Yang Pan","doi":"10.1111/acel.14445","DOIUrl":"https://doi.org/10.1111/acel.14445","url":null,"abstract":"While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter. The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14445"},"PeriodicalIF":8.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805541","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}

引用次数: 0

Associations of combined accelerated biological aging and genetic susceptibility with incidence of heart failure in a population-based cohort study. 在一项基于人群的队列研究中，联合加速生物衰老和遗传易感性与心力衰竭发病率的关系。

IF 8 1区医学

Aging Cell Pub Date : 2024-12-11 DOI: 10.1111/acel.14430

Hao Zhao, Xuening Zhang, Yanzhi Li, Wanxin Wang, Wenjian Lai, Wenjing Zhang, Kai Kang, Xiali Zhong, Lan Guo

{"title":"Associations of combined accelerated biological aging and genetic susceptibility with incidence of heart failure in a population-based cohort study.","authors":"Hao Zhao, Xuening Zhang, Yanzhi Li, Wanxin Wang, Wenjian Lai, Wenjing Zhang, Kai Kang, Xiali Zhong, Lan Guo","doi":"10.1111/acel.14430","DOIUrl":"https://doi.org/10.1111/acel.14430","url":null,"abstract":"The global aging population raises concerns about heart failure (HF), yet its association with accelerated biological age (BA) remains inadequately understood. We aimed to examine the longitudinal association between BA acceleration and incident HF risk, assess its modifying effect on genetic susceptibility, and how much BA acceleration mediates the impact of modifiable health behaviors on incident HF. We analyzed 274,608 UK Biobank participants without HF at baseline. Two BA accelerations (Biological Age Acceleration [BioAgeAccel] and Phenotypic Age Acceleration [PhenoAgeAccel]) were calculated by regressing clinical biomarker-based BA on chronological age, with higher values indicating accelerated aging. Health behavior scores were computed based on diet, physical activity, tobacco/nicotine, sleep, and BMI. Genetic risk scores (GRS) were calculated by 12 HF-associated loci. During a median follow-up of 13.5 years, 8915 HF cases were documented. Each standard deviation increase in BioAgeAccel and PhenoAgeAccel was associated with an increased incident HF risk, yielding HRs of 1.45 (95% CI, 1.42-1.48) and 1.42 (95% CI, 1.40-1.45), respectively. Participants with high GRS and highest quartile of BioAgeAccel had an HR of 2.69 (95% CI, 2.42-2.99), and for PhenoAgeAccel, an HR of 2.83 (95% CI, 2.52-3.18), compared to those with low GRS, and lowest quartile. Additive interactions were observed between GRS and BA accelerations. Health behaviors reduced HF risk, with 21.1% (95% CI, 19.5%-22.8%) mediated by decreased BioAgeAccel and 20.9% (95% CI, 19.5%-22.6%) by decreased PhenoAgeAccel. Accelerated BA is associated with an increased incident HF risk, with an additive effect when combined with genetic susceptibility. Maintaining health behaviors may help mitigate BA aging and reduce HF risk.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14430"},"PeriodicalIF":8.0,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811508","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}

引用次数: 0

Estradiol deficiency as a consequence of aging contributes to the depletion of the satellite cell pool in female mice. 雌二醇缺乏是衰老导致的雌性小鼠卫星细胞池耗竭的原因之一。

IF 8 1区医学

Aging Cell Pub Date : 2024-12-06 DOI: 10.1111/acel.14441

Brian P Sullivan, Alexie A Larson, Ahmed S Shams, Shawna L McMillin, Mara C Ebeling, Sydney Peng, Michael Kyba, Dawn A Lowe

{"title":"Estradiol deficiency as a consequence of aging contributes to the depletion of the satellite cell pool in female mice.","authors":"Brian P Sullivan, Alexie A Larson, Ahmed S Shams, Shawna L McMillin, Mara C Ebeling, Sydney Peng, Michael Kyba, Dawn A Lowe","doi":"10.1111/acel.14441","DOIUrl":"10.1111/acel.14441","url":null,"abstract":"The effects of aging on the satellite cell pool have primarily been studied in male mice, where the role of cell-intrinsic versus environmental changes on satellite cell function remains contentious. Estradiol is necessary for maintenance of satellite cell pool size in adult female mice-here we investigate the hypothesis that in females, estradiol is a major environmental driver of age-associated effects on satellite cells. In 24-26 month-old ovarian senescent mice, we find the satellite cell pool size is severely diminished in certain muscles (TA and EDL) but only marginally affected in others (soleus and gastrocnemius). Supplementation with 17-beta estradiol significantly increases satellite cell pool size in the TA and EDL. To assess cell-intrinsic versus environmental regulation, we perform two transplantation experiments, Adult or Aged satellite cells transplanted into Adult recipients, and Adult satellite cells transplanted into Adult or Aged mice. These results demonstrate that the aged environment dominates over cell-autonomous age in terms of the specification of satellite cell pool size. Transcriptional profiling on satellite cells from Adult, Aged and ovariectomized mice revealed commonalities across the two estradiol-deficient conditions, Aged and ovariectomized, in GO terms from differentially expressed genes. Our findings support the hypothesis that the lack of estradiol contributes to reductions in satellite cell number in Aged female muscle, yet cells that remain are functional in terms of proliferative potential and self-renewal capacity. These findings have implications for sex hormone treatment of menopausal women and highlight the vital role of estradiol in the maintenance of the satellite cell pool.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14441"},"PeriodicalIF":8.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783443","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}

引用次数: 0

IF 8 1区医学

Aging Cell Pub Date : 2024-12-06 DOI: 10.1111/acel.14428

Matthew C Mosley, Holly E Kinser, Olivier M F Martin, Nicholas Stroustrup, Tim Schedl, Kerry Kornfeld, Zachary Pincus

{"title":"Similarities and differences in the gene expression signatures of physiological age versus future lifespan.","authors":"Matthew C Mosley, Holly E Kinser, Olivier M F Martin, Nicholas Stroustrup, Tim Schedl, Kerry Kornfeld, Zachary Pincus","doi":"10.1111/acel.14428","DOIUrl":"https://doi.org/10.1111/acel.14428","url":null,"abstract":"Across all taxa of life, individuals within a species exhibit variable lifespans. Differences in genotype or environment are not sufficient to explain this variance, as even isogenic Caenorhabditis elegans nematodes reared under uniform conditions show significant variability in lifespan. To investigate this phenomenon, we used lifespan-predictive biomarkers to isolate, at mid-adulthood, prospectively long- and short-lived individuals from an otherwise identical population. We selected two biomarkers which correlated positively with lifespan, lin-4p::GFP and mir-243p::GFP, and two which correlated negatively, mir-240/786p::GFP and autofluorescence. The gene-expression signature of long versus short future lifespan was strikingly similar across all four biomarkers tested. Since these biomarkers are expressed in different tissues, these results suggest a shared connection to a global health state correlated with future lifespan. To further investigate this underlying state, we compared the transcriptional signature of long versus short future lifespan to that of chronologically young versus old individuals. By comparison to a high-resolution time series of the average aging transcriptome, we determined that subpopulations predicted to be long- or short-lived by biomarker expression had significantly different transcriptional ages despite their shared chronological age. We found that this difference in apparent transcriptional age accounted for the majority of differentially expressed genes associated with future lifespan. Interestingly, we also identified several genes whose expression consistently separated samples by biomarker expression independent of apparent transcriptional age. These results suggest that the commonalities in the long-lived versus short-lived state reported across different biomarkers of aging extends beyond simply transcriptionally young versus transcriptionally old.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14428"},"PeriodicalIF":8.0,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783423","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}

引用次数: 0

Phenotypic upregulation of hexocylceramides and ether-linked phosphocholines as markers of human extreme longevity. 己基神经酰胺和醚连接的磷酸胆碱作为人类极端长寿的标志的表型上调。

IF 8 1区医学

Aging Cell Pub Date : 2024-12-05 DOI: 10.1111/acel.14429

Anna Fernàndez-Bernal, Joaquim Sol, José Daniel Galo-Licona, Natàlia Mota-Martorell, Cristina Mas-Bargues, Ángel Belenguer-Varea, Èlia Obis, José Viña, Consuelo Borrás, Mariona Jové, Reinald Pamplona

{"title":"Phenotypic upregulation of hexocylceramides and ether-linked phosphocholines as markers of human extreme longevity.","authors":"Anna Fernàndez-Bernal, Joaquim Sol, José Daniel Galo-Licona, Natàlia Mota-Martorell, Cristina Mas-Bargues, Ángel Belenguer-Varea, Èlia Obis, José Viña, Consuelo Borrás, Mariona Jové, Reinald Pamplona","doi":"10.1111/acel.14429","DOIUrl":"https://doi.org/10.1111/acel.14429","url":null,"abstract":"Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age-related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass-spectrometry-based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether-PC and ether-LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether-linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14429"},"PeriodicalIF":8.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783420","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}

引用次数: 0

Gut microbiota metabolism of branched-chain amino acids and their metabolites can improve the physiological function of aging mice. 肠道菌群代谢支链氨基酸及其代谢物可改善衰老小鼠的生理功能。

IF 8 1区医学

Aging Cell Pub Date : 2024-12-04 DOI: 10.1111/acel.14434

Hongchao Wang, Ling Feng, Zhangming Pei, Jianxin Zhao, Shourong Lu, Wenwei Lu

{"title":"Gut microbiota metabolism of branched-chain amino acids and their metabolites can improve the physiological function of aging mice.","authors":"Hongchao Wang, Ling Feng, Zhangming Pei, Jianxin Zhao, Shourong Lu, Wenwei Lu","doi":"10.1111/acel.14434","DOIUrl":"https://doi.org/10.1111/acel.14434","url":null,"abstract":"The metabolism of branched-chain amino acids by gut microbiota can improve overall health and may reverse aging. In this study, we investigated Parabacteroides merdae, a gut microbe that is known to catabolise branched-chain amino acids (BCAAs). Three metabolites of BCAAs isovalerate, 2-methylbutyrate, and isobutyrate were used to treat D-gal induced aging mice. The results showed that these treatments could delay aging in mice by providing health benefits in reducing oxidative stress and inflammation, improving muscle capacity, reversing brain acetylcholine levels, and regulating blood glucose. The mechanism was preliminarily explored by combining the gut microbiota metagenome and faecal serum metabolome. Parabacteroides merdae altered the species composition and structure of the gut microbiota in mice. Increasing the abundance of beneficial bacteria, such as Bifidobacterium pseudolongum. Three metabolites affects the gut microbiota and the body's pathways of protein and improves the overall health through a variety of signaling pathways. Overall, regulating the gut microbiota involved in branched-chain amino acid metabolism to bring health benefits may be a new way of reversing aging.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14434"},"PeriodicalIF":8.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765049","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}

引用次数: 0

Accelerated biological aging, healthy behaviors, and genetic susceptibility with incidence of stroke and its subtypes: A prospective cohort study. 加速生物老化、健康行为和遗传易感性与脑卒中及其亚型的发病率：一项前瞻性队列研究

IF 8 1区医学

Aging Cell Pub Date : 2024-12-04 DOI: 10.1111/acel.14427

Xuening Zhang, Hao Zhao, Zilin Li, Xinjie Liu, Yurong Zhang, Ning Yang, Tongchao Zhang, Xiaorong Yang, Ming Lu

{"title":"Accelerated biological aging, healthy behaviors, and genetic susceptibility with incidence of stroke and its subtypes: A prospective cohort study.","authors":"Xuening Zhang, Hao Zhao, Zilin Li, Xinjie Liu, Yurong Zhang, Ning Yang, Tongchao Zhang, Xiaorong Yang, Ming Lu","doi":"10.1111/acel.14427","DOIUrl":"https://doi.org/10.1111/acel.14427","url":null,"abstract":"Stroke risk increases with chronological age, but the relationship with biological age (BA) acceleration is poorly understood. We aimed to examine the association between BA acceleration and incident stroke and its subtypes, explore the modifying effects on genetic susceptibility, and assess how BA acceleration mediates the effect of behavior score. We studied 253,932 UK Biobank participants and computed two BA measures (Klemera-Doubal Method [KDM], Phenotypic Age [PhenoAge]), with BA acceleration calculated by regressing BA on chronological age. The polygenic risk score (PRS) was derived from 87 genetic loci. The behaviors score was based on diet, physical activity, tobacco/nicotine, sleep, and BMI. During a median follow-up of 13.6 years, 5460 strokes, 4337 ischemic stroke (IS), 951 intracerebral hemorrhage (ICH), and 553 subarachnoid hemorrhage (SAH) cases were documented. Adjusting for confounding factors, each standard deviation increase in BA acceleration was associated with higher stroke risk: for KDM-BA acceleration, stroke (HR = 1.28, 95% CI = 1.25-1.32), IS (1.32, 1.28-1.36), ICH (1.15, 1.08-1.23), and SAH (1.16, 1.07-1.27); for PhenoAge acceleration, stroke (1.22, 1.19-1.25), IS (1.26, 1.22-1.29), ICH (1.08, 1.02-1.16), and SAH (1.08, 1.00-1.18). Compared to participants with the lowest PRS and BA acceleration, those with the highest PRS and BA acceleration had the highest stroke risk (KDM-BA acceleration: 2.19, 1.85-2.59; PhenoAge acceleration: 2.03, 1.69-2.42). Additionally, there was an additive interaction between KDM-BA acceleration and PRS. The mediation proportion of BA acceleration in associations of behaviors score with incident stroke and its subtypes ranged from 15.84% to 33.08%. BA acceleration may raise stroke risk, especially in those with high genetic risk. Maintaining healthy behaviors may help mitigate this risk.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14427"},"PeriodicalIF":8.0,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142778681","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}

引用次数: 0

Tissue-specific methylomic responses to a lifestyle intervention in older adults associate with metabolic and physiological health improvements. 老年人生活方式干预与代谢和生理健康改善相关的组织特异性甲基组反应

IF 8 1区医学

Aging Cell Pub Date : 2024-12-01 DOI: 10.1111/acel.14431

Lucy Sinke, Marian Beekman, Yotam Raz, Thies Gehrmann, Ioannis Moustakas, Alexis Boulinguiez, Nico Lakenberg, Eka Suchiman, Fatih A Bogaards, Daniele Bizzarri, Erik B van den Akker, Melanie Waldenberger, Gillian Butler-Browne, Capucine Trollet, C P G M de Groot, Bastiaan T Heijmans, P Eline Slagboom

{"title":"Tissue-specific methylomic responses to a lifestyle intervention in older adults associate with metabolic and physiological health improvements.","authors":"Lucy Sinke, Marian Beekman, Yotam Raz, Thies Gehrmann, Ioannis Moustakas, Alexis Boulinguiez, Nico Lakenberg, Eka Suchiman, Fatih A Bogaards, Daniele Bizzarri, Erik B van den Akker, Melanie Waldenberger, Gillian Butler-Browne, Capucine Trollet, C P G M de Groot, Bastiaan T Heijmans, P Eline Slagboom","doi":"10.1111/acel.14431","DOIUrl":"https://doi.org/10.1111/acel.14431","url":null,"abstract":"Across the lifespan, diet and physical activity profiles substantially influence immunometabolic health. DNA methylation, as a tissue-specific marker sensitive to behavioral change, may mediate these effects through modulation of transcription factor binding and subsequent gene expression. Despite this, few human studies have profiled DNA methylation and gene expression simultaneously in multiple tissues or examined how molecular levels react and interact in response to lifestyle changes. The Growing Old Together (GOTO) study is a 13-week lifestyle intervention in older adults, which imparted health benefits to participants. Here, we characterize the DNA methylation response to this intervention at over 750 thousand CpGs in muscle, adipose, and blood. Differentially methylated sites are enriched for active chromatin states, located close to relevant transcription factor binding sites, and associated with changing expression of insulin sensitivity genes and health parameters. In addition, measures of biological age are consistently reduced, with decreases in grimAge associated with observed health improvements. Taken together, our results identify responsive molecular markers and demonstrate their potential to measure progression and finetune treatment of age-related risks and diseases.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14431"},"PeriodicalIF":8.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765094","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}

引用次数: 0

The ultrastructural and proteomic analysis of mitochondria-associated endoplasmic reticulum membrane in the midbrain of a Parkinson's disease mouse model. 帕金森病小鼠模型中脑线粒体相关内质网膜超微结构和蛋白质组学分析

IF 8 1区医学

Aging Cell Pub Date : 2024-11-29 DOI: 10.1111/acel.14436

Jin Liu, Yi Liu, Chao Gao, Hong Pan, Pei Huang, Yuyan Tan, Shengdi Chen

{"title":"The ultrastructural and proteomic analysis of mitochondria-associated endoplasmic reticulum membrane in the midbrain of a Parkinson's disease mouse model.","authors":"Jin Liu, Yi Liu, Chao Gao, Hong Pan, Pei Huang, Yuyan Tan, Shengdi Chen","doi":"10.1111/acel.14436","DOIUrl":"https://doi.org/10.1111/acel.14436","url":null,"abstract":"Recent studies indicated that the dysregulation of mitochondria-associated endoplasmic reticulum membrane (MAM) could be a significant hub in the pathogenesis of Parkinson's disease (PD). However, little has been known about how MAM altered in PD. This study was aimed to observe morphological changes and analyze proteomic profiles of MAM in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. In MPTP-treated mice, transmission electron microscopy was applied for MAM ultrastructural visualization. Nano ultra-high performance liquid chromatography-tandem mass spectrum and bioinformatic analysis were adopted to obtain underlying molecular data of MAM fractions. The loosened, shortened and reduced MAM tethering was found in substantia nigral neurons from MPTP-treated mice. In midbrain MAM proteomics, 158 differentially expressed proteins (DEPs) were identified between two groups. Specific DEPs were validated by western blot and exhibited significantly statistical changes, aligning with proteomic results. Bioinformatic analysis indicated that membrane, cytoplasm and cell projection were three major localizations for DEPs. Biological processes including metabolism, lipid transport, and immunological and apoptotic signaling pathways were greatly affected. For consensus MAM proteins, the enriched pathway analysis revealed the potential relationship between neurodegenerative diseases and MAM. Several biological processes such as peroxisome function and clathrin-mediated endocytosis, were clustered, which provided additional insights into the fundamental molecular pathways associated with MAM. In our study, we demonstrated disrupted ER-mitochondria contacts in an MPTP-induced PD mouse model. The underlying signatures of MAM were revealed by proteomics and bioinformatic analysis, providing valuable insights into its potential role in PD pathogenesis.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14436"},"PeriodicalIF":8.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754368","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}

引用次数: 0

Piezo1 exacerbates inflammation-induced cartilaginous endplate degeneration by activating mitochondrial fission via the Ca²⁺/CaMKII/Drp1 axis. Piezo1通过Ca2+/CaMKII/Drp1轴激活线粒体裂变，从而加剧炎症诱导的软骨终板变性。

IF 8 1区医学

Aging Cell Pub Date : 2024-11-28 DOI: 10.1111/acel.14440

Zhidi Lin, Guangyu Xu, Xiao Lu, Hongli Wang, Feizhou Lu, Xinlei Xia, Jian Song, Jianyuan Jiang, Xiaosheng Ma, Fei Zou

{"title":"Piezo1 exacerbates inflammation-induced cartilaginous endplate degeneration by activating mitochondrial fission via the Ca2+/CaMKII/Drp1 axis.","authors":"Zhidi Lin, Guangyu Xu, Xiao Lu, Hongli Wang, Feizhou Lu, Xinlei Xia, Jian Song, Jianyuan Jiang, Xiaosheng Ma, Fei Zou","doi":"10.1111/acel.14440","DOIUrl":"https://doi.org/10.1111/acel.14440","url":null,"abstract":"Mitochondrial homeostasis plays a crucial role in degenerative joint diseases, including cartilaginous endplate (CEP) degeneration. To date, research into mitochondrial dynamics in IVDD is at an early stage. Since Piezo1 is a novel Ca2+-permeable channel, we asked whether Piezo1 could modulate mitochondrial fission through Ca2+ signalling during CEP degeneration. In vitro and in vivo models of inflammation-induced CEP degeneration were established with lipopolysaccharide (LPS). We found increased expression of Piezo1 in degenerated CEP tissues and LPS-treated CEP cells. The Piezo1 activator Yoda1 exacerbated CEP cell senescence and apoptosis by triggering Ca2+ influx. Yoda1 also induced mitochondrial fragmentation and dysfunction. In contrast, the Piezo1 inhibitor GsMTx4 exerted cytoprotective effects in LPS-treated CEP cells. Additionally, the CaMKII inhibitor KN-93 reversed Yoda1-induced mitochondrial fission and restored mitochondrial function. Mechanistically, the phosphorylation and mitochondrial translocation of Drp1 were regulated by the Ca2+/CaMKII signalling. The Drp1 inhibitor Mdivi-1 suppressed mitochondrial fission, then reduced mitochondrial dysfunction and CEP cell death. Moreover, knockdown of Piezo1 by siRNA hindered CaMKII and Drp1 activation, facilitating the redistribution of mitochondrial Drp1 to the cytosol in LPS-treated CEP cells. Piezo1 silencing improved mitochondrial morphology and function, thereby rescuing CEP cell senescence and apoptosis under inflammatory conditions. Finally, subendplate injection of GsMTx4 or AAV-shPiezo1 alleviated CEP degeneration in a rat model. Thus, Piezo1 may exacerbate inflammation-induced CEP degeneration by triggering mitochondrial fission and dysfunction via the Ca2+/CaMKII/Drp1 axis.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e14440"},"PeriodicalIF":8.0,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749392","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}

引用次数: 0