Aging Cell最新文献

{"title":"Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia","authors":"Nathalie Launay,&nbsp;Maria Espinosa-Alcantud,&nbsp;Edgard Verdura,&nbsp;Gorka Fernández-Eulate,&nbsp;Jon Ondaro,&nbsp;Pablo Iruzubieta,&nbsp;Maria Marsal,&nbsp;Agatha Schlüter,&nbsp;Montserrat Ruiz,&nbsp;Stephane Fourcade,&nbsp;Agustí Rodríguez-Palmero,&nbsp;Miren Zulaica,&nbsp;Andone Sistiaga,&nbsp;Garazi Labayru,&nbsp;Pablo Loza-Alvarez,&nbsp;Alejandro Vaquero,&nbsp;Adolfo Lopez de Munain,&nbsp;Aurora Pujol","doi":"10.1111/acel.14355","DOIUrl":"10.1111/acel.14355","url":null,"abstract":"<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":55543,"journal":{"name":"Aging Cell","volume":"24 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709099/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aβ -induced excessive mitochondrial fission drives type H blood vessels injury to aggravate bone loss in APP/PS1 mice with Alzheimer's diseases","authors":"Weidong Zhang,&nbsp;Fan Ding,&nbsp;Xing Rong,&nbsp;Qinghua Ren,&nbsp;Tomoka Hasegawa,&nbsp;Hongrui Liu,&nbsp;Minqi Li","doi":"10.1111/acel.14374","DOIUrl":"10.1111/acel.14374","url":null,"abstract":"<p>Alzheimer's diseases (AD) patients suffer from more serious bone loss than cognitively normal subjects at the same age. Type H blood vessels were tightly associated with bone homeostasis. However, few studies have concentrated on bone vascular alteration and its role in AD-related bone loss. In this study, APP/PS1 mice (4- and 8-month-old) and age-matched wild-type mice were used to assess the bone vascular alteration and its role in AD-related bone loss. Transmission electron microscopy, immunofluorescence staining and iGPS 1.0 software database were utilized to investigate the molecular mechanism. Mitochondrial division inhibitor (Mdivi-1) and GSK-3β inhibitor (LiCl) were used to rescue type H blood vessels injury and verify the molecular mechanism. Our results revealed that APP/PS1 mice exhibited more serious bone blood vessels injury and bone loss during ageing. The bone blood vessel injury, especially in type H blood vessels, was accompanied by impaired vascularized osteogenesis in APP/PS1 mice. Further exploration indicated that beta-amyloid (Aβ) promoted the apoptosis of vascular endothelial cells (ECs) and resulted in type H blood vessels injury. Mechanistically, Aβ-induced excessive mitochondrial fission was found to be essential for the apoptosis of ECs. GSK-3β was identified as a key regulatory target of Aβ-induced excessive mitochondrial fission and bone loss. The findings delineated that Aβ-induced excessive mitochondrial fission drives type H blood vessels injury, leading to aggravate bone loss in APP/PS1 mice and GSK-3β inhibitor emerges as a potential therapeutic strategy.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 2","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The translation initiation factor eIF2α regulates lipid homeostasis and metabolic aging","authors":"Haipeng Huang,&nbsp;Yilie Liao,&nbsp;Ning Li,&nbsp;Xingfan Qu,&nbsp;Chaocan Li,&nbsp;Jiaqi Hou","doi":"10.1111/acel.14348","DOIUrl":"10.1111/acel.14348","url":null,"abstract":"<p>Aging is usually accompanied by excessive body fat gain, leading to increased susceptibility to comorbidities. This study aimed to explore an unexpected function for the eukaryotic initiation factor-2α (eIF2α) during aging. Reducing the eIF2α dose led to a reconfiguration of the metabolic equilibrium, promoting catabolism, facilitating lipolysis, and decreasing body fat accumulation while maintaining healthy glucose and lipid metabolism during aging. Specifically, eIF2α enhanced the expression of distinct messenger RNAs encoding mitochondrial electron transport chain proteins at the translation level. The mitochondrial respiration increased in eIF2α heterozygotes, even during aging. Deceleration of translation was demonstrated as a conserved mechanism for promoting longevity across various species. Our findings demonstrated that the restriction of translation by reducing eIF2α expression could fend off multiple tissue damage and improve metabolic homeostasis during aging. Hence, eIF2α was a crucial target for benefiting mammalian aging achieving delayed mammalian aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The N6-methyladenosine landscape of ovarian development and aging highlights the regulation by RNA stability and chromatin state","authors":"Xiujuan Hu,&nbsp;Jiafeng Lu,&nbsp;Chenyue Ding,&nbsp;Jincheng Li,&nbsp;Qinyan Zou,&nbsp;Wenjuan Xia,&nbsp;Chunfeng Qian,&nbsp;Hong Li,&nbsp;Boxian Huang","doi":"10.1111/acel.14376","DOIUrl":"10.1111/acel.14376","url":null,"abstract":"<p>The versatile epigenetic modification known as N6-methyladenosine (m⁶A) has been demonstrated to be pivotal in numerous physiological and pathological contexts. Nonetheless, the precise regulatory mechanisms linking m⁶A to histone modifications and the involvement of transposable elements (TEs) in ovarian development and aging are still not completely understood. First, we discovered that m⁶A modifications are highly expressed during ovarian aging (OA), with significant contributions from decreased m⁶A demethylase FTO and overexpressed m⁶A methyltransferase METTL16. Then, using FTO knockout mouse model and KGN cell line, we also observed that FTO deletion and METTL16 overexpression significantly increased m⁶A levels. This led to the downregulation of the methyltransferase SUV39H1, resulting in reduced H3K9me3 expression. The downregulation of SUV39H1 and H3K9me3 primarily activated LTR7 and LTR12, subsequently activating ERV1. This resulted in a decrease in cell proliferation, while the levels of apoptosis, cellular aging markers, and autophagy markers significantly increased in OA. In summary, our study offers intriguing insights into the role of m⁶A in regulating DNA epigenetics, including H3K9me3 and TEs, as well as autophagy, thereby accelerating OA.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 2","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14376","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senolytic therapy combining Dasatinib and Quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro-anabolic mediators","authors":"Svenja Maurer,&nbsp;Valeria Kirsch,&nbsp;Leonie Ruths,&nbsp;Rolf E. Brenner,&nbsp;Jana Riegger","doi":"10.1111/acel.14361","DOIUrl":"10.1111/acel.14361","url":null,"abstract":"<p>Cellular senescence is associated with various age-related disorders and is assumed to play a major role in the pathogenesis of osteoarthritis (OA). Based on this, we tested a senolytic combination therapy using Dasatinib (D) and Quercetin (Q) on aged isolated human articular chondrocytes (hACs), as well as in OA-affected cartilage tissue (OARSI grade 1–2). Stimulation with D + Q selectively eliminated senescent cells in both, cartilage explants and isolated hAC. Furthermore, the therapy significantly promoted chondroanabolism, as demonstrated by increased gene expression levels of COL2A1, ACAN, and SOX9, as well as elevated collagen type II and glycosaminoglycan biosynthesis. Additionally, D + Q treatment significantly reduced the release of SASP factors (IL6, CXCL1). RNA sequencing analysis revealed an upregulation of the anabolic factors, inter alia, FGF18, IGF1, and TGFB2, as well as inhibitory effects on cytokines and the YAP-1 signaling pathway, explaining the underlying mechanism of the chondroanabolic promotion upon senolytic treatment. Accordingly, stimulation of untreated hAC with conditioned medium of D + Q-treated cells similarly induced the expression of chondrogenic markers. Detailed analyses demonstrated that chondroanabolic effects could be mainly attributed to Dasatinib, while monotherapeutical application of Quercetin or Navitoclax did not promote the chondroanabolism. Overall, D + Q therapy restored the chondrogenic phenotype in OA hAC most likely by creating a pro-chondroanabolic environment through the reduction of SASP factors and upregulation of growth factors. This senolytic approach could therefore be a promising candidate for further testing as a disease-modifying osteoarthritis drug.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells","authors":"T. Blake Monroe,&nbsp;Ann V. Hertzel,&nbsp;Deborah M. Dickey,&nbsp;Thomas Hagen,&nbsp;Simon Vergara Santibanez,&nbsp;Islam A. Berdaweel,&nbsp;Catherine Halley,&nbsp;Patrycja Puchalska,&nbsp;Ethan J. Anderson,&nbsp;Christina D. Camell,&nbsp;Paul D. Robbins,&nbsp;David A. Bernlohr","doi":"10.1111/acel.14367","DOIUrl":"10.1111/acel.14367","url":null,"abstract":"<p>Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) or 4-oxo-2-nonenal (4-ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells. In such cells, lipid enals induced accumulation of γH2AX foci, increased p53 signaling, enhanced expression of p21^Cip1, and upregulated the expression and secretion of numerous cytokines, chemokines, and regulatory factors independently from NF-κB activation. Concomitantly, lipid enal treatment resulted in covalent modification of mitochondrial proteins, reduced mitochondrial spare respiratory capacity, altered nucleotide pools, and increased the phosphorylation of AMP kinase. Lipid-induced senescent cells upregulated <i>BCL2L1</i> (Bcl-xL) and <i>BCL2L2</i> (Bcl-w). and were resistant to apoptosis while pharmacologic inhibition of BAX/BAK macropores attenuated lipid-induced senescence. In situ, the 4-HNE scavenger L-carnosine ameliorated the development of the cellular senescence, while in visceral fat of obese C57BL/6J mice, L-carnosine reduced the abundance of 4-HNE-modified proteins and blunted the expression of senescence biomarkers <i>CDKN1A</i> (p21^Cip1), <i>PLAUR</i>, <i>BCL2L1</i>, and <i>BCL2L2.</i> Taken together, the results suggest that lipid enals are endogenous regulators of cellular senescence and that biogenic lipid-induced senescence (BLIS) may represent a mechanistic link between oxidative stress and age-dependent pathologies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 1","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142453917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contextualizing aging clocks and properly describing biological age","authors":"Adiv A. Johnson,&nbsp;Maxim N. Shokhirev","doi":"10.1111/acel.14377","DOIUrl":"10.1111/acel.14377","url":null,"abstract":"<p>Usage of the phrase “biological age” has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue-specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric. We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO₂ max, or any other aging biomarker is biologically young, we should be careful not to conflate an aging clock with whole-body biological aging. To address this, we recommend that researchers describe the output of an aging clock based on the type of input data used or the name of the clock itself. Epigenetic aging clocks produce epigenetic age, transcriptomic aging clocks produce transcriptomic age, and so forth. If a clock has a unique name, such as our recently developed epigenetic aging clock CheekAge, the name of the clock can double as the output. As a compromise solution, aging biomarkers can be described as indicators of biological age. We feel that these recommendations will help scientists and the public differentiate between aging biomarkers and the much more elusive concept of biological age.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 12","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Additional Cover","authors":"Yuichiro Ukon,&nbsp;Takashi Kaito,&nbsp;Hiromasa Hirai,&nbsp;Takayuki Kitahara,&nbsp;Masayuki Bun,&nbsp;Joe Kodama,&nbsp;Daisuke Tateiwa,&nbsp;Shinichi Nakagawa,&nbsp;Masato Ikuta,&nbsp;Takuya Furuichi,&nbsp;Yuya Kanie,&nbsp;Takahito Fujimori,&nbsp;Shota Takenaka,&nbsp;Tadashi Yamamuro,&nbsp;Satoru Otsuru,&nbsp;Seiji Okada,&nbsp;Masakatsu Yamashita,&nbsp;Takeshi Imamura","doi":"10.1111/acel.14381","DOIUrl":"https://doi.org/10.1111/acel.14381","url":null,"abstract":"<p>Cover legend: The cover image is based on the Article <i>Cellular senescence by loss of Men1 in osteoblasts is critical for age-related osteoporosis</i> by Yuichiro Ukon et al.,\u0000https://doi.org/10.1111/acel.14254\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142429798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Additional Cover","authors":"Kangkang Yu,&nbsp;Feifei Li,&nbsp;Ling Ye,&nbsp;Fanyuan Yu","doi":"10.1111/acel.14379","DOIUrl":"https://doi.org/10.1111/acel.14379","url":null,"abstract":"<p>Cover legend: The cover image is based on the Article <i>Accumulation of DNA G-quadruplex in mitochondrial genome hallmarks mesenchymal senescence</i> by Kangkang Yu et al.,\u0000https://doi.org/10.1111/acel.14265\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142429796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Featured Cover","authors":"Florencia Herbstein,&nbsp;Melanie Sapochnik,&nbsp;Alejandra Attorresi,&nbsp;Cora Pollak,&nbsp;Sergio Senin,&nbsp;David Gonilski-Pacin,&nbsp;Nicolas Ciancio del Giudice,&nbsp;Manuel Fiz,&nbsp;Belén Elguero,&nbsp;Mariana Fuertes,&nbsp;Lara Müller,&nbsp;Marily Theodoropoulou,&nbsp;Lucas B. Pontel,&nbsp;Eduardo Arzt","doi":"10.1111/acel.14378","DOIUrl":"https://doi.org/10.1111/acel.14378","url":null,"abstract":"<p>Cover legend: The cover image is based on the Article <i>The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent\u0000noncanonical pathway</i> by Florencia Herbstein et al., https://doi.org/10.1111/acel.14258<figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14378","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142429794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}