Aging Cell最新文献

{"title":"Corrigendum to: REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons","authors":"","doi":"10.1111/acel.13900","DOIUrl":"https://doi.org/10.1111/acel.13900","url":null,"abstract":"<p>Rocchi, A., Carminati, E., De Fusco, A., Kowalska, J.A., Floss, T., Benfenati, F. REST/NRSF deficiency impairs autophagy and leads to cellular senescence in neurons. <i>Aging Cell</i>. 2021 Oct;20(10):e13471. 10.1111/acel.13471.</p><p>In the published version of the above article, the authors noticed that one of the funding grants from the Italian Ministry of Health was mistakenly omitted. The last sentence in the Acknowledgment section should read as follows:</p><p>‘This work was supported by Ministero Istruzione, Università e Ricerca (PRIN-2017A9MK4R to FB), Compagnia di San Paolo Torino (n. 34760 to FB), and Ministero della Salute Ricerca Finalizzata (GR-2016-02363972 and <b>GR-2019-12370176</b> to AR)’.</p><p>The authors apologize for the error.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13900","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6209837","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":"Explainable machine learning framework to predict personalized physiological aging","authors":"David Bernard,&nbsp;Emmanuel Doumard,&nbsp;Isabelle Ader,&nbsp;Philippe Kemoun,&nbsp;Jean-Christophe Pagès,&nbsp;Anne Galinier,&nbsp;Sylvain Cussat-Blanc,&nbsp;Felix Furger,&nbsp;Luigi Ferrucci,&nbsp;Julien Aligon,&nbsp;Cyrille Delpierre,&nbsp;Luc Pénicaud,&nbsp;Paul Monsarrat,&nbsp;Louis Casteilla","doi":"10.1111/acel.13872","DOIUrl":"https://doi.org/10.1111/acel.13872","url":null,"abstract":"<p>Attaining personalized healthy aging requires accurate monitoring of physiological changes and identifying subclinical markers that predict accelerated or delayed aging. Classic biostatistical methods most rely on supervised variables to estimate physiological aging and do not capture the full complexity of inter-parameter interactions. Machine learning (ML) is promising, but its black box nature eludes direct understanding, substantially limiting physician confidence and clinical usage. Using a broad population dataset from the National Health and Nutrition Examination Survey (NHANES) study including routine biological variables and after selection of XGBoost as the most appropriate algorithm, we created an innovative explainable ML framework to determine a Personalized physiological age (PPA). PPA predicted both chronic disease and mortality independently of chronological age. Twenty-six variables were sufficient to predict PPA. Using SHapley Additive exPlanations (SHAP), we implemented a precise quantitative associated metric for each variable explaining physiological (i.e., accelerated or delayed) deviations from age-specific normative data. Among the variables, glycated hemoglobin (HbA1c) displays a major relative weight in the estimation of PPA. Finally, clustering profiles of identical contextualized explanations reveal different aging trajectories opening opportunities to specific clinical follow-up. These data show that PPA is a robust, quantitative and explainable ML-based metric that monitors personalized health status. Our approach also provides a complete framework applicable to different datasets or variables, allowing precision physiological age estimation.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13872","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6228495","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":"Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease","authors":"Stephanie A. Schultz,&nbsp;Zahra Shirzadi,&nbsp;Aaron P. Schultz,&nbsp;Lei Liu,&nbsp;Colleen D. Fitzpatrick,&nbsp;Eric McDade,&nbsp;Nicolas R. Barthelemy,&nbsp;Alan Renton,&nbsp;Bianca Esposito,&nbsp;Nelly Joseph-Mathurin,&nbsp;Carlos Cruchaga,&nbsp;Charles D. Chen,&nbsp;Alison Goate,&nbsp;Ricardo Francisco Allegri,&nbsp;Tammie L. S. Benzinger,&nbsp;Sarah Berman,&nbsp;Helena C. Chui,&nbsp;Anne M. Fagan,&nbsp;Martin R. Farlow,&nbsp;Nick C. Fox,&nbsp;Brian A. Gordon,&nbsp;Gregory S. Day,&nbsp;Neill R. Graff-Radford,&nbsp;Jason J. Hassenstab,&nbsp;Bernard J. Hanseeuw,&nbsp;Anna Hofmann,&nbsp;Clifford R. Jack Jr,&nbsp;Mathias Jucker,&nbsp;Celeste M. Karch,&nbsp;Robert A. Koeppe,&nbsp;Jae-Hong Lee,&nbsp;Allan I. Levey,&nbsp;Johannes Levin,&nbsp;Ralph N. Martins,&nbsp;Hiroshi Mori,&nbsp;John C. Morris,&nbsp;James Noble,&nbsp;Richard J. Perrin,&nbsp;Pedro Rosa-Neto,&nbsp;Stephen P. Salloway,&nbsp;Raquel Sanchez-Valle,&nbsp;Peter R. Schofield,&nbsp;Chengjie Xiong,&nbsp;Keith A. Johnson,&nbsp;Randall J. Bateman,&nbsp;Reisa A. Sperling,&nbsp;Jasmeer P. Chhatwal,&nbsp;the Dominantly Inherited Alzheimer Network Investigators","doi":"10.1111/acel.13871","DOIUrl":"https://doi.org/10.1111/acel.13871","url":null,"abstract":"<p>Although pathogenic variants in <i>PSEN1</i> leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within <i>PSEN1. PSEN1</i> pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13871","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6133292","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":"Mendelian randomization supports causality between overweight status and accelerated aging","authors":"Zong Chen,&nbsp;Zhiyou Chen,&nbsp;Xiaolei Jin","doi":"10.1111/acel.13899","DOIUrl":"https://doi.org/10.1111/acel.13899","url":null,"abstract":"<p>It is reported that overweight may lead to accelerated aging. However, there is still a lack of evidence on the causal effect of overweight and aging. We collected genetic variants associated with overweight, age proxy indicators (telomere length, frailty index and facial aging), etc., from genome-wide association studies datasets. Then we performed MR analyses to explore associations between overweight and age proxy indicators. MR analyses were primarily conducted using the inverse variance weighted method, followed by various sensitivity and validation analyses. MR analyses indicated that there were significant associations of overweight on telomere length, frailty index, and facial aging (<i>β</i> = −0.018, 95% CI = −0.033 to −0.003, <i>p</i> = 0.0162; <i>β</i> = 0.055, 95% CI = 0.030–0.079, <i>p</i> &lt; 0.0001; <i>β</i> = 0.029, 95% CI = 0.013–0.046, <i>p</i> = 0.0005 respectively). Overweight also had a significant negative causality with longevity expectancy (90th survival percentile, <i>β</i> = −0.220, 95% CI = −0.323 to −0.118, <i>p</i> &lt; 0.0001; 99th survival percentile, <i>β</i> = −0.389, 95% CI = −0.652 to −0.126, <i>p</i> = 0.0038). Moreover, the findings tend to favor causal links between body fat mass/body fat percentage on aging proxy indicators, but not body fat-free mass. This study provides evidence of the causality between overweight and accelerated aging (telomere length decreased, frailty index increased, facial aging increased) and lower longevity expectancy. Accordingly, the potential significance of weight control and treatment of overweight in combating accelerated aging need to be emphasized.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13899","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6101775","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 D3-creatine dilution method non-invasively measures muscle mass in mice","authors":"Lauren Wimer,&nbsp;Elena Goncharova,&nbsp;Sofiya Galkina,&nbsp;Edna Nyangau,&nbsp;Mahalakshmi Shankaran,&nbsp;Asia Davis,&nbsp;Leandro Prado,&nbsp;Maria Castro Munoz,&nbsp;Sharon Epstein,&nbsp;Cavan Patterson,&nbsp;Nicholas Shaum,&nbsp;Mark Hellerstein,&nbsp;William Evans,&nbsp;Simon Melov","doi":"10.1111/acel.13897","DOIUrl":"https://doi.org/10.1111/acel.13897","url":null,"abstract":"<p>Developing accurate methods to quantify age-related muscle loss (sarcopenia) could greatly accelerate development of therapies to treat muscle loss in the elderly, as current methods are inaccurate or expensive. The current gold standard method for quantifying sarcopenia is dual-energy X-ray absorptiometry (DXA) but does not measure muscle directly—it is a composite measure quantifying “lean mass” (muscle) excluding fat and bone. In humans, DXA overestimates muscle mass, which has led to erroneous conclusions about the importance of skeletal muscle in human health and disease. In animal models, DXA is a popular method for measuring lean mass. However, instrumentation is expensive and is potentially limited by anesthesia concerns. Recently, the D₃-creatine (D₃Cr) dilution method for quantifying muscle mass was developed in humans and rats. This method is faster, cheaper, and more accurate than DXA. Here, we demonstrate that the D₃Cr method is a specific assay for muscle mass in mice, and we test associations with DXA and body weight. We evaluated the D₃Cr method compared to DXA-determined lean body mass (LBM) in aged mice and reported that DXA consistently overestimates muscle mass with age. Overall, we provide evidence that the D₃Cr dilution method directly measures muscle mass in mice. Combined with its ease of use, accessibility, and non-invasive nature, the method may prove to more quickly advance development of preclinical therapies targeting sarcopenia.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13897","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6101778","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":"Age- and sex-dependent alterations in primary somatosensory cortex neuronal calcium network dynamics during locomotion","authors":"Sami L. Case,&nbsp;Ruei-Lung Lin,&nbsp;Olivier Thibault","doi":"10.1111/acel.13898","DOIUrl":"https://doi.org/10.1111/acel.13898","url":null,"abstract":"<p>Over the past 30 years, the calcium (Ca²⁺) hypothesis of brain aging has provided clear evidence that hippocampal neuronal Ca²⁺ dysregulation is a key biomarker of aging. Age-dependent Ca²⁺-mediated changes in intrinsic excitability, synaptic plasticity, and activity have helped identify some of the mechanisms engaged in memory and cognitive decline based on work done mostly at the single-cell level and in the slice preparation. Recently, our lab identified age- and Ca²⁺-related neuronal network dysregulation in the cortex of the anesthetized animal. Still, investigations in the awake animal are needed to test the generalizability of the Ca²⁺ hypothesis of brain aging. Here, we used <i>in vigilo</i> two-photon imaging in ambulating mice, to image GCaMP8f in the primary somatosensory cortex (S1), during ambulation and at rest. We investigated aging- and sex-related changes in neuronal networks in the C56BL/6J mouse. Following imaging, gait behavior was characterized to test for changes in locomotor stability. During ambulation, in both young adult and aged mice, an increase in network connectivity and synchronicity was noted. An age-dependent increase in synchronicity was seen in ambulating aged males only. Additionally, females displayed increases in the number of active neurons, Ca²⁺ transients, and neuronal activity compared to males, particularly during ambulation. These results suggest S1 Ca²⁺ dynamics and network synchronicity are likely contributors of locomotor stability. We believe this work raises awareness of age- and sex-dependent alterations in S1 neuronal networks, perhaps underlying the increase in falls with age.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13898","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5683551","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":"Geroscience and climate science: Oppositional or complementary?","authors":"Colin Farrelly","doi":"10.1111/acel.13890","DOIUrl":"https://doi.org/10.1111/acel.13890","url":null,"abstract":"Two of this century's most significant public health challenges are climate change and healthy aging. The future of humanity will be both warmer and older than it is today. Is it socially responsible, in a warming planet of a population exceeding 8 billion people, for science to aspire to develop gerotherapeutic drugs that aim to reduce the burden of aging‐related diseases that may also increase lifespan? This question is the “elephant in the room” for geroscience advocacy. Science communication concerning what constitutes empirically valid and morally defensible ways of navigating the dual public health predicaments of climate change and healthy aging must be sensitive to both the interdependence of the environment (including planetary health) and the mechanisms of aging, as well as the common (mis)perceptions about the potential conflict between the goals of climate science and geroscience. Geroscience advocacy can transcend narratives of intergenerational conflict by highlighting the shared aspirations of climate science and geroscience, such as the goals of promoting health across the lifespan, redressing health disparities, and improving the economic prospects of current and future generations.","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13890","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5652200","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":"Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants","authors":"Rui Liu,&nbsp;Meiruo Xiang,&nbsp;Luke C. Pilling,&nbsp;David Melzer,&nbsp;Lihong Wang,&nbsp;Kevin J. Manning,&nbsp;David C. Steffens,&nbsp;Jack Bowden,&nbsp;Richard H. Fortinsky,&nbsp;George A. Kuchel,&nbsp;Taeho G. Rhee,&nbsp;Breno S. Diniz,&nbsp;Chia-Ling Kuo","doi":"10.1111/acel.13808","DOIUrl":"https://doi.org/10.1111/acel.13808","url":null,"abstract":"<p>Telomere attrition is one of biological aging hallmarks and may be intervened to target multiple aging-related diseases, including Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD). The objective of this study was to assess associations of leukocyte telomere length (TL) with AD/ADRD and early markers of AD/ADRD, including cognitive performance and brain magnetic resonance imaging (MRI) phenotypes. Data from European-ancestry participants in the UK Biobank (<i>n</i> = 435,046) were used to evaluate whether mid-life leukocyte TL is associated with incident AD/ADRD over a mean follow-up of 12.2 years. In a subsample without AD/ADRD and with brain imaging data (<i>n</i> = 43,390), we associated TL with brain MRI phenotypes related to AD or vascular dementia pathology. Longer TL was associated with a lower risk of incident AD/ADRD (adjusted Hazard Ratio [aHR] per SD = 0.93, 95% CI 0.90–0.96, <i>p</i> = 3.37 × 10⁻⁷). Longer TL also was associated with better cognitive performance in specific cognitive domains, larger hippocampus volume, lower total volume of white matter hyperintensities, and higher fractional anisotropy and lower mean diffusivity in the fornix. In conclusion, longer TL is inversely associated with AD/ADRD, cognitive impairment, and brain structural lesions toward the development of AD/ADRD. However, the relationships between genetically determined TL and the outcomes above were not statistically significant based on the results from Mendelian randomization analysis results. Our findings add to the literature of prioritizing risk for AD/ADRD. The causality needs to be ascertained in mechanistic studies.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 7","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13808","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5930476","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":"Alterations of bovine nucleus pulposus cells with aging","authors":"Maria Molinos,&nbsp;Morena F. Fiordalisi,&nbsp;Joana Caldeira,&nbsp;Catarina R. Almeida,&nbsp;Mário A. Barbosa,&nbsp;Raquel M. Gon?alves","doi":"10.1111/acel.13873","DOIUrl":"https://doi.org/10.1111/acel.13873","url":null,"abstract":"<p>Aging is one of the major etiological factors driving intervertebral disc (IVD) degeneration, the main cause of low back pain. The nucleus pulposus (NP) includes a heterogeneous cell population, which is still poorly characterized. Here, we aimed to uncover main alterations in NP cells with aging. For that, bovine coccygeal discs from young (12 months) and old (10–16 years old) animals were dissected and primary NP cells were isolated. Gene expression and proteomics of fresh NP cells were performed. NP cells were labelled with propidium iodide and analysed by flow cytometry for the expression of CD29, CD44, CD45, CD146, GD2, Tie2, CD34 and Stro-1. Morphological cell features were also dissected by imaging flow cytometry. Elder NP cells (up-regulated bIL-6 and bMMP1 gene expression) presented lower percentages of CD29+, CD44+, CD45+ and Tie2+ cells compared with young NP cells (upregulated bIL-8, bCOL2A1 and bACAN gene expression), while GD2, CD146, Stro-1 and CD34 expression were maintained with age. NP cellulome showed an upregulation of proteins related to endoplasmic reticulum (ER) and melanosome independently of age, whereas proteins upregulated in elder NP cells were also associated with glycosylation and disulfide bonds. Flow cytometry analysis of NP cells disclosed the existence of 4 subpopulations with distinct auto-fluorescence and size with different dynamics along aging. Regarding cell morphology, aging increases NP cell area, diameter and vesicles. These results contribute to a better understanding of NP cells aging and highlighting potential anti-aging targets that can help to mitigate age-related disc disease.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5880861","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":"Accelerated replicative senescence of ataxia-telangiectasia skin fibroblasts is retained at physiologic oxygen levels, with unique and common transcriptional patterns","authors":"Majd Haj,&nbsp;Amit Levon,&nbsp;Yann Frey,&nbsp;Noa Hourvitz,&nbsp;Judith Campisi,&nbsp;Yehuda Tzfati,&nbsp;Ran Elkon,&nbsp;Yael Ziv,&nbsp;Yosef Shiloh","doi":"10.1111/acel.13869","DOIUrl":"https://doi.org/10.1111/acel.13869","url":null,"abstract":"<p>The genetic disorder, ataxia-telangiectasia (A-T), is caused by loss of the homeostatic protein kinase, ATM, and combines genome instability, tissue degeneration, cancer predisposition, and premature aging. Primary fibroblasts from A-T patients exhibit premature senescence when grown at ambient oxygen concentration (21%). Here, we show that reducing oxygen concentration to a physiological level range (3%) dramatically extends the proliferative lifespan of human A-T skin fibroblasts. However, they still undergo senescence earlier than control cells grown under the same conditions and exhibit high genome instability. Comparative RNA-seq analysis of A-T and control fibroblasts cultured at 3% oxygen followed by cluster analysis of differentially expressed genes and functional enrichment analysis, revealed distinct transcriptional dynamics in A-T fibroblasts senescing in physiological oxygen concentration. While some transcriptional patterns were similar to those observed during replicative senescence of control cells, others were unique to the senescing A-T cells. We observed in them a robust activation of interferon-stimulated genes, with undetected expression the interferon genes themselves. This finding suggests an activation of a non-canonical cGAS-STING-mediated pathway, which presumably responds to cytosolic DNA emanating from extranuclear micronuclei detected in these cells. Senescing A-T fibroblasts also exhibited a marked, intriguely complex alteration in the expression of genes associated with extracellular matrix (ECM) remodeling. Notably, many of the induced ECM genes encode senescence-associated secretory phenotype (SASP) factors known for their paracrine pro-fibrotic effects. Our data provide a molecular dimension to the segmental premature aging observed in A-T patients and its associated symptoms, which develop as the patients advance in age.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"22 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2023-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.13869","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5870853","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}