Author Correction: L1 drives IFN in senescent cells and promotes age-associated inflammation.
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ABSTRACT:
SUBMITTER: De Cecco M
PROVIDER: S-EPMC7017651 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
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Author Correction: L1 drives IFN in senescent cells and promotes age-associated inflammation.
De Cecco Marco M Ito Takahiro T Petrashen Anna P AP Elias Amy E AE Skvir Nicholas J NJ Criscione Steven W SW Caligiana Alberto A Brocculi Greta G Adney Emily M EM Boeke Jef D JD Le Oanh O Beauséjour Christian C Ambati Jayakrishna J Ambati Kameshwari K Simon Matthew M Seluanov Andrei A Gorbunova Vera V Slagboom P Eline PE Helfand Stephen L SL Neretti Nicola N Sedivy John M JM
Nature 20190801 7767
An Amendment to this paper has been published and can be accessed via a link at the top of the paper. ...[more]
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Project description:Sterile inflammation, also known as inflammaging, is a hallmark of tissue ageing. Cellular senescence contributes to tissue aging in part through secretion of proinflammatory factors known as senescence-associated secretory phenotype (SASP). Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living, and physical performance at old age. TXNRD1 role in regulating tissue ageing has been attributed to its enzymatic role in regulating cellular redox. Here we show that TXNRD1 drives SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragment and interacts with cGAS in a senescence status dependent manner. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 and its interaction with cGAS is necessary for the SASP. TXNRD1 is required for both the tumor-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. Treatment of aged mice with an TXNRD1 inhibitor that disrupts its interaction with cGAS, but not an inhibitor of its enzymatic activity, downregulated inflammaging in several tissues. In summary, our results report TXNRD1 promotes inflammaging via the innate immune response. They indicate that TXNRD1 and cGAS interaction is a relevant target for selectively suppressing inflammaging.
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Project description:Sterile inflammation, also known as “inflammaging”, is a hallmark of tissue ageing. Cellular senescence contributes to tissue aging in part through secretion of proinflammatory factors known as senescence-associated secretory phenotype (SASP). Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living, and physical performance at old age. TXNRD1’s role in regulating tissue ageing has been attributed to its enzymatic role in reducing reactive oxygen species. Here we show that TXNRD1 drives SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independent of its enzymatic activity
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Project description:PurposeThe molecular mechanisms of age-related bone loss are unclear and without valid drugs yet. The aims of this study were to explore the molecular changes that occur in bone tissue during age-related bone loss, to further clarify the changes in function, and to predict potential therapeutic drugs.MethodsWe collected bone tissues from children, middle-aged individuals, and elderly people for protein sequencing and compared the three groups of proteins pairwise, and the differentially expressed proteins (DEPs) in each group were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). K-means cluster analysis was then used to screen out proteins that continuously increased/decreased with age. Canonical signaling pathways that were activated or inhibited in bone tissue along with increasing age were identified by Ingenuity Pathway Analysis (IPA). Prediction of potential drugs was performed using the Connectivity Map (CMap). Finally, DEPs from sequencing were verified by Western blot, and the drug treatment effect was verified by quantitative real-time PCR.ResultsThe GO and KEGG analyses show that the DEPs were associated with inflammation and bone formation with aging, and the IPA analysis shows that pathways such as IL-8 signaling and acute-phase response signaling were activated, while glycolysis I and EIF2 signaling were inhibited. A total of nine potential drugs were predicted, with rapamycin ranking the highest. In cellular experiments, rapamycin reduced the senescence phenotype produced by the H2O2-stimulated osteocyte-like cell MLO-Y4.ConclusionWith age, inflammatory pathways are activated in bone tissue, and signals that promote bone formation are inhibited. This study contributes to the understanding of the molecular changes that occur in bone tissue during age-related bone loss and provides evidence that rapamycin is a drug of potential clinical value for this disease. The therapeutic effects of the drug are to be further studied in animals.
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