NFκB nuclear dynamics orchestrate inflammatory aging

Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. NFκB activity plays a critical role in transcriptional regulation and cell fate determination; however, its physiological function in inflammatory aging remains unclear. Here, we demonstrate that dysfunction of negative feedback regulators of NFκB, IκBα and A20, alters the NFκB nuclear dynamics from oscillatory to sustained, thereby promoting cellular senescence. Sustained NFκB activity by IκBα downregulation enhances inflammatory gene expression through increased NFκB-DNA binding, promotes purine catabolism by downregulating hypoxanthine phosphoribosyltransferase, and arrests the cell cycle. This regulatory mechanism was confirmed in aged mice heart tissues, suggesting that prolonged nuclear localization of NFκB drives chronic inflammation and metabolic rewiring associated with aging.

[1]  M. Serrano,et al.  Hallmarks of aging: An expanding universe , 2022, Cell.

[2]  A. Dopazo,et al.  Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration , 2022, Nature.

[3]  S. Gambaryan,et al.  Purine nucleoside phosphorylase controls nicotinamide riboside metabolism in mammalian cells , 2022, The Journal of biological chemistry.

[4]  A. Hoffmann,et al.  Author Correction: IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells , 2022, npj Systems Biology and Applications.

[5]  M. Okada,et al.  Encoding and decoding NF-κB nuclear dynamics. , 2022, Current opinion in cell biology.

[6]  M. Serrano,et al.  Senescence-associated morphological profiles (SAMPs): an image-based phenotypic profiling method for evaluating the inter and intra model heterogeneity of senescence , 2022, Aging.

[7]  Mariko Okada,et al.  Systems approaches to investigate the role of NF-κB signaling in aging , 2022, The Biochemical journal.

[8]  S. Tay,et al.  NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli , 2022, bioRxiv.

[9]  A. Hoffmann,et al.  IκBα is required for full transcriptional induction of some NFκB-regulated genes in response to TNF in MCF-7 cells , 2021, NPJ systems biology and applications.

[10]  M. Herrmann,et al.  TNF induces glycolytic shift in fibroblast like synoviocytes via GLUT1 and HIF1A , 2021, Scientific Reports.

[11]  Rong Li,et al.  The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages , 2021, Cell & Bioscience.

[12]  A. Page,et al.  Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models , 2021, Cells.

[13]  S. Cook,et al.  Inhibitory feedback control of NF-κB signalling in health and disease , 2021, The Biochemical journal.

[14]  Brooks Taylor,et al.  Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses , 2021, Immunity.

[15]  E. Jacinto,et al.  Regulation and metabolic functions of mTORC1 and mTORC2. , 2021, Physiological reviews.

[16]  Brooks Taylor,et al.  NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages , 2020, Science.

[17]  Simon C Watkins,et al.  Purine nucleoside phosphorylase inhibition ameliorates age-associated lower urinary tract dysfunctions , 2020, JCI insight.

[18]  Brian R. Kotajarvi,et al.  The senescence-associated secretome as an indicator of age and medical risk. , 2020, JCI insight.

[19]  A. Hoffmann,et al.  Gene Regulatory Strategies that Decode the Duration of NFκB Dynamics Contribute to LPS- versus TNF-Specific Gene Expression. , 2020, Cell systems.

[20]  C. Schmitt,et al.  Cellular Senescence: Defining a Path Forward , 2019, Cell.

[21]  K. Shirasuna,et al.  S100A8, which increases with age, induces cellular senescence‐like changes in bovine oviduct epithelial cells , 2019, American journal of reproductive immunology.

[22]  Jun Sese,et al.  ChIP‐Atlas: a data‐mining suite powered by full integration of public ChIP‐seq data , 2018, EMBO reports.

[23]  C. Franceschi,et al.  Inflammaging: a new immune–metabolic viewpoint for age-related diseases , 2018, Nature Reviews Endocrinology.

[24]  J. Timmer,et al.  Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds , 2018, npj Systems Biology and Applications.

[25]  J. Sáez-Rodríguez,et al.  Benchmark and integration of resources for the estimation of human transcription factor activities , 2018, bioRxiv.

[26]  M. Karin,et al.  NF-κB, inflammation, immunity and cancer: coming of age , 2018, Nature Reviews Immunology.

[27]  Jordan Woodrick,et al.  Mutagenic potential of hypoxanthine in live human cells. , 2017, Mutation research.

[28]  D. Baker,et al.  Cellular senescence in aging and age-related disease: from mechanisms to therapy , 2015, Nature Medicine.

[29]  C. Franceschi,et al.  Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[30]  N. Perkins,et al.  Friend or foe: emerging role of nuclear factor kappa-light-chain-enhancer of activated B cells in cell senescence , 2013, OncoTargets and therapy.

[31]  V. Gorgoulis,et al.  The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage. , 2012, Cellular signalling.

[32]  ToshiroFujita,et al.  Blockade of the Nuclear Factor-κB Pathway in the Endothelium Prevents Insulin Resistance and Prolongs Life Spans , 2012 .

[33]  J. Ruland.  Return to homeostasis: downregulation of NF-κB responses , 2011, Nature Immunology.

[34]  Robert L. Sutherland,et al.  Cyclin D as a therapeutic target in cancer , 2011, Nature Reviews Cancer.

[35]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[36]  D. S. Broomhead,et al.  Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription , 2009, Science.

[37]  David Baltimore,et al.  Encoding NF-kappaB temporal control in response to TNF: distinct roles for the negative regulators IkappaBalpha and A20. , 2008, Genes & development.

[38]  J. Marshall.  Coming of age. , 2008, Surgical infections.

[39]  M. Netea,et al.  The role of TNF- a in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk , 2007 .

[40]  D. Bernard,et al.  cRel induces mitochondrial alterations in correlation with proliferation arrest. , 2001, Free radical biology & medicine.

[41]  W. Souba,et al.  Tumor necrosis factor stimulates amino acid transport in plasma membrane vesicles from rat liver. , 1993, The Journal of clinical investigation.

[42]  H. P. Robertson,et al.  The Expanding Universe , 1934, Science.