Senescence

  • Article
    | Open Access

    Several bacteria in the gut microbiota have been associated with colorectal cancer (CRC) but it is not completely clear whether they have a role in tumourigenesis. Here, the authors show enrichment of 12 bacterial taxa in two cohorts of CRC patients and that two Porphyromonas species accelerate CRC onset through butyrate secretion.

    • Shintaro Okumura
    • , Yusuke Konishi
    •  & Eiji Hara
  • Article
    | Open Access

    RAS-induced senescence is a safeguarding process against tumour development. Here, the authors show that RAS activation destabilises the transcription factor ZNF768, which blocks ZNF768- dependent repression of p53 activity and thus induces senescence.

    • Romain Villot
    • , Audrey Poirier
    •  & Mathieu Laplante
  • Article
    | Open Access

    BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.

    • Riccardo Biavasco
    • , Emanuele Lettera
    •  & Eugenio Montini
  • Article
    | Open Access

    GATA3 has been considered to be primarily associated with CD4+ Th2 cell function. Using CD4+ effector memory that re-express CD45RA (EMRA) T cells the authors show that in response to DNA damage GATA3 can regulate increase of mitochondrial mass and biogenesis involving AMPK.

    • Lauren A. Callender
    • , Johannes Schroth
    •  & Sian M. Henson
  • Article
    | Open Access

    Senescence-associated secretory phenotype (SASP) involves secretion of factors such as pro-inflammatory cytokines. Here the authors show that MIR31HG regulates the expression and secretion of a subset of SASP components that induce paracrine invasion, through interaction with YBX1 and induction of IL1A translation.

    • Marta Montes
    • , Michal Lubas
    •  & Anders H. Lund
  • Article
    | Open Access

    Glucocorticoids (GCs) inhibit bone angiogenesis and affect bone development, but the underlying mechanisms remain unclear. Here, the authors show that GCs induce vascular cell senescence during bone development by inhibiting angiogenin secretion from osteoclasts, impairing angiogenesis via endothelial Plexin B2, resulting in unpaired bone growth.

    • Xiaonan Liu
    • , Yu Chai
    •  & Mei Wan
  • Article
    | Open Access

    Contacts between mitochondria and endoplasmatic reticulum (ER), and the transfer of calcium between them, have an important role in the regulation of cellular phenotypes, including senescence. Here the authors show that ITPR2 deficient mice display improved aging, associated with a decreased number of contacts between the mitochondria and the ER.

    • Dorian V. Ziegler
    • , David Vindrieux
    •  & David Bernard
  • Article
    | Open Access

    Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Here, the authors develop a morphology-based deep learning system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells to evaluate the effects of anti-senescent reagents.

    • Dai Kusumoto
    • , Tomohisa Seki
    •  & Shinsuke Yuasa
  • Article
    | Open Access

    Senescence is a state of stable proliferative arrest. Here, the authors perform Hi-C analysis on oncogenic RAS-induced senescence in human fibroblasts and characterize the changes in the 3D genome folding associated with the senescence-specific gene expression profile, which are mediated in part through cohesin redistribution on chromatin.

    • Ioana Olan
    • , Aled J. Parry
    •  & Masashi Narita
  • Article
    | Open Access

    The mechanisms that control the deleterious behaviour of senescent cells is unclear. Here, the authors show that G3BP1 is required for the induction of the senescence-associated secretory phenotype (SASP), without affecting senescence, and that SASP secretion is a primary mediator of senescence-associated tumour growth.

    • Amr Omer
    • , Monica Cruz Barrera
    •  & Imed-Eddine Gallouzi
  • Article
    | Open Access

    Telomere function is regulated by the telomere repeat binding proteins TRF1 and TRF2. Here the authors show that decreased levels of TRF1 proteins at shortened telomeres in aged human cells results in persistent telomere cohesion, protecting from premature senescence.

    • Kameron Azarm
    • , Amit Bhardwaj
    •  & Susan Smith
  • Article
    | Open Access

    Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.

    • Sunita Shankar
    • , Jean Ching-Yi Tien
    •  & Arul M. Chinnaiyan
  • Article
    | Open Access

    Here, the authors show that the topoisomerase 1-DNA covalent cleavage complex plays a critical role in mediating cytoplasmic chromatin fragments recognition by cyclic GMP-AMP synthase during senescence. The proposed axis is crucial to promote the inflammatory senescence-associated secretory phenotype and to enable the response to immune checkpoint blockade.

    • Bo Zhao
    • , Pingyu Liu
    •  & Rugang Zhang
  • Article
    | Open Access

    Cell senescence involves stable arrest of cell proliferation and changes in gene expression and 3D genome reorganization. Here, the authors show that human condensin II complex participates in reorganization of the chromatin compartments, primarily through switching from heterochromatic B to euchromatic A compartments.

    • Osamu Iwasaki
    • , Hideki Tanizawa
    •  & Ken-ichi Noma
  • Article
    | Open Access

    Senolytic compounds have the ability to eliminate senescent cells from tissues and have been shown to be beneficial in various animal models of age-related diseases. Here the authors show that cardiac glycosides commonly used for heart diseases have senolytic properties in humanized mouse models of tumorigenesis and lung fibrosis.

    • Francisco Triana-Martínez
    • , Pilar Picallos-Rabina
    •  & Manuel Collado
  • Article
    | Open Access

    In regenerative animals, how cells respond to injury signals inducing senescence is unclear. Here, the authors show that cells from highly regenerative mammals are resistant to ROS-induced cellular senescence, but non-regenerating species exhibit mitochondrial dysfunction/senescence in response to hydrogen peroxide exposure.

    • Sandeep Saxena
    • , Hemendra Vekaria
    •  & Ashley W. Seifert
  • Article
    | Open Access

    DGCR8 is a component of the canonical microprocessor complex for microRNA biogenesis. Here the authors implicate DGCR8 in heterochromatin maintenance and aging attenuation independent of its miRNA-processing activity through Lamin B1, KAP1 and HP1 interaction. DGCR8 overexpression can alleviate aging and senescence

    • Liping Deng
    • , Ruotong Ren
    •  & Guang-Hui Liu
  • Article
    | Open Access

    Muscle regeneration depends on self-renewal of muscle stem cells but how this is regulated on aging is unclear. Here, the authors identify Slug as regulating p16Ink4a in quiescent muscle stem cells, and when Slug expression reduces in aged stem cells, p16Ink4a accumulates, causing regenerative defects.

    • Pei Zhu
    • , Chunping Zhang
    •  & Wen-Shu Wu
  • Article
    | Open Access

    Senescent cells increase with ageing and may cause inflammatory conditions, but how this accumulation is mediated is still unclear. Here the authors show that senescent cells express HLA-E to suppress NKG2A-mediated natural killer and CD8 T cell activation to avoid targeted elimination, while blocking NKG2A helps promote immunity against senescent cells.

    • Branca I. Pereira
    • , Oliver P. Devine
    •  & Arne N. Akbar
  • Article
    | Open Access

    Senescent cells accumulate with aging contributing to age-related disease and the role of the immune system in removing senescent cells is not completely understood. Here, the authors show that perforin deficient mice accumulate more senescent cells and have a shorter lifespan, and that this phenotype can be reversed with administration of a senolytic drug.

    • Yossi Ovadya
    • , Tomer Landsberger
    •  & Valery Krizhanovsky
  • Article
    | Open Access

    MicroRNA miR-181a has been implicated in the regulation of T cell activation and development. Here the authors show that miR-181a is regulated by a transcription factor, YY1, with reduced YY1 expression linked to reduced miR-181a in old individuals, while silencing YY1 impairs T cell functions largely through influencing the expression of miR-181a targets.

    • Zhongde Ye
    • , Guangjin Li
    •  & Jörg J. Goronzy
  • Article
    | Open Access

    The integrity of the stratified epithelia relies on controlled cell turnover but it is unclear how mRNA binding proteins regulates this. Here, the authors show that the RNA binding protein Y-box binding protein-1 translationally represses cytokines, so preventing senescence and maintaining epidermal homeostasis.

    • Eunjeong Kwon
    • , Kristina Todorova
    •  & Anna Mandinova
  • Article
    | Open Access

    Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies.

    • Sofia Ferreira-Gonzalez
    • , Wei-Yu Lu
    •  & Stuart J. Forbes
  • Article
    | Open Access

    Osteochondroprogenitors are essential cells for skeletal development and homeostasis. Here the authors show that the desumoylase SENP6 suppresses p53 activity by desumoylating and stabilising TRIM28, and that SENP6 ablation leads to skeletal abnormalities, senescence in osteochondroprogenitors and chondrocytes, and premature ageing.

    • Jianshuang Li
    • , Di Lu
    •  & Tao Yang
  • Article
    | Open Access

    Mesenchymal stem cells are essential for bone development, but it is unclear if their activity is maintained after late puberty, when bone growth decelerates. The authors show that during late puberty in mice, these cells undergo senescence under the epigenetic control of Ezh2.

    • Changjun Li
    • , Yu Chai
    •  & Mei Wan
  • Article
    | Open Access

    The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.

    • Heike Fuhrmann-Stroissnigg
    • , Yuan Yuan Ling
    •  & Paul D. Robbins
  • Article
    | Open Access

    Therapy induced senescence (TIS) is a growth suppressive program activated by cytostatic agents in some cancer cells. Here the authors show that the chromatin remodeling enzyme ATRX is a regulator of TIS and drives cells into this state via multiple mechanisms.

    • Marta Kovatcheva
    • , Will Liao
    •  & Andrew Koff
  • Article
    | Open Access

    Non-alcoholic fatty liver disease is more common among older individuals. Here, the authors show that senescent cells in the liver promote fat accumulation and steatosis in the liver, and that clearance of senescent cells reduces hepatic steatosis in old, obese or diabetic mice.

    • Mikolaj Ogrodnik
    • , Satomi Miwa
    •  & Diana Jurk
  • Article
    | Open Access

    Although senescent cell secretome can promote the growth of surrounding cancer cells, the role of extracellular vesicles in this process has not been well understood. Here the authors show that ROS increase the sorting of EphA2 into extracellular vesicles in senescent cells, which promotes proliferation of cancer cells.

    • Masaki Takasugi
    • , Ryo Okada
    •  & Eiji Hara
  • Article
    | Open Access

    The role of exosomes in intercellular communication is well established, however less in known about the biological roles of exosome secretion in exosome-secreting cells. Here the authors show that exosome secretion controls cellular homeostasis in exosome-secreting cells by removing harmful cytoplasmic DNA from cells.

    • Akiko Takahashi
    • , Ryo Okada
    •  & Eiji Hara
  • Article
    | Open Access

    Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.

    • Marissa J. Schafer
    • , Thomas A. White
    •  & Nathan K. LeBrasseur
  • Article
    | Open Access

    The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.

    • Megan K. Ruhland
    • , Andrew J. Loza
    •  & Sheila A. Stewart
  • Article
    | Open Access

    The accumulation of senescent cells within tissues plays a role in numerous age-related pathologies. Yosef and Pilpel et al. demonstrate that the resistance of these cells to apoptosis is driven by upregulation of survival proteins, whose pharmacological inhibition triggers senescent cell elimination in mice.

    • Reut Yosef
    • , Noam Pilpel
    •  & Valery Krizhanovsky