In vivo role of checkpoint kinase 2 in signaling telomere dysfunction.

Abstract:

:Checkpoint kinase 2 (CHK2) is a downstream effector of the DNA damage response (DDR). Dysfunctional telomeres, either owing to critical shortening or disruption of the shelterin complex, activate a DDR, which eventually results in cell cycle arrest, senescence and/or apoptosis. Successive generations of telomerase-deficient (Terc) mice show accelerated aging and shorter lifespan due to tissue atrophy and impaired organ regeneration associated to progressive telomere shortening. In contrast, mice deficient for the shelterin component TRF1 in stratified epithelia show a rapid and massive induction of DDR, leading to perinatal lethality and severe skin defects. In both mouse models, p53 deficiency can rescue survival. Here, we set to address the role of CHK2 in signaling telomere dysfunction in both mouse models. To this end, we generated mice doubly deficient for Chk2 and either Terc (Chk2(-/-) Terc(-/-) ) or Trf1 (Trf1(Δ/Δ) K5Cre Chk2(-/-) ). We show that Chk2 deletion improves Terc-associated phenotypes, including lifespan and age-associated pathologies. Similarly, Chk2 deficiency partially rescues perinatal mortality and attenuates degenerative pathologies of Trf1(Δ/Δ) K5Cre mice. In both cases, we show that the effects are mediated by a significant attenuation of p53/p21 signaling pathway. Our results represent the first demonstration of a role for CHK2 in the in vivo signaling of dysfunctional telomeres.

journal_name

Aging Cell

journal_title

Aging cell

authors

García-Beccaria M,Martínez P,Flores JM,Blasco MA

doi

10.1111/acel.12237

subject

Has Abstract

pub_date

2014-10-01 00:00:00

pages

810-6

issue

5

eissn

1474-9718

issn

1474-9726

journal_volume

13

pub_type

杂志文章
  • Ambient temperature influences aging in an annual fish (Nothobranchius rachovii).

    abstract::Extending lifespan by lowering ambient temperature in the habitat has been shown in a variety of organisms. Its mechanism, however, remains elusive. In this study, we examined the survivorship and the aging process of the annual fish (Nothobranchius rachovii) reared under high (30 degrees C), moderate (25 degrees C) a...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2009.00525.x

    authors: Hsu CY,Chiu YC

    更新日期:2009-12-01 00:00:00

  • Cellular senescence as a potential mediator of COVID-19 severity in the elderly.

    abstract::SARS-CoV-2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID-19), a complex respiratory distress syndrome. Epidemiological data show that COVID-19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association ...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/acel.13237

    authors: Nehme J,Borghesan M,Mackedenski S,Bird TG,Demaria M

    更新日期:2020-10-01 00:00:00

  • Dynamics of the action of dFOXO on adult mortality in Drosophila.

    abstract::The insulin/insulin growth factor (IGF)-like signaling (IIS) pathway has a conserved role in regulating lifespan in Caenorhabditis elegans, Drosophila and mice. Extension of lifespan by reduced IIS has been shown in C. elegans to require the key IIS target, forkhead box class O (FOXO) transcription factor, DAF-16. dFO...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2007.00290.x

    authors: Giannakou ME,Goss M,Jacobson J,Vinti G,Leevers SJ,Partridge L

    更新日期:2007-08-01 00:00:00

  • Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension.

    abstract::Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimics events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to a...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13089

    authors: Rocha LR,Nguyen Huu VA,Palomino La Torre C,Xu Q,Jabari M,Krawczyk M,Weinreb RN,Skowronska-Krawczyk D

    更新日期:2020-02-01 00:00:00

  • Hot topics in stem cells and self-renewal: 2010.

    abstract::In many tissues, mammalian aging is associated with a decline in the replicative and functional capacity of somatic stem cells and other self-renewing compartments. Understanding the basis of this decline is a major goal of aging research. In particular, therapeutic approaches to ameliorate or reverse the age-associat...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2010.00592.x

    authors: Sharpless NE

    更新日期:2010-08-01 00:00:00

  • MiR-103-3p targets the m6 A methyltransferase METTL14 to inhibit osteoblastic bone formation.

    abstract::Impaired osteoblast function is involved in osteoporosis, and microRNA (miRNA) dysregulation may cause abnormal osteoblast osteogenic activity. However, the influence of miRNA on osteoblast activity and the underlying mechanisms remain elusive. In this study, miR-103-3p was found to be negatively correlated with bone ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13298

    authors: Sun Z,Wang H,Wang Y,Yuan G,Yu X,Jiang H,Wu Q,Yang B,Hu Z,Shi F,Cao X,Zhang S,Guo T,Zhao J

    更新日期:2021-01-13 00:00:00

  • The acceleration of reproductive aging in Nrg1flox/flox ;Cyp19-Cre female mice.

    abstract::Irregular menstrual cycles, reduced responses to exogenous hormonal treatments, and altered endocrine profiles (high FSH/high LH/low AMH) are observed in women with increasing age before menopause. In this study, because the granulosa cell-specific Nrg1 knockout mice (gcNrg1KO) presented ovarian and endocrine phenotyp...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12662

    authors: Umehara T,Kawai T,Kawashima I,Tanaka K,Okuda S,Kitasaka H,Richards JS,Shimada M

    更新日期:2017-12-01 00:00:00

  • Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice.

    abstract::Neurogenesis, which may contribute to the ability of the adult brain to function normally and adapt to disease, nevertheless declines with advancing age. Adult neurogenesis can be enhanced by administration of growth factors, but whether the aged brain remains responsive to these factors is unknown. We compared the ef...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1046/j.1474-9728.2003.00046.x

    authors: Jin K,Sun Y,Xie L,Batteur S,Mao XO,Smelick C,Logvinova A,Greenberg DA

    更新日期:2003-06-01 00:00:00

  • Dietary restriction of rodents decreases aging rate without affecting initial mortality rate -- a meta-analysis.

    abstract::Dietary restriction (DR) extends lifespan in multiple species from various taxa. This effect can arise via two distinct but not mutually exclusive ways: a change in aging rate and/or vulnerability to the aging process (i.e. initial mortality rate). When DR affects vulnerability, this lowers mortality instantly, wherea...

    journal_title:Aging cell

    pub_type: 杂志文章,meta分析

    doi:10.1111/acel.12061

    authors: Simons MJ,Koch W,Verhulst S

    更新日期:2013-06-01 00:00:00

  • The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans.

    abstract::The general control nonderepressible 2 (GCN2) kinase is a nutrient-sensing pathway that responds to amino acids deficiency and induces a genetic program to effectively maintain cellular homeostasis. Here we established the conserved role of Caenorhabditis elegans GCN-2 under amino acid limitation as a translation init...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12101

    authors: Rousakis A,Vlassis A,Vlanti A,Patera S,Thireos G,Syntichaki P

    更新日期:2013-10-01 00:00:00

  • Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p- syndrome.

    abstract::Telomerase, which maintains the ends of chromosomes, consists of two core components, the telomerase reverse transcriptase (TERT) and the telomerase RNA (TERC). Haploinsufficiency for TERC or TERT leads to progressive telomere shortening and autosomal dominant dyskeratosis congenita (DC). The clinical manifestations o...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2007.00324.x

    authors: Du HY,Idol R,Robledo S,Ivanovich J,An P,Londono-Vallejo A,Wilson DB,Mason PJ,Bessler M

    更新日期:2007-10-01 00:00:00

  • DLP1-dependent mitochondrial fragmentation and redistribution mediate prion-associated mitochondrial dysfunction and neuronal death.

    abstract::Mitochondrial malfunction is a universal and critical step in the pathogenesis of many neurodegenerative diseases including prion diseases. Dynamin-like protein 1 (DLP1) is one of the key regulators of mitochondrial fission. In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12693

    authors: Li C,Wang D,Wu W,Yang W,Ali Shah SZ,Zhao Y,Duan Y,Wang L,Zhou X,Zhao D,Yang L

    更新日期:2018-02-01 00:00:00

  • Protein translation, 2007.

    abstract::Translation of RNA to protein is essential for life. It should perhaps not be surprising, therefore, that appropriate regulation of translation plays a key role in determining longevity. This Hot Topic article discusses papers published in the last year related to the importance of translation and its regulation by si...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/j.1474-9726.2007.00341.x

    authors: Kaeberlein M,Kennedy BK

    更新日期:2007-12-01 00:00:00

  • Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice.

    abstract::We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD(+) intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 ± 5% vs. 84 ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12461

    authors: de Picciotto NE,Gano LB,Johnson LC,Martens CR,Sindler AL,Mills KF,Imai S,Seals DR

    更新日期:2016-06-01 00:00:00

  • Systematic age-, organ-, and diet-associated ionome remodeling and the development of ionomic aging clocks.

    abstract::Aging involves coordinated yet distinct changes in organs and systems throughout life, including changes in essential trace elements. However, how aging affects tissue element composition (ionome) and how these changes lead to dysfunction and disease remain unclear. Here, we quantified changes in the ionome across eig...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13119

    authors: Zhang B,Podolskiy DI,Mariotti M,Seravalli J,Gladyshev VN

    更新日期:2020-05-01 00:00:00

  • Fat tissue, aging, and cellular senescence.

    abstract::Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mu...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/j.1474-9726.2010.00608.x

    authors: Tchkonia T,Morbeck DE,Von Zglinicki T,Van Deursen J,Lustgarten J,Scrable H,Khosla S,Jensen MD,Kirkland JL

    更新日期:2010-10-01 00:00:00

  • Testing the 'free radical theory of aging' hypothesis: physiological differences in long-lived and short-lived colubrid snakes.

    abstract::We test the 'free radical theory of aging' using six species of colubrid snakes (numerous, widely distributed, non-venomous snakes of the family Colubridae) that exhibit long (> 15 years) or short (< 10 years) lifespans. Because the 'rate of living theory' predicts metabolic rates to be correlated with rates of aging ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2007.00287.x

    authors: Robert KA,Brunet-Rossinni A,Bronikowski AM

    更新日期:2007-06-01 00:00:00

  • NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice.

    abstract::While NLRP3-inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inf...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13050

    authors: Marín-Aguilar F,Lechuga-Vieco AV,Alcocer-Gómez E,Castejón-Vega B,Lucas J,Garrido C,Peralta-Garcia A,Pérez-Pulido AJ,Varela-López A,Quiles JL,Ryffel B,Flores I,Bullón P,Ruiz-Cabello J,Cordero MD

    更新日期:2020-01-01 00:00:00

  • "Amyloid-beta accumulation cycle" as a prevention and/or therapy target for Alzheimer's disease.

    abstract::The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad-spectrum anticancer drugs. Cyclin-dependent kinases (CDKs) are drivers of c...

    journal_title:Aging cell

    pub_type: 杂志文章,评审

    doi:10.1111/acel.13109

    authors: Rao CV,Asch AS,Carr DJJ,Yamada HY

    更新日期:2020-03-01 00:00:00

  • Loss of HDAC3 contributes to meiotic defects in aged oocytes.

    abstract::Maternal age-related decline in oocyte quality is associated with meiotic defects, but the underlying mechanisms remain to be explored. Histone deacetylase 3 (HDAC3) has been shown to govern multiple cellular events via deacetylating diverse substrates. We previously found that HDAC3 could promote meiotic apparatus as...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13036

    authors: He Y,Li X,Gao M,Liu H,Gu L

    更新日期:2019-12-01 00:00:00

  • A neuroprotective role for the DNA damage checkpoint in tauopathy.

    abstract::ATM and p53, effectors of the DNA damage checkpoint, are generally considered pro-apoptotic in neurons. We show that DNA damage and checkpoint activation occurs in postmitotic neurons in animal models of tauopathy, neurodegenerative disorders that include Alzheimer's disease. Surprisingly, checkpoint attenuation poten...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2011.00778.x

    authors: Khurana V,Merlo P,DuBoff B,Fulga TA,Sharp KA,Campbell SD,Götz J,Feany MB

    更新日期:2012-04-01 00:00:00

  • Increased dosage of tumor suppressors limits the tumorigenicity of iPS cells without affecting their pluripotency.

    abstract::Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self-renewal and pluripotency of ES and iPS cells make them tumorigenic, and hence, the risk of tumor developmen...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2011.00754.x

    authors: Menendez S,Camus S,Herreria A,Paramonov I,Morera LB,Collado M,Pekarik V,Maceda I,Edel M,Consiglio A,Sanchez A,Li H,Serrano M,Belmonte JC

    更新日期:2012-02-01 00:00:00

  • Chronic calorie restriction increases susceptibility of laboratory mice (Mus musculus) to a primary intestinal parasite infection.

    abstract::Long-term calorie restriction (CR) has numerous benefits; however, effects of CR on susceptibility to intact pathogens are not well understood. Because CR enhances immune function of laboratory mice (Mus musculus), it was hypothesized that mice subjected to CR would be less susceptible to experimental infections of th...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2007.00345.x

    authors: Kristan DM

    更新日期:2007-12-01 00:00:00

  • The Piwi-piRNA pathway: road to immortality.

    abstract::Despite its medical, social, and economic significance, understanding what primarily causes aging, that is, the mechanisms of the aging process, remains a fundamental and fascinating problem in biology. Accumulating evidence indicates that a small RNA-based gene regulatory machinery, the Piwi-piRNA pathway, represents...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12630

    authors: Sturm Á,Perczel A,Ivics Z,Vellai T

    更新日期:2017-10-01 00:00:00

  • Senescence-associated DNA methylation is stochastically acquired in subpopulations of mesenchymal stem cells.

    abstract::Replicative senescence has a major impact on function and integrity of cell preparations. This process is reflected by continuous DNA methylation (DNAm) changes at specific CpG dinucleotides in the course of in vitro culture, and such modifications can be used to estimate the state of cellular senescence for quality c...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12544

    authors: Franzen J,Zirkel A,Blake J,Rath B,Benes V,Papantonis A,Wagner W

    更新日期:2017-02-01 00:00:00

  • Free radical generation by skeletal muscle of adult and old mice: effect of contractile activity.

    abstract::Oxidative modification of cellular components may contribute to tissue dysfunction during aging. In skeletal muscle, contractile activity increases the generation of reactive oxygen and nitrogen species (ROS). The question of whether contraction-induced ROS generation is further increased in skeletal muscle of the eld...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/j.1474-9726.2006.00198.x

    authors: Vasilaki A,Mansouri A,Van Remmen H,van der Meulen JH,Larkin L,Richardson AG,McArdle A,Faulkner JA,Jackson MJ

    更新日期:2006-04-01 00:00:00

  • Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer's disease via C/EBPα/miR-125b pathway.

    abstract::Impairments of dendritic trees and spines have been found in many neurodegenerative diseases, including Alzheimer's disease (AD), in which the deficits of melatonin signal pathway were reported. Melatonin receptor 2 (MT2) is widely expressed in the hippocampus and mediates the biological functions of melatonin. It is ...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12902

    authors: Tang H,Ma M,Wu Y,Deng MF,Hu F,Almansoub HAMM,Huang HZ,Wang DQ,Zhou LT,Wei N,Man H,Lu Y,Liu D,Zhu LQ

    更新日期:2019-04-01 00:00:00

  • Flagellin-dependent TLR5/caveolin-1 as a promising immune activator in immunosenescence.

    abstract::The age-associated decline of immune responses causes high susceptibility to infections and reduced vaccine efficacy in the elderly. However, the mechanisms underlying age-related deficits are unclear. Here, we found that the expression and signaling of flagellin (FlaB)-dependent Toll-like receptor 5 (TLR5), unlike th...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12383

    authors: Lim JS,Nguyen KC,Nguyen CT,Jang IS,Han JM,Fabian C,Lee SE,Rhee JH,Cho KA

    更新日期:2015-10-01 00:00:00

  • FOXO3 targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16INK4a increase.

    abstract::Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MS...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.13226

    authors: Voisin J,Farina F,Naphade S,Fontaine M,Tshilenge KT,Galicia Aguirre C,Lopez-Ramirez A,Dancourt J,Ginisty A,Sasidharan Nair S,Lakshika Madushani K,Zhang N,Lejeune FX,Verny M,Campisi J,Ellerby LM,Neri C

    更新日期:2020-11-01 00:00:00

  • The conserved Mediator subunit MDT-15 is required for oxidative stress responses in Caenorhabditis elegans.

    abstract::Reactive oxygen species (ROS) play important signaling roles in metazoans, but also cause significant molecular damage. Animals tightly control ROS levels using sophisticated defense mechanisms, yet the transcriptional pathways that induce ROS defense remain incompletely understood. In the nematode Caenorhabditis eleg...

    journal_title:Aging cell

    pub_type: 杂志文章

    doi:10.1111/acel.12154

    authors: Goh GY,Martelli KL,Parhar KS,Kwong AW,Wong MA,Mah A,Hou NS,Taubert S

    更新日期:2014-02-01 00:00:00