title: Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries.
abstract: Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone γ-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening.
authors.affiliation: George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Morgan
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ives
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Lesniewski
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cawthon
authors.forename: Robert H I
authors.initials: RH
authors.lastname: Andtbacka
authors.forename: R Dirk
authors.initials: RD
authors.lastname: Noyes
authors.forename: Russell S
authors.initials: RS
authors.lastname: Richardson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Donato
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D001158:Arteries / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001167:Arteritis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D016922:Cellular Senescence; D018932:Chemokine CCL2 / Q000235:genetics; D016009:Chi-Square Distribution; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D055553:Prescription Drugs / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D016209:Interleukin-8; D055553:Prescription Drugs; D012333:RNA, Messenger; C504753:TERF2 protein, human; C495901:TP53 protein, human; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53
keywords: aging; arteries; inflammation; senescence; telomeres